British Pharmacopoeia 2016 (PDFDrive)

British Pharmacopoeia 2016
Volume III
British Pharmacopoeia 2016
Volume III
The British Pharmacopoeia Commission has caused this British |

Pharmacopoeia 2016 to be prepared under regulation 317(1) of the Human
Medicines Regulations 2012 and, in accordance with regulation 317(4), the
Ministers have arranged for it to be published. It has been notified in draft
to the European Commission in accordance with Directive 98/34/EEC.
The monographs of the Eighth Edition of the European Pharmacopoeia

(2013), as amended by Supplements 8.1 to 8.5, published by the Council
of Europe are reproduced either in this edition of the British
Pharmacopoeia or in the associated edition of the British Pharmacopoeia
(Veterinary).
ee General Notices
Effective date: 1“
see Notices
London: The Stationery Office

Be ee ow,
In respect of Great Britain:
THE DEPARTMENT OF HEALTH

Aww ae
In respect of Northern Ireland:
THE DEPARTMENT OF HEALTH, SOCIAL SERVICES AND

PUBLIC SAFETY
© Crown Copyright 2015
Published by The Stationery Office on behalf of the Medicines and

Healthcare products Regulatory Agency (MHRA) except that: Aeris
sae
European Pharmacopoeia monographs are reproduced with the permission

of the Council of Europe and are not Crown Copyright. These are
identified in the publication by a chaplet of stars.
This publication is a ‘value added’ product. If you wish to re-use the

Crown Copyright material from this publication, applications must be made
writing, clearly stating the material requested for re-use, and the purpose
. forewhich it is required. Applications should be sent to: Dr S Atkinson, Pe as
5" Floor, 151 Buckingham Palace Road, London SW1W 9SZ.
151 Buckingham Pa
London SW1W 9SZ
E-mail: bpcom@mhra.gsi-5
Web site: http://www.phar
Laboratory:
British Pharmacopoeia Commission L
Queen’s Road
Teddington
Middlesex TW11 OLY
Telephone: +44 (0)20 8943 8960
E-mail: bpcrs@mhra.gsi.gov.uk
Web site: http://www.pharmacopoeia.com ’
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Contents
Contents of Volume I
FOREWORD
NOTICES
PREFACE
BRITISH PHARMACOPOEIA COMMISSION
EXPERT ADVISORY GROUPS, PANELS OF EXPERTS AND

WORKING PARTIES
CODE OF PRACTICE
WAEMBERSHIP
mmission, Expert Advisory Groups, Panels of Experts, Working
eia, BP Laboratory, Publisher
INTRODUCTIG
Additions, Omissi al Changes, Changes in Title

GENERAL NOTICES
MONOGRAPHS
Medicinal and Pharmaceutical S
Contents of Volume II
NOTICES
GENERAL NOTICES
MONOGRAPHS
Medicinal and Pharmaceutical Substances J - Z)
Contents of Volume III
NOTICES
GENERAL NOTICES
MONOGRAPHS
Formulated Preparations: General Monographs
Formulated Preparations: Specific Monographs
III-v
Pe NE
Contents of Volume IV
NOTICES
GENERAL NOTICES
MONOGRAPHS
Herbal Drugs, Herbal Drug Preparations and Herbal Medicinal Products
Materials for use in the Manufacture of Homoeopathic Preparations
Blood-related Products
Immunological Products
Radiopharmaceutical Preparations
Surgical Materials
ontents of Volume V
4 \L NOTICES
FERENCE SPECTRA
IlI-vi
Notices
Monographs of the European Pharmacopoeia are distinguished by a chaplet

of stars against the title. The term European Pharmacopoeia, used without
qualification, means the eighth edition of the European Pharmacopoeia
comprising, unless otherwise stated, the main volume, published in 2013, as
amended by any subsequent supplements and revisions.
Patents In this Pharmacopoeia certain drugs and preparations have been included
notwithstanding the existence of actual or potential patent rights. In so far
as such substances are protected by Letters Patent their inclusion in this
Pharmacopoeia neither conveys, nor implies, licence to manufacture.
New and revised monographs of national origin enter into force on

1 January 2016. ‘The monographs are brought into effect under regulation
20(2) of the Human Medicines Regulations 2012.
aphs of the European Pharmacopoeia have previously been

ished by the European Directorate for the Quality of Medicines &
>in accordance with the Convention on the Elaboration of a
macopoeia and have been brought into effect under
: tives 2001/82/EC, 2001/83/EC and 2003/63/EC, as
amended, ori medicines for human and veterinary use.
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II-2 General Notices 2016
CONTENTS OF THE GENERAL NOTICES
Part I Implementation of Pharmacopoeial Methods

Italic introduction Conventional Terms
European Pharmacopoeia Interchangeable Methods
References to Regulatory Documents
Part II
Ee Other Provisions Applying to General
Italic introduction
Chapters and Monographs
Official Standards
Quantities
Definition of Terms
Apparatus and Procedures
Expression of Standards
Water-bath
Temperature
Drying and Ignition to Constant Mass :
Weights and Measures
Reagents
Atomic si
Solvents
Constan
Expression of Content
Expressio fe entrations
Temperature
Water Bath ia
Reagents O 1.3 General Chapters
Indicators Containers
Caution Statements O 1.4 Monographs
Titles <= Titles
Chemical Formulae Relative Atomic and Molecular Masses
Definition A) Chemical Abstracts Service (CAS) Registry
Production Number
Manufacture of Formulated Prepar., Definition
Freshly and Recently Prepared S o Limits of Content
Methods of Sterilisation Herbal Drugs
Water Production
Excipients Choice of Vaccine Strain, Choice of
Colouring Agents Vaccine Composition
Antimicrobial Preservatives tial Adulteration
Characteristics
Solubility
Identification
Reference Spectra
Assays and Tests cond Identifications
Biological Assays and Tests Powd al Drugs
Reference Substances and Reference Preparations Tests and a
Chemical Reference Substances Scope
Biological Reference Preparations Calculation
Storage Limits
Labelling Indication of Perm Limit of Impurities
CO
Action and Use Herbal Drugs ¢
Crude Drugs; Traditional Herbal and Equivalents
Complementary Medicines Culture Media
Monograph Title Storage
Definition Labelling
Characteristics Warnings
Control Methods Impurities
Homoeopathic Medicines Functionality-related Characteristics of
Unlicensed Medicines Excipients
Reference Standards
Part Il
Ttalic introduction 1.5 Abbreviations and Symbols
General Notices of the European Pharmacopoeia Abbreviations used in the Monographs on
1.1 General Statements Immunoglobulins, Immunosera and
Quality Systems Vaccines
Alternative Methods Collections of Micro-organisms
Demonstration of Compliance with the 1.6 Units of the International System (SI) used
Pharmacopoeia in the Pharmacopoeia and Equivalence
Grade of Materials with other Units
General Monographs International System of Units (SI)
Validation of Pharmacopoeial Methods Notes
2016 General Notices III-3
General Notices
Part I
Ms The British Pharmacopoeia comprises the entire text within this publication. The
0
word ‘official’ 1s used in the Pharmacopoeia to signify ‘of the Pharmacopoeia’. It
applies to any title, substance, preparation, method or statement included in the
general notices, monographs and appendices of the Pharmacopoeia. The
O ere for British Pharmacopoeia is BP.
Europe phs of the European Pharmacopoeia are reproducedin this edition

FN ty itish Pharmacopoeia by incorporation of the text published under
ion of the Council of Europe (Partial Agreement) in accordance
aad Qe on the Elaboration of a European Pharmacopoeia
witsED rN: 32 (1974) CMND 5763) as amended by the Protocol to
theBa oa oO eaty Series No. MISC16 (1990) CMND 1133). They
are included for nvenience of users of the British Pharmacopoeia. In
cases of doubt or So should be made to the Council of
Europe text.
wx**, Monographs o pean Pharmacopoeia are distinguished by a
* »* chaplet of stars aga title and by reference to the European
Bh Pharmacopoeia monograph number included immediately below the
title in italics. The beginning an text from the European
Pharmacopoeia are denoted by me hogizontal lines with the symbol
‘Ph Eur ranged left and right, respec
The general provisions of the Europea acopoeia relating to
different types of dosage form are included appropriate general
monograph in that section of the British Pha ery entitled
Monographs: Formulated Preparations. These generalprovisions apply to
all dosage forms of the type defined, whether or notea i
monographis includedin the British Pharmacopoeia. ition, the
provisions of the European Pharmacopoeia General Mon
Pharmaceutical Preparations apply to all dosage forms, whe
individual monograph is included in the British Pharmacopoeia
Texts of the European Pharmacopoeia are governed by the General
Notices of the European Pharmacopoeia. These are reproduced as Part III
of these notices.
IlI-4 General Notices 2016
Part II
The following general notices apply to the statements made in the monographs of
the British Pharmacopoeia other than those reproduced from the European
Pharmacopoeia and to the statements made in the Appendices of the British
Pharmacopoeia other than when a method, test or other matter described in an
appendix 1s invoked in a monograph reproduced from the European
Pharmacopoeia.
onion The requirements stated in the monographs of the Pharmacopoeia apply to

articles that are intended for medicinal use but not necessarily to articles
that may be sold under the same name for other purposes. An article
O intended for medicinal use that is described by means of an official title
ust comply with the requirements of the relevant monograph. A
ulated preparation must comply throughout its assigned shelf-life
eriOd, of validity). The subject of any other monograph must comply
its period of use.
that is con in this edition and that is applicable to that monograph.

All gee ed in the monographs, except where a specific general
notice indicates and with the exceptions given below, constitute
standards for the offici icles. An article is not of pharmacopoeial quality
unless it complies wi the requirements stated. This does not imply
that a manufacturer is ob orm all the tests in a monograph in
order to assess compliance harmacopoeia before release of a
product. The manufacturer ure himself that a product is of
pharmacopoeial quality by other m r example, from data derived
from validation studies of the manufactwzing process, from in-process
controls or from a combination of the , etric release in
appropriate circumstances is thus not preclud ss the need to comply with
the Pharmacopoeia. The general notice on Ass d Tests indicates that
analytical methods other than those described in Oo may be
employed for routine purposes.
Requirements in monographs have been framed to prowid@a
limitation of potential impurities rather than to provide agains
impurities. Material found to contain an impurity not detecta D
of the prescribed tests is not of pharmacopoeial quality if the na
amount of the impurity found is incompatible with good pharmace
practice.
The status of any statement given under the headings Definition,
Production, Characteristics, Storage, Labelling or Action and use is defined
within the general notice relating to the relevant heading. In addition to any
exceptions indicated by one of the general notices referred to above, the
following parts of a monograph do not constitute standards: (a) a graphic or
molecular formula given at the beginning of a monograph; (b) a molecular
weight; (c) a Chemical Abstracts Service Registry Number; (d) any
information given at the end of a monograph concerning impurities known
to be limited by that monograph; (e) information in any annex to a
monograph. Any statement containing the word ‘should’ constitutes non-

mandatory advice or recommendation.
The expression ‘unless otherwise justified and authorised’ means that the
requirement in question has to be met, unless a competent authority
authorises a modification or exemption where justified in a particular case.
The term ‘competent authority’ means the national, supranational or
international body or organisation vested with the authority for making
decisions concerning the issue in question. It may, for example, be a
licensing authority or an official control laboratory. For a formulated
preparation that is the subject of monograph in the British Pharmacopoeia
any justified and authorised modification to, or exemption from, the
requirements of the relevant general monograph of the European
%
Pharmacopoeia is stated in the individual monograph. For example, the
general monograph for Tablets requires that Uncoated Tablets, except for
“6O
chewable tablets, disintegrate within 15 minutes; for Calctum Lactate
Tablets a time of 30 minutes is permitted.
Many of the general monographs for formulated preparations include
statements and requirements additional to those of the European
armacopoeia that are applicable to the individual monographs of the
lh Pharmacopoeia. Such statements and requirements apply to all
phs for that dosage form included in the Pharmacopoeia unless
Oo ise indicated in the individual monograph.
onograph on a biological substance or preparation refers to a
strain, a es a substance, etc., using the qualifications ‘suitable’
or ‘appropriate? out further definition in the text, the choice of such
strain, test, m , substance, etc., is made in accordance with any
international agre r national regulations affecting the subject
concerned.
Definition of Terms Where the term ‘about’ d in a monograph or test it should be

taken to mean approxim inly correct or accurate; near to the actual
value).
Where the term ‘corresponds’ isae in a monograph or test it
should be taken to mean similar or equiyaleht in character or quantity.
Where the term ‘similar’ is included in a/monograph or test it should be
taken to mean alike though not necessarily 1 jent al.
Further qualifiers (such as numerical accep cy for the above
terms are not included in the BP. The acceptan teria for any individual
case is set based on the range of results obtained ae a reference
samples, the level of precision of the equipment or ap sed and the
level of accuracy required for the particular application.The ws should
determine the variability seen in his/her own laboratory and set 1 use
acceptance criteria that he/she judges to be appropriate based om the local
operating conditions.
Expression of Where the standard for the content of a substance described in a

Standards monograph is expressed in terms of the chemical formula for that substance
an upper limit exceeding 100% may be stated. Such an upper limit applies
to the result of the assay calculated in terms of the equivalent content of the
specified chemical formula. For example, the statement ‘contains not less
than 99.0% and not more than 101.0% of Cs9H24N202,HCI’ implies that
the result of the assay is not less than 99.0% and not more than 101.0%,
calculated in terms of the equivalent content of C2)H24N202,HCl.
III-6 General Notices 2016
Where the result of an assay or test is required to be calculated with

reference to the dried, anhydrous or ignited substance, the substance free
from a specified solvent or to the peptide content, the determination of loss
on drying, water content, loss on ignition, content of the specified solvent
or peptide content is carried out by the method prescribed in the relevant
test in the monograph.
Temperature The Celsius thermometric scale is used in expressing temperatures.
Weights and The metric system of weights and measures is employed; SI Units have
Measures generally been adopted. Metric measures are required to have been
%
graduated at 20° and all measurements involved in the analytical operations
of the Pharmacopoeia are intended, unless otherwise stated, to be made at
that temperature. Graduated glass apparatus used in analytical operations
“0
should comply with Class A requirements of the appropriate International
Standard issued by the International Organization for Standardization. The
abbreviation for litre is ‘L’ throughout the Pharmacopoeia. In line with
am Directive 80/181/EEC, the abbreviation ‘l is also permitted for
Atomic Weights weights adopted are the values given in the Table of Relative
Atomi hts 2001 published by the International Union of Pure and
Applied try (Appendix XXV).
Constant Weight The term hig ly ight’, used in relation to the process of drying or the
process of ignition, meams that two consecutive weighings do not differ by
more than 0.5 mg, se€ond weighing being made after an additional
period of drying or ignitiof the specified conditions appropriate to
the nature and quantity o idue (1 hour is usually suitable).
Expression of The term ‘per cent’ or more y the symbol ‘%’ is used with one of four
Concentrations different meanings in the expressio Rp brat according to
circumstances. In order that the mean attached to the expression
in each instance is clear, the following n nus used:
Per cent w/w (% w/w) (percentage weight i O expresses the
number of grams of solute in 100 g of product
Per cent w/v (% w/v) (percentage weight in volufe) ) xpresses the
number of grams of solute in 100 mL of product.
Per cent v/v (% v/v) (percentage volume in volume) €xpresSes the
number of millilitres of solute in 100 mL of product.
Per cent v/w (% v/w) (percentage volume in weight) express
number of millilitres of solute in 100 g of product.
Usually the strength of solutions of solids in liquids is expressed €s
percentage weight in volume, of liquids in liquids as percentage vol
volume and of gases in liquids as percentage weight in weight.
When the concentration of a solution is expressed as parts per million
(ppm), it means weight in weight, unless otherwise specified.
When the concentration of a solution is expressed as parts of dissolved
substance in parts of the solution, it means parts by weight (g) of a solid in
parts by volume (mL) of the final solution; or parts by volume (mL) of a
liquid in parts by volume (mL) of the final solution; or parts by weight (g)
of a gas in parts by weight (g) of the final solution.
When the concentration of a solution is expressed in molarity designated

by the symbol m preceded by a number, it denotes the number of moles of
the stated solute contained in sufficient Purified Water (unless otherwise
stated) to produce 1 litre of solution.
Water Bath The term ‘water bath’ means a bath of boiling water, unless water at some
other temperature is indicated in the text. An alternative form of heating
may be employed providing that the required temperature is approximately
maintained but not exceeded.
Reagents The reagents required for the assays and tests of the Pharmacopoeia are
defined in appendices. The descriptions set out in the appendices do not
%
imply that the materials are suitable for use in medicine.
oO” Indicators, the colours of which change over approximately the same range
of pH, may be substituted for one another but in the event of doubt or
dispute as to the equivalence of indicators for a particular purpose, the
. indicator specified in the text is alone authoritative.
The quantity of an indicator solution appropriate for use in acid-base
ions described in assays or tests is 0.1 mL unless otherwise stated in
y solvent required in an assay or test in which an indicator is specified

is prévi neutralised to the indicator, unless a blank test is prescribed.
Caution Statements A number erials described in the monographs and some of the
reagents specified OPuse in the assays and tests of the Pharmacopoeia may
be injurious to he: ess adequate precautions are taken. The principles
the United Kingdom in accordance with

. Act 1974 should be observed at all times
ests of the Pharmacopoeia.
Attention is drawn to particu ds in certain monographs by means
of an italicised statement; the saeeog sueh a statement should not
however be taken to mean that no h ists.
Titles Subsidiary titles, where included, have the

63 ificance as the main
titles. An abbreviated title constructed in acc cys with the directions
given in Appendix XXI A has the same signific as the main title.
Titles that are derived by the suitable inversion of of a main or
subsidiary title, with the addition of a preposition if a fate, are also
official titles. Thus, the following are all official titles: As
Tablets of Aspirin; Atropine Injection, Injection of Atropine.
name of the active ingredient or ingredients, where this is not included in

the title of the monograph, is also an official title. For example, the title
Promethazine Hydrochloride Oral Solution has the same significance as
Promethazine Oral Solution and the title Brompheniramine Maleate Tablets
has the same significance as Brompheniramine Tablets.
Where the English title at the head of a monograph in the European
Pharmacopoeia is different from that at the head of the text incorporated
into the British Pharmacopoeia, an Approved Synonym has been created on
the recommendation of the British Pharmacopoeia Commission. Approved
Synonyms have the same significance as the main title and are thus official
titles. A cumulative list of such Approved Synonyms is provided in

Appendix XXI B.
Where the names of pharmacopoeial substances, preparations and other
materials occur in the text they are printed with capital initial letters and
this indicates that materials of Pharmacopoeial quality must be used. Words
in the text that name a reagent or other material, a physical characteristic or
a process that is described or defined in an appendix are printed in italic
type, for example, methanol, absorbance, gas chromatography, and these imply
compliance with the requirements specified in the appropriate appendix.
Chemical Formulae When the chemical composition of an official substance is known or

generally accepted, the graphic and molecular formulae, the molecular
weight and the Chemical Abstracts Service Registry Number are normally
iy. given at the beginning of the monograph for information. This information
? refers to the chemically pure substance and is not to be regarded as an
indication of the purity of the official material. Elsewhere, in statements of
standards of purity and strength and in descriptions of processes of assay, it
na from the context that the formulae denote the chemically pure
ances.
si e absolute stereochemical configuration is specified, the
al Union of Pure and Applied Chemistry (TUPAC) R/S and E/Z
systems of/designation have been used. If the substance is an enantiomer of
unkno olute stereochemistry the sign of the optical rotation, as
determine Ec and under the conditions specified in the
monograph, has attached to the systematic name. An indication of
sign of rotation has@lsojbeen given where this is incorporated in a trivial
name that appears o AC preferred list.
All amino acids, exceptglycine, have the t-configuration unless otherwise
indicated. The three-lette Ce etter symbols used for amino acids in
peptide and protein seque ct ose recommended by the Joint
Commission on Biochemica enclature of the International Union of
Pure and Applied Chemistry an ational Union of Biochemistry
and Molecular Biology.
In the graphic formulae the following eViations are used:
Me -CH, Bu’ -cr(cfi CH;

Et -CH,CH; Buti GHG 2GFGES
Pi aie-@GH(CGH.)s Bu’ -C(CH)3
Pr” —-CH,CH2CH; Ph —C.Hs «
Bu’ -CH,CH(CHs3), Ac -COCH; O
Definition Statements given under the heading Definition constitute an offi¢ial

definition of the substance, preparation or other article that is the subject of
the monograph. They constitute instructions or requirements and ar
mandatory in nature.
Certain medicinal or pharmaceutical substances and other articles are
defined by reference to a particular method of manufacture. A statement
that a substance or article zs prepared or obtained by a certain method
constitutes part of the official definition and implies that other methods are
not permitted. A statement that a substance may be prepared or obtained by
a certain method, however, indicates that this is one possible method and
does not imply that other methods are proscribed.
Additional statements concerning the definition of formulated

preparations are given in the general notice on Manufacture of Formulated
Preparations.
Production Statements given under the heading Production draw attention to particular
aspects of the manufacturing process but are not necessarily comprehensive.
They constitute mandatory instructions to manufacturers. They may relate,
for example, to source materials, to the manufacturing process itself and its
validation and control, to in-process testing or to testing that is to be
carried out by the manufacturer on the final product (bulk material or
dosage form) either on selected batches or on each batch prior to release.
These statements cannot necessarily be verified on a sample of the final
product by an independent analyst. The competent authority may establish
Py. that the instructions have been followed, for example, by examination of
7? data received from the manufacturer, by inspection or by testing
appropriate samples.
O The absence of a section on Production does not imply that attention to
features such as those referred to above is not required. A substance,
eparation or article described in a monograph of the Pharmacopoeia is to
anufactured in accordance with the principles of good manufacturing
ie@ and in accordance with relevant international agreements and
supranational and national regulations governing medicinal products.
e section under the heading Production a monograph on a
vaccine ar characteristics of the vaccine strain to be used, any test
methods gi n onfirming these characteristics are provided as examples
of suitable methods“The use of these methods is not mandatory.
Additional statenféntseconcerning the production of formulated
preparations are giv eneral notice on Manufacture of Formulated
Preparations.
Manufacture of Attention is drawn to the‘ne serve adequate hygienic precautions in

Formulated the preparation and dispensing o aceutical formulations. The
Preparations principles of good pharmaceutical cturing practice should be
observed.
The Definition in certain monographs f aceutical preparations is
given in terms of the principal ingredients o y ingredient, other than
those included in the Definition, must comp e general notice on
Excipients and the product must conform with armacopoeial
requirements. ¢
The Definition in other monographs for pharmaceuti arations is
presented as a full formula. No deviation from the stated la is
permitted except those allowed by the general notices on Co Agents
and Antimicrobial Preservatives. Where additionally directions iven
under the heading Extemporaneous Preparation these are intended for the
extemporaneous preparation of relatively small quantities for short-term
supply and use. When so prepared, no deviation from the stated directions
is permitted. If, however, such a pharmaceutical preparation is
manufactured on a larger scale with the intention that it may be stored,
deviations from the stated directions are permitted provided that the final
product meets the following criteria:
(1) compliance with all of the requirements stated in the monograph;

(2) retention of the essential characteristics of the preparation made strictly
in accordance with the directions of the Pharmacopoeia.
Monographs for yet other pharmaceutical preparations include both a
Definition in terms of the principal ingredients and, under the side-heading
Extemporaneous Preparation, a full formula together with, in some cases,
directions for their preparation. Such full formulae and directions are
intended for the extemporaneous preparation of relatively small quantities
for short-term supply and use. When so prepared, no deviation from the
stated formula and directions is permitted. If, however, such a
pharmaceutical preparation is manufactured on a larger scale with the
intention that it may be stored, deviations from the formula and directions
stated under the heading Extemporaneous Preparation are permitted
provided that any ingredient, other than those included in the Definition,
complies with the general notice on Excipients and that the final product
meets the following criteria:
(1) accordance with the Definition stated in the monograph;
O compliance with all of the requirements stated in the monograph;
=) ntion of the essential characteristics of the preparation made strictly
rdance with the formula and directions of the Pharmacopoeia.
In nufacture of any official preparation on a large scale with the
intentio should be stored, in addition to following any instruction
under the roduction, it is necessary to ascertain that the product
is satisfactorywit ect to its physical and chemical stability and its state
of preservation over laimed shelf-life. This applies irrespective of
whether the formu harmacopoeia and any instructions given under
the heading Extempor Preparation are followed precisely or
modified. Provided that ion has been shown to be stable in
other respects, deteriorati icrobial contamination may be
inhibited by the incorporati itable antimicrobial preservative. In
such circumstances the label s es Tilate storage conditions, the date
after which the product should not be the identity and
concentration of the antimicrobial pre 1
Freshly and The direction, given under the heading Exte eous Preparation, that a
Recently Prepared preparation must be freshly prepared indicates Lita ust be made not
more than 24 hours before it is issued for use. Thedine ction that a
preparation should be recently prepared indicatesthat deterieration is likely
if the preparation is stored for longer than about 4 weeks at [5s.to 25°.
Methods of The methods of sterilisation used in preparing the sterile mat

Sterilisation described in the Pharmacopoeia are given in Appendix XVIII. For aqueous
preparations, steam sterilisation (heating in an autoclave) is the method of
choice wherever it is known to be suitable. Any method of sterilisation must
be validated with respect to both the assurance of sterility and the integrity
of the product and to ensure that the final product complies with the
requirements of the monograph.
Water The term water used without qualification in formulae for formulated
preparations means either potable water freshly drawn direct from the
public supply and suitable for drinking or freshly boiled and cooled Purified
Water. The latter should be used if the public supply is from a local storage
tank or if the potable water is unsuitable for a particular preparation.
Excipients Where an excipient for which there is a pharmacopoeial monograph is used

in preparing an official preparation it shall comply with that monograph.
Any substance added in preparing an official preparation shall be
innocuous, shall have no adverse influence on the therapeutic efficacy of the
active ingredients and shall not interfere with the assays and tests of the
Pharmacopoeia. Particular care should be taken to ensure that such
substances are free from harmful organisms.
O.
Colouring Agents If in a monograph for a formulated preparation defined by means of a full
formula a specific colouring agent or agents is prescribed, suitable
alternatives approvedin the country concerned may be substituted.
‘Tp. When the term ‘suitable antimicrobial preservative’ is used it is implied that
bial
Pres the preparation concerned will be effectively preserved according to the
appropriate criteria applied and interpreted as describedin the test for
CE of antimicrobial preservation (Appendix XVI C). In certain
ANE for formulated preparations defined by means of a full formula,
c antimicrobial agent or agents may be prescribed; suitable
Ash es may be substituted provided that their identity and
conc Or stated on the label.
Characteristics A der the heading Characteristics are not to be

interpreted 1 sense and are not to be regarded as official
requirements. Stat on taste are provided only in cases where this
property is a guideCo tability of the material (for example, a
material used primari ring). The status of statements on
solubility is given in th otice on Solubility.
Solubility Statements ity given under the heading
Characteristics are intended as 1 tion on the approximate solubility at
a temperature between 15° and 25% ss otherwise stated, and are not to
be considered as official requiremen
Statements given under headings su bility in ethanol express
exact requirements and constitute part o eda for the substances
under which they occur. 2.
The following table indicates the meanings o erms used in
statements of approximate solubilities. &()
Descriptive term Approximate volume o

solvent in millilitres per
gram of solute
very soluble less than 1
freely soluble from 1 to 10
soluble from 10 to 30
sparingly soluble from 30 to 100
slightly soluble from 100 to 1000
very slightly soluble from 1000 to 10,000
practically insoluble more than 10,000
The term ‘partly soluble’ is used to describe a mixture of whichonly

some of the components dissolve.
Identification The tests described or referred to under the heading Identification are not
necessarily sufficient to establish absolute proof of identity. They provide a
means of verifying that the identity of the material being examined is in
accordance with the label on the container.
Unless otherwise prescribed, identification tests are carried out at a
temperature between 15° and 25°.
Reference spectra Where a monograph refers to an infrared reference
spectrum, this spectrum is provided in a separate section of the
Pharmacopoeia. A sample spectrum is considered to be concordant with a
reference spectrum if the transmission minima (absorption maxima) of the
principal bands in the sample correspond in position, relative intensities and
shape to those of the reference. Instrumentation software may be used to
%,
calculate concordance with a previously recorded reference spectrum.
When tests for infrared absorption are applied to material extracted from
formulated preparations, strict concordance with the specified reference
spectrum may not always be possible, but nevertheless a close resemblance
O
between the spectrum of the extracted material and the specified reference
spectrum should be achieved.
Assays and Tests ON and tests described are the official methods upon which the
f the Pharmacopoeia depend. The analyst is not precluded from
empl Iternative methods, including methods of micro-analysis, in any
assay or is known that the method used will give a result of
equivalent Oi Local reference materials may be used for routine
analysis, provided these are calibrated against the official reference
materials. In the*ev doubt or dispute, the methods of analysis, the
reference materials a reference spectra of the Pharmacopoeia are
alone authoritative.
Where the solvent use ion is not named, the solvent is
Purified Water.
Unless otherwise prescrib agSays and tests are carried out at a
temperature between 15° and 25°.
A temperature in a test for Loss onope here no temperature range
is given, implies a range of +2° about value.
Visual comparative tests, unless otherwise ibed, are carried out
using identical tubes of colourless, anspor glass with a flat
base. The volumes of liquid prescribed are for use ubes 16 mm in
internal diameter; tubes with a larger internal diam ay be used but the
volume of liquid examined must be increased so that the of liquid in
the tubes is not less than that obtained when the Sites
liquid and tubes 16 mm in internal diameter are used. Equa s of the
liquids to be compared are examined down the vertical axis o
against a white background or, if necessary, against a black backgr
The examination is carried out in diffuse light.
Where a direction is given that an analytical operation is to be carried out
‘in subdued light’, precautions should be taken to avoid exposure to direct
sunlight or other strong light. Where a direction is given that an analytical
operation is to be carried out ‘protected from light’, precautions should be
taken to exclude actinic light by the use of low-actinic glassware, working in
a dark room or similar procedures.
For preparations other than those of fixed strength, the quantity to be
taken for an assay or test is usually expressed in terms of the active
ingredient. This means that the quantity of the active ingredient expected to
be present and the quantity of the preparation to be taken are calculated

from the strength stated on the label.
In assays the approximate quantity to be taken for examination is
indicated but the quantity actually used must not deviate by more than
10% from that stated. The quantity taken is accurately weighed or
measured and the result of the assay is calculated from this exact quantity.
Reagents are measured and the procedures are carried out with an accuracy
commensurate with the degree of precision implied by the standard stated
for the assay.
In tests the stated quantity to be taken for examination must be used
unless any divergence can be taken into account in conducting the test-and
calculating the result. The quantity taken is accurately weighed or measured
with the degree of precision implied by the standard or, where the standard
is not stated numerically (for example, in tests for Clarity and colour of
solution), with the degree of precision implied by the number of significant
figures stated. Reagents are measured and the procedures are carried out
with an accuracy commensurate with this degree of precision.
The limits stated in monographs are based on data obtained in normal
lytical practice; they take account of normal analytical errors, of
table variations in manufacture and of deterioration to an extent
d acceptable. No further tolerances are to be applied to the limits
prescri o determine whether the article being examined complies with
the req ts of the monograph.
In dete compliance with a numerical limit, the calculated result of
a test or assay rounded to the number of significant figures stated,
unless otherwis reseribed. The last figure is increased by 1 when the part
rejected is equal t eds one half-unit, whereas it is not modified
when the part reject 2an a half-unit.
In certain tests, the c¢ on of impurity is given in parentheses
either as a percentage 0 arts per million by weight (ppm). In
chromatographic tests sucsefision are stated as a percentage
irrespective of the limit. In 0 sts®they are usually stated in ppm unless
the limit exceeds 500 ppm. In thos ographic tests in which a
secondary spot or peak in a chromato tained with a solution of the
substance being examined is described as onding to a named
impurity and is compared with a spot or G romatogram obtained
with a reference solution of the same impurity,fepwn given in
parentheses indicates the limit for that impurity. Ti those chromatographic
tests in which a spot or peak in a chromatogram obfaiffed With a solution of
the substance being examined is described in terms o Fa as
corresponding to a named impurity (commonly, for example y (other)
secondary spot or peak) but is compared with a spot or peak i
chromatogram obtained with a reference solution of a named i y, the
percentage given in parentheses indicates an impurity limit expressed in
terms of a nominal concentration of the named impurity. In
chromatographic tests in which a comparison is made between spots or
peaks in chromatograms obtained with solutions of different concentrations
of the substance being examined, the percentage given in parentheses
indicates an impurity limit expressed in terms of a nominal concentration of
the medicinal substance itself. In some monographs, in particular those for
certain formulated preparations, the impurity limit is expressed in terms of a
nominal concentration of the active moiety rather than of the medicinal
substance itself. Where necessary for clarification the terms in which the
limit is expressed are stated within the monograph.
In all cases where an impurity limit is given in parentheses, the figures
given are approximations for information only; conformity with the
requirements is determined on the basis of compliance or otherwise with
the stated test.
The use of a proprietary designation to identify a material used in an
assay or test does not imply that another equally suitable material may not
be used.
Methods of assay described as Suggested methods are not obligatory, but-

Biological Assays
Se ests when another method is used its precision must be not less than that
required for the Suggested method.
For those antibiotics for which the monograph specifies a microbiological
“0
Oe
a
assay the potency requirement is expressed in the monograph in
International Units (IU) per milligram. The materialis not of
quality if the upper fiducial limit of error is less than the
ed potency. For such antibiotics the required precision of the assay is
the monographin terms of the fiducial limits of error about the
otency.
substances and preparations for which the monograph specifies
a e unless otherwise stated, the precision of the assay is such
that aia) “shits of error, expressed as a percentage of the estimated
potency, =) range not wider than that obtained by multiplying by ©
a factor of 10of q e roots of the limits given in the monograph for the
fiducial limits of e out the stated potency.
In all cases fiducia
(P = 0.95).
Where the biological ass used to ascertain the purity of the
material, the stated potenc € potency stated on the label in terms
of International Units (IU) o hits per gram, per milligram or per
millilitre. When no such statemenwatus the label, the stated potency
means the fixed or minimum potency in the monograph. This
interpretation of stated potency ep 1 cases except where the
monograph specifically directs otherwise.
Where the biological assay is being used to ine the total activity in
the container, the stated potency means the total r of International
Units (IU) or other Units stated on the label or, if nO such.statement
appears, the total activity calculated in accordance wi fe rton in
the monograph.
Wherever possible the primary standard used in an assay o
respective International Standard or Reference Preparation establis Vv
the World Health Organization for international use and the biologic
activity is expressed in International Units (IU).
In other cases, where Units are referred to in an assay or test, the Unit
for a particular substance or preparation is, for the United Kingdom, the
specific biological activity contained in such an amount of the respective
primary standard as the appropriate international or national organisation
indicates. The necessary information is provided with the primary standard.
Unless otherwise directed, animals used in an assay or a test are healthy
animals, drawn from a uniform stock, that have not previously been treated
with any material that will interfere with the assay or test. Unless otherwise
stated, guinea-pigs weigh not less than 250 g or, when used in systemic
2016 General Notices ITII-15
toxicity tests, not less than 350 g. When used in skin tests they are white or
light coloured. Unless otherwise stated, mice weigh not less than 17 g and
not more than 22 g.
Certain of the biological assays and tests of the Pharmacopoeia are such
that in the United Kingdom they may be carried out only in accordance
with the Animals (Scientific Procedures) Act 1986. Instructions included in
such assays and tests in the Pharmacopoeia, with respect to the handling of
animals, are therefore confined to those concerned with the accuracy and
reproducibility of the assay or test.
Reference Certain monographs require the use of a reference substance, a reference

Substances and preparation or a reference spectrum. These are chosen with regard to their
erence intended use as prescribed in the monographs of the Pharmacopoeia and
rations are not necessarily suitable in other circumstances.
Any information necessary for proper use of the reference substance or
reference preparation is given on the label or in the accompanying leaflet or
brochure. Where no drying conditions are stated in the leaflet or on the
abel, the substance is to be used as received. No certificate of analysis or
her data not relevant to the prescribed use of the product are provided.
om dispatch when stored under the appropriate conditions. The

e contents of opened containers cannot be guaranteed. The
Commission. The @ Viation CRS or EPCRS indicates a Chemical

Reference Substance“establishted by the European Pharmacopoeia
Rey erence Substances are used for the
NW. s.and their activity is stated, in
International Units, on theMabel the accompanying leaflet and defined
in the same manner as for aie fs erence Preparations.
Biological Reference Prepara majority of the primary
e the appropriate
established Biological Reference Preparations (ind the

abbreviation BRP or EPBRP) where appropriate. Wh licable, the
potency of the Biological Reference Preparations is exp
International Units. For some Biological Reference Prepa here an
international standard or reference preparation does not exist ency is
expressed in European Pharmacopoeia Units.
Storage Statements under the side-heading Storage constitute non-mandatory

advice. The substances and preparations described in the Pharmacopoeia
are to be stored under conditions that prevent contamination and, as far as
possible, deterioration. Unless otherwise stated in the monograph, the
substances and preparations described in the Pharmacopoeia are kept in
well-closed containers and stored at a temperature not exceeding 25°.
Precautions that should be taken in relation to the effects of the
atmosphere, moisture, heat and light are indicated, where appropriate, in
the monographs. Further precautions may be necessary when some

materials are stored in tropical climates or under other severe conditions.
The expression ‘protected from moisture’ means that the product is to be
stored in an airtight container. Care is to be taken when the container is
opened in a damp atmosphere. A low moisture content may be maintained,
if necessary, by the use of a desiccant in the container provided that direct
contact with the product is avoided.
The expression ‘protected from light’ means that the product is to be
stored either in a container made of a material that absorbs actinic light
sufficiently to protect the contents from change induced by such light or in
a container enclosed in an outer cover that provides such protection or -
stored in a place from which all such light is excluded.
Ys The expression ‘tamper-evident container’ means a closed container fitted

with a device that reveals irreversibly whether the container has been
“0
opened, whereas, the expression ‘tamper-proof container’ means a closed
container in which access to the contents is prevented under normal
Cyne of use. The two terms are considered to be synonymous by the
opean Pharmacopoeia Commission.
Labelling Lb lat elling requirements of the Pharmacopoeia are not comprehensive,

d= isions of regulations issued in accordance with the
requirém the territory in which the medicinal product is to be used
should be
Licensed me s intended for use within the United Kingdom must
comply with the uirements of The Human Medicines Regulations 2012
and European Dir 001/83/EC, Title V (as amended) in respect of
their labelling and pa aflets, together with those regulations for the
labelling of hazardous
Best practice guidance o elling and packaging of medicines for
use in the United Kingdo that certain items of information are
deemed critical for the safe us dicine (see ““Best Practice
Guidance on the Labelling and Paekaging*ef Medicines”’ issued by the
MHRA, 2012). Further information a ce on the labelling of
medicinal products can be found in Sup entary Chapter I G.
Such matters as the exact form of wordin sed and whether a
particular item of information should appear iG), imary label and
additionally, or alternatively, on the package or exc ally in a leaflet are,
in general, outside the scope of the Pharmacopoeia. en the term ‘label’
is used in Labelling statements of the Pharmacopoeia, Gedisio&s as to where
the particular statement should appear should therefore be we
accordance with relevant legislation.
The label of every official formulated preparation other than thos
fixed strength also states the content of the active ingredient or ingredients
expressed in the terms required by the monograph. Where the content of
active ingredient is required to be expressed in terms other than the weight
of the official medicinal substance used in making the formulation, this is
specifically stated under the heading Labelling. Unless otherwise stated in
the monograph, the content of the active ingredient is expressed in terms of
the official medicinal substance used in making the formulation.
These requirements do not necessarily apply to unlicensed preparations
supplied in accordance with a prescription. For requirements for unlicensed
medicines see the general monograph on Unlicensed Medicines.
Action and Use The statements given under this heading in monographs are intended only
as information on the principal pharmacological actions or the uses of the
materials in medicine or pharmacy. It should not be assumed that the
substance has no other action or use. The statements are not intended to be
binding on prescribers or to limit their discretion.
Crude Drugs; Herbal and complementary medicines are classed as medicines under European
Traditional Herbal Directive 2001/83/EC as amended. It is emphasised that, although requirements
and Complementary for the quality of the material are provided in the monograph to assist the
Medicines registration scheme by the UK Licensing Authority, the British Pharmacopoeia
Commission has not assessed the safety or efficacy of the material in traditional
use.
Ys
Monograph Title For traditional herbal medicines, the monograph title
is a combination of the binomial name together with a description of use.
“O
Monographs for the material that has not been processed (the herbal drug)
and the processed material (the herbal drug preparation) are published
where possible. To distinguish between the two, the word ‘Processed’ is
O Spel in the relevant monograph title.
efinition Under the heading Definition, the botanical name together
any
synonym is given. Where appropriate, for material that has not
cessed, information on the collection/harvesting and/or treatment/
dryin e whole herbal drug may be given. For processed materials, the
meth ocessing, where appropriate, will normally be given in a
separate Sect
(a) macroscopical and pical descriptions and chemical/

chromatographic t
(b) tests for absence of any
(c) microbial test to assure
(d) tests for inorganic impurities an ecific purity tests, including
extractive tests, Sulfated ash and tals where appropriate
(e) test for Loss on drying or Water O
(f) wherever possible, a method for assaying tieadv constituent(s) or
suitable marker constituent(s).
The macroscopical characteristics include those fe that can be seen
by the unaided eye or by the use of a hand lens. Whe
subspecies of the same plant are included in the Definiti
differences between the two are indicated where possible.
The description of the microscopical characteristics of the powdered drug
includes information on the dominant or the most specific characters.
Where it is considered to be an aid to identification, illustrations of the
powdered drug may be provided.
The following aspects are controlled by the general monograph for
Herbal Drugs: they are required to be free from moulds, insects, decay,
animal matter and animal excreta. Unless otherwise prescribed the amount
of foreign matter is not more than 2% w/w. Microbial contamination should
be minimal.
In determining the content of the active constituents or the suitable

marker substances measurements are made with reference to the dried or
anhydrous herbal drug. In the tests for Acid-insoluble ash, Ash, Extractive
soluble in ethanol, Loss on drying, Sulfated ash, Water, Water-soluble ash
and Water-soluble extractive of herbal drugs, the calculations are made with
reference to the herbal drug that has not been specifically dried unless
otherwise prescribed in the monograph.
Homoeopathic Homoeopathic medicines are classed as medicines under European Directive

Medicines 2001/83/EC as amended. It 1s emphasised that, although requirements for the
quality of the material are provided in the relevant monograph in order to assist -
%
the simplified registration scheme by the UK Licensing Authority, the British
Pharmacopoeia Commission has not assessed the safety or efficacy of the material
“O
mm USe.
All materials used for the production of homoeopathic medicines,
including excipients, must comply with European Pharmacopoeia or British
Choe monographs for those materials. Where such European
etlwed or British Pharmacopoeia monographs do not exist, each
ial used for the production of homoeopathic medicines must comply
ial national pharmacopoeia of a Member State.
shyPharmacopoeia monographs for homoeopathic medicines apply to
homoe6pa ni and mother tinctures only, but may be prefaced by a
section whi ails the quality requirements applicable to the principle
component
ments on the methods of preparation or refer to

specific methods of pri n given in the European Pharmacopoeia.
Homoeopathic stocks a inctures undergo the further process
referred to as potentisation. ion is a term specific to homoeopathic
medicine and is a process o stocks and mother tinctures to
produce the final product.
Identification tests are establish excomponents in homoeopathic
stocks and usually relate to those applied teythe’materials used in the
identification test, usually chromatographic, is e nsed and, where

applicable, an assay for the principle component(s); # appropriate,
other tests, related to the solvent, dry matter or known®adulterants, are
included. .
Specifications have not been set for final homoeopathic due to
the high dilution used in their preparation and the subsequen in
applying analytical methodology.
Statements under Crude Drugs; Traditional Herbal and Complemensary
Medicines also apply to homoeopathic stocks and mother tinctures, when
appropriate.
Unlicensed The General Monograph for Unlicensed Medicines applies to those

Medicines formulations used in human medicine that are prepared under a
Manufacturer’s ‘Specials’ Licence or prepared extemporaneously under the
supervision of a pharmacist, whether or not there is a published monograph
for the specific dosage form.
An article intended for medicinal use that is described by means of an
official title must comply with the requirements of the relevant monograph.
A formulated preparation must comply throughout its assigned shelf-life

(period of validity). The subject of any other monograph must comply
throughout its period of use.
Unlicensed medicines that are prepared under a Manufacturer’s
‘Specials’ Licence comply with the requirements of the General Monograph
. for Pharmaceutical Preparations, the requirements of the General
Monograph for Unlicensed Medicines and, where applicable, the
requirements of the individual monograph for the specific dosage form.
Unlicensed medicines prepared extemporaneously under the supervision
of a pharmacist comply with the requirements of the General Monograph
for Pharmaceutical Preparations, the requirements of the General
Monograph for Unlicensed Medicines and, where applicable, the
requirements of the individual monograph for the specific dosage form.
While it is expected that extemporaneous preparations will demonstrate
pharmacopoeial compliance when tested, it is recognised that it might not
be practicable to carry out the pharmacopoeial tests routinely on such
formulations. In the event of doubt or dispute, the methods of analysis, the
eference materials and the reference spectra of the Pharmacopoeia are
%
IWI-20 General Notices 2016
Part III
Monographs and other texts of the European Pharmacopoeia that are incorporated
in this edition of the British Pharmacopoeia are governed by the general notices of
the European Pharmacopoeia; these are reproduced below.
GENERAL NOTICES OF THE EUROPEAN

PHARMACOPOEIA
Ys
1.1. GENERAL STATEMENTS
The General Notices apply to all monographs and other texts of the
“0 European Pharmacopoeia.
The official texts of the European Pharmacopoeia are published in
English and French. Translations in other languages may be prepared by
signatory States of the European Pharmacopoeia Convention. In case of
ts of the European Pharmacopoeia, the word ‘Pharmacopoeia’

lification means the European Pharmacopoeia. The official
abbreviati sshb. Eur. may be used to indicate the European
Pharmacopoéig
The use o or the subtitle of a monograph implies that the article
irements of the relevant monograph. Such references
to monographs in ts of the Pharmacopoeia are shown using the
monograph title and e number in ztalics.
A preparation must c \ oughout its period of validity; a distinct
period of validity and/or spéc tical ions for opened or broached containers
may be decided by the competént authority. The subject of any other
monograph must comply throwrugine of use. The period of
validity that is assigned to any gi i nd the time from which that
period is to be calculated are decided mpetent authority in light of
experimental results of stability studies.
Unless otherwise indicated in the General or in the monographs,
statements in monographs constitute mandato ents. General
chapters become mandatory when referred to in a non¢ graph, unless such
reference is made in a way that indicates that it is not the intention to make
the text referred to mandatory but rather to cite it for inf ion.
The active substances, excipients, pharmaceutical preparati nd other
articles described in the monographs are intended for human inary
use (unless explicitly restricted to one of these uses).
Quality systems The quality standards represented by monographs are valid only where the
articles in question are produced within the framework of a suitable quality
system. The quality system must assure that the articles consistently meet
the requirements of the Pharmacopoeia.
Alternative methods ‘The tests and assays described are the official methods upon which the
standards of the Pharmacopoeia are based. With the agreement of the
competent authority, alternative methods of analysis may be used for
control purposes, provided that the methods used enable an unequivocal
decision to be made as to whether compliance with the standards of the
monographs would be achieved if the official methods were used. In the

event of doubt or dispute, the methods of analysis of the Pharmacopoeia are
Demonstration of (1) An article is not of Pharmacopoeia quality unless it complies with all
compliance with the the requirements stated in the monograph. This does not imply that
Pharmacopoeia performance of all the tests in a monograph is necessarily a prerequisite
for a manufacturer in assessing compliance with the Pharmacopoeia
before release of a product. The manufacturer may obtain assurance
that a product is of Pharmacopoeia quality on the basis of its design,
together with its control strategy and data derived, for example, from
validation studies of the manufacturing process. i
Ys
(2) An enhanced approach to quality control could utilise process analytical
technology (PAT) and/or real-time release testing (including parametric
“0O
release) strategies as alternatives to end-product testing alone. Real-time
release testing in circumstances deemed appropriate by the competent
authority is thus not precluded by the need to comply with the
Pharmacopoeia.
Reduction of animal testing: the European Pharmacopoeia is dedicated
o phasing out the use of animals for test purposes, in accordance with
Rs (Replacement, Reduction, Refinement) set out in the European
Convention for the Protection of Vertebrate Animals used for
see and Other Scientific Purposes. In demonstrating
com vith the Pharmacopoeia as indicated above (1),
authority, the ice of tests performed to assess compliance with the

Pharmacopoeia anim
a way that animal
Grade of materials Certain materials that are‘the ct.of a pharmacopoeial monograph may
exist in different grades suita different purposes. Unless otherwise
indicated in the monograph, the Gn s apply to all grades of the
material. In some monographs, parti y those on excipients, a list of
functionality-related characteristics that a nt to the use of the
substance may be appended to the monogr formation. Test
methods for determination of one or moretse of gharctrisics may be
given, also for information.
General Substances and preparations that are the subject of an

monographs monograph are also required to comply with relevant, ap
monographs. Cross-references to applicable general monogra
normally given in individual monographs.
General monographs apply to all substances and preparations within the
scope of the Definition section of the general monograph, except where a
preamble limits the application, for example to substances and preparations
that are the subject of a monograph of the Pharmacopoeia.
General monographs on dosage forms apply to all preparations of the
type defined. The requirements are not necessarily comprehensive for a
given specific preparation and requirements additional to those prescribed
in the general monograph may be imposed by the competent authority.
General monographs and individual monographs are complementary. If

the provisions of a general monograph do not apply to a particular product,
this is expressly stated in the individual monograph.
Validation of The test methods given in monographs and general chapters have been
pharmacopoeial validated in accordance with accepted scientific practice and current
methods recommendations on analytical validation. Unless otherwise stated in the
monograph or general chapter, validation of the test methods by the analyst
is not required.
Implementation of When implementing a pharmacopoeial method, the user must assess

pharmacopoeial whether and to what extent the suitability of the method under the actual
9" conditions of use needs to be demonstrated according to relevant
monographs, general chapters and quality systems.
Consens The term ‘competent authority’ means the national, supranational or

. international body or organisation vested with the authority for making
cisions concerning the issue in question. It may, for example, be a
nal pharmacopoeia authority, a licensing authority or an official control
b ry.
ession ‘unless otherwise justified and authorised’ means that the
requirements have to be met, unless the competent authority authorises a
modifica n exemption where justified in a particular case.
Stateme ining the word ‘should’ are informative or advisory.
In certain oO hs or other texts, the terms ‘suitable’ and
‘appropriate’ are Use describe a reagent, micro-organism, test method
etc.; if criteria for stitability are not described in the monograph, suitability
is demonstrated to the tion of the competent authority.
Medicinal product (a C
presented as having proper eating or preventing disease in human
beings and/or animals; or (b),anyes ance or combination of substances
that may be used in or administet man beings and/or animals with a
view either to restoring, correctin ifying, physiological functions by
exerting a pharmacological, immunolo etabolic action, or to
making a medical diagnosis.
Herbal medicinal product Any medicin fodder, exclusively
containing as active ingredients one or more herbe or one or more
herbal drug preparations, or one or more such ade in combination
with one or more such herbal drug preparations. o
Active substance Any substance intended to be used eamanufacture
of a medicinal product and that, when so used, becomes an tive
ingredient of the medicinal product. Such substances are intendedyto
furnish a pharmacological activity or other direct effect in the dia 1S
cure, mitigation, treatment or prevention of disease, or to affect the
structure and function of the body.
Excipient (auxiliary substance). Any constituent of a medicinal product
that is not an active substance. Adjuvants, stabilisers, antimicrobial
preservatives, diluents, antioxidants, for example, are excipients.
Interchangeable Certain general chapters contain a statement that the text in question is
methods harmonised with the corresponding text of the Japanese Pharmacopoeia
and/or the United States Pharmacopeia and that these texts are
interchangeable. This implies that if a substance or preparation is found to
comply with a requirement using an interchangeable method from one of

these pharmacopoeias it complies with the requirements of the European
Pharmacopoeia. In the event of doubt or dispute, the text of the European
Pharmacopoeia is alone authoritative.
References to Monographs and general chapters may contain references to documents

regulatory issued by regulatory authorities for medicines, for example directives and
documents notes for guidance of the European Union. These references are provided
for information for users for the Pharmacopoeia. Inclusion of such a
reference does not modify the status of the documents referred to, which
may be mandatory or for guidance.
S 1.2. OTHER PROVISIONS APPLYING TO GENERAL

CHAPTERS AND MONOGRAPHS
_Mesantities
In tests with numerical limits and assays, the quantity stated to be taken for
examination is approximate. The amount actually used, which may deviate
by not more than 10 per cent from that stated, is accurately weighed or
O . measured and the result is calculated from this exact quantity. In tests
here the limit is not numerical, but usually depends upon comparison
the behaviour of a reference substance in the same conditions, the
uantity is taken for examination. Reagents are used in the
prescribed amounts.
are weighed or measured with an accuracy commensurate with
the in ee of precision. For weighings, the precision corresponds
to plus or min units after the last figure stated (for example, 0.25 g is to
be interpreted as,0-245 g to 0.255 g). For the measurement of volumes, if
the figure after eeimal point is a zero or ends in a zero (for example,
10.0 mL or 0.50 m volume is measured using a pipette, a volumetric
flask or a burette, as late; otherwise, a graduated measuring cylinder
or a graduated pipette d. Volumes stated in microlitres are
measured using a micropi r/microsyringe.
It is recognised, however, tha rtain cases the precision with which
quantities are stated does not Corr to, the number of significant
figures stated in a specified numeri The weighings and
measurements are then carried out with a iently improved accuracy.
Apparatus and Volumetric glassware complies with Class A ents of the appropriate
procedures International Standard issued by the Internatio rganisation for
Standardisation. e
Unless otherwise prescribed, analytical procedures are ied out ata
temperature between 15 °C and 25 °C.
Unless otherwise prescribed, comparative tests are carri ing
identical tubes of colourless, transparent, neutral glass with a e; the
volumes of liquid prescribed are for use with tubes having an intefnal
diameter of 16 mm, but tubes with a larger internal diameter may be used
provided the volume of liquid used is adjusted (2.1.5). Equal volumes of
the liquids to be compared are examined down the vertical axis of the tubes
against a white background, or if necessary against a black background. The
examination is carried out in diffuse light.
Any solvent required in a test or assay in which an indicator is to be used
is previously neutralised to the indicator, unless a blank test is prescribed.
III-24 General Notices 2016
Water-bath The term ‘water-bath’ means a bath of boiling water unless water at
another temperature is indicated. Other methods of heating may be
substituted provided the temperature is near to but not higher than 100 °C
or the indicated temperature.
Drying and ignition The terms ‘dried to constant mass’ and ‘ignited to constant mass’ mean
to constant mass__ that 2 consecutive weighings do not differ by more than 0.5 mg, the 2"¢
weighing following an additional period of drying or of ignition respectively
appropriate to the nature and quantity of the residue.
Where drying is prescribed using one of the expressions ‘in a desiccator’
or ‘7m vacuo’, it is carried out using the conditions described in chapter
2.2.32. Loss on drying.
Sheen The proper conduct of the analytical procedures described in the

Pharmacopoeia and the reliability of the results depend, in part, upon the
quality of the reagents used. The reagents are described in general chapter
O 4, It is assumed that reagents of analytical grade are used; for some
CO: gents, tests to determine suitability are included in the specifications.
Solvents he e name of the solvent is not stated, the term ‘solution’ implies a
SO Gog ingwater.
use of water is specified or implied in the analytical
procedur: ibed in the Pharmacopoeia or for the preparation of
reagents, lying with the requirements of the monograph Purified
water (0008) isdise cept that for many purposes the requirements for
bacterial endotoxims ified water in bulk) and microbial contamination
(Purified water in contaiwersjeare not relevant. The term ‘distilled water’
indicates purified water ed by distillation.
The term ‘ethanol’ wit ation means anhydrous ethanol. The
neans ethanol (96 per cent). Other
é term ‘ethanol’ or ‘alcohol’ followed
by a statement of the percentage e of ethanol (C,H,O) required.
Expression of In defining content, the expression ‘per sed according to

content circumstances with one of 2 meanings:
— per cent m/m (percentage, mass in mass) ex sress es the number of
grams of substance in 100 g of final product;
— percent V/V (percentage, volume in volume) expf€sses = number of
millilitres of substance in 100 mL of final product. ,
The expression ‘parts per million’ (or ppm) refers to mass% s, unless
otherwise specified.
Temperature Where an analytical procedure describes temperature without a figure, the

general terms used have the following meaning:
— ina deep-freeze: below —15 °C;
— ina refrigerator: 2 °C to 8 °C;
— cold or cool: 8 °C to 15 °C;
— room temperature: 15 °C to 25 °C,
1.3. GENERAL CHAPTERS

Containers Materials used for containers are described in general chapter 3.1. General
names used for materials, particularly plastic materials, each cover a range
of products varying not only in the properties of the principal constituent
but also in the additives used. The test methods and limits for materials
depend on the formulation and are therefore applicable only for materials
whose formulation is covered by the preamble to the specification. The use
of materials with different formulations, and the test methods and limits
applied to them, are subject to agreement by the competent authority.
The specifications for containers in general chapter 3.2 have been
developed for general application to containers of the stated category, but in
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view of the wide variety of containers available and possible new
developments, the publication of a specification does not exclude the use, in
“O
justified circumstances, of containers that comply with other specifications,
subject to agreement by the competent authority.
Reference may be made within the monographs of the Pharmacopoeia to
the definitions and specifications for containers provided in chapter 3.2.
ontainers. The general monographs for pharmaceutical dosage forms may,
der the heading Definition/Production, require the use of certain types of
Aimer; certain other monographs may, under the heading Storage,
e type of container that is recommended for use.
Titles
Relative Atomic and The relative atomic edu or the relative molecular mass (V/,) is shown,
Molecular Masses as and where appropriatef at.th@ybeginning of each monograph. The relative
atomic and molecular ma ges 4 nd the molecular and graphic formulae do
not constitute analytical tand Le. substances described.
Chemical Abstracts CAS registry numbers are incltded o“mation in monographs, where
Service (CAS) applicable, to provide convenient a eful information for users.
Registry Number CAS Registry Number™ is a registered ra rk of the American
Chemical Society.
Definition Statements under the heading Definition consti n official definition of

the substance, preparation or other article that is the subject of the
monograph.
Limits of content Where limits of content are prescitif,jh are those
determined by the method described under Assay.
Herbal drugs In monographs on herbal drugs, the definitio ates
whether the subject of the monograph is, for example, the whole g or
the drug in powdered form. Where a monograph applies to the drug in
several states, for example both to the whole drug and the drug in
powdered form, the definition states this.
Production Statements under the heading Production draw attention to particular

aspects of the manufacturing process but are not necessarily comprehensive.
They constitute mandatory requirements for manufacturers, unless
otherwise stated. They may relate, for example, to source materials; to the
manufacturing process itself and its validation and control; to in-process
testing; or to testing that is to be carried out by the manufacturer on the

final article, either on selected batches or on each batch prior to release.
These statements cannot necessarily be verified on a sample of the final
article by an independent analyst. The competent authority may establish
that the instructions have been followed, for example, by examination of
data received from the manufacturer, by inspection of manufacture or by
testing appropriate samples.
The absence of a Production section does not imply that attention to
features such as those referred to above is not required.
Choice of vaccine strain, Choice of vaccine composition The
Production section of a monograph may define the characteristics ofa_-
vaccine strain or vaccine composition. Unless otherwise stated, test methods
x
given for verification of these characteristics are provided for information as
examples of suitable methods. Subject to approval by the competent
“0
authority, other test methods may be used without validation against the
method shown in the monograph.
Poten e to the increasing number of fraudulent activities and cases of

Adulteration ration, information may be made available to Ph. Eur. users to help
erated materials (i.e. active substances, excipients, intermediate
ulk products and finished products).
ose, a method for the detection of potential adulterants and
ogether with a reminder that all stages of production and
sourcing ar d to a suitable quality system, may be included in this
section of mono on substances for which an incident has occurred or
that present a ris deliberate contamination. The frequency of testing by
manufacturers or by .g. manufacturers of intermediate products,
bulk products and finis s, where relevant) depends ona risk
assessment, taking into acc evel of knowledge of the whole supply
chain and national require
This section constitutes requirements for the whole supply chain, from
manufacturers to users (e.g. ma rers, of intermediate products, bulk
products and finished products, where relt . The absence of this section
does not imply that attention to features those referred to above is
not required.
Characters The statements under the heading Characters are nt9 be interpreted in a
strict sense and are not requirements.
Solubility In statements of solubility in the Charactérsfsection, the terms
used have the following significance, referred to a temper een
15 °C and 25 °C.
Descriptive term Approximate volume of solvent in millilitres

per gram of solute
Very soluble less than 1
Freely soluble from 1 to 10
Soluble from 10 to 30
Sparingly soluble from 30 to 100
Slightly soluble from 100 to 1000
Very slightly soluble from 1000 to 10 000
Practically insoluble more than 10 000

The term ‘partly soluble’ is used to describe a mixture where only some
of the components dissolve. The term ‘miscible’ is used to describe a liquid
that is miscible in all proportions with the stated solvent.
Identification Scope The tests given in the Identification section are not designed to give
a full confirmation of the chemical structure or composition of the product;
they are intended to give confirmation, with an acceptable degree of
assurance, that the article conforms to the description on the label.
First and second identifications Certain monographs have
subdivisions entitled ‘First identification’ and ‘Second identification’. The
test or tests that constitute the ‘First identification’ may be used in all -
circumstances. The test or tests that constitute the ‘Second identification’
%
may be used in pharmacies provided it can be demonstrated that the
substance or preparation is fully traceable to a batch certified to comply
caO
with all the other requirements of the monograph.
Certain monographs give two or more sets of tests for the purpose of the
first identification, which are equivalent and may be used independently.
One or more of these sets usually contain a cross-reference to a test
scribed in the Tests section of the monograph. It may be used to
ify,the work of the analyst carrying out the identification and the
d tests. For example, one identification set cross-refers to a test for
enanti ic purity while the other set gives a test for specific optical
rotati intended purpose of the two is the same, that is, verification
that the antiomer is present.
Powdered herbal drugs Monographs on herbal drugs may contain
schematic drawingsof the powdered drug. These drawings complement the
description given i levant identification test.
Tests and Assays Scope The requiremen amed to take account of all possible
impurities. It is not to b , for example, that an impurity that is
not detectable by means prescribed tests is tolerated if common sense
and good pharmaceutical practi S that it be absent. See also below
under Impurities.
Calculation Where the result of a orjassay is required to be
calculated with reference to the dried or us substance or on some
other specified basis, the determination of | ing, water content or
other property is carried out by the method pres d in the relevant test
in the monograph. The words ‘dried substance’ 6r“anhydrous substance’
etc. appear in parentheses after the result. ,
Where a quantitative determination of a residual so ried out
and a test for loss on drying is not carried out, the ot: idual
solvent is taken into account for the calculation of the assay t f the
substance, the specific optical rotation and the specific absorbarice. No
further indication is given in the specific monograph.
Limits The limits prescribed are based on data obtained in normal
analytical practice; they take account of normal analytical errors, of
acceptable variations in manufacture and compounding and of deterioration
to an extent considered acceptable. No further tolerances are to be applied
to the limits prescribed to determine whether the article being examined
complies with the requirements of the monograph.
In determining compliance with a numerical limit, the calculated result of
a test or assay is first rounded to the number of significant figures stated,
unless otherwise prescribed. The limits, regardless of whether the values are
IlIl-28 General Notices 2016
expressed as percentages or as absolute values, are considered significant to

the last digit shown (for example 140 indicates 3 significant figures). The
last figure of the result is increased by one when the part rejected is equal to
or exceeds one half-unit, whereas it is not modified when the part rejected
is less than a half-unit.
Indication of permitted limit of impurities The acceptance criteria
for related substances are expressed in monographs either in terms of
comparison of peak areas (comparative tests) or as numerical values. For
comparative tests, the approximate content of impurity tolerated, or the
sum of impurities, may be indicated in brackets for information only.
Acceptance or rejection is determined on the basis of compliance or non--
compliance with the stated test. If the use of a reference substance for the
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named impurity is not prescribed, this content may be expressed as a
nominal concentration of the substance used to prepare the reference
“O
solution specified in the monograph, unless otherwise described.
Herbal drugs For herbal drugs, the sulfated ash, total ash, water-soluble
matter, alcohol-soluble matter, water content, content of essential oil and
@ntent of active principle are calculated with reference to the drug that has
valents Where an equivalent is given, for the purposes of the

2 eia only the figures shown are to be used in applying the
requirements.of the monograph.
Cultur ia The culture media described in monographs and general
chapters ha ound to be satisfactory for the intended purpose.
However, the components of media, particularly those of biological origin,
are of variable quality, and it may be necessary for optimal performance to
modulate the concen f some ingredients, notably:
— peptones and meat Cy with respect to their nutritive
properties;
— buffering substances;
— bile salts, bile extract, es colouring matter, depending
on their selective properties;
— antibiotics, with respect to their ac u
Storage The information and recommendations given&) e heading Storage do

not constitute a pharmacopoeial requirement but petent authority
may specify particular storage conditions that must et.
The articles described in the Pharmacopoeia are eye a way as
to prevent contamination and, as far as possible, deteriorati ere
special conditions of storage are recommended, including a
container (see section 1.3. General chapters) and limits of tempefat they
are stated in the monograph.
The following expressions are used in monographs under Storage with
the meaning shown.
In an airtight container Means that the product is stored in an airtight
container (3.2). Care is to be taken when the container is opened in a damp
atmosphere. A low moisture content may be maintained, if necessary, by
the use of a desiccant in the container provided that direct contact with the
product is avoided.
Protected from light Means that the product is stored either in a
container made of a material that absorbs actinic light sufficiently to protect
the contents from change induced by such light, or in a container enclosed
in an outer cover that provides such protection, or is stored in a place from

which all such light is excluded.
Labelling In general, labelling of medicines is subject to supranational and national

regulation and to international agreements. The statements under the
heading Labelling are not therefore comprehensive and, moreover, for the
purposes of the Pharmacopoeia only those statements that are necessary to
demonstrate compliance or non-compliance with the monograph are
mandatory. Any other labelling statements are included as
recommendations. When the term ‘label’ is used in the Pharmacopoeia, the
labelling statements may appear on the container, the package, a leaflet
accompanying the package, or a certificate of analysis accompanying the
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article, as decided by the competent authority.
Materials described in monographs and reagents specified for use in the
O
Pharmacopoeia may be injurious to health unless adequate precautions are
taken. The principles of good quality control laboratory practice and the
rovisions of any appropriate regulations are to be observed at all times.
ention is drawn to particular hazards in certain monographs by means of
ing statement; absence of such a statement is not to be taken to
at no hazard exists.
| Impurities Alis own and potential impurities that have been shown to be
| detecte bare in a monograph may be given. See also chapter 5.0.
Control of impuritiesin substances for pharmaceutical use. The impurities are
designated by’a lettemor letters of the alphabet. Where a letter appears to be
missing, the imputi ignated by this letter has been deleted from the list
during monograph sep t prior to publication or during monograph
revision.
Functionality- Monographs on excipien e a section on functionality-related

Related characteristics. The characteristi test methods for determination and
Characteristics of any tolerances are not mandatory r i ts; they may nevertheless be
Excipients relevant for use of the excipient and for information (see also
section 1.1. General statements).
Reference Certain monographs require the use of refere Cy (chemical

Standards reference substances, herbal reference standards,Wbidlogical reference
preparations, reference spectra). See also chapter 5.42 rence standards.
The European Pharmacopoeia Commission cabinet ficial reference
standards, which are alone authoritative in case of arbitratCny
reference standards are available from the European Director
Quality of Medicines & HealthCare (EDOM). Information on
reference standards and a batch validity statement can be obtained via the
EDQM website.
1.5. ABBREVIATIONS AND SYMBOLS
A Absorbance mp Melting point

AA Specific absorbance ne Refractive index
fk Relative atomic mass _ Ph. Eur. U. European Pharmacopoeia Unit
[ol Specific optical rotation ppb Parts per billion (micrograms per kilogram)
bp Boiling point ppm Parts per million (milligrams per kilogram)
BRP Biological Reference Preparation R Substance or solution defined under
CRS Chemical Reference Substance 4. Reagents
a Relative density Re Retardation factor (see chapter 2.2.46)
Rst Used in chromatography to indicate the ratio
a Wavel
avelenet of the distance travelled by a substance to the
HRS erbal reference standard distance travelled by a reference substance
TU ional Unit RV Substance used as a primary standard in
M yay volumetric analysis (chapter 4.2. /)
M, ef mass
Abbreviations use onographs on immunoglobulins, immunosera and vaccines
LD59 The statistically dete ined tity of a Lo/10 dose The largest quantity of a toxin that, in the
substance that, when admini by the conditions of the test, when mixed with 0.1 IU
specified route, may be expected to.cause the of antitoxin and administered by the specified
death of 50 per cent of the t i within route, does not cause symptoms of toxicity in
a given period the test animals within a given period
MLD Minimum lethal dose Lf dose The quantity of toxin or toxoid that flocculates
L+/10 dose The smallest quantity of a toxin that, in th in the shortest time with 1 TU of antitoxin
conditions of the test, when mixed with 0.1 I CIDs0 The statistically determined quantity of virus
of antitoxin and administered by the specifie that may be expected to infect 50 per cent of
route, causes the death of the test animals the cell cultures to which it is added
within a given period The statistically determined quantity of virus
L+ dose The smallest quantity of a toxin that, in the at may be expected to infect 50 per cent of
conditions of the test, when mixed with 1 IU ertilised eggs into which it is inoculated
of antitoxin and administered by the specified
tistically determined quantity of a virus
route, causes the death of the test animals xpected to infect 50 per cent of
within a given period
into which it is inoculated
Ir/100 dose The smallest quantity of a toxin that, in the PDso Saks dareeriined’ dds Ghatwantine
conditions of the test, when mixed with that. in Mee ions of the test, may be
. . aie 2 >
wo cen oa ges eced ahi expected to protecw50 per cent of the animals
intracutaneously causes a characteristic against a challenfé RIS EAE cro:
reactionjat the site!of injection) within a organisms or to: against which it is active
given period oe Fe
: ’ ’ EDso The statistically determined dose of a vaccine
Lp/10 dose The smallest quantity of toxin that, in the NEVE COnGIRGHEO ane
oe . . =
conditions of thetest; when mixed with0.1 TU expected to induce specific a ae
of antitoxin and administered by the specified 50 per cent of the animals fo :
route, causes paralysis in the test animals waceihe autigens
within a given period 5 4 ;
PFU Pock-forming units or plaque-forming units
SPF Specified-pathogen-free.
Collections of micro-organisms
ATCC American Type Culture Collection NCTC National Collection of Type Cultures
10801 University Boulevard Central Public Health Laboratory
Manassas, Virginia 20110-2209, USA Colindale Avenue
Give: Collection de Bactéries de l’Institut Pasteur London NW9 5HT, Great Britain
B.P. 52, 25 rue du Docteur Roux NCYC National Collection of Yeast Cultures
75724 Paris Cedex 15, France AERC Food Research Institute
Colney Lane
IMI International Mycological Institute
Bakeham Lane Norwich NR4 7UA, Great Britain
Surrey TW20 9TY, Great Britain NITE Biological Resource Center
Department of Biotechnology
|e, Collection Nationale de Culture de
Microorganismes (C.N.C.M.) National Institute of Technology and ~
Institut Pasteur Evaluation
e du Docteur Roux 2-5-8 Kazusakamatari, Kisarazu-shi, Chiba,
24 Paris Cedex 15, France
292-0818
Japan
NCIMB Nationa
S.S.I. Statens Serum Institut
achar Drive 80 Amager Boulevard, Copenhagen, Denmark
Aberdee ABI 1RY, Great Britain
NCPF National Céllecti f Pathogenic Fungi
London School o: ene and Tropical
Medicine A)
Keppel Street
London WC1E 7HT, eat Britain
1.6. O HE INTERNATIONAL SYSTEM (SI) USED IN

THE PHA POEIA AND EQUIVALENCE WITH OTHER
UNITS
International The International S its comprises 3 classes of units, namely base
System Of Units units, derived units an ntary units!. The base units and their
(SI) definitions are set out i
The derived units may by combining the base units according
to the algebraic relationships li he corresponding quantities. Some of
these derived units have special nares bols. The SI units used in
the Pharmacopoeia are shown in Table
Some important and widely used units the International System
are shown in Table 1.6-3.
The prefixes shown in Table 1.6-4 are used t¢[tor the names and
symbols of the decimal multiples and submultiples*of SI units.
CO
¢
! The definitions of the units used in the International System are given in the booklet ‘“‘Le Systéme International d’Unités (SI)”’ published by
the Bureau International des Poids et Mesures, Pavillion de Breteuil, F-92310 Sevres.
I-32 General Notices 2016
Notes In the Pharmacopoeia, the Celsius temperature is used (symbol 2).

This is defined by the following equation:
t=T—Tp
where Ty) = 273.15 K by definition. The Celsius or centigrade

temperature is expressed in degree Celsius (symbol °C). The unit
‘degree Celsius’ is equal to the unit ‘kelvin’.
The practical expressions of concentrations used in the Pharmacopoeia
bo
are defined in the General Notices.
The radian is the plane angle between two radii of a circle that cut off
%,
on the circumference an arc equal in length to the radius.
In the Pharmacopoeia, conditions of centrifugation are defined by
reference to the acceleration due to gravity (g):
O g = 9.806 65m-s?
ertain quantities without dimensions are used in the Pharmacopoeia:

ive density (2.2.5), absorbance (2.2.25), specific absorbance
and refractive index (2.2.6).
T icrokatal is defined as the enzymic activity that, under defined
con roduces the transformation (e.g. hydrolysis) of 1 micromole
of the er second.
Table 1.6.1.
Quantity Unit Definition
Name Symbol Name Symbol
Tena I neta a The metre is Wreden ath travelled by light in a vacuum during a time
8 interval of 1/299 792 d.
Mass m kilogram kg The kilogram is equal to thi ternational prototype of the kilogram.
The second is the duration of periods of the radiation corresponding

Time t second s to the transition between the two hyperfine levels of the ground state of the
caesium-133 atom.
Electric current I ampere A The ampere is that constant current whi ained in two straight parallel
conductors of infinite length, of negligible circu o§s-section and placed 1 metre
apart in vacuum would produce between these€o ctors a force equal to 2 x 10°*
newton per metre of length.
Thermodynamic fT kelvin K The kelvin is the fraction 1/273.16 of the thermodynami ture of the triple
temperature point of water.
Amount of substance n mole mol The mole is the amount of substance of a system containing as
entities as there are atoms in 0.012 kilogram of carbon-12°.
Luminous intensity te candela cd The candela is the luminous intensity in a given directionofa source
monochromatic radiation with a frequency of 540 x 10! hertz and whos
intensity in that direction is 1/683 watt per steradian.
* When the mole is used, the elementary entities must be specified and may be atoms, molecules, ions, electrons, other particles or specified groups of
such particles.
Table 1.6.-2. — S/ units used in the European Pharmacopoeia and equivalence with other units
Quantity Unit
Name Symbol Name Symbol | Expression in SI | Expression in other Conversion of other units into SI units
3 base units SI units
Wave number i one per metre 1/m m!
Wavelength A micrometre ym 10-*m

nanometre nm 10-°m
Area A, S square metre H m?
Volume V cubic metre m? m? 1 mL = 1 cm*= 10°° m*
Frequency Vi hertz Hz a -
De Pp kilogram per cubic | kg/m? kgm? 1 g/mL = 1 g/cm*= 10° kgm?

metre
v metre per second m/s ms!
Fore PF newton N mkg-s~? 1 dyne = 1 gcms** = 1075 N

1 kp = 9.806 65 N
Pressure pascal Pa m7 !kgs-? Nm? 1 dyne/cm? = 10°! Pa = 10°! Nm~?

1 atm = 101 325 Pa = 101.325 kPa
1 bar
= 10° Pa = 0.1 MPa
1 mm Hg = 133.322 387 Pa
1 Torr = 133.322 368 Pa
1 psi = 6.894 757 kPa
Dynamic 7 pascal s Nsm-? 1P=10°' Pas =10°'Nsm?

viscosity 1 cP =1 mPas
Kinematic v square metre p Pasm*kg"! 1 St= 1 cm*s“! = 107-' m?s"!

viscosity second Nmskg!
Energy Ww joule Nm 1 erg = 1 cm*g:s-? = 1 dynecm = 1077

J
1 cal = 4.1868 J
Power P watt Nms7! 1 erg/s = 1 dynecm:s! =
Radiant flux Js"! 1077 W = 10°? Nims"! = 10°? Jes!
Absorbed dose D gray Jkgo! 1 rad = 10°? Gy
(of radiant
energy)
Electric U volt wa"!

potential,
electromotive
force
Electric R ohm Q m* ke-s"A-?
resistance
Quantity of Q coulomb Cc As
electricity
Activity of a A becquerel Bq s? 10° Bq = 37-10? s*!
radionuclide
Concentration c mole per cubic mol/m* molm-? lm M = 1 mol/dm* = 10° mokm™*
(of amount of metre
substance), Sd
molar
concentration
Mass Pp kilogram per cubic | kg/m" kgm-3 1g/L=1 ¢/dm*=

concentration metre
Table 1.6.-3. - Units used with the International System

Quantity Unit Value in SI units
Name Symbol
Time minute min 1 min = 60s
hour h 1h =60 min = 3600 s

day d 1d=24h=86 400s
Plane angle degree S 1° = (1/180) rad
Volume litre L 1L=1dm$= 10-7 m*

Mass tonne t 1t= 10° kg
Rotational revolution r/min 1 r/min = (1/60) s“!

Pe. frequency per minute
OC: ble 1.6.-4. - Decimal multiples and sub-multiples of units
0 Prefix Symbol Factor Prefix Symbol
a E 10°! deci d
10 a P 10° centi c
10” Hy 10-3 milli m
10° G 107° micro u

10° mega 10-° nano n
10° kilo 10°” pico Pp

10° hecto ee femto f
10! deca 19 atto a
Yo,
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ea
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a
Monographs
Formulated Preparations:
General Monographs
a on re ee pee’,
2a res Boa SpE
Sek henna Eh on
2016 General Monographs III-37
FORMULATED PREPARATIONS: ETHICAL CONSIDERATIONS AND GUIDANCE IN

THE PREPARATION OF UNLICENSED
GENERAL MONOGRAPHS PHARMACEUTICAL PREPARATIONS
The underlying principle of legislation for pharmaceutical
preparations is that, subject to specific exemptions, no
pharmaceutical preparation may be placed on the market
Pharmaceutical Preparations ee without an appropriate marketing authorisation.

: . *
*
The exemptions from the formal licensing requirement allow
(Ph. Eur. monograph 2619) eae the supply of unlicensed products to meet the special needs
of individual patients. However, when deciding to use an
Ph Eur
unlicensed preparation all health professionals involved
INTROQUCTION (e.g. the prescribing practitioners and/or the preparing
pharmacists) have, within their area of responsibilities, a duty
uropean Pharmacopoeia on active of care to the patient receiving the pharmaceutical
ts and dosage forms, which are to be preparation.
In considering the preparation of an unlicensed
pharmaceutical preparation, a suitable level of risk assessment
guidance availa is undertaken.
associated controls.
The risk assessment identifies:
It does not cover inve — the criticality of different parameters (e.g. quality of active
competent authorities ma substances, excipients and containers; design of the
when authorising clinical tri preparation process; extent and significance of testing;
products. stability of the preparation) to the quality of the
DEFINITION preparation; and
— the risk that the preparation may present to a particular
patient group.
excipients, formulated into a dosage form suitable fe Based on the risk assessment, the person responsible for the
intended use, where necessary after reconstitutiog, preparation must ensure, with a suitable level of assurance,
in a suitable and appropriately labelled container. that the pharmaceutical preparation is, throughout its shelf-
Pharmaceutical preparations may be licensed by the life, of an appropriate quality and suitable and fit for its
competent authority, or unlicensed and made to the sp ose. For stock preparations, storage conditions and shelf-
needs of patients according to legislation. There are 2 . e to be justified on the basis of, for example,
categories of unlicensed pharmaceutical preparations: eal data or professional judgement, which may be
— extemporaneous preparations, i.e. pharmaceutical
preparations individually prepared for a specific patient or
patient group, supplied after preparation; paration must take place within the
— stock preparations, 1.e. pharmaceutical preparations uitsible quality system and be compliant with
prepared in advance and stored until a request for a
supply is received.
In addition to this monograph, pharmaceutical preparations their licence. For: d products a risk assessment as
also comply with the General Notices and with the relevant outlined in the sec ical considerations and guidance
general chapters of the Pharmacopoeia. General chapters are in the preparation of unk
normally given for information and become mandatory when is of special importance,
referred to in a general or specific monograph, unless such
reference is made in a way that indicates that it is not the
intention to make the text referred to mandatory but rather During pharmaceutical developm
to cite it for information. manufacture/preparation, suitable in
Where relevant, pharmaceutical preparations also comply
with the dosage form monographs (e.g. Capsules (0016),
Tablets (0478)) and general monographs relating to purpose. This includes consideration of the prop
pharmaceutical preparations (e.g. Allergen products (1063), required in order to identify whether specific ingredient
Herbal teas (1435), Homoeopathic preparations (1038), properties or process steps are critical to the required quality
ata
Immunosera for human use, animal (0084), Immunosera for of the pharmaceutical preparation.
veterinary use (0030), Monoclonal antibodies for human
Active substances and excipients
use (2031), Radiopharmaceutical preparations (0125), Vaccines
Active substances and excipients used in the formulation of
for human use (0153), Vaccines for veterinary use (0062)).
pharmaceutical preparations comply with the requirements of
Where pharmaceutical preparations are the relevant general monographs, e.g. Substances for
manufactured/prepared using materials of human or animal pharmaceutical use (2034), Essential oils (2098), Extracts
origin, the general requirements of general chapters5.1. 7. (0765), Herbal drugs (1433), Herbal drug preparations (1434),
Viral safety, 5.2.6. Evaluation of safety of veterinary vaccines Herbal drugs for homoeopathic preparations (2045), Mother
and immunosera and 5.2.8. Minimising the risk of transmitting tinctures for homoeopathic preparations (2029), Methods of
animal spongiform encephalophathy agents via human and preparation of homoeopathic stocks and potentisation (2371),
veterinary medicinal products apply, where appropriate. Products offermentation (1468), Products with risk of
transmitting agents of animal spongiform encephalopathies (1483),
III-38 General Monographs 2016
Products of recombinant DNA technology (0784), Vegetable fatty and/or the immediate container must be assessed. Depending
oils (1579). on the result of this assessment, limits of degradation and/or
In addition, where specific monographs exist, the quality of reaction products are set and monitored in the
the active substances and excipients used complies with the pharmaceutical preparation. Licensed products require a
corresponding monographs. stability exercise.
Where no specific monographs exist, the required quality Methods used for the purpose of stability testing for all
must be defined, taking into account the intended use and relevant characteristics of the preparation are validated as
the involved risk. stability indicating, i.e. the methods allow the quantification
of the relevant degradation products and physical
When physicochemical characteristics of active substances
characteristic changes.
and functionality-related characteristics (FRCs) of excipients:
(e.g. particle-size distribution, viscosity, polymorphism) are TESTS
ation to their role in the manufacturing process Relevant tests to apply in order to ensure the appropriate
sttgibutes.of the pharmaceutical preparation, they quality of a particular dosage form are described in the
d controlled. specific dosage form monographs.
Where it is not practical, for unlicensed pharmaceutical
preparations, to carry out the tests (e.g. batch size, time
Microbiological qualit restraints), other suitable methods are implemented to ensure
The formulation of the that the appropriate quality is achieved in accordance with
container must ensure tha the risk assessment carried out and any local guidance or
suitable for the intended us legal requirements.
During development, it shall be Stock preparations are normally tested to a greater extent
antimicrobial activity of the prep: Q than extemporaneous preparations. |
necessary, with the addition of a suitablé’p The following tests are applicable to many preparations and
preservatives, or by the selection of an appr are therefore listed here.
provides adequate protection from adverse ef Appearance
The appearance (e.g. size, shape and colour) of the
pharmaceutical preparation is controlled.
method together with criteria for evaluating the presérvati
Identity and purity tests
properties of the formulation are provided in general chap
Where applicable, the following tests are carried out on the
5.1.3. Efficacy of antimicrobial preservation.
pharmaceutical preparation:
If preparations do not have adequate antimicrobial efficacy : fication of the active substance(s);
and do not contain antimicrobial preservatives they are tion of specific excipient(s), such as
supplied in single-dose containers, or in multidose containers
that prevent microbial contamination of the contents after
opening.
In the manufacture/preparation of non-sterile pharmaceutical
preparations, suitable measures are taken to ensure their
microbial quality; recommendations on this aspect are
provided in general chapters 5.1.4. Microbiological quahty of
non-sterile pharmaceutical preparations and substances for
pharmaceutical use and 5.1.8. Microbiological quality of herbal
medicinal products for oral use and extracts used 1n their
preparation.
Sterile preparations are manufactured/prepared using
materials and methods designed to ensure sterility and to
with general chapter 2.9.40 is not requs
avoid the introduction of contaminants and the growth of
— for homoeopathic preparations, the provisions of general
micro-organisms; recommendations on this aspect are
chapters 2.9.6 and 2.9.40 are normally not apprepriate,
provided in general chapter 5.1.1. Methods ofpreparation of
however in certain circumstances compliafice with ‘these
sterile products.
chapters may be required by the competent duthofity;
Containers — for single- and multivitamin and trace-element ~*
A suitable container is selected. Consideration is given to the preparations, compliance with general chapters 2.9.6 and
intended use of the preparation, the properties of the 2.9.40 (content uniformity only) is not required;
container, the required shelf-life, and product/container — in justified and authorised circumstances, for other
incompatibilities. Where applicable, containers for preparations, compliance with general chapters 2.9.6 and
pharmaceutical preparations comply with the requirements 2.9.40 may not be required by the competent authority.
for containers (3.2 and subsections) and materials used for
Reference standards
the manufacture of containers (3.1 and subsections).
Reference standards may be needed at various stages for
Stability quality control of pharmaceutical preparations. They are
Stability requirements of pharmaceutical preparations are established and monitored taking due account of general
dependent on their intended use and on the desired storage chapter 5.12. Reference standards.
time.
ASSAY
Where applicable, the probability and criticality of possible
Unless otherwise justified and authorised, contents of active
degradation products of the active substance(s) and/or
substances and specific excipients such as preservatives are
reaction products of the active substance(s) with an excipient
determined in pharmaceutical preparations. Limits must be (2.9), but that are not defined within them. Where relevant,
defined and justified. reference 1s made to other equivalent terms that may be found in
Suitable and validated methods are used. If assay methods other publications or contexts.
prescribed in the respective active substance monographs are This glossary 1s published for information.
used, it must be demonstrated that they are not affected by Active substance
the presence of the excipients and/or by the formulation. Equivalent terms: active ingredient, drug substance,
Reference standards medicinal substance, active pharmaceutical ingredient.
See Tests. Basis
LABELLING AND STORAGE A basis 1s the carrier, composed of one or more excipients,
The relevant labelling requirements given in the general for the active substance(s) in semi-solid and solid
dosage form monographs apply. In addition, relevant preparations.
Colloidal dispersion
A colloidal dispersion is a system in which particles of
colloidal size (a dimension of approximately between 1 nm
and 500 nm) of any nature (solid, liquid or gas) are
dispersed in a continuous phase of a different composition
and/or state.
Conventional-release dosage form
A conventional-release dosage form is a preparation showing
Licensed pharmaceutic a release of the active substance(s) which is not deliberately
A medicinal product that hasebs modified by a special formulation design and/or
authorisation by a competent au manufacturing method. In the case of a solid dosage form,
pharmaceutical preparation. the dissolution profile of the active substance depends
essentially on its intrinsic properties. Equivalent term:
Manufacture immediate-release dosage form.
All operations of purchase of materials and*$ro.
Production, Quality Control, release, storage, Delayed-release dosage form
medicinal products and the related controls. A delayed-release dosage form is a modified-release dosage
form showing a release of the active substance(s) which is
Preparation (of an unlicensed pharmaceutical delayed. Delayed release is achieved by a special formulation
preparation) " ign and/or manufacturing method. Delayed-release dosage
The ‘manufacture’ of unlicensed pharmaceutical preparations
include gastro-resistant preparations as definedin the
by or at the request of pharmacies or other healthcare -monographs on solid oral dosage forms.
establishments (the term ‘preparation’ is used instead of
‘manufacture’ in order clearly to distinguish it from the
industrial manufacture of licensed pharmaceutical
preparations).
ispersedin the other as droplets.
Reconstitution
Manipulation to enable the use or application of a medicinal teral
product with a marketing authorisation in accordance with upplied in a container with a
the instructions given in the summary of product
characteristics or the patient information leaflet.
Risk assessment
The identification of hazards and the analysis and evaluation rate and/or place of releas he active substance(s) is
of risks associated with exposure to those hazards. different from that of a convention release dosage form
an f
pete
Unlicensed pharmaceutical preparation

ce
is achieved by a special formulatioti®

.
A medicinal product that is exempt from the need of having

eet
manufacturing method. Modified-re

an
a marketing authorisation issued by a competent authority

:
but is made for specific patients’ needs according to

.
release dosage forms.

my
:
legislation.
"2
Prolonged-release dosage form

soa
so?
es
Ph Eur
A prolonged-release dosage form is a modified-release dosage
out te
caa .
form showing a slower release of the active substance(s) than

a
eye Ce:
that of a conventional-release dosage form administered by

errareen
the same route. Prolonged release is achieved by a special

ary
*
.
GLOSSARY ™ formulation design and/or manufacturing method. Equivalent

4+%
* term: extended-release dosage form.

(Ph Eur monograph 1502) * em
Pulsatile-release dosage form
A glossary of terms relating to formulated preparations 1s included A pulsatile-release dosage form is a modified-release dosage
in the European Pharmacopoeia. The glossary 1s reproduced below. form showing a sequential release of the active substance(s).
Ph Eur Sequential release is achieved by a special formulation design
and/or manufacturing method.
The following introductory text provides definitions andlor
explanations of terms that may be found in, or used in association Small-volume parenteral
with, the general monographs on dosage forms and the An infusion or injection supplied in a container with a
corresponding chapters on Pharmaceutical technical procedures nominal content of 100 mL or less.
IlI-40 General Monographs 2016
Solution — gastro-resistant capsules;

A solution is a mixture forming a single phase containing one — modified-release capsules;
or more dissolved substances, i.e. substances in a molecular — cachets.
state dispersed in a solvent or in miscible solvents.
PRODUCTION
Spheroids In the manufacture, packaging, storage and distribution of
Spheroids are considered to be spherical or approximately capsules, suitable measures are taken to ensure their
spherical granules with a usually increased mechanical microbial quality; recommendations on this aspect are
resistance compared to conventional granules (0499). They provided in the text on 5.1.4. Microbiological quality of non-
possess a smooth, uniform surface, with a typical size range sterile pharmaceutical preparations and substances for
of 200 um to 2.8 mm. Spheroids may be prepared by any pharmaceutical use.
suitable method.
TESTS
Uniformity of dosage units
persed system containing solid particles Capsules comply with the test for uniformity of dosage units
semi-solid, continuous phase, in (2.9.40) or, where justified and authorised, with the tests for
s are practically insoluble. uniformity of content and/or uniformity of mass shown
below. Herbal drugs and herbal drug preparations present in
the dosage form are not subject to the provisions of this
paragraph.
containers used have beeri%es Uniformity of content (2.9.6)
Pharmacopoeia Commission*3} Unless otherwise prescribed or justified and authorised,
publication on Standard Terms: capsules with a content of active substance less than 2 mg or
Vehicle Os less than 2 per cent of the fill mass comply with test B for
A vehicle is the carrier, composed of one'or_ uniformity of content of single-dose preparations. If the
for the active substance(s) in a liquid prepgr preparation has more than one active substance, the
requirement applies only to those ingredients which
correspond to the above conditions.
Uniformity of mass (2.9.5)
Capsules comply with the test for uniformity of mass of
CAPSULES ingle-dose preparations. If the test for uniformity of content
prescribed for all the active substances, the test for
(Ph. Eur. monograph 0016)
tity of mass is not required.
Capsules comply with the requirements of the European
Pharmacopoeia. These requirements are reproduced below.
Ph Eur
The requirements of this monograph do not necessarily apply to

preparations that are presented as capsules intended for use other
than by oral administration. Requirements for such preparations
may be found, where appropriate, in other general monographs, may not be requ cd.
for example Rectal preparations (1145) and Vaginal
preparations (1164). STORAGE
DEFINITION
Capsules are solid preparations with hard or soft shells of LABELLING
various shapes and capacities, usually containing a The label states the name of a:
single dose of active substance(s). They are intended for oral preservative.
administration.
The capsule shells are made of gelatin or other substances, HARD CAPSULES
the consistency of which may be adjusted by the addition of
DEFINITION
substances such as glycerol or sorbitol. Excipients such as
Hard capsules have shells consisting of 2 prefabritat
surface-active agents, opaque fillers, antimicrobial
preservatives, sweeteners, colouring matter authorised by the cylindrical sections, each of which has one rounded
competent authority and flavouring substances may be end and one open end.
added. The capsules may bear surface markings. PRODUCTION
te ee
nite
waa
etn
The contents of capsules may be solid, liquid or of a paste- The active substance(s), usually in solid form (powder or
granules), are filled into one of the sections that is then
Ne
like consistency. They consist of one or more active
substances with or without excipients such as solvents, closed by slipping the other section over it. The security of
diluents, lubricants and disintegrating agents. The contents the closure may be strengthened by suitable means.
do not cause deterioration of the shell. The shell, however, is TESTS
attacked by the digestive fluids and the contents are released. Disintegration (2. 9. 1)
Where applicable, containers for capsules comply with the Hard capsules comply with the test. Use water R as the liquid
requirements of Materials used for the manufacture of containers medium. When justified and authorised, 0.1 M hydrochloric
(3.1 and subsections) and Containers (3.2 and subsections). acid or artificial gastric juice R may be used as the liquid
Several categories of capsules may be distinguished: medium. If the capsules float on the surface of the water, a
— hard capsules; disc may be added. Operate the apparatus for 30 min, unless
— soft capsules; otherwise justified and authorised.
SOFT CAPSULES Examine the state of the capsules. The time of resistance to
the acid medium varies according to the formulation of the
DEFINITION
capsules to be examined. It is typically 2 h to 3 h but even
Soft capsules have thicker shells than those of hard capsules. with authorised deviations it must not be less than 1 h.
The shells consist of a single part and are of various shapes. No capsule shows signs of disintegration or rupture
PRODUCTION permitting the escape of the contents. Replace the acid by
Soft capsules are usually formed, filled and sealed in one phosphate buffer solution pH 6.8 R. When justified and
operation, but for extemporaneous use the shell may be authorised, a buffer solution of pH 6.8 with added pancreas
prefabricated. The shell material may contain an active powder (for example, 0.35 g of pancreas powder R per
substance. 100 mL of buffer solution) may be used. Add a disc to each
Liquids may be enclosed directly; solids are usually dissolved tube. Operate the apparatus for 60 min. If the capsules fail to
1 in a suitable vehicle to give a solution or comply because of adherence to the discs, the results are
invalid. Repeat the test on a further 6 capsules omitting the
discs.
capsule conte the shell and vice versa because of the Dissolution
nature of the: '.and the surfaces in contact. For capsules prepared from granules or particles already
covered with a gastro-resistant coating, a suitable test is
TESTS . carried out to demonstrate the appropriate release of the
Disintegration (2.9. active substance(s), for example the test described in
Soft capsules comply wi e test. Use water R as the liquid Dissolution test for solid dosage forms (2.9.3).
medium. When justified a érised, 0.1 M hydrochloric
acid or artificial gastric juice used as the liquid
medium. Add a disc to each 1 “active substances
CACHETS
dispensed in soft capsules may sc; in such DEFINITION
circumstances and where authorised, thet Cachets are solid preparations consisting of a hard shell
omitted. Operate the apparatus for 30 mi containing a single dose of one or more active substances.
justified and authorised. If the capsules
fa The cachet shell is made of unleavened bread usually from
because of adherence to the discs, the results aj rice flour and consists of 2 prefabricated flat cylindrical
Repeat the test on a further 6 capsules omitting th sections. Before administration, the cachets are immersed in
water for a few seconds, placed on the tongue and swallowed
with a draught of water.
MODIFIED-RELEASE CAPSULES
ELLING
DEFINITION :
states the method of administration of the cachets.
Modified-release capsules are hard or soft capsules in which
the contents or the shell or both contain special excipients or Ph Eur
are prepared by a special process designed to modify the rate,

the place or the time at which the active substance(s) are
released.
of i the
ove,
British Pharmacopoeia
Modified-release capsules include prolonged-release capsules requirements of the European
and delayed-release capsules.
Pharmacopoeia, ‘the fellowing statements apply to those capsules
PRODUCTION that are the subject vidual monograph in the British
A suitable test is carried out to demonstrate the appropriate Pharmacopoeia.
release of the active substance(s).
GASTRO-RESISTANT CAPSULES Assay and tests described in the monogr

DEFINITION Content of active ingredient in
The range for the content of activ
Gastro-resistant capsules are delayed-release capsules that are
intended to resist the gastric fluid and to release their active
substance or substances in the intestinal fluid. Usually they
are used in the Assay. In the circumstances wiie
are prepared by filling capsules with granules or with particles
20 capsules cannot be obtained, a smaller numbér.
covered with a gastro-resistant coating, or in certain cases, by
must not be less than 5, may be used, but to allow for
providing hard or soft capsules with a gastro-resistant shell
sampling errors the tolerances are widened in accordance
(enteric capsules).
with Table I.
PRODUCTION The requirements of Table I apply when the stated limits are
For capsules filled with granules or filled with particles 90 to 110%. For limits other than 90 to 110%,
covered with a gastro-resistant coating, a suitable test is proportionately smaller or larger allowances should be made.
carried out to demonstrate the appropriate release of the
Disintegration
active substance(s).
Comply with the disintegration test for tablets and capsules,
TESTS Appendix XII Al, unless otherwise stated in the individual
Disintegration (2.9. /) monographs.
Capsules with a gastro-resistant shell comply with the test For those Hard Capsules or Soft Capsules for which a
with the following modifications. Use 0.1 M hydrochloric acid requirement for Dissolution is included in the individual
as the liquid medium and operate the apparatus for 2 h, or monograph, the requirement for Disintegration does not
other such time as may be authorised, without the discs. apply.
I-42 General Monographs 2016
Table I
Weight of active ingredient Subtract from the lower Add to the upper limit
in each capsule limit for samples of for samples of
15 10 5 15 10 5
0.12 g or less 0.2 0.7 1.6 0.3 0.8 1.8
More than 0.12 0.2 0.5 1.2 0.3 0.6 1.5
and less than 0.3 g
0.3 g or more 0.1 0.2 0.8 0.2 0.4 1.0
tent PRODUCTION
cal method to be employed for During development of a liquid preparation for cutaneous
application whose formulation contains an antimicrobial
preservative, the need for and the efficacy of the chosen
preservative shall be demonstrated to the satisfaction of the
competent authority. A suitable test method together with
ividually, show a gross criteria for judging the preservative properties of the
ot official. formulation are provided in the text on Efficacy of
antimicrobial preservation (5.1.3).
During development, it must be demonstrated that the
nominal content can be withdrawn from the container of
** liquid preparations for cutaneous application presented in
LIQUIDS FOR CUTANEOUS single-dose containers.
%4
APPLICATION Dk ak In the manufacture, packaging, storage and distribution of

(Liquid Preparations for Cutaneous Application, liquid preparations for cutaneous application, suitable
Ph Eur monograph 0927) measures are taken to ensure their microbial quality;
recommendations on this aspect are provided in the text on
Liquids for Cutaneous Apphcation comply with the requiremey
5.1.4. Microbiological quahty of non-sterile pharmaceutical
the European Pharmacopoeia monograph for Liquid Preparatiot
tions and substances for pharmaceutical use.
for Cutaneous Application. These requirements are reproduced
below. id preparations for cutaneous application are
sing materials and methods designed to ensure
Ph Eur
1 to avoid the introduction of contaminants and
Where justified and authorised, the requirements of this monograph ‘micro-organisms; recommendations on this
do not apply to preparations intended for systemic and veterinary vided in the text on Methods of preparation of
use.
DEFINITION In the manufaé iquid preparations for cutaneous
Liquid preparations for cutaneous application are application containing ispersed particles, measures are taken
preparations of a variety of viscosities intended for local or to ensure a suitable a controlled particle size with regard to
transdermal delivery of active ingredients. They are solutions, the intended use.
emulsions or suspensions that may contain 1 or more active
TESTS
substances in a suitable vehicle. They may contain suitable
Sterility (2.6. 1)
antimicrobial preservatives, antioxidants and other excipients
Where the label indicates that the eparation 1s sterile, it
such as stabilisers, emulsifiers and thickeners.
complies with the test for sterility.
Emulsions may show evidence of phase separation but are
readily redispersed on shaking. Suspensions may show a STORAGE
sediment that is readily dispersed on shaking to give a tamper-
suspension that is sufficiently stable to enable a homogeneous proof container.
preparation to be delivered. LABELLING
Where applicable, containers for liquid preparations for The label states:
cutaneous application comply with the requirements of — the name of any added antimicrobial preservative;
Materials used for the manufacture of containers (3.1 and — where applicable, that the preparation is sterile.
subsections) and Containers (3.2 and subsections).
When liquid preparations for cutaneous application are SHAMPOOS
dispensed in pressurised containers, the containers comply
with the requirements of the monograph on Pressurtsed — DEFINITION
pharmaceutical preparations (0523). | Shampoos are liquid or, occasionally, semi-solid preparations
Preparations specifically intended for use on severely injured
intended for application to the scalp and subsequent washing
away with water. Upon rubbing with water they usually form
skin are sterile.
a foam.
Several categories of liquid preparations for cutaneous
They are emulsions, suspensions or solutions. Shampoos
application may be distinguished, for example:
— shampoos; normally contain surface active agents.
— cutaneous foams.
ets
CUTANEOUS FOAMS active substance, the requirement applies only to those

substances which correspond to the above conditions.
DEFINITION
Cutaneous foams comply with the requirements of the Uniformity of Mass
monograph on Medicated foams (1105). Single-dose Powders for Lotions comply with the test for
uniformity of weight (mass), Appendix XII C1. If the test for
Ph Eur
uniformity of content is prescribed for all the active
substances, the test for uniformity of mass is not required.
PAINTS
Liquids for CutaneousApplication of the
DEFINITION
i Pharmacopoeia Paints are Liquids for Cutaneous Applications and are
solutions or dispersions of one or more active ingredients.
e following statements apply to any collodion, They are intended for application to the skin or, in some
yr.paint that is the subject of an individual cases, mucous membranes.
STORAGE
Paints should be Kept in airtight containers.
COLLODIONS
DEFINITION
Collodions are Liquids eous Application, usually
. *
containing Pyroxylinina tmixtur f Ether and Ethanol.
When they are allowed to d : Ear Preparations eo
+4
site of application. (Ph. Eur. monograph 0652) eae
STORAGE é Ear Preparations comply with the requirements of the European
Collodions should be stored remote fro Pharmacopoeia. These requirements are reproduced below.
Ph Eur
LINIMENTS DEFINITION
DEFINITION : Ear preparations are liquid, semi-solid or solid preparations
Liniments are Liquids for Cutaneous Application that intended for instillation, for spraying, for insufflation, for
intended to be applied to the unbroken skin with frictio: lication to the auditory meatus or as an ear wash.
STORAGE eparations usually contain 1 or more active substances
Certain plastic containers, such as those made from
polystyrene, are unsuitable for Liniments. 5 to adjust tonicity or viscosity, to adjust or stabilise
to increasethe solubility of the active substances, to
LABELLING
The label states, if appropriate, that the contents of the
container should be shaken before use.
LOTIONS
DEFINITION
sterile and, unless othe sstified and authorised, free
Lotions are Liquids for Cutaneous Application that are
from antimicrobial pres and supplied in single-dose
intended to be applied to the unbroken skin without friction.
containers.
LABELLING
The label states that the Lotion should be shaken before use. containers, provided, if necessar
administration device, which may b
POWDERS FOR LOTIONS introduction of contaminants.
DEFINITION
Powders for Lotions are preparations consisting of solid, preparations supplied in multidose containers céntain a
loose, dry particles containing one or more active substances, suitable antimicrobial preservative at a suitable concentration,
with or without excipients, intended for reconstitution using except where the preparation itself has adequate
a suitable solvent prior to cutaneous application. They may antimicrobial properties.
contain colouring matter if authorised by the competent Where applicable, containers for ear preparations comply
a4
.
with the requirements of chapters 3.1. Materials used for the

eS
authority.
oN
:
ee
manufacture of containers (and subsections) and 3.2. Containers

te
Powders for Lotions are presented for use as single-dose or

a
cto
multi-dose preparations. (and subsections).

on .
Peet
Several categories of ear preparations may be distinguished:

TESTS
uo
— ear drops and sprays;

ue
Uniformity of Content
te
— semi-solid ear preparations;

OS
Unless otherwise prescribed or justified and authorised,

we
— ear powders;
woof
single-dose Powders for Lotions with a content of active

— ear washes;
:
substance less than 2 mg or less than 2 per cent of the total

eee eoer:
— ear tampons.
te
bs hese
mass comply with test B for uniformity of content,

t
ae a
Appendix XII C3. If the preparation has more than one

Ch)
aera
PRODUCTION EAR DROPS AND EAR SPRAYS

During development of an ear preparation whose formulation
DEFINITION
contains an antimicrobial preservative, the need for and the
Ear drops and ear sprays are solutions, emulsions or
efficacy of the chosen preservative shall be demonstrated to
suspensions of one or more active substances in liquids
the satisfaction of the competent authority. A suitable test
suitable for application to the auditory meatus without
method together with criteria for judging the preservative
exerting harmful pressure on the eardrum (for example,
properties of the formulation are provided in chapter 5.1.3.
water, glycols or fatty oils). They may also be placed in the
Efficacy of antimicrobial preservation.
auditory meatus by means of a tampon impregnated with the
During development of ear washes, it must be demonstrated liquid.
that the nominal content can be withdrawn from the
container of preparations presented in single-dose containers.
readily redispersed on shaking. Suspensions may show a
In the manufacture, packaging, storage and distribution of sediment, which is readily dispersed on shaking to give a
5 suitable measures are taken to ensure their suspension that remains sufficiently stable to enable the
; mmoendations on this aspect are correct dose to be delivered.
provided in chgpte 4. Microbiological quality of
Ear drops are usually supplied in multidose containers of
pharmaceutical pré ts
glass or suitable plastic material that are fitted with an
Sterile ear preparati integral dropper or with a screw cap of suitable materials
ility and to avoid the incorporating a dropper and rubber or plastic teat.
dsthe growth of micro- Alternatively, such a cap assembly is supplied separately.
Ear sprays are usually supplied in multidose containers fitted
with an appropriate applicator. When ear sprays are supplied
in pressurised containers, these comply with the requirements
of the monograph Pressunsed pharmaceutical
preparations (0523).
TESTS
Uniformity of dosage units SEMI-SOLID EAR PREPARATIONS
Single-dose ear preparations comply with the test: ‘
DEFINITION
uniformity of dosage units (2.9.40) or, where justified'a
authorised, with the tests for uniformity of content and/ Semi-solid ear preparations are intended for application to
uniformity of mass shown below. Herbal drugs and herba e external auditory meatus, if necessary by means of a
drug preparations present in the dosage form are not subjec impregnated with the preparation.
to the provisions of this paragraph.
Uniformity of content (2.9.6)
single-dose ear preparations with a content of active
mass comply with test B for uniformity of content of single-
dose preparations. If the preparation has more than one
active substance, the requirement applies only to those
ingredients that correspond to the above conditions. DEFINITION é
Ear powders are intend
the external auditory mea
Single-dose ear preparations comply with the test for
requirements of the monogra’
uniformity of mass of single-dose preparations. If the test for
application (1166).
uniformity of content is prescribed for all the active
for application or insufflation.
Sterility (2.6.1)
Where the label indicates that the ear preparation is sterile, it
complies with the test for sterility. EAR WASHES
STORAGE DEFINITION
If the preparation is sterile, store in a sterile, airtight, tamper- Ear washes are preparations intended to cleanse the’external
proof container. auditory meatus. They are usually aqueous solutions with a
pH within physiological limits.
LABELLING
The label states: Ear washes intended for application to injured parts or prior
— the name of any added antimicrobial preservative; to a surgical operation are sterile.
— where applicable, that the preparation is sterile;
— for multidose containers, the period after opening the EAR TAMPONS
container after which the contents must not be used. This
DEFINITION
period does not exceed 4 weeks, unless otherwise justified
and authorised. Ear tampons are intended to be inserted into the external
auditory meatus. They comply with the requirements of the
monograph Medicated tampons (1155).
Ph Eur
2016 General MonographsGeneral Monographs ITI-45
. *
Eye Preparations me Eye drops may contain excipients, for example, to adjust the
tonicity or the viscosity of the preparation, to adjust or
+t
4
(Ph. Eur. monograph 1163) wae stabilise the pH, to increase the solubility of the active
Eye preparations comply with the requirements of the European substance, or to stabilise the preparation. These substances
Pharmacopoeia. These requirements are reproduced below. do not adversely affect the intended medicinal action or, at
the concentrations used, cause undue local irritation.
Ph Eur
Aqueous preparations supplied in multidose containers
DEFINITION contain a suitable antimicrobial preservative in appropriate
Eye preparations are sterile liquid, semi-solid or solid concentration except when the preparation itself has adequate
preparations intended for administration upon the eyeball antimicrobial properties. The antimicrobial preservative
and/or to the conjunctiva, or for insertion in the conjunctival chosen must be compatible with the other ingredients of the
preparation and must remain effective throughout the period
of time during which eye drops are in use.
If eye drops do not contain antimicrobial preservatives they
are supplied in single-dose containers or in multidose
containers preventing microbial contamination of the
contents after opening.
— eye drops; Eye drops intended for use in surgical procedures do not
— eye lotions; contain antimicrobial preservatives.
Eye drops that are solutions, examined under suitable
conditions of visibility, are practically clear and practically
ophthalmic inserts. free from particles.
PRODUCTION Eye drops that are suspensions may show a sediment that is
readily redispersed on shaking to give a suspension which
remains sufficiently stable to enable the correct dose to be
delivered.
Multidose preparations are supplied in containers that allow
authority. A suitable test method together with ¢ t successive drops of the preparation to be administered.
judging the preservative properties of the formulatig The containers contain at most 10 mL of the preparation,
provided in chapter 5.1.3. Efficacy of antimicrobial preseg unless otherwise justified and authorised.
Eye preparations are prepared using materials and meth
designed to ensure sterility and to avoid the introduction
contaminants and the growth of micro-organisms;
recommendations on this aspect are provided in chapter
suspension comply with the following test:
5.1.1. Methods of preparation of sterile products.
uitable quantity of the suspension into a
In the manufacture of eye preparations containing dispersed Coy g with a micropipette ontoa slide, as
particles, measures are taken to ensure a suitable and approprié ah under a microscope an area
controlled particle size with regard to the intended use. correspon te
During development, it must be demonstrated that the reasons, it is fécomy
nominal contents can be withdrawn from the container of on (e.g. x 50) and particles
liquid and semi-solid eye preparations supplied in single-dose ntified. These larger particles can
containers. agnification
TESTS ‘ach 10 ug of solid active
Sterility (2.6.1) £ have a maximum
Eye preparations comply with the test. Applicators supplied dimension greater than 25 um, ahd net more than 2 of these
separately also comply with the test. Remove the applicator particles have a maximum dimensi#hgreater than 50 um.
with aseptic precautions from its package and transfer it to a None of the particles has a maximum. dimension greater than
tube of culture medium so that it is completely immersed. 90 Lum.
Incubate and interpret the results as described in the test. LABELLING
STORAGE The label states, for multidose containers, the périod after
Unless otherwise justified and authorised, store ina sterile, opening the container after which the contents must not be
tamper-proof container. used. This period does not exceed 4 weeks, unless otherwise
justified and authorised.
aN
wry
aa.
4
LABELLING
At
The label states the name of any added antimicrobial

ver 4
preservative. EYE LOTIONS

Ph Eur
EYE DROPS DEFINITION

Ph Eur
Eye lotions are sterile aqueous solutions intended for use in
rinsing or bathing the eye or for impregnating eye dressings.
DEFINITION
Eye lotions may contain excipients, for example to adjust the
Eye drops are sterile aqueous or oily solutions, emulsions or tonicity or the viscosity of the preparation or to adjust or
suspensions of one or more active substances intended for stabilise the pH. These substances do not adversely affect the
instillation into the eye.
IlI-46 General MonographsGeneral Monographs 2016
intended action or, at the concentrations used, cause undue SEMI-SOLID EYE PREPARATIONS
local irritation.
Ph Eur
Eye lotions supplied in multidose containers contain a
suitable antimicrobial preservative in appropriate DEFINITION
concentration except when the preparation itself has adequate Semi-solid eye preparations are sterile ointments, creams or
antimicrobial properties. The antimicrobial preservative gels intended for application to the conjunctiva or to the
chosen is compatible with the other ingredients of the eyelids. They contain one or more active substances dissolved
preparation and remains effective throughout the period of or dispersed in a suitable basis. They have a homogeneous
time during which the eye lotions are in use. appearance.
If eye lotions do not contain antimicrobial preservatives, they Semi-solid eye preparations comply with the requirements of
are supplied 1in single-dose containers. Eye lotions intended the monograph Semi-solid preparations for cutaneous application
for use in surgical procedures or in first-aid treatment do not (0132). The basis is non-irritant to the conjunctiva.
contain iicrabial preservative and are suppliedin Semi-solid eye preparations are packed in small, sterilised
single-dos , collapsible tubes fitted or provided with a sterilised cannula.
Eye lotions, exami nder suitable conditions of visibility, The containers contain at most 10 g of the preparation,
are practically cléar ana” tically free from particles. unless otherwise justified and authorised. The tubes must be
The containers for niulti reparations do not contain well-closed to prevent microbial contamination. Semi-solid
more than 200 mL of ey tion, unless otherwise justified eye preparations may also be packed in suitably designed
and authorised. single-dose containers. The containers, or the nozzles of
tubes, are of such a shape as to facilitate administration
LABELLING without contamination.
The label states:
TESTS
— where applicable, that the con’ e used on one
Particle size
occasion only;
Semi-solid eye preparations containing dispersed solid
— for multidose containers, the period aft
particles comply with the following test: spread gently a
container after which the contents mus
quantity of the preparation corresponding to at least 10 pg of
period does not exceed 4 weeks, unless oth
solid active substance as a thin layer. Scan under a
and authorised.
microscope the whole area of the sample. For practical
reasons, it is recommended that the whole sample is first
POWDERS FOR EYE DROPS AND anned at a small magnification (e.g. x 50) and particles
POWDERS FOR EYE LOTIONS ter than 25 um are identified. These larger particles can
i asured at a larger magnification (e.g. x 200 to
Ph Eur
rx each 10 ug of solid active substance, not more
DEFINITION
Powders for the preparation of eye drops and eye lotions are jotmore than 2 of these particles have a
supplied in a dry, sterile form to be dissolved or suspended fision greater than 50 um. None of the
in an appropriate liquid vehicle at the time of administration. um dimension greater than 90 um.
They may contain excipients to facilitate dissolution or
dispersion, to prevent caking, to adjust the tonicity, to adjust The label states, ‘fc dose containers, the period after
or stabilise the pH or to stabilise the preparation. opening the container.@ y hich the contents must not be
After dissolution or suspension in the prescribed liquid, they used. This period does yt exceed 4 weeks, unless otherwise
comply with the requirements for eye drops or eye lotions, as justified and authorised
appropriate.
TESTS OPHTHALMIC INSE
Uniformity of dosage units (2.9.40) Ph Eur
Single-dose powders for eye drops and eye lotions comply
DEFINITION
with the test or, where justified and authorised, with the tests
Ophthalmic inserts aresterile, solid or se
for uniformity of content and/or uniformity of mass shown
paragraph.
embeddedin a matrix or bounded bya rate-controlling
Uniformity of content (2.9.6) membrane. The active substance, which is more or less
Unless otherwise prescribed or justified and authorised, soluble in lacrymal liquid, is released over a determined
single-dose powders for eye drops and eye lotions with a period of time.
content of active substance less then 2 mg or less than Ophthalmic inserts are individually distributed into sterile
2 per cent of the total mass comply with test B. If the
containers.
preparation has more than one active substance, the
requirement applies only to those substances that correspond PRODUCTION
to the above condition. In the manufacture of ophthalmic inserts, measures are taken
to ensure a suitable dissolution behaviour.
Single-dose powders for eye drops and eye lotions comply TESTS
with the test. If the test for uniformity of content is Uniformity of dosage units (2.9.40)
nt Ad prescribed for all the active substances, the test for uniformity Ophthalmic inserts comply with the test or, where justified
oraa
and authorised, with the test for uniformity of content shown

im,
of mass is not required.

ae
2a a
een
Swe a

the dosage form are not subject to the provisions of this PRODUCTION
paragraph. Methods of sterilisation that may be used in the manufacture
Uniformity of content (2.9.6) of Eye Ointments are described in Appendix XVIII.
Ophthalmic inserts comply, where applicable, with test A. In preparing Eye Ointments in tropical or subtropical
LABELLING countries where the prevailing high temperatures otherwise
make the basis too soft for convenient use, the proportions of
The label states:
Yellow Soft Paraffin and Liquid Paraffin specified in the
— where applicable, the total quantity of active substance
individual monograph may be varied, or Hard Paraffin may
per insert;
be added, but the proportions of active ingredients must not
— where applicable, the dose released per unit time.
be changed.
Ph Eur
STORAGE
Single-dose containers for Eye Ointments, or the nozzles of
tubes, are of such a shape as to facilitate administration
without contamination. The former type of container is
individually wrapped. Tubes are tamper-evident.
Pharmacopoeia, the fo
eye ointment that is the
MEDICATED FOAMS pte
British Pharmacopoeia.
* oe
EYE DROPS Medicated Foams comply with the requirements of the European
DEFINITION Pharmacopoeia. These requirements are reproduced below.
Definition of particular Eye Drops as a Ph Eur
suspension in Purified Water does not p Additional requirements for medicated foams may be found,
of suitable additional substances where necess¢ where appropriate, in other general monographs, for
purposes referred to above under the requirements example, on Rectal preparations (1145), Vaginal preparations
European Pharmacopoeia. However, if buffering agent (1164) and Ligud preparations for cutaneous application (0927).
used in preparations intended for use in surgical proce
great care should be taken to ensure that the nature an DEFINITION
concentration of the chosen agent are suitable. Medicated foams are preparations consisting of large volumes
Where the active ingredient is susceptible to oxidative ee ispersed in a liquid generally containing one or more
degradation, appropriate precautions such as the addition of
a suitable antioxidant should be taken. If an antioxidant is
added, care should be taken to ensure compatibility between
the antioxidant and the antimicrobial preservative.
‘liquid preparation in a pressurised
PRODUCTION
r is equipped with a device consisting
Methods of sterilisation that may be used in the manufacture
of Eye Drops are described in Appendix XVIII.
STORAGE
Eye Drops are supplied in tamper-evident containers.
The compatibility of plastic or rubber components should be
confirmed before use.
Containers for multi-dose Eye Drops are fitted with an pharmaceutical preparations (0523).
integral dropper or with a sterile screw cap of suitable
PRODUCTION
materials incorporating a dropper and rubber or plastic teat.
Alternatively such a cap assembly is supplied, sterilised,
methods designed to ensure sterility and t6’avoi
separately.
out
introduction of contaminants and the growth*o

oy
LABELLING
a
rr?
For multi-dose containers the label states that care should be the text on Methods of preparation of sterile products (5.1.1).
Se
taken to avoid contamination of the contents during use.

TESTS
eye
Single-dose containers that because of their size bear only an

vet’
Relative foam density

a>
indication of the active ingredient and the strength of the

DOP
Maintain the container at about 25 °C for at least 24 h.

preparation do so by use of an approved code, Taking care not to warm the container, fit a rigid tube
Appendix XXI C, together with an expression of the 70 mm to 100 mm long and about 1 mm in internal
percentage present. When a code is used on the container, diameter onto the push button. Shake the container to
the code is also stated on the package. homogenise the liquid phase of the contents and dispense
5 mL to 10 mL of foam to waste. Tare a flat-bottomed dish
EYE OINTMENTS with a volume of about 60 mL and about 35 mm high. Place
DEFINITION the end of the rigid tube attached to the push button in the
_
Eye Ointments of the British Pharmacopoeia that are corner of the dish, press the push button and fill the dish
uniformly, using a circular motion. After the foam has
wth
er
et
ae e intended to be used solely or primarily as a suitable eye-
ointment basis contain no active ingredient. completely expanded, level off by removing the excess foam
ote .
awe
et
1
with a slide. Weigh. Determine the mass of the same volume Sterility (2.6. 1)
wyyye
of water R by filling the same dish with water R. When the label indicates that the preparation is sterile, it
The relative foam density is equivalent to the ratio: complies with the test for sterility.
LABELLING
m The label states, where applicable, that the preparation is
e sterile.
Ph Eur
m = mass of the test sample of foam, in grams;
eé = mass of same volume of water R, in grams.
x%
Carry out three measurements. None of the individual values
Granules ete
xO
SA ANS
Anan
(Ph. Eur. monograph 0499) * ee
AAA,
veer
|
Granules comply with the requirements of the European
int. diameter 15 mm
Ph Eur
Requirements for granules to be used for the preparation of oral

solutions or suspensions are given in the monograph on Liquid
preparations for oral use (0672). Where justified and authorised,
vee ee the requirements of this monograph do not apply to granules for
veterinary use.
reese
ae)
DEFINITION
Granules are preparations consisting of solid, dry aggregates
wees
of powder particles sufficiently resistant to withstand

handling. They are intended for oral administration. Some
are swallowed as such, some are chewed and some are
dissolved or dispersed in water or another suitable liquid
before being administered.
Granules contain one or more active substances with or
stopcock 4mm push button ithout excipients and, if necessary, colouring matter
vey
ed by the competent authority and flavouring
se)
plastic tube ,
int. diameter 4 mm
max. length 50 mm I pressurized e presented as single-dose or multidose
ners) container
Each dose of a multidose preparation is
quant es For single-dose granules, each dose is

enclosed in 4 idvial container, for example a sachet or a
seed
L, vial.
Figure 1105.-1. — Apparatus for the determination of the requirements of Mater; for the manufacture of containers
duration of expansion (3.1 and subsections) a aeae rs (3.2 and subsections).
we eee
verse
Several categories of granulés may be distinguished:
— effervescent granules;
|
Figure 1105.-1. — Apparatus for the determination of the
— coated granules;
duration of expansion
— gastro-resistant granules;
tet
Duration of expansion — modified-release granules.
The apparatus (Figure 1105.-1) consists of a 50 mL burette,
PRODUCTION
15 mm in internal diameter, with 0.1 mL graduations and
In the manufacture, packaging, storage and distrib’
fitted with a 4 mm single bore stopcock. The graduation
granules, suitable measures are taken to ensure t
corresponding to 30 mL is at least 210 mm from the axis of
the stopcock. The lower part of the burette is connected by microbial quality; recommendations on this aspect’are
provided in the text on 5.1.4. Microbiological quality of non-
means of a plastic tube not longer than 50 mm and 4 mm in
internal diameter to the foam-generating container equipped sterile pharmaceutical preparations and substances for
with a push button fitted to this connection. Maintain the pharmaceutical use.
container at about 25 °C for at least 24 h. Shake the TESTS
container, taking care not to warm it, to homogenise the Uniformity of dosage units
vee
va
liquid phase of the contents and dispense 5 mL to 10 mL of Single-dose granules comply with the test for uniformity of
Sees
the foam to waste. Connect the push button to the outlet of dosage units (2.9.40) or, where justified and authorised, with
the burette. Press the button and introduce about 30 mL of the tests for uniformity of content and/or uniformity of mass
foam in a single delivery. Close the stopcock and at the same shown below. Herbal drugs and herbal drug preparations
naan
time start the chronometer and read the volume of foam in present in the dosage form are not subject to the provisions
vue
SANA
the burette. Every 10 s read the growing volume until the of this paragraph.
maximum volume is reached. Uniformity of content (2.9.6)
Carry out three measurements. None of the times needed to Unless otherwise prescribed or justified and authorised,
obtain the maximum volume is more than 5 min. single-dose granules with a content of active substance less
htetete
wees
as
.
he
.
.
-
:
tote
mG
a

rn
stop t
wie
wy
than 2 mg or less than 2 per cent of the total mass comply place or the time at which the active substance or substances
with test B for uniformity of content of single-dose are released.
preparations. If the preparation has more than one active Modified-release granules include prolonged-release granules
substance, the requirement applies only to those substances and delayed-release granules.
which correspond to the above conditions.
PRODUCTION
A suitable test is carried out to demonstrate the appropriate
Single-dose granules except for coated granules comply with release of the active substance(s).
the test for uniformity of mass of single-dose preparations.
If the test for uniformity of content is prescribed for all the TESTS
active substances, the test for uniformity of mass is not Dissolution
required. Carry out a suitable test to demonstrate the appropriate
release of the active substance(s), for example the test
described in Dissolution test for solid dosage forms (2.9.3).
GASTRO-RESISTANT GRANULES
DEFINITION
Gastro-resistant granules are delayed-release granules that are
intended to resist the gastric fluid and to release the active
substance(s) in the intestinal fluid. These properties are
EFFERVESCENT ¢ achieved by covering the granules with a gastro-resistant

material (enteric-coated granules) or by other suitable means.
DEFINITION PRODUCTION
A suitable test 1s carried out to demonstrate the appropriate
release of the active substance(s).
carbonates which react rapidlyin thep eseny,
release carbon dioxide. They are intended: TESTS
dispersed in water before administration. Dissolution
Carry out a suitable test to demonstrate the appropriate
TESTS
release of the active substance(s), for example the test
Disintegration described in Dissolution test for solid dosage forms (2.9.3).
Place one dose of the effervescent granulesin a beakef
Ph Eur
contaming 200 mL of water R at 15-25 °C; numerous **
bubbles of gas are evolved. When the evolution of gas aroun
the individual grains ceases, the granules have disintegrated,
being either dissolved or dispersed in the water. Repeat the
CATED CHEWING GUMS 3" x&
+
operation on 5 other doses. The preparation complies with
the test if each of the 6 doses used disintegrates within re
5 min.
STORAGE European a. These requirements are reproduced
In an airtight container. below.
Ph Eur
COATED GRANULES
DEFINITION
DEFINITION Medicated chewing gum olid, single-dose preparations
Coated granules are usually multidose preparations and with a base consisting mainly:‘of that are intended to be
consist of granules coated with one or more layers of chewed but not swallowed.
mixtures of various excipients. They contain one or more active which are
PRODUCTION released by chewing. After dissolution:
The substances used as coatings are usually applied as a active substances in saliva, chewing gums<
solution or suspension in conditions in which evaporation of used for:
the vehicle occurs. — local treatment of mouth diseases;
— systemic delivery after absorption through the buccal
TESTS
mucosa or from the gastrointestinal tract.
Dissolution
A suitable test may be carried out to demonstrate the PRODUCTION
appropriate release of the active substance(s), for example Medicated chewing gums are made witha tasteless
one of the tests described in Dissolution test for solid dosage masticatory gum base that consists of natural or synthetic
forms (2.9.3). elastomers. They may contain other excipients such as fillers,
softeners, sweetening agents, flavouring substances, stabilisers
and plasticisers and authorised colouring matter.
MODIFIED-RELEASE GRANULES
Medicated chewing gums are manufactured by compression
DEFINITION or by softening or melting the gum bases and adding
Modified-release granules are coated or uncoated granules successively the other substances. In the latter case, chewing
which contain special excipients or which are prepared by gums are then further processed to obtain the desired gum
DS
Ses special procedures, or both, designed to modify the rate, the presentation. The medicated chewing gums may be coated,
ree os
for example, if necessary to protect from humidity and light.

Unless otherwise justified and authorised, a suitable test 1s Preparations for inhalation may, depending on the type of
carried out to demonstrate the appropriate release of the preparation, contain propellants, cosolvents, diluents,
active substance(s). The method Dissolution test for medicated antimicrobial preservatives, solubilising and stabilising agents,
chewing gums (2.9.25) may be used to that purpose. etc. These excipients do not adversely affect the functions of
In the manufacture, packaging, storage and distribution of the mucosa of the respiratory tract or its cilia.
medicated chewing gums, suitable measures must be taken to Suspensions and emulsions are readily dispersible on shaking
ensure their microbial quality; recommendations related to and they remain sufficiently stable to enable the correct dose
this aspect are provided in the general chapter on 5S. 1.4. to be delivered.
Microbiological quality of non-sterile pharmaceutical preparations Preparations for inhalation are supplied in multidose or
and substances for pharmaceutical use. single-dose containers. When supplied in pressurised
TESTS containers, they comply with the requirements of the
monograph Pressurised pharmaceutical preparations (0523).
Preparations intended to be administered as aerosols
(dispersions of solid or liquid particles in a gas) are
administered by one of the following devices:
— a nebuliser;
— an inhaler (pressurised metered-dose inhaler, non-
provisions of this paragra pressurised metered-dose inhaler or powder inhaler).
Uniformity of content Several categories of preparations for inhalation may be
distinguished:
medicated chewing gums with — preparations to be converted into vapour;
less than 2 mg or less than 2 pe — liquid preparations for nebulisation;
— pressurised metered-dose preparations for inhalation;
preparations. If the preparation contains — non-pressurised metered-dose preparations for inhalation;
active substance, the requirement applies 61 — inhalation powders.
substances which correspond to the above c PRODUCTION
Uniformity of mass (2.9.5) é During the development of a preparation for inhalation that
Uncoated medicated chewing gums and, unless other | contains an antimicrobial preservative, the effectiveness of the
justified and authorised, coated medicated chewing gums chosen preservative shall be demonstrated to the satisfaction
comply with the test for uniformity of mass of single-dose « af the competent authority. A suitable test method together
preparations. If the test for uniformity of content is
prescribed for all the active substances, the test for uniformity —
of mass is not required. preservation.
STORAGE cture, packaging, storage and distribution of
Store uncoated medicated chewing gums protected from
humidity and light.
Ph Eur
quality of non-stexts
for pharmaceutical ys
“delivered dose of a multidose
4ést.a single inhaler.
INFUSIONS
nity into account.
DEFINITION
ighaler test would be
Infusions are dilute solutions containing the readily-soluble
constituents of crude drugs. They are usually prepared by
middle and end of the number of wo ,
‘ Te
afot
diluting one volume of a concentrated Infusion to ten

from separate inhalers.
volumes with Water.
etC
oe
For dispensing purposes, Infusions should be used within LABELLING é

.
For preparations administered by an inhaler, the J

a
12 hours of their preparation.

te
— the delivered dose; alternatively, where the dose.fia

:
established as a metered dose or as a pre--dispensed dose,

a
ae
Late
‘
a
the label states either the metered dose or the pre-

vs Br Ceesyet ce
dispensed dose, as appropriate;

eee
> oeren re
PREPARATIONS FOR “
4t%
— where applicable, the number of deliveries from the

A
+ 4%
INHALATION Ky
inhaler to provide the minimum recommended dose;
— the number of deliveries per inhaler.
The label states, where applicable, the name of any added
Ph Eur antimicrobial preservative.
DEFINITION PREPARATIONS TO BE CONVERTED INTO
Preparations for inhalation are liquid or solid preparations VAPOUR
intended for administration as vapours or aerosols to the lung DEFINITION
in order to obtain a local or systemic effect. They contain Preparations intended to be converted into vapour are
one or more active substances that may be dissolved or solutions, suspensions, emulsions or solid preparations. They
dispersed in a suitable vehicle.
are usually added to hot water and the vapour generated is pressure with (a) suitable propellant(s), which can act also as
inhaled. a solvent.
Se ae
vawed
LIQUID PREPARATIONS FOR NEBULISATION The delivered dose is the dose delivered from the inhaler.
wwe
DEFINITION For some preparations the dose has been established as a

Liquid preparations for nebulisation are solutions, metered dose. The metered dose is determined by adding the
amount deposited on the inhaler to the delivered dose.
see ed
suspensions or emulsions intended to be converted into

It may also be determined directly.
aerosols by nebulisers.
Liquid preparations for nebulisation in concentrated form are PRODUCTION
diluted to the prescribed volume with the prescribed liquid The size of aerosol particles to be inhaled is controlled so
before use. Liquid preparations for nebulisation may also be that a consistent portion is deposited in the lungs. The fine-
prepared from powders. particle characteristics of pressurised metered-dose
A aaAAd
preparations for inhalation are determined using the method
Meee
eat
weees
described in general chapter 2.9.18. Preparations for
inhalation: aerodynamic assessment offine particles.
for nebulisation supplied in multidose
tain a suitable antimicrobial preservative Pressurised metered-dose inhalers are tested for leakage.
TESTS
For breath-triggered pressurised metered-dose inhalers, the test
conditions described below may need to be modified to ensure that
containers that do not ¢é ntimicrobial preservative, actuation occurs for the inhaler under test.
and where the preparatio es not have adequate Prepare the inhaler as directed 1n the instructions to the patient.
antimicrobial properties, are
Uniformity of delivered dose
containers preventing microby
Pressurised metered-dose inhalers usually operate in a valve-
ween
reas
contents during storage and use.
down position. For inhalers that operate in a valve-up
at
Liquid preparations for nebulisation sup position, an equivalent test is applied using methods that
containers are sterile and preservative-free, ut ensure the complete collection of the delivered dose.
The dose collection apparatus must be capable of
ca
quantitatively capturing the delivered dose.
high-pressure gases, ultrasonic vibration or other
The following apparatus (Figure 0671.-1) and procedure may
They allow the dose to be inhaled at an appropriate actiy
be used.
substance delivery rate over an extended period of time
involving consecutive inspirations and with a particle size pparatus consists of a filter-support base with an open-
ensures deposition of the preparation in the lungs.
tube that is clamped or screwed to the filter-
Nebulisers may be breath-triggered or use other means to
se, and a mouthpiece adapter to ensure an airtight
ra
set
synchronise or modify the nebuliser operation with the
patient’s breathing.
PRODUCTION
The active substance delivery rate and the total active
substance delivered are determined using the methods
nebulisation: characterisation. Where justified and authorised, a air through the complete
different apparatus and procedure may be used. assembly, including t | the inhaler to be tested, at
peuee
For liquid preparations for nebulisation that are solutions or 28.3 L/min (+ 5 per cent). Air should be drawn
suspensions, determine the particle-size distribution using an continuously through the apparatu to avoid loss of the active
substance into the atmosphere.’ THe filter-support base is
wee
apparatus and procedure described in general chapter 2.9. 44.

Te ee,
wana Preparations for nebulisation: characterisation. Where justified designed to accommodate 25 mm.di
and authorised, a different apparatus and procedure may be The filter disk and other materials us ie construction of
used. the apparatus must be compatible wi ‘e Substance
TESTS
Prepare the liquid preparation for nebulisation as directed in the hold the filter disk tightly against the filter-supp
instructions to the patient. When assembled, the joints between the components of the
Aerodynamic assessment of nebulised aerosols apparatus are airtight so that when a vacuum is applied to
For liquid preparations for nebulisation that are suspensions, the base of the filter, all of the air drawn through the
determine fine-particle mass using an apparatus and collection tube passes through the inhaler.
procedure described in general chapter 2.9.44. Preparations for
sue
Unless otherwise prescribed in the instructions to the patient,

yaaa
wNany
nebulisation: characterisation. Where justified and authorised, a shake the inhaler for 5 s and discharge 1 delivery to waste.
VASE
different apparatus and procedure may be used. Discharge the inverted inhaler into the apparatus, depressing
PRESSURISED METERED-DOSE PREPARATIONS the valve for a sufficient time to ensure complete discharge.
FOR INHALATION Repeat the procedure until the number of deliveries that
constitute the minimum recommended dose have been
DEFINITION
sampled. Quantitatively collect the contents of the apparatus
Pressurised metered-dose preparations for inhalation are
uve d
saAAAY
and determine the amount of active substance.
solutions, suspensions or emulsions supplied in containers
equipped with a metering valve and which are held under Repeat the procedure for a further 2 doses.
vee
Internal threads
OD 38.1
© 35.5
© 32.8
DO 31.8
© 28.6
©D 27.2
©@ 26.7
DQ 25.7
OD 21.8
Tube
External threads 74
Internal threads
es 20
[38.0 —| | 16.6
1 85
2 eeA
Lititry
LLETTT
Litt
Vacuum connector
Mouthpiece adapters
237]
wien
aac
Metered-dose inhale
Figure 0671.-1. - Dose collection apparatus for pressurised metered-dose inhalers

Dimensions in millimetres
Discharge the inhaler to waste, waiting not less than 5 s Unless otherwise justified and authorised, the preparation
between actuations, until (7/2) + 1 deliveries remain, where n complies with the test if 9 out of 10 results lie between
is the number of deliveries stated on the label. Collect 75 per cent and 125 per cent of the average value and all lie
4 doses using the procedure described above. between 65 per cent and 135 per cent. If 2 or 3 values lie
Discharge the inhaler to waste, waiting not less than 5 s outside the limits of 75 per cent to 125 per cent, repeat the
between actuations, until 3 doses remain. Collect these test for 2 more inhalers. Not more than 3 of the 30 values lie
3 doses using the procedure described above. outside the limits of 75 per cent to 125 per cent and no
value lies outside the limits of 65 per cent to 135 per cent.
For preparations containing more than | active substance,
carry out the test for uniformity of delivered dose for each Fine particle dose
active substance. Using an apparatus and procedure described in general
chapter 2.9.18. Preparations for inhalation: aerodynamic
awe 4
2016 General Monographs ITI-53
assessment offine particles (apparatus C, D or E), calculate the For preparations containing more than | active substance,
fine particle dose. carry out the test for uniformity of delivered dose for each
Number of deliveries per inhaler active substance.
Take 1 inhaler and discharge the contents to waste, actuating Unless otherwise justified and authorised, the preparation
the valve at intervals of not less than 5 s. The total number complies with the test if 9 out of 10 results lie between
of deliveries so discharged from the inhaler is not less than 75 per cent and 125 per cent of the average value and all lie
the number stated on the label (this test may be combined between 65 per cent and 135 per cent. If 2 or 3 values lie
with the test for uniformity of delivered dose). outside the limits of 75 per cent to 125 per cent, repeat the
NON-PRESSURISED METERED-DOSE test for 2 more inhalers. Not more than 3 of the 30 values lie
PREPARATIONS FOR INHALATION outside the limits of 75 per cent to 125 per cent and no
value lies outside the limits of 65 per cent to 135 per cent.
DEFINITION
Where justified and authorised, another apparatus and
sed metered-dose preparations for inhalation are
procedure may be used.
Stons or emulsions for use with inhalers that
Fine particle dose
Using an apparatus and procedure described in general
into an aerosolis pre-metered or chapter 2.9.18. Preparations for inhalation: aerodynamic
that the dose delivered from the assessment offine particles (apparatus C, D or E), calculate the
fine particle dose. Use the same procedure as for pressurised
Non-pressurised mete inhalers with appropriate adaptation of the methodology to
supplied in multidose conti non-pressurised inhalers. Depending on the characteristics of
the non-pressurised metered-dose preparations for inhalation,
relative humidity and/or temperature may need to be
controlled during the test.
Non-pressurised metered-dose preparati Number of deliveries per inhaler

supplied in multidose containers that d Take 1 inhaler and discharge the contents to waste. The total
number of deliveries so discharged from the inhaler is not
does not have adequate antimicrobial properties, are: less than the number stated on the label (this test may be
and are supplied in containers preventing microbisi combined with the test for uniformity of delivered dose).
contamination of the contents during storage and us¢ INHALATION POWDERS
Non-pressurised metered-dose preparations for inhalatiéi DEFINITION
supplied in single-dose containers are sterile and preserv lation powders are supplied in single-dose or multidose
free, unless otherwise justified and authorised. rs. To facilitate their use, active substances may be
PRODUCTION sd with a suitable carrier. They are administered by
The size of aerosol particles to be inhaled is controlled so inhalers. For pre-metered inhalers, the inhaler is
that a consistent portion is deposited in the lung. The fine-
particle characteristics of non-pressurised metered-dose
inhalation: aerodynamic assessment offine particles.
Alternatively, laser diffraction analysis may be used, when labelled dose has been established
.
‘ee
at
as a metered dose O ispensed dose.

oa)
properly validated against method 2.9.18 (apparatus

: Ege ee,
to
C, D or E). The metered dose is dete: by adding the amount

ae get
vp Py es eer a
“?
deposited on the inhaler t delivered dose. It may also be

eae
eho he
TESTS
ee
determined directly.
For breath-triggered non-pressurised metered-dose inhalers, the test
48 J
eae,
, wt ehh wee
PRODUCTION
‘
conditions described below may need to be modified to ensure that

ate,
oe ,
aa
actuation occurs for the inhaler under test. The size of aerosol particles to be inhajed is controlled so
a vy
Typ
an .
Prepare the inhaler as directed in the instructions to the patient. that a consistent portion is deposited inthe laf
eats
particle characteristics of powders for inhalati

ces
..
-
.

'reyto
determined using the method describedin geriéra

‘
‘
The dose collection apparatus must be capable of

:
:
2.9.18. Preparations for inhalation: aerodynamic assessment of

:
so
quantitatively capturing the delivered dose. The apparatus

va
fine particles.
"ts
fae
described in the test for uniformity of delivered dose for

Ge bole
foe
et
oo
Fy
pressurised metered-dose preparations may be used. TESTS

Per tase
>see et
yrraye
Prepare the inhaler as directed in the instructions to the patient.

Pa
TyQ
Discharge the inhaler into the apparatus. Repeat the

ves
Pays
“o¢

a>
ey
procedure until the number of deliveries that constitute the

minimum recommended dose have been sampled. The dose collection apparatus must be capable of
Quantitatively collect the contents of the apparatus and quantitatively capturing the delivered dose. A dose collection
determine the amount of active substance. apparatus similar to that described for the evaluation of
Repeat the procedure for a further 2 doses. pressurised metered-dose inhalers may be used provided that
the dimensions of the tube and the filter can accommodate
Discharge the inhaler to waste until (7/2) + 1 deliveries
the measured flow rate. A suitable tube is defined in
remain, where 7 is the number of deliveries stated on the
Table 0671.-1. Connect the tube to a flow system according
label. Collect 4 doses using the procedure described above.
: ~
to the scheme specified in Figure 0671.-2 and Table 0671.-1.
Lea
we
oem
"eat
~'}
Discharge the inhaler to waste until 3 doses remain. Collect
these 3 doses using the procedure described above.
A
G Sample collection tube
Timer
F Pi
P3 P2
a|
Vacuum
Flow |
Two-way control N
solenoid valve valve Filter
E B
Connector Vacuum Mouthpiece

tubing adaptor
C D
— Apparatus suitable for measuring the uniformity of delivered dose for powder inhalers
e test flow rate and Prepare the inhaler for use and connect it to the inlet of the
apparatus using a mouthpiece adapter to ensure an airtight
seal. Use a mouthpiece adapter that ensures that the front
volumetric flowmeter, calibrat ‘ face of the inhaler mouthpiece is flush with the front face of
meter, according to the following procédurs the sample collection tube. Connect one port of a differential
pressure meter to the pressure reading point P1 in
Table 0671.-1. - Specifications of the app Figure 0671.-2, and let the other be open to the atmosphere.
powder inhalers described in Figure Switch on the pump, open the 2-way solenoid valve and
adjust the flow control valve until the pressure drop across
Code Item Description
the inhaler is 4.0 kPa (40.8 cm H,O) as indicated by the
A Sample collection Capable of quantitatively capturing thé d
tube ered dose, e.g. dose collection tube simila:
differential pressure meter. Remove the inhaler from the
that described in Figure 0671.-1 with dime mouthpiece adapter and, without touching the flow control
sions of 34.85 mm ID x 12 cm length (e.g nnect a flowmeter to the inlet of the sampling
product number XX40 047 00, Millipore Corpo-
ration, Bedford, MA 01732, USA with modified Use a flowmeter calibrated for the volumetric flow
exit tube, ID 2 8 mm, fitted with Gelman pro- meter, or calculate the volumetric flow leaving the
duct number 61631), or equivalent. using the ideal gas law. For a meter calibrated
Filter 47 mm filter, e.g. A/E glass fibre filter (Gelman
ateruge volumetric flow (Q;,), use the following
Sciences, Ann Arbor, MI 48106, USA), or equiv-
alent.
Connector ID 28 mm, e.g., short metal coupling, with low-
diameter branch to P3.
Vacuum tubing A length of suitable tubing having an [ID 28 mm
and an internal volume of 25 +5 mL.
2-way solenoid A 2-way, 2-port solenoid valve having a mini-
valve mum airflow resistance orifice with ID = 8 mm
and an opening time < 100 ms (eg. type
256-A08, Burkert GmbH, 74653 Ingelfingen,
Deutschland), or equivalent.
Vacuum pump Pump must be capable of drawing the required
flow rate through the assembled apparatus
with the powder inhaler in the mouthpiece
adapter (e.g. product type 1023, 1423 or 2565,
Gast Manufacturing Inc., Benton Harbor, MI
49022, USA), or equivalent. Connect the pump
to the 2-way solenoid valve using short and/or
air is drawn from the mouthpiece of the inhaler
wide (2 10 mm ID) vacuum tubing and connec- flow rate, Qour-
tors to minimise pump capacity requirements.
Ensure that critical flow occurs in the flow controf'valve by
Timer Timer capable of driving the 2-way sole-
noid valve for the required time period (e.g. the following procedure: with the inhaler in place and the test
type G814, RS Components International, Cor- flow rate Q,,,, measure the absolute pressure on both sides of
by, NN17 ORS, UK), or equivalent.
the control valve (pressure reading points P2 and P3 in
PI Pressure tap 2.2 mm ID, 3.1 mm OD, flush with internal sur-
Figure 0671.-2); a ratio P3/P2 of less than or equal to 0.5
face of the sample collection tube, centred and
burr-free, 59 mm from its inlet. The pressure indicates critical flow; switch to a more powerful pump and
tap P1 must never be open to the atmosphere. re-measure the test flow rate if critical flow is not indicated.
Differential pressure to atmosphere is meas-
ured at Pl. Pre-dispensed systems Connect the inhaler to the apparatus
P2 Pressure Absolute pressures. using an adapter that ensures a good seal. Draw air through
P3 measurements the inhaler using the predetermined conditions. Repeat the
Flow control valve Adjustable regulating valve with maximum procedure until the number of deliveries that constitute the
Cv 2 1 (e.g. type 89FVI2LNSS, Parker Hannifin
minimum recommended dose have been sampled.
plc., Barnstaple, EX31 INP, UK), or equivalent.
Quantitatively collect the contents of the apparatus and
determine the amount of active substance.
Repeat the procedure for a further 9 doses.
Reservoir systems Connect the inhaler to the apparatus using and, where appropriate, the particle size of the active
an adapter that ensures a good seal. Draw air through the ingredient should be controlled so that, when the pressurised
inhaler under the predetermined conditions. Repeat the inhalation is used in accordance with the manufacturer’s
aan
tang
procedure until the number of deliveries that constitute the recommendations, an adequate proportion of the active
Sy
I
minimum recommended dose have been sampled. ingredient is made available for inhalation. A proportion of
Quantitatively collect the contents of the apparatus and the active ingredient is deposited on the inner surface of the
determine the amount of active substance. actuator; the amount available for inhalation is therefore less
Repeat the procedure for a further 2 doses. than the amount released by actuation of the valve.
Discharge the inhaler to waste until (7/2) + 1 deliveries Pressurised Inhalations should be manufactured in conditions
remain, where 7 is the number of deliveries stated on the designed to minimise microbial and particulate
label. If necessary, store the inhaler to discharge electrostatic contamination.
chargessCollect 4 doses using the procedure described Content of active ingredient delivered by actuation of
the valve
ler to waste until 3 doses remain. Remove the pressurised container from the actuator and
the inhaler to discharge electrostatic remove all labels and markings which may be present on the
container with a suitable solvent. Dry the container, replace
in its actuator, shake for about 30 seconds and prime the
For preparations ¢ ) more than 1 active substance, metering valve as follows. Discharge once to waste, wait for
carry out the test for ity of delivered dose for each not less than 5 seconds and discharge again to waste.
active substance. Remove the pressurised container from its actuator, clean the
valve stem (internally and externally) and the valve ferrule by
washing with a suitable solvent. Dry the complete valve
results lie between 75 per ce
assembly using an air line fitted with an appropriate narrow
average value and all lie between 65¢
jet to ensure that all solvent is removed from the inside of the
135 per cent. If 2 or 3 values lie outside
valve stem.
Place a stainless steel base plate that has three legs and a
central circular indentation with a hole about 1.5 mm in
outside the limits of 65 per cent to 135 per cent diameter in a small vessel suitable for shaking and add the
volume of solvent specified in the monograph. The size of
In justified and authorised cases, these ranges may
the vessel is such that when the pressurised inhalation is
extended but no value should be greater than 150 per
discharged into the specified volume of solvent as described
less than 50 per cent of the average value.
Fine particle dose
Using an apparatus and procedure described in general
chapter 2.9.18. Preparations for inhalation: aerodynamic
assessment offine particles (apparatus C, D or E), calculate the
fine particle dose.
Number of deliveries per inhaler for multidose inhalers cal plane and discharging the pressurised
Discharge doses from the inhaler until empty, at the ,e hole in the centre of the base plate.
predetermined flow rate. Record the deliveries discharged. (It may be necessa
The total number of deliveries so discharged from the inhaler to shake the pres ntainer between each actuation of
is not less than the number stated on the label (this test may e shaking should be carried out
be combined with the test for uniformity of delivered dose).
Ph Eur position in the vessel.) Réfme
wash it with the specified solven
solution and washings to the vol
monograph. Determine the amoutit’ af ingredient by
the method described under the Assa¥..ané aiculate the
Preparations for Inhalation of the British amount delivered from each actuation o
Pharmacopoeia The result lies within the range for the conte
ingredient stated in the monograph.
In addition to the above requirements of the European
Pharmacopoeia, the following statements apply to any pressurised
inhalation that 1s the subject of an individual monograph in the
British Pharmacopoeia. KX %
Preparations For Irrigation ;
+4
PRESSURISED INHALATIONS (Ph. Eur. monograph 1116)

Kk
DEFINITION Preparations for Irrigation comply with the requirements of the

Pressurised Inhalations are Pressurised Metered-dose European Pharmacopoeia. These requirements are reproduced
Preparations for Inhalation. They are intended to be inhaled below.
in controlled amounts. Ph Eur
PRODUCTION DEFINITION
The formulation of the inhalation and the components of the Preparations for irrigation are sterile, aqueous, large-volume
delivery device (that is the pressurised container with its preparations intended to be used for irrigation of body
integral metering valve and the actuator) should be designed
cavities, wounds and surfaces, for example during surgical substances in a suitable vehicle; they may, however, consist
procedures. of liquid active substances used as such (oral liquids).
Preparations for irrigation are either solutions prepared by Some preparations for oral use are prepared by dilution of
dissolving one or more active substances, electrolytes or concentrated liquid preparations, or from powders or
osmotically active substances in water complying with the granules for the preparation of oral solutions or suspensions,
requirements for Water for injections (0169) or they consist of for oral drops or for syrups, using a suitable vehicle.
such water alone. In the latter case, the preparation may be The vehicle for any preparations for oral use is chosen having
labelled as ‘water for irrigation’. Irrigation solutions are regard to the nature of the active substance(s) and to provide
usually adjusted to make the preparation isotonic with organoleptic characteristics appropriate to the intended use of
respect to blood. the preparation.
Examined in suitable conditions of visibility, preparations for Liquid preparations for oral use may contain suitable
«clear and practically free from particles. antimicrobial preservatives, antioxidants and other excipients
such as dispersing, suspending, thickening, emulsifying,
buffering, wetting, solubilising, stabilising, flavouring and
requirements for « sweetening agents and colouring matter, authorised by the
administration (3° 2. competent authority.
es not allow the preparation readily redispersed on shaking. Suspensions may show a
math such equipment. sediment, which is readily dispersed on shaking to give a
suspension that remains sufficiently stable to enable the
Preparations for irrigation are p correct dose to be delivered.
methods designed to ensure ster}, Where applicable, containers for liquid preparations for oral
i use comply with the requirements of Materials used for the
a
5 manufacture of containers (3.1 and subsections) and Containers
(3.2 and subsections).
i
a
1
|
the text on Methods ofpreparation of sterile
~|
Several categories of preparations may be distinguished;
=]
1 During development, it must be demonstrate
-|
so
|
nominal content can be withdrawn from the container. — oral solutions, emulsions and suspensions;
— powders and granules for oral solutions and suspensions;
-+{
~ od
aiul
TESTS
— oral drops;
Sterility (2.6.1) |
powders for oral drops;
Preparations for irrigation comply with the test for sterility
Bacterial endotoxins (2.6. 14)
Less than 0.5 IU/mL.
Pyrogens (2.6.8)
Preparations for which a validated test for bacterial
endotoxins cannot be carried out comply with the test for
pyrogens. Inject per kilogram of the rabbit’s mass 10 mL of
the preparation, unless otherwise justified and authorised. ether with criteria for judging the
LABELLING formulation are provided in the
The label states: preservation (5.1.3).
— that the preparation is not to be used for injection; During development, 1 «demonstrated that the
— that the preparation is to be used on one occasion only nominal content can be withdraw from the container, for
and that any unused portion of the preparation is to be liquid preparations for oral u: sented in single-dose
discarded. containers.
Ph Eur In the manufacturing, packaging, st distribution of
liquid preparations for oral use, suitab sures are taken
to ensure their microbial quality; recommeng
aspect are provided in the text on 5.1.4. Micregiolo
aK of non-sterile pharmaceutical preparations and substagices f
Oral Liquids pharmaceutical use. :
+4+
Ys
(Liquid Preparations for Oral Use,

x yk In the manufacture of liquid preparations for oral use
containing dispersed particles, measures are taken to ensure a
Ph Eur monograph 0672)
suitable and controlled particle size with regard to the
Oral Liquids comply with the requirements of the European
intended use.
Pharmacopoeia monograph for Liquid Preparations for Oral Use.
These requirements are reproduced below. TESTS
Ph Eur
Solutions, suspensions and emulsions in single-dose
Where justified and authorised, the requirements of this monograph
containers comply with the test for uniformity of dosage units
do not apply to liquid preparations for oral use intended for
(2.9.40) or, where justified and authorised, with the test for
veterinary use.
uniformity of content or uniformity of mass shown below.
DEFINITION Herbal drugs and herbal drug preparations present in the
Liquid preparations for oral use are usually solutions, dosage form are not subject to the provisions of this
emulsions or suspensions containing one or more active paragraph.
Uniformity of content (2.9.6) content and/or uniformity of mass shown below. Herbal
Unless otherwise prescribed or justified and authorised, drugs and herbal drug preparations present in the dosage
single-dose preparations that are suspensions comply with the form are not subject to the provisions of this paragraph.
following test. After shaking, empty each container as Uniformity of content (2.9.6)
completely as possible and carry out the test on the Unless otherwise prescribed or justified and authorised,
individual contents. They comply with test B for uniformity single-dose powders and single-dose granules with a content
of content of single-dose preparations. of active substance less than 2 mg or less than 2 per cent of
Uniformity of mass the total mass comply with test B for uniformity of content of
Single-dose preparations that are solutions or emulsions single-dose preparations. If the preparation has more than
comply with the following test: weigh individually the one active substance, the requirement applies only to those
contents of 20 containers, emptied as completely as possible, substances that correspond to the above conditions.
and de rmine the average mass. Not more than 2 of the Uniformity of mass (2.9.5)
Single-dose powders and single-dose granules comply with
the test for uniformity of mass of single-dose preparations.
If the test for uniformity of content is prescribed for all the
active substances, the test for uniformity of mass is not
required.
LABELLING
The label states:
exceed 2 drops per sec
— the method of preparation of the solution or suspension;
addition, weigh again an
— the conditions and the duration of storage after
and weighing until a total of
reconstitution.
No single mass deviates by midre er cent from the
‘not differ by more
ORAL DROPS
If necessary, measure the total volume O
DEFINITION
The volume does not differ by more tha
Oral drops are solutions, emulsions or suspensions that are
the nominal volume of 10 doses.
administered in small volumes such as drops by the means of
Uniformity of mass of delivered doses from ‘mul a suitable device.
containers (2.9.27) :
LABELLING
Liquid preparations for oral use suppliedin multidos
containers comply with the test. Oral drops are not subje t. label states the number of drops per millilitre of
the provisions of this test.
LABELLING
The label states the name of any added antimicrobial
preservative.
ORAL SOLUTIONS, EMULSIONS AND

SUSPENSIONS
DEFINITION
Oral solutions, emulsions and suspensions are supplied in
single-dose or multidose containers. Each dose from a
multidose container is administered by means of a device
suitable for measuring the prescribed volume. The device is TESTS é
usually a spoon or a cup for volumes of 5 mL or multiples Uniformity of dosage units
thereof or an oral syringe for other volumes. Single-dose powders for oral dro
POWDERS AND GRANULES FOR ORAL

SOLUTIONS AND SUSPENSIONS drug preparations present in the dosage form a :Snot subject
DEFINITION to the provisions of this paragraph.
Powders and granules for the preparation of oral solutions or Uniformity of content (2.9.6)
suspensions generally conform to the definitions in the Unless otherwise prescribed or justified and authorised,
monographs on Oral powders (1165) or Granules (0499) as single-dose powders for oral drops with a content of active
appropriate. They may contain excipients, in particular to substance less than 2 mg or less than 2 per cent of the total
facilitate dispersion or dissolution and to prevent caking. mass comply with test B for uniformity of content of single-
After dissolution or suspension, they comply with the dose preparations. If the preparation has more than one
requirements for oral solutions or oral suspensions, as active substance, the requirement applies only to those
appropriate. substances that correspond to the above conditions.
TESTS Uniformity of mass (2.9.5)
Uniformity of dosage units Single-dose powders for oral drops comply with the test for
Single-dose powders and single-dose granules comply with uniformity of mass of single-dose preparations. If the test for
the test for uniformity of dosage units (2.9.40) or, where uniformity of content is prescribed for all the active
justified and authorised, with the tests for uniformity of substances, the test for uniformity of mass is not required.
II-58 General Monographs 2016
SYRUPS LABELLING
The label states for Oral Emulsions, Oral Suspensions and,
DEFINITION
where appropriate, for Mixtures, that the bottle should be
Syrups are aqueous preparations characterised by a sweet
shaken before use.
taste and a viscous consistency. They may contain sucrose at
a concentration of at least 45 per cent m/m. The sweet taste If the Oral Liquid is supplied as granules or powder to be
can also be obtained by using other polyols or sweetening constituted just before issue for use, the label states that the
agents. Syrups usually contain aromatic or other flavouring contents of the container are granules or powder for the
agents. Each dose from a multidose container is administered preparation of an Oral Liquid.
by means of a device suitable for measuring the
prescribed volume. The device is usually a spoon or a cup ELIXIRS
for volumes of 5 mL or multiples thereof.
DEFINITION
Elixirs are clear, flavoured Oral Liquids containing one or
me and concentration of the polyol or more active ingredients dissolved in a vehicle that usually
contains a high proportion of Sucrose or a suitable
polyhydric alcohol or alcohols and may also contain Ethanol
(96 per cent) or a Dilute Ethanol.
POWDERS RANULES FOR SYRUPS
DEFINITION
LINCTUSES
Powders and granules fo generally conform to the
definitions in the monograp ialpowders (1165) or DEFINITION
Granules (0499). They may Linctuses are viscous Oral Liquids that may contain one or
dissolution. more active ingredients in solution. The vehicle usually
After dissolution, they comply w contains a high proportion of Sucrose, other sugars or a
syrups. suitable polyhydric alcohol or alcohols. Linctuses are
intended for use in the treatment or relief of cough, and are
TESTS sipped and swallowed slowly without the addition of water.
Uniformity of dosage units :
Single-dose powders and granules for syrups comply
MIXTURES
test for uniformity of dosage units (2.9.40) or, where: just
and authorised, with the tests for uniformity of content®
and/or uniformity of mass shown below. Herbal drugs and.
herbal drug preparations present in the dosage form are not '
subject to the provisions of this paragraph.
single-dose powders and granules for syrups with a content of
active substance less than 2 mg or less than 2 per cent of the
total mass comply with test B for uniformity of content of
single-dose preparations. If the preparation has more than
soofe
active ingredients. A't

one active substance, the requirement applies only to those
oo
dispersions, either or #5
o
substances that correspond to the above conditions.

.
.
dissolved solids. Solids may :

.
vole
:

us
Emulsions. ‘
.
Single-dose powders and granules for syrups comply with the

MA
area le,
When issued for use, Oral Ernu

test for uniformity of mass of single-dose preparations. If the
wide-mouthed bottles.
test for uniformity of content is prescribed for all the active
Extemporaneous preparation —;
Z ee

ee
In Oral Emulsions prepared according

. Dee ee
Ee Ne TT
Ph Eur
directions given for Extemporaneous pre
we
quantity of emulsifying agent specified in

monographs may be reduced to yield a preparatioxs
.
4
suitable consistency provided that by so doing the stability of

7
Oral Liquids of the British the preparation is not adversely affected.

ay ree
ae
:
Pharmacopoeia
1
vate heer
Vey

x
Nasal Preparations x. “
;
Pharmacopoeia, the following statements apply to any elixir,

.
Oe
linctus, mixture or oral emulsion that 1s the subject of an

ta
individual monograph in the British Pharmacopoeia. (Ph. Eur. monograph 0676) “ha
wm oa
leek
8G whetaaee.
et
DEFINITION Ph Eur
ecg
Oral Liquids other than Oral Emulsions may be supplied as DEFINITION

liquids or prepared just before issue for use by dissolving or Nasal preparations are liquid, semi-solid or solid preparations
an
wa
dispersing granules or powder in the liquid stated on the

arn
intended for administration to the nasal cavities to obtain a

ea
label. systemic or local effect. They contain one or more active

ee
substances. Nasal preparations are as far as possible non-

C8)
Pee eed
Oo
aber,
irritating and do not adversely affect the functions of the

yor
nasal mucosa and its cilia. Aqueous nasal preparations are NASAL DROPS AND LIQUID NASAL
usually isotonic and may contain excipients, for example, to SPRAYS
adjust the viscosity of the preparation, to adjust or stabilise
“a
the pH, to increase the solubility of the active substance, or DEFINITION

to stabilise the preparation. Nasal drops and liquid nasal sprays are solutions, emulsions
Nasal preparations are supplied in multidose or single-dose or suspensions intended for instillation or spraying into the
nasal cavities.
containers, provided, if necessary, with a suitable
administration device, which may be designed to avoid the Emulsions may show evidence of phase separation but are
introduction of contaminants. easily redispersed on shaking. Suspensions may show a
sediment, which is readily dispersed on shaking to give a
Unless otherwise justified and authorised, aqueous nasal
preparations supplied in multidose containers contain a suspension that remains sufficiently stable to enable the
correct dose to be delivered.
imicrobial preservative in an appropriate
m, except where the preparation itself has Nasal drops are usually supplied in multidose containers
provided with a suitable applicator.
Liquid nasal sprays are supplied in containers with atomising
als used for the manufacture of containers devices or in pressurised containers fitted with a suitable
d Containers (3.2 and subsections). adapter and with or without a metering dose valve, which
comply with the requirements of the monograph on
Several categories of nasal preparations may be distinguished:
Pressurised pharmaceutical preparations (0523).
— nasal drops and idsnasal sprays;
tee tl
, aay .t 2 : :
— nasal powders; c The size of droplets of the spray is such as to localise their
— semi-solid nasal prepa deposition in the nasal cavity.
a ae, whe
att iee a.Oe
— nasal washes; TESTS

— nasal sticks. Unless otherwise prescribed or justified and authorised, nasal
we ee
Py Ty
ei toa be La
PRODUCTION drops supplied in single-dose containers and single doses of

ep
seat
op
metered-dose nasal sprays, both intended for systemic action,

comply with the following tests.
efficacy of the chosen preservative shall be defrionstéate NASAL DROPS IN SINGLE-DOSE CONTAINERS
the satisfaction of the competent authority. A suifab Uniformity of dosage units
method together with criteria for judging the preserwati Nasal drops in single-dose containers comply with the test for
properties of the formulation are provided in the text ef uniformity of dosage units (2.9.40) or, where justified and
Efficacy of antimicrobial preservation (5.1.3). thorised, with the test for uniformity of mass or uniformity
In the manufacture, packaging, storage and distribution of ent shown below. Herbal drugs and herbal drug
nasal preparations, suitable measures are taken to ensure parations present in the dosage form are not subject to the
their microbial quality; recommendations on this aspect are sions of this paragraph.
provided in the text on 5.1.4. Microbiological quality of non- “of mass
sterile pharmaceutical preparations and substances for
pharmaceutical use. ie contents of 10 containers emptied as
Sterile nasal preparations are prepared using materials and and determine the average mass.
methods designed to ensure sterility and to avoid the
introduction of contaminants and the growth of micro- than 10 per cent ‘fr
organisms; recommendations on this aspect are provided in more than 20 per c
the text on Methods of preparation of sterile products (5.1.1).
In the manufacture of nasal preparations containing dispersed
particles, measures are taken to ensure a suitable and mpletely as possible
controlled particle size with regard to the intended use. entents. They
TESTS comply with test B for uniformity of ¢onte1
Sterility (2.6.1) METERED-DOSE NASAL SPRAYS
Where the label states that the preparation is sterile, it Uniformity of dosage units
complies with the test for sterility.
STORAGE
If the preparation is sterile, store in a sterile, airtight, tamper- authorised, with the test for uniformity of mass or the test for
proof container. uniformity of delivered dose shown below. Herbal drugs and
herbal drug preparations present in the dosage form are not
LABELLING subject to the provisions of this paragraph.
The label states:
In the case of metered-dose nasal sprays that are solutions, proceed
— the name of any added antimicrobial preservative;
as follows Discharge once to waste. Wait for a minimum of
— where applicable, that the preparation is sterile.
5 s, shake for 5 s and discharge again to waste. Repeat this
procedure for a further 3 actuations. Weigh the container,
discharge once to waste and weigh the container again.
Calculate the difference between the 2 masses. Repeat the
procedure for a further 9 containers. Determine the mass
variation (2.9.40).
In the case of metered-dose nasal sprays that are suspensions or SEMI-SOLID NASAL PREPARATIONS
emulsions, proceed as follows Use an apparatus capable of
DEFINITION
quantitatively retaining the dose leaving the actuator of the
atomising device. Shake the container for 5 s and discharge Semi-solid nasal preparations comply with the requirements
once to waste. Wait for a minimum of 5 s, shake for 5 s and of the monograph on Semi-solid preparations for cutaneous
discharge again to waste. Repeat this procedure for a further application (0132).
3 actuations. After 2 s, fire 1 dose of the metered-dose nasal The containers are adapted to deliver the product to the site
spray into the collecting vessel by actuating the atomising of application.
device. Collect the contents of the collecting vessel by
successive rinses. Determine the content of active substance NASAL WASHES
in the combined rinses. Repeat the procedure for a further
9 containers. Determine the content uniformity (2.9.40). DEFINITION
Nasal washes are generally aqueous isotonic solutions
intended to cleanse the nasal cavities.
rays that are solutions comply with the
7 ze once to waste. Wait for a minimum Nasal washes intended for application to injured parts or
prior to a surgical operation are sterile.
PRODUCTION
discharge once to wast During development, it must be demonstrated that the
Calculate the difference nominal content can be withdrawn from the container, for
nasal washes presented in single-dose containers.
The preparation complies witk
the individual values deviate b
the average value and none deviste'!
NASAL STICKS
35 per cent. DEFINITION
Uniformity of delivered dose Nasal sticks comply with the monograph on Sticks (1154).
Ph Eur
atomising device. Shake the container for 5 s and dis harg

once to waste. Wait for a minimum of5 s, shake for 5 s and
discharge again to waste. Repeat this procedure for a furth asal Preparations of the British
3 actuations. After 2 s, fire 1 dose of the metered-dose nasal fmacopoeia
spray into the collecting vessel by actuating the atomising
device. Collect the contents of the collecting vessel by
successive rinses. Determine the content of active substance
nasal suspension, nasal drops, nasal ointment or
in the combined rinses. Repeat the procedure for a further
at 1s.the subject of an individual monograph in the
9 containers.
Unless otherwise justified and authorised, the preparation
complies with the test if not more than 1 of the individual
contents is outside the limits of 75 per cent to 125 per cent
aeesTA et a ett
soe
and none are outside the limits of 65 per cent to INTRANASAL

ro
135 per cent of the average content.

DEFINITION
8
If 2 or at most 3 individual contents are outside the limits of uspensions are intended
ey
75 per cent to 125 per cent but within the limits of r local or systemic effects.
65 per cent to 135 per cent, repeat the test for 20 more
containers. The preparation complies with the test if not they may be entitled Nasal Spray.
more than 3 individual contents of the 30 individual contents
are outside the limits of 75 per cent to 125 per cent and LABELLING
none are outside the limits of 65 per cent to 135 per cent of
the average content. ingredient; (2) the name and quantity of any add d
substance; (3) that the preparation is for intranasa
administration; (4) the date after which the preparation is not
NASAL POWDERS intended to be used; (5) the conditions under which the
DEFINITION preparation should be stored.
Nasal powders are powders intended for insufflation into the
nasal cavity by means of a suitable device. NASAL DROPS
They comply with the requirements of the monograph on
LABELLING
Powders for cutaneous application (1166).
The label states (1) the name and quantity of the active
The size of the particles is such as to localise their deposition ingredient; (2) the instructions for using the Nasal Drops;
in the nasal cavity and is verified by adequate methods of (3) the date after which the Nasal Drops are not intended to
particle-size determination. be used; (4) the conditions under which the Nasal Drops
should be stored.
OROMUCOS AL PREPARATIO NS wr” *, properties of the formulation are provided in general chapter
**c x* 5.1.3.
1.3. EEfficacy of antumicrobial
microbt. preservation.
s Ne
A (Ph. Eur. monograph 1807) *e In the manufacture, packaging, storage and distribution of
Oromucosal Preparations comply with the requirements of the oromucosal preparations, suitable measures are taken to
European Pharmacopoeia. These requirements are reproduced ensure their microbiological quality; recommendations on this
below. aspect are provided in the text on 5.1.4. Microbiological quality
Ph Eur
of non-sterile pharmaceutical preparations and substances for
pharmaceutical use.
This monograph does not apply to dental preparations or to
In the manufacture of semi-solid and liquid oromucosal
preparations such as chewable tablets (0478), medicated chewing
preparations containing dispersed particles, measures are
gums (1239), oral lyophilisates and other solid or semi-solid
preparations that are not specifically listed in this monograph. taken to ensure a suitable and controlled particle size with
regard to the intended use.
TESTS
Single-dose oromucosal preparations comply with the test for
uniformity of dosage units (2.9.40) or, where justified and
authorised, with the test for uniformity of content and/or
uniformity of mass shown below. Herbal drugs and herbal
stemic effect. Preparations
drug preparations present in the dosage form are not subject
intended for a local effeé ve designed for application to
a specific site within the o3
(gingival preparations) or the Uniformity of content (2. 9.6)
preparations). Preparations ifitende Unless otherwise prescribed or justified and authorised,
designed to be absorbed primarily ag single-dose oromucosal preparations with a content of active
oral mucosa (e.g. sublingual preparatiq: scoadhesive substance less than 2 mg or less than 2 per cent of the total
preparations are intended to be retained: ral cavity by mass comply with test A (compressed and moulded dosage
¥ systemic forms) or test B (capsules) for the uniformity of content of
single-dose preparations. If the preparation contains more
oromucosal preparations, it is likely that some préport than one active substance, this requirement applies only to
the active substance(s) will be swallowed and may be those substances that correspond to the above conditions.
absorbed via the gastrointestinal tract. Uniformity of mass (2.9.5)
Oromucosal preparations may contain suitable antimicrot 1single-dose oromucosal preparations comply with the
preservatives and other excipients such as dispersing,
suspending, thickening, emulsifying, buffering, wetting, s prescribed, or justified and authorised, for all
solubilising, stabilising, flavouring and sweetening agents. bstances, the test for uniformity of mass is not
Solid preparations may in addition contain glidants,
lubricants and excipients capable of modifying the release of
the active substance(s).
Where applicable, containers for oromucosal preparations
comply with the requirements for Materials used for the
manufacture of containers (3.1 and subsections) and Containers
(3.2 and subsections). GARGLES
Several categories of preparations for oromucosal use may be DEFINITION
distinguished:
— gargles;
— mouthwashes; supplied as ready-to-use solutions
— gingival solutions; to be diluted. They may also be prep
—- oromucosal solutions and oromucosal suspensions; tablets to be dissolved in water befor
— semi-solid oromucosal preparations (including for Gargles may contain excipients to adjust uich, as far
example gingival gel, gingival paste, oromucosal gel, as possible, is neutral.
oromucosal paste);
— oromucosal drops, oromucosal sprays and sublingual
sprays (including oropharyngeal sprays); MOUTHWASHES
— lozenges and pastilles; DEFINITION
— compressed lozenges; Mouthwashes are aqueous solutions intended for use in
— sublingual tablets and buccal tablets; contact with the mucous membrane of the oral cavity. They
— oromucosal capsules; are not to be swallowed. They are supplied as ready-to-use
— mucoadhesive preparations; solutions or concentrated solutions to be diluted. They may
— orodispersible films. also be prepared from powders or tablets to be dissolved in
PRODUCTION water before use.
During the development of an oromucosal preparation Mouthwashes may contain excipients to adjust the pH which,
containing an antimicrobial preservative, the effectiveness of as far as possible, is neutral.
the chosen preservative shall be demonstrated to the
satisfaction of the competent authority. A suitable test
method together with the criteria for judging the preservative
IWf-62 General Monographs 2016
GINGIVAL SOLUTIONS uniformity of content shown below. Herbal drugs and herbal
drug preparations present in the dosage form are not subject
DEFINITION
Gingival solutions are intended for administration to the
gingivae by means of a suitable applicator. Uniformity of mass
Oromucosal drops that are solutions comply with the following test.
Weigh individually the contents of 10 containers emptied as
OROMUCOSAL SOLUTIONS AND completely as possible, and determine the average mass.
OROMUCOSAL SUSPENSIONS Maximum 2 of the individual masses deviate by more than
DEFINITION 10 per cent from the average mass and none deviates by
more than 20 per cent.
Oromucosal solutions and oromucosal suspensions are liquid
preparations intended for administration to the oral cavity by Uniformity of content (2.9.6)
Oromucosal drops that are suspensions or emulsions comply with
fons may show a sediment which is the following test. Empty each container as completely as
readily dispers le 4.shaking to give a suspension which possible and carry out the test on the individual contents.
remains sufficiet le to enable the correct dose to be They comply with test B of uniformity of content.
delivered. METERED-DOSE OROMUCOSAL SPRAYS AND
SUBLINGUAL SPRAYS
SEMI-SOLID OROML OSAL Uniformity of dosage units
PREPARATIONS Metered-dose oromucosal sprays and sublingual sprays
comply with the test for uniformity of dosage units (2.9.40)
DEFINITION or, where justified and authorised, with the test for
uniformity of mass or the test for uniformity of delivered
dose shown below. Herbal drugs and herbal drug
“5
eh
ey
ryt
preparations present in the dosage form are not subject to the

to
oa
.
gel, gingival paste). They may be provided as sinol

.
provisions of this paragraph.

.
.
preparations.
'
In the case of metered-dose oromucosal sprays and sublingual

eae
Semi-solid oromucosal preparations comply with” sprays that are solutions, proceed as follows Discharge once to
requirements of the monograph Sem-solid preparatiotis fo: waste. Wait for a minimum of 5 s, shake for 5 s and
ae
cutaneous use (0132). discharge again to waste. Repeat this procedure for a further
‘
3 actuations. Weigh the container, discharge once to waste

.
sweigh the container again. Calculate the difference

OROMUCOSAL DROPS, OROMUCOSAL
2 masses. Repeat the procedure for a further
SPRAYS AND SUBLINGUAL SPRAYS . Determine the mass variation (2.9.40).
DEFINITION f metered-dose oromucosal sprays and sublingual
Oromucosal drops, oromucosal sprays and sublingual sprays spensions or emulsions proceed as follows Use an
are solutions, emulsions or suspensions intended for local or
systemic effect. They are applied by instillation or spraying
into the oral cavity or onto a specific part of the oral cavity » s and discharge once to waste.
such as spraying under the tongue (sublingual spray) or into Wait for a minimtim @ shake for 5 s and discharge again
the throat (oropharyngeal spray). to waste. Repeat this’ pré e for a further 3 actuations.
Emulsions may show evidence of phase separation but are After 2 s, fire 1 dose of" -d-dose spray into the
readily redispersed on shaking. Suspensions may show a collecting vessel by actuating’ the mising device. Collect
sediment which is readily dispersed on shaking to give a the contents of the collecting’. sel by successive rinses.
suspension which remains sufficiently stable to enable the Determine the content of active sub in the combined
correct dose to be delivered. rinses. Repeat the procedure for a fu 9 containers.
Liquid oromucosal sprays are supplied in containers with Determine the content uniformity (2.9
atomising devices or in pressurised containers having a Uniformity of mass
suitable adaptor, with or without a metering dose valve, Metered-dose oromucosal sprays and sublingual s¢ ffiat are
which comply with the requirements of the monograph solutions comply with the following test.Discharge grice
Pressurised pharmaceutical preparations (0523). waste. Wait for a minimum of 5 s, shake for 5 s and
The size of the droplets of the spray is such as to localise discharge again to waste. Repeat this procedure for a further
their deposition in the oral cavity or the throat as intended. 3 actuations. Weigh the container, discharge once to waste
and weigh the container again. Calculate the difference
TESTS
between the 2 masses. Repeat the procedure for a further
9 containers.
oromucosal drops supplied in single-dose containers, single
doses of metered-dose oromucosal sprays and sublingual The preparation complies with the test if maximum 2 of the
sprays, all intended for systemic action, comply with the individual values deviate by more than 25 per cent from the
following tests. average value and none deviates by more than 35 per cent.
OROMUCOSAL DROPS IN SINGLE-DOSE
Metered-dose oromucosal sprays and sublingual sprays that are
CONTAINERS
suspensions or emulsions comply with the following test. Use an
apparatus capable of quantitatively retaining the dose leaving
Oromucosal drops in single-dose containers comply with the
the actuator of the atomising device.
test for uniformity of dosage units (2.9.40) or, where justified
and authorised, with the test for uniformity of mass or
Shake the container for 5 s and discharge once to waste. granulations into tablets with a shape suited for the intended
Wait for a minimum of 5 s, shake for 5 s and discharge again use.
to waste. Repeat this procedure for a further 3 actuations. Sublingual tablets and buccal tablets conform to the general
After 2 s, fire 1 dose of the metered-dose spray into the definition of tablets.
collecting vessel by actuating the atomising device. Collect
the contents of the collecting vessel by successive rinses. PRODUCTION
Determine the content of active substance in the combined In the manufacture of sublingual tablets and buccal tablets,
rinses. Repeat the procedure for a further 9 containers. measures are taken to ensure that they possess suitable
mechanical strength to resist handling without crumbling or
Unless otherwise justified and authorised, the preparation
breaking. This may be demonstrated by examining the
complies with the test if maximum 1 of the individual
Friability of uncoated tablets (2.9.7) and the Resistance to
contents is outside the limits of 75 per cent to 125 per cent
crushing of tablets (2.9.8).
is outside the limits of 65 per cent to 135 per cent
TESTS
*3 individual contents are outside the limits Dissolution
<4 25 per cent but within the limits of Unless otherwise justified and authorised, a suitable test is
active substance(s).
OROMUCOSAL CAPSULES
the average content. DEFINITION
Oromucosal capsules are soft capsules to be chewed or
sucked.
LOZENGES AND PAST
DEFINITION MUCOADHESIVE PREPARATIONS
Lozenges and pastilles are solid, single-désé:
intended to be sucked to obtain, usually, a DEFINITION
oral cavity and the throat. They contain one ¢ 3 Mucoadhesive preparations contain one or more active
substances, usually in a flavoured and sweetenedsbase,; substances intended for systemic absorption through the
are intended to dissolve or disintegrate slowly in the’ buccal mucosa over a prolonged period of time. They may be
when sucked. supplied as mucoadhesive buccal tablets, as buccal films or as
ther mucoadhesive solid or semi-solid preparations. They
Lozenges are hard preparations prepared by moulding. *.,
contain hydrophilic polymers, which on wetting with
Pastilles are soft, flexible preparations prepared by moulding
a produce a hydrogel that adheres to the buccal
of mixtures containing natural or synthetic polymers or gums
and sweeteners.
hesive buccal tablets are prepared by compression
aysbe single- or multilayer tablets.
COMPRESSED LOZENGES
DEFINITION
Compressed lozenges are solid, single-dose preparations
intended to be sucked to obtain a local or systemic effect.
oadhesive buccal tablets and of
They are prepared by compression and are often rhomboid
sn to ensure that they possess
in shape.
Compressed lozenges conform with the general definition of
tablets.
PRODUCTION tablets (2.9.7) and the Resistancej
In the manufacture of compressed lozenges, measures are TESTS
taken to ensure that they possess suitable mechanical strength Dissolution
to resist handling without crumbling or breaking. This may Unless otherwise justified and authorised,
be demonstrated by examining the Friability of uncoated tablets carried out to demonstrate the appropriate réle
(2.9.7) and the Resistance to crushing of tablets (2.9.8). active substance(s).
TESTS
Dissolution ORODISPERSIBLE FILMS
For compressed lozenges intended for a systemic effect, a
suitable test is carried out to demonstrate the appropriate DEFINITION
release of the active substance(s). Orodispersible films are single- or multilayer sheets of
suitable materials, to be placed in the mouth where they
disperse rapidly.
SUBLINGUAL TABLETS AND BUCCAL
PRODUCTION
TABLETS
In the manufacture of orodispersible films, measures are
DEFINITION taken to ensure that they possess suitable mechanical strength
Sublingual tablets and buccal tablets are solid, single-dose to resist handling without being damaged.
preparations to be applied under the tongue or to the buccal
cavity, respectively, to obtain a systemic effect. They are
prepared by compression of mixtures of powders or
TESTS PRODUCTION
Dissolution During the development of a parenteral preparation, the
Unless otherwise justified and authorised, a suitable test is formulation for which contains an antimicrobial preservative,
carried out to demonstrate the appropriate release of the the effectiveness of the chosen preservative shall be
active substance(s). demonstrated to the satisfaction of the competent authority.
wt tt
Ph Eur
A suitable test method together with criteria for judging the
preservative properties of the formulation are provided under
Efficacy of antimicrobial preservation (5.1.3).
Parenteral preparations are prepared using materials and
Kk
% methods designed to ensure sterility and to avoid the
Parenteral Preparations x
4 >t
introduction of contaminants and the growth of micro-
Kak organisms. Recommendations on this aspect are provided in
the text Methods ofpreparation of sterile products (5.1.1).
Water used in the manufacture of parenteral preparations
complies with the requirements of water for injections in bulk
stated in the monograph Water for injections (0169).
TESTS
Particulate contamination: sub-visible particles (2.9. 19)
intended. For preparations for human use, solutions for infusion or
solutions for injection comply with the test.
DEFINITION
In the case of preparations for subcutaneous or intramuscular
Parenteral preparations are steri * intended for
injection, higher limits may be appropriate.
administration by injection, infusi tation into the
Radiopharmaceutical preparations are exempt from these
human or animal body.
requirements. Preparations for which the label states that the
ients, for product is to be used with a final filter are exempt from these
example to make the preparation isotonicwit requirements, providing it has been demonstrated that the
blood, to adjust the pH, to increase solubility, filter delivers a solution that complies with the test.
deterioration of the active substances or to provide adgqua
For preparations for veterinary use, when supplied in
antimicrobial properties, but not to adversely affect the
containers with a nominal content of more than 100 mL and
intended medicinal action of the preparation or, at the
hen the content is equivalent to a dose of more than
concentrations used, to cause toxicity or undue local
er Kilogram of bodymass, solutions for infusion or
irritation.
Containers for parenteral preparations are made as far as
possible from materials that are sufficiently transparent to
permit the visual inspection of the contents, except for
implants and in other justified and authorised cases.
Where applicable, the containers for parenteral preparations
comply with the requirements for Materials used for the In a sterile, ariper-proof container.
manufacture of containers (3.1 and subsections) and Containers LABELLING
(3.2 and subsections). The label states:
Parenteral preparations intended for chronic use or total — the name and concefitrati any added antimicrobial
parenteral nutrition should have appropriate limits for preservative;
specific components or elements, taking long-term toxicity — where applicable, that the solugion is to be used in
into account. conjunction with a final filter;
Parenteral preparations are supplied in glass containers — where applicable, that the prepa
(3.2.1) or in other containers such as plastic containers bacterial endotoxins or that it is
(3.2.2, 3.2.2.1 and 3.2.9) and prefilled syringes. The tightness
of the container is ensured by suitable means. Closures INJECTIONS
ensure a good seal, prevent the access of micro-organisms
DEFINITION
and other contaminants and usually permit the withdrawal of
Injections are sterile solutions, emulsions or suspensions.
a part or the whole of the contents without removal of the
They are prepared by dissolving, emulsifying or suspending
closure. The plastic materials or elastomers (3.2.9) used to
the active substance(s) and any added excipients in water, in
manufacture the closures are sufficiently firm and elastic to
a suitable non-aqueous liquid, that may be non-sterile where
allow the passage of a needle with the least possible shedding
of particles. Closures for multidose containers are sufficiently justified, or in a mixture of these vehicles.
elastic to ensure that the puncture is resealed when the Solutions for injection, examined under suitable conditions of
needle is withdrawn. visibility, are clear and practically free from particles.
Several categories of parenteral preparations may be Emulsions for injection do not show any evidence of phase
distinguished: separation. Suspensions for injection may show a sediment
— injections; which is readily dispersed on shaking to give a suspension
— infusions; which remains sufficiently stable to enable the correct dose to
— concentrates for injections or infusions; be withdrawn.
— powders for injections or infusions; Multidose preparations Multidose aqueous injections contain a
— gels for injections; suitable antimicrobial preservative at an appropriate
— implants. concentration except when the preparation itself has adequate
antimicrobial properties. When a preparation for parenteral INFUSIONS

administration is presented in a multidose container, the
DEFINITION
precautions to be taken for its administration and more
particularly for its storage between successive withdrawals are Infusions are sterile, aqueous solutions or emulsions with
given. water as the continuous phase. They are usually made
isotonic with respect to blood. They are principally intended
Antumuicrobial preservatives Aqueous preparations which are
for administration in large volume. Infusions do not contain
prepared using aseptic precautions and which cannot be
any added antimicrobial preservative.
terminally sterilised may contain a suitable antimicrobial
preservative in an appropriate concentration. Solutions for infusion, examined under suitable conditions of
visibility, are clear and practically free from particles.
No antimicrobial preservative is added when:
— the volume to be injected in a single dose exceeds 15 mL, Emulsions for infusion do not show any evidence of phase
erwise justified; separation.
ation is intended for administration by routes PRODUCTION
dical reasons, an antimicrobial preservative In the manufacture of infusions containing dispersed
particles, measures are taken to ensure a suitable and
ny route giving access to the controlled particle size with regard to the intended use.
intra- or retro-ocularly. The volume of the infusion in the container is sufficient to
permit the withdrawal and administration of the
PRODUCTION nominal dose using a normal technique (2.9.17).
In the manufacture of injée TESTS
particles, measures are taken” Bacterial endotoxins - pyrogens
controlled particle s: ize with£ They comply with a test for bacterial endotoxins (2.6.14) or,
where justified and authorised, with the test for pyrogens
single-dose container is sufficient to pefrni (2.6.8). For the latter test inject 10 mL per kilogram of body
and administration of the nominal dose t mass into each rabbit, unless otherwise justified and
technique (2.9.17). authorised.
TESTS
Uniformity of dosage units CONCENTRATES FOR INJECTIONS OR
Single-dose suspensions for injection comply with the : INFUSIONS
uniformity of dosage units (2.9.40) or, where justified an
ZFINITION
authorised, with the test for uniformity of content shown =
trates for injections or infusions are sterile solutions
d for injection or infusion after dilution. They are
‘© a prescribed volume with a prescribed liquid before
paragraph.
ation. After dilution, they comply with the
single-dose suspensions for injection with a content of active
substance less than 2 mg or less than 2 per cent of the total iS - pyrogens
mass comply with test A for uniformity of content of single- quirements prescribed for injections
dose preparations. If the preparation contains more than one
active substance, the requirement applies only to those
substances that correspond to the above conditions. POWDERS FOR [|
Bacterial endotoxins - pyrogens INFUSIONS
A test for bacterial endotoxins (2.6.14) is carried out or,
DEFINITION
where justified and authorised, the test for pyrogens (2.6.8).
Recommendations on the limits for bacterial endotoxins are
given in general chapter 5.1.10.
Preparations for human use The preparation complies with a
test for bacterial endotoxins (2.6.14) or with the test for
pyrogens (2.6.8). suspension, they comply with the requirements for injections
Preparations for veterinary use When the volume to be injected or for infusions.
in a single dose is 15 mL or more and is equivalent to a dose Freeze-dried products for parenteral administration are
of 0.2 mL or more per kilogram of body mass, the considered as powders for injections or infusions.
preparation complies with a test for bacterial endotoxins
(2.6.14) or with the test for pyrogens (2.6.8). PRODUCTION
The uniformity of content and uniformity of mass of freeze-
Any preparation Where the label states that the preparation is
dried products for parenteral administration are ensured by
free from bacterial endotoxins or apyrogenic, respectively, the
the in-process control of the amount of the solution prior to
preparation complies with a test for bacterial endotoxins
freeze-drying.
(2.6.14) or with the test for pyrogens (2.6.8), respectively.
TESTS
Powders for injections or infusions comply with the test for
uniformity of dosage units (2.9.40) or, where justified and
authorised, with the tests for uniformity of content and/or
uniformity of mass shown below. Herbal drugs and herbal other suitable substances. However if buffering agents are
drug preparations present in the dosage form are not subject used in preparations intended for intraocular or intracardiac
to the provisions of this paragraph. injection, or in preparations that may gain access to the
Uniformity of content (2.9.6) cerebrospinal fluid, great care should be taken to ensure that
Unless otherwise prescribed or justified and authorised, the nature and concentration of the chosen agent are suitable
powders for injections or infusions with a content of active for the intended route of administration.
substance less than 2 mg or less than 2 per cent of the total Where the active ingredient is susceptible to oxidative
mass, or with a unit mass equal to or less than 40 mg comply degradation appropriate precautions, such as the addition of
with test A for uniformity of content of single-dose a suitable antioxidant or storage under oxygen-free nitrogen
preparations. If the preparation contains more than one or other suitable inert gas, should be taken.
active substance, the requirement applies only to those PRODUCTION
substances that.correspond to the above conditions.
Methods of sterilisation that may be used in the manufacture
Uniformity ¢ $8°(2.9.5) of Parenteral Preparations are described in Appendix XVIII.
Powders for'injgé r infusions comply with the test for Where a direction is given to use Water for Injections in the
uniformity of magé’ of le-dose preparations. If the test for manufacture of a Parenteral Preparation, Water for Injections
uniformity of conten: cribed for all the active in bulk is used. Where the use of Water for Injections free
mity of mass is not required. from dissolved air or Water for Injections free from dissolved
carbon dioxide is specified, water freshly prepared by the
They comply with the req rescribed for injections process described under Water for Injections is boiled for at
or for infusions, after dissolu pension in a suitable least 10 minutes with as little exposure to air as possible,
volume of liquid. cooled with precautions to exclude air and carbon dioxide,
and sterilised by heating in an autoclave.
LABELLING
STORAGE
injections and infusions. Closures used for containers of oily parenteral preparations
should be made of oil-resistant materials.
GELS FOR INJECTIONS
DEFINITION
INJECTIONS
Gels for injections are sterile gels with a viscosity suitable LABELLING
guarantee a modified release of the active substance(s) at e label states that the injection should not be used if
site of injection. isibleparticles are present.
IMPLANTS
DEFINITION
Implants are sterile, solid preparations of a size and shape
suitable for parenteral implantation and release of the active
substance(s) over an extended period of time. Each dose is
provided in a sterile container.
TESTS INJECTIONS
A suitable test is carried out to demonstrate the appropriate LABELLING
release of the active substance(s). The label states that the solution st be diluted before use.
Ph Eur Do not use if visible particles are pre
K*
ORAL POWDERS
4+
Parenteral Preparations of the British

Pharmacopoeia
Pharmacopoeia, the following statements apply to any injections,
infusions, powders for injections or concentrated solutions for Ph Eur
injections that are the subject of an individual monograph in the Requirements ofpowders to be used for the preparation of oral
British Pharmacopoeia. solutions or suspensions are given in the monograph for Liquid
preparations for oral use (0672). Where justified and authorised,
DEFINITION
the requirements of this monograph do not apply to oral powders
Definition of a particular Parenteral Preparation as a
intended for veterinary use.
solution, emulsion or suspension in Water for Injections does
not preclude the inclusion of suitable excipients where DEFINITION
necessary for the purposes referred to in the requirements of Oral powders are preparations consisting of solid, loose, dry
the European Pharmacopoeia above. In particular, aqueous particles of varying degrees of fineness. They contain one or
Parenteral Preparations for administration by the more active substances, with or without excipients and, if
subcutaneous, intradermal, intramuscular, or, in the case of necessary, colouring matter authorised by the competent
larger volumes, intravenous route, should if possible be made authority and flavouring substances. They are generally
isotonic with blood by the addition of Sodium Chloride or administered in or with water or another suitable liquid.
They may also be swallowed directly. They are presented as KX

%
Topical Powders
t%
single-dose or multidose preparations.
+ 4%
Kym
Te
Where applicable, containers for oral powders comply with (Powders for Cutaneous Application, Ph. Eur.
the requirements of Materials used for the manufacture of monograph 1166)
yA
containers (3.1 and subsections) and Containers (3.2 and Topical Powders comply with the requirements of the European
subsections). Pharmacopoeia monograph for Powders for Cutaneous
Multidose oral powders require the provision of a measuring Application. These requirements are reproduced below.
device capable of delivering the quantity prescribed. Ph Eur
Each dose of a single-dose powder is enclosed in an
Where justified and authorised, the requirements of this
individual container, for example a sachet or a vial.
monograph do not apply to powders for cutaneous
PRODUCTION application intended for veterinary use.
reaafacture of oral powders, measures are taken to DEFINITION
particle size with regard to the intended use.
Powders for cutaneous application are preparations consisting
e, packaging, storage and distribution of of solid, loose, dry particles of varying degrees of fineness.
measures are taken to ensure their They contain one or more active substances, with or without
microbial quali immendations on this aspect are excipients and, if necessary, colouring matter authorised by
provided in the t wal. 4. Microbiological quality of non- the competent authority.
sterile pharmaceutical arazions and substances for Powders for cutaneous application are presented as single-
pharmaceutical use.
dose powders or multidose powders. They are free from
TESTS grittiness. Powders specifically intended for use on large open
Uniformity of dosage units wounds or on severely injured skin are sterile.
Single-dose oral powders corfiply:with 4 test for uniformity Multidose powders for cutaneous application may be
of dosage units (2.9.40) or, where justific dispensed in sifter-top containers, containers equipped with a
with the tests for uniformity of content mechanical spraying device or in pressurised containers.
mass shown below. Herbal drugs and he Powders dispensed in pressurised containers comply with the
preparations present in the dosage form ar requirements of Pressurised pharmaceutical preparations (0523).
provisions of this paragraph.
Where applicable, containers for powders comply with the
Uniformity of content (2.9.6) requirements of Materials used for the manufacture of containers
Unless otherwise prescribed or justified and authorised (3.1 and subsections) and Containers (3.2 and subsections).
single-dose oral powders with a content of active substan:
less than 2 mg or less than 2 per cent of the total mass
comply with test B for uniformity of content of single-dose anufacture of powders for cutaneous application,
preparations. If the preparation has more than one active are taken to ensure a suitable particle size with
substance, the requirement applies only to those substances »the intended use.
which correspond to the above conditions. sfacture, packaging, storage and distribution of
Single-dose oral powders comply with the test for uniformity
of mass of single-dose preparations. If the test for uniformity this aspect ar
of content is prescribed for all the active substances, the test quality of non-ste
for uniformity of mass is not required. for pharmaceutical*
Sterile powders for
Uniformity of mass of delivered doses from multidose
containers (2.9.27)
Oral powders supplied in multidose containers comply with
avoid the introduction of yataminants
cor and the growth of
micro-organisms; recommendation ;Of. this aspect are
the test.
provided in the text Methods of pre;
STORAGE (5.1.1).
If the preparation contains volatile ingredients, or the
TESTS
contents have to be protected, store in an airtight container.
Fineness
EFFERVESCENT POWDERS
Effervescent powders are presented as single-dose or Uniformity of dosage units
multidose preparations and generally contain acid substances Single-dose powders for cutaneous application comply with
and carbonates or hydrogen carbonates which react rapidly in the test for uniformity of dosage units (2.9.40) or, where
the presence of water to release carbon dioxide. They are justified and authorised, with the tests for uniformity of
intended to be dissolved or dispersed in water before content and/or uniformity of mass shown below. Herbal
administration. drugs and herbal drug preparations present in the dosage
form are not subject to the provisions of this paragraph.
STORAGE
In an airtight container. Uniformity of content (2.9.6)
Ph Eur
single-dose powders for cutaneous application with a content
of active substance less than 2 mg or less than 2 per cent of
the total mass comply with test B for uniformity of content of
single-dose preparations. If the preparation has more than
Ill-68 General Monographs 2016
one active substance, the requirement applies only to those inhalation. Suitable excipients may also be used, for example
substances that correspond to the above conditions. solvents, solubilisers, emulsifying agents, suspending agents
Uniformity of mass (2.9.5) and lubricants for the valve to prevent clogging.
Single-dose powders for cutaneous application comply with Propellants Vhe propellants are either gases liquefied under
the test for uniformity of mass of single-dose preparations. pressure or compressed gases or low-boiling liquids.
If the test for uniformity of content is prescribed for all the Liquefied gases are, for example, fluorinated hydrocarbons
active substances, the test for uniformity of mass is not and low-molecular-mass hydrocarbons (such as propane and
required. butane). Compressed gases are, for example, carbon dioxide,
nitrogen and nitrous oxide.
Sterility (2.6.1)
Where the label indicates that the preparation is sterile, it Mixtures of these propellants may be used to obtain optimal
complies with the test for sterility. solution properties and desirable pressure, delivery and spray
characteristics.
Containers The containers are tight and resistant to the
internal pressure and may be made of metal, glass, plastic or
combinations of these materials. They are compatible with
their contents. Glass containers are protected with a plastic
Ph Eur
coating.
Spraying device The valve keeps the container tightly closed
when not in use and regulates the delivery of the contents
Topical Powders of during use. The spray characteristics are influenced by the
type of spraying device, in particular by the dimensions,
Pharmacopoeia number and location of orifices. Some valves provide a
In addition to the above requirements oj ean continuous release, others (‘“‘metering dose valves’’) deliver a
Pharmacopoeia, the following statements a ply £8 those dusting defined quantity of product upon each valve actuation.
powders that are the subject of an individualmost The various valve materials in contact with the contents are
British Pharmacopoeia. | compatible with them.
Requirements for pressurised pharmaceutical
DUSTING POWDERS preparations
DEFINITION Pressurised preparations are provided with a delivery device
Dusting Powders are finely divided powders that are ppropriate torthe intended application.
intended to be applied to the skin for therapeutic,
prophylactic or lubricant purposes.
STORAGE
Dusting Powders should be stored in a dry place.
PRESSURISED PHARMACEUTICAL>
PREPARATIONS See
Ph Eur
Pressurised Pharmaceutical Preparations comply with the
requirements of the European Pharmacopoeia. These requirements
are reproduced below.
Rectal Preparations =
' *
+4
+4>
Ph Eur
Additional requirements for preparations presented in pressurized (Ph. Eur. monograph 1145)
Kw yk
containers may be found, where appropriate, in other general

Rectal Preparations comply with the requireme European
monographs, for example preparations for inhalation (0671),
Pharmacopoeia. These requirements are reproduced b
liquid preparations for cutaneous application (0927), powders for
cutaneous application (1166), nasal preparations (0676) and ear Ph Eur
preparations (0652). DEFINITION

DEFINITION Rectal preparations are intended for rectal use in order to
Pressurised pharmaceutical preparations are presented in obtain a systemic or local effect, or they may be intended for
special containers under pressure of a gas and contain one or diagnostic purposes.
Y)
re
ey
more active substances. The preparations are released from Where applicable, containers for rectal preparations comply
the container, upon actuation of an appropriate valve, in the with the requirements for materials used for the manufacture
Ee
form of an aerosol (dispersion of solid or liquid particles in a of containers (3.1 and subsections) and containers (3.2 and
ee
gas, the size of the particles being adapted to the intended subsections).
use) or of a liquid or semisolid jet such as a foam. Several categories of rectal preparations may be
The pressure for the release is generated by suitable
,
distinguished:
,
propellants. — suppositories;
The preparations consist of a solution, an emulsion or a — rectal capsules;
eeYSyh? os
hs ‘ L
suspension and are intended for local application to the skin — rectal solutions, emulsions and suspensions;
— powders and tablets for rectal solutions and suspensions;
eR
or to mucous membranes of various body orifices, or for

th
eg
a
2016 General Monographs ITII-69
— semi-solid rectal preparations; They contain 1 or more active substances dispersed or

— rectal foams; dissolved in a suitable basis that may be soluble or dispersible
— rectal tampons. in water or may melt at body temperature. Excipients such as
PRODUCTION diluents, adsorbents, surface-active agents, lubricants,
antimicrobial preservatives and colouring matter, authorised
During the development of a rectal preparation whose
by the competent authority, may be added if necessary.
formulation contains an antimicrobial preservative, the need
for and the efficacy of the chosen preservative shall be PRODUCTION
demonstrated to the satisfaction of the competent authority. Suppositories are prepared by compression or moulding.
A suitable test method together with criteria for judging the If necessary, the active substance(s) are previously ground
preservative properties of the formulation are provided in and sieved through a suitable sieve. When prepared by
chapter 5.1.3. Efficacy of antimicrobial preservation. moulding, the medicated mass, sufficiently liquefied by
lopment, it must be demonstrated that the heating, 1s poured into suitable moulds. The suppository
can be withdrawn from the container of solidifies on cooling. Various excipients are available for this
process, such as hard fat, macrogols, cocoa butter, and
various gelatinous mixtures consisting of, for example,
gelatin, water and glycerol. The determination of the
softening time of lipophilic suppositories (2.9.22) is carried
out.

release of the active substance(s) from suppositories intended
for modified release or for prolonged local action.
preparations containing dispe eS, Measures are In the manufacture of suppositories containing dispersed
taken to ensure a suitable and co article size with active substances, measures are taken to ensure a suitable
regard to the intended use. and controlled particle size.
TESTS TESTS
Uniformity of dosage units (2. 9. 40) Disintegration (2. 9. 2)
Liquid and semi-solid single-dose rectal preparati Unless intended for modified release or for prolonged local
with the test. Solid single-dose rectal preparations co action, they comply with the test. For suppositories with a
with the test or, where justified and authorised, wi fatty base, examine after 30 min, and for suppositories with a
for uniformity of content and/or uniformity of mass sh water-soluble base, examine after 60 min, unless otherwise
below. Herbal drugs and herbal drug preparations prese ified and authorised.
paragraph. ‘AL CAPSULES
Unless otherwise prescribed or justified and authorised, solid
single-dose rectal preparations with a content of active
mass comply with test A (tablets) or test B (suppositories,
rectal capsules). If the preparation contains more than one
active substance, this requirement applies only to those
substances that correspond to the above conditions.
Uniformity of mass (2.9.5) A suitable test is carried : emonstrate the appropriate
Solid single-dose rectal preparations comply with the test. release of the active subst ets) from rectal capsules
If the test for uniformity of content is prescribed for all active r fer*prolonged local action.
substances, the test for uniformity of mass is not required. TESTS
Dissolution Disintegration (2. 9. 2)
A suitable test may be required to demonstrate the
appropriate release of the active substance(s) from solid
single-dose rectal preparations, for example 2.9.42. Dissolution capsules after 30 min, unless otherwise justifie
test for lipophilic sold dosage forms. authorised.
Where a dissolution test is prescribed, a disintegration test
may not be required. RECTAL SOLUTIONS, EMULSIONS
LABELLING AND SUSPENSIONS
The label states the name of any added antimicrobial DEFINITION
preservative. Rectal solutions, emulsions and suspensions are liquid
preparations intended for rectal use in order to obtain a
SUPPOSITORIES systemic or local effect, or they may be intended for
diagnostic purposes.
DEFINITION
Rectal solutions, emulsions and suspensions are supplied in
Suppositories are solid, single-dose preparations.
single-dose containers and contain 1 or more active
The shape, volume and consistency of suppositories are
substances dissolved or dispersed in water, glycerol or
suitable for rectal administration.
macrogols or other suitable solvents. Emulsions may show
evidence of phase separation but are readily redispersed on
IWI-70 General Monographs 2016
shaking. Suspensions may show a sediment that is readily

TOPICAL SEMI-SOLID sn
%4+
dispersible on shaking to give a suspension that remains
PREPARATIONS Na
»
sufficiently stable to enable the correct dose to be delivered.
Rectal solutions, emulsions and suspensions may contain (Semi-solid Preparations for Cutaneous Application,
excipients, for example to adjust the viscosity of the Ph Eur monograph 0132)
preparation, to adjust or stabilise the pH, to increase the Topical Semi-solid Preparations comply with the requirements of
solubility of the active substance(s) or to stabilise the the European Pharmacopoeia monograph for Semi-solid
preparation. These substances do not adversely affect the Preparations for Cutaneous Application. These requirements are
intended medical action or, at the concentrations used, cause reproduced below.
undue local irritation.
Ph Eur
Rectal solutions, emulsions and suspensions are suppliedin
The requirements of this monograph apply to all semi-solid
ining a volumein the range of 2.5 mL to
preparations for cutaneous application. Where appropriate,
sontainer is adapted to deliver the preparation
additional requirements spectfic to semi-solid preparations intended
companied by a suitable applicator.
to be applied to parnicular surfaces or mucous membranes may be
found in other general monographs, for example Ear
POWDERS { LETS FOR RECTAL preparations (0652), Nasal preparations (0676), Rectal
SOLUTIONS SPENSIONS preparations (1145), Eye preparations (1163) and Vaginal
preparations (1164).
DEFINITION
DEFINITION
Semi-solid preparations for cutaneous application are
dissolved or dispersed in water 0 intended for local or transdermal delivery of active
the time of administration. They: substances, or for their emollient or protective action. They
facilitate dissolution or dispersion or to , are of homogeneous appearance.
of the particles. Semi-solid preparations for cutaneous application consist of a
After dissolution or suspension, they comply : simple or compound basis in which, usually, 1 or more active
requirements for rectal solutions or rectal suspensi substances are dissolved or dispersed. According to its
appropriate. composition, the basis may influence the activity of the
preparation.
TESTS
he basis may consist of natural or synthetic substances and
Disintegration (2.9. /)
ay be single phase or multiphase. According to the nature
Tablets for rectal solutions or suspensions disintegrate withi
Jagis, the preparation may have hydrophilic or
3 min, using water R at 15-25 °C as the liquid medium.
LABELLING
The label states: thickeners and penetration enhancers.
— the method of preparation of the rectal solution or uirations for cutaneous application intended
suspension;
— the conditions and duration of storage of the solution or
ers for semi-solid preparations for
suspension after constitution.
cutaneous appl mply with the requirements of
Materials used for the geeture
menufacty of containers (3.1 and
SEMI-SOLID RECTAL PREPARATIONS subsections) and Contai#ers (3,2 and subsections).
DEFINITION Several categories of semi86i rations for cutaneous
Semi-solid rectal preparations are ointments, creams or gels. application may be distinguis.
— ointments;
They are often supplied as single-dose preparations in
— creams;
containers provided with a suitable applicator.
— gels;
Semi-solid rectal preparations comply with the requirements — pastes;
of the monograph Semi-sohd preparations for cutaneous — poultices;
application (0132). — medicated plasters;
— cutaneous patches.
RECTAL FOAMS
generally show viscoelastic behaviour and are non-Newtonian
DEFINITION
in character, e.g. plastic, pseudoplastic or thixotropic type
Rectal foams comply with the requirements of the
flow at high shear rates. Pastes frequently exhibit dilatancy.
monograph Medicated foams (1105).
PRODUCTION
DEFINITION
During development of semi-solid preparations for cutaneous
Rectal tampons are solid, single-dose preparations intended
application whose formulation contains an antimicrobial
to be inserted into the lower part of the rectum for a limited
preservative, the need for and the efficacy of the chosen
time.
preservative shall be demonstrated to the satisfaction of the
They comply with the requirements of the monograph competent authority. A suitable test method together with
Medicated tampons (1155). criteria for judging the preservative properties of the
Ph Eur formulation are provided in Efficacy of antimicrobial
preservation (5.1.3). In the manufacture, packaging, storage
and distribution of semi-solid preparations for cutaneous
application, suitable measures are taken to ensure their the procedure for a further 9 containers. Determine the
microbiological quality; recommendations on this are content uniformity (2.9.40).
provided in 5.1.4. Microbiological qualty of non-sterile
we Nee
Nw! Sterility (2. 6. 1)

pharmaceutical preparations and substances for pharmaceutical Where the label indicates that the preparation is sterile, it
use. Sterile semi-solid preparations for cutaneous application complies with the test for sterility.
are prepared using materials and methods designed to ensure
sterility and to avoid the introduction of contaminants and STORAGE
the growth of micro-organisms; recommendations on this are If the preparation contains water or other volatile ingredients,
provided in Methods of preparation of sterile products (5.1.1). store in an airtight container. If the preparation is sterile,
store in a sterile, airtight, tamper-proof container.
During development, it must be demonstrated that the
nominal content can be withdrawn from the container of LABELLING
reparations for cutaneous application presented The label states:
— the name of any excipient;
— where applicable, that the preparation is sterile.
OINTMENTS
DEFINITION
An ointment consists of a single-phase basis in which solids
or liquids may be dispersed.
substance(s). Hydrophobic ointments
In the manufacture of sem1- Hydrophobic ointments can absorb only small amounts of
application containing 1 or water. Typical bases used for their formulation are hard,
liquid and light liquid paraffins, vegetable oils, animal fats,
measures are taken to ensure appropria synthetic glycerides, waxes and liquid polyalkylsiloxanes.
preparation to be delivered. Water-emulsifying ointments
Water-emulsifying ointments can absorb larger amounts of
water and thereby produce water-in-oil or oil-in-water
to ensure a suitable and controlled particle size with emulsions after homogenisation, depending on the nature of
the intended use. the emulsifiers: water-in-oil emulsifying agents such as wool
TESTS ieohols, sorbitan esters, monoglycerides and fatty alcohols,
Uniformity of dosage units -water emulsifying agents such as sulfated fatty
Semi-solid preparations that are supplied either in single-dos » polysorbates, macrogol cetostearyl ether or esters of
containers that represent 1 dose of medicinal product or in ickds with macrogols may be used for this purpose.
metered-dose containers, and that are intended for
transdermal delivery of the active substance(s) in view of a
systemic effect, comply with the test for uniformity of
dosage units (2.9.40). Semi-solid preparations in which the
active substance(s) are dissolved comply with the test for
mass variation; semi-solid preparations in which the active
substance(s) are suspended comply with the test for content
uniformity. Follow the procedure described for liquid dosage
forms. Herbal drugs and herbal drug preparations present in CREAMS
the dosage form are not subject to the provisions of this DEFINITION
paragraph.
For semi-solid preparations presented in metered-dose phase and an aqueous phase.
containers and in which the active substance(s) are dissolved, Lipophilic creams
proceed as follows. Discharge once to waste. Wait for a Lipophilic creams have as the continuou pha he lipophilic
minimum of 5 s, shake for 5 s if necessary, and discharge phase. They usually contain water-in-oil emailsifyiig agents
again to waste. Repeat this procedure for a further 3 such as wool alcohols, sorbitan esters and monsglycerides.
actuations. Weigh the container, discharge once to waste and
Hydrophilic creams
weigh the container again. Calculate the difference between
the 2 masses. Repeat the procedure for a further 9 Hydrophilic creams have as the continuous phase the
containers. Determine the mass variation (2.9.40). aqueous phase. They contain oil-in-water emulsifying agents
such as sodium or trolamine soaps, sulfated fatty alcohols,
For semi-solid preparations supplied in metered-dose
polysorbates and polyoxyl fatty acid and fatty alcohol esters
containers and in which the active substance(s) are
combined, if necessary, with water-in-oil emulsifying agents.
suspended, proceed as follows. Use an apparatus capable of
quantitatively retaining the dose leaving the metered-dose
container. Shake 1 container for 5 s and discharge once to GELS
waste. Wait for a minimum of 5 s, shake for 5 s and
DEFINITION
discharge again to waste. Repeat this procedure for a further
Gels consist of liquids gelled by means of suitable gelling
3 actuations. After 2 s, fire 1 dose from the metered-dose
agents.
container into the collecting vessel. Collect the contents of
the collecting vessel by successive rinses. Determine the Lipophilic gels
content of active substance in the combined rinses. Repeat
II-72 General Monographs 2016
Lipophilic gels (oleogels) are preparations whose bases or synthetic material. The adhesive basis is not irritant or
usually consist of liquid paraffin with polyethylene or fatty sensitising to the skin. The adhesive layer is covered by a
oils gelled with colloidal silica or aluminium or zinc soaps. suitable protective liner, which is removed before applying
Hydrophilic gels the patch to the skin. When removed, the protective liner
Hydrophilic gels (hydrogels) are preparations whose bases does not detach the preparation from the outer, supporting
layer.
usually consist of water, glycerol or propylene glycol gelled
with suitable gelling agents such as poloxamers, starch, Cutaneous patches are presented in a range of sizes adapted
cellulose derivatives, carbomers and magnesium-aluminium to their intended use. They adhere firmly to the skin when
silicates. gentle pressure is applied and can be peeled off without
causing appreciable injury to the skin or detachment of the
preparation from the outer, supporting layer.
PASTES
TESTS
Dissolution
reparations for cutaneous application
A suitable test may be required to demonstrate the
containing largé pr ons of solids finely dispersed in the
appropriate release of the active substance(s), for example
basis.
one of the tests described in Dissolution test for transdermal
patches (2.9.4).
POULTICES Ph Eur
DEFINITION
Poultices consist of a hydrop retentive basis in
which solid or liquid active subs
are usually spread thickly on a sui g and heated
before application to the skin. Topical Semi-solid Preparations of the
British Pharmacopoeia
MEDICATED PLASTERS In addition to the above requirements of the European
Pharmacopoeia, the following statements apply to any cream, gel,
DEFINITION :
ointment or paste that 1s the subject of an individual monograph
Medicated plasters are flexible preparations containing
in the British Pharmacopoeia. Eye ointments are described in the
more active substances. They are intended to be appliedsto
onograph for Eye Preparations.
the skin. They are designed to maintain the active
substance(s) in close contact with the skin such that these
may be absorbed slowly, or act as protective or keratolytic
agents.
Medicated plasters consist of an adhesive basis, which may ormulated to provide preparations that are
be coloured, containing 1 or more active substances, spread ciple with the skin secretion. They are intended
as a uniform layer on an appropriate support made of natural
or synthetic material. They are not irritant or sensitising to
the skin. The adhesive layer is covered by a suitable
protective liner, which is removed before applying the plaster
to the skin. When removed, the protective liner does not
dilution be necessary ¢a “should be taken, in particular, to
detach the preparation from the outer, supporting layer.
prevent microbial contariin, he appropriate diluent
Medicated plasters are presented in a range of sizes directly should be used and heating s avoided during mixing.
adapted to their intended use or as larger sheets to be cut Excessive dilution may affect th ability of some creams.
before use. Medicated plasters adhere firmly to the skin when If diluted, creams should normallysbe ¥ within two weeks
gentle pressure is applied and can be peeled off without of their preparation.
causing appreciable injury to the skin or detachment of the
preparation from the outer, supporting layer. STORAGE
Creams should not be allowed to freeze.
TESTS
Dissolution
A suitable test may be required to demonstrate the GELS
appropriate release of the active substance(s), for example STORAGE
one of the tests described in Dissolution test for transdermal Gels should not be allowed to freeze.
patches (2.9.4).
OINTMENTS
CUTANEOUS PATCHES
DEFINITION
DEFINITION
Ointments are formulated to provide preparations that are
Cutaneous patches are flexible preparations containing 1 or immiscible, miscible or emulsifiable with the skin secretion.
more active substances. They are intended to be applied to
Hydrophobic ointments and water-emulsifying ointments are
the skin. They are designed to maintain the active
intended to be applied to the skin or certain mucous
substance(s) in close contact with the skin such that these
membranes for emollient, protective, therapeutic or
may act locally.
prophylactic purposes where a degree of occlusion is desired.
Cutaneous patches consist of an adhesive basis, which may Hydrophilic ointments are miscible with the skin secretion
be coloured, containing 1 or more active substances, spread and are less emollient as a consequence.
as a uniform layer on an appropriate support made of natural
In tropical and subtropical countries varying quantities of TESTS

Arachis Oil, White Beeswax, Wool Fat, Hard Paraffin, White Sterility (2. 6.1)
Soft Paraffin, Yellow Soft Paraffin or Liquid Paraffin may be Urethral sticks and sticks for insertion into wounds comply
used in the preparation of the Ointments of the with the test for sterility.
Pharmacopoeia when prevailing high temperatures otherwise LABELLING
make them too soft for convenient use, but the specified
i. i, The label states:
proportions of the active ingredients must be maintained.
— the quantity of active substance(s) per stick;
Ointments should not normally be diluted. However, should — for urethral sticks and sticks to be inserted into wounds
dilution be necessary care should be taken in the selection of that they are sterile.
diluents to avoid risk of incompatibility or instability. One
uf
PAS
: **
DEF | | Tablets xt
wereld
Pastes are.4 ntended to be applied to small, localised xk o*

areas of the ¢ (Ph Eur monograph 0478) * ae
Tablets comply with the requirements of the European
Ph Eur
SPIRITS The requirements of this monograph do not necessarily apply to
DEFINITION preparations that are presented as tablets intended for use other
Spirits are solutions of one a: nces in Ethanol than by oral administration. Requirements for such preparations
(96 %) or a Dilute Ethanol. They may be found, where appropriate, in other general monographs;
of Water. for example Rectal preparations (1145), Vaginal
preparations (1164) and Oromucosal preparations (1807). This
STORAGE monograph does not apply to lozenges, oral pastes and oral gums.
Spirits should be kept in well-closed contaiti Where justified and authorised, the requirements of this monograph
other suitable materials. do not apply to tablets for veterinary use.
DEFINITION
Tablets are solid preparations each containing a single dose
yne Or more active substances. They are obtained by
Sticks * essing uniform volumes of particles or by another
wm manufacturing technique, such as extrusion,
Sticks comply with the requirements of the European
Ph Eur
Additional requirements for sticks may be found, where

appropriate, in other general monographs, for example Nasal The particles |
preparations (0676). or without excipi¢ kh as diluents, binders, disintegrating
DEFINITION agents, glidants, lubr stances capable of modifying
,; Lo, Lo. the behaviour of the prer min the digestive tract,
Sticks are solid preparations intended for local application. colouring matter authoris
They are rod-shaped or conical preparations consisting of q e
avouring substances. .
one or more active substances alone or which are dissolved ©
or dispersed in a suitable basis which may dissolve or melt at
surfaces of which are flat or conv
body temperature.
Urethral sticks and sticks for insertion into wounds are may be bevelled. ‘They may have bre a
sterile.
PRODUCTION requirements for materials used for the manu

In the manufacture, packaging, storage and distribution of containers (3.1 and subsections) and containers (3. 2 and
sticks, suitable measures are taken to ensure their microbial subsections).
quality; recommendations on this aspect are provided in the
Several categories of tablets for oral use may be
text on 5.1.4. Microbiological quality of non-sterile
distinguished:
pharmaceutical preparations and substances for pharmaceutical
— uncoated tablets;
Use. — coated tablets;
Urethral sticks and other sterile sticks are prepared using — gastro-resistant tablets;
materials and methods designed to ensure sterility and to — modified-release tablets;
avoid the introduction of contaminants and the growth of — effervescent tablets;
micro-organisms; recommendations on this aspect are — soluble tablets;
provided in the text on Methods ofpreparation of sterile products — dispersible tablets;
(5.1.1). — orodispersible tablets;
In the manufacture of sticks measures are taken to ensure — chewable tablets;
that the preparation complies with a test for mass uniformity — tablets for use in the mouth;
or, where appropriate, a test for uniformity of content. — oral lyophilisates.
PRODUCTION Where a dissolution test is prescribed, a disintegration test

Tablets are usually prepared by compressing uniform may not be required.
volumes of particles or particle aggregates produced by
granulation methods. In the manufacture of tablets, measures UNCOATED TABLETS
are taken to ensure that they possess a suitable mechanical
strength to avoid crumbling or breaking on handling or DEFINITION
subsequent processing. This may be demonstrated using the Uncoated tablets include single-layer tablets resulting from a
tests described in general chapters 2.9.7. Friability of uncoated single compression of particles and multi-layer tablets
tablets and 2.9.8. Resistance to crushing of tablets. consisting of concentric or parallel layers obtained by
successive compression of particles of different composition.
Subdivision of tablets Tablets may bear a break-mark or break-
The excipients used are not specifically intended to modify
marks and may be subdivided in parts, either to ease the
the release of the active substance in the digestive fluids.
dicinal product or to comply with the
latter case, subdivision must be assessed and Uncoated tablets conform to the general definition of tablets.
A broken section, when examined undera lens, shows either
a relatively uniform texture (single-layer tablets) or a stratified
ssessed during the development texture (multi-layer tablets) but no signs of coating.
uniformity of mass of the TESTS
subdivided parts. Eac Disintegration (2. 9. 1)
the following test. Uncoated tablets comply with the test using water R as the
liquid medium. Add a disc to each tube. Operate the
the parts obtained from 1 tabl apparatus for 15 min, unless otherwise justified and
reject the other part(s). Weigh e parts authorised, and examine the state of the tablets. If the tablets
individually and calculate the averag tablets fail to comply because of adherence to the discs, the results
comply with the test if not more than are invalid. Repeat the test on a further 6 tablets, omitting
outside the limits of 85 per cent to 115 pe the discs.
average mass. The tablets fail to complywi
COATED TABLETS
125 per cent of the average mass. DEFINITION
Coated tablets are tablets covered with one or more layers of
In the manufacture, packaging, storage and distribution o
ixtures of various substances such as natural or synthetic
tablets, suitable measures are taken to ensure their
, tums, gelatin, inactive and insoluble fillers, sugars,
microbiological quality; recommendations on this aspect are
polyols, waxes, colouring matter authorised by
provided in general chapter 5.1.4. Microbiological quality of
ent authority and sometimes flavouring substances
non-sterile pharmaceutical preparations and substances for
vbstances. The substances used as coatings are
pharmaceutical use.
d.as a solution or suspension in conditions in
TESTS
Uniformity of dosage units (2.9.40) a very thin p
Tablets comply with the test or, where justified and coated tablets.
authorised, with the tests for uniformity of content and/or
uniformity of mass shown below. Herbal drugs and herbal coloured and may be®p
drug preparations present in the dosage form are not subject examined under a lens, re surrounded by one or
to the provisions of this paragraph. more continuous layers w
Uniformity of content (2.9.6) PRODUCTION
tablets with a content of active substance less than 2 mg or
of coatedtablets other than film-coat
less than 2 per cent of the total mass comply with test A.
ensured by control of the cores.
If the preparation has more than 1 active substance, the
requirement applies only to those substances that correspond TESTS
to the above conditions. Disintegration (2.9. 1)
Unless otherwise justified and authorised, coated tablets
other than film-coated tablets comply with test A irrespective test using water R as the liquid medium. Add adiscto each
of their content of active substance(s). tube. Operate the apparatus for 60 min, unless otherwise
justified and authorised, and examine the state of the tablets.
Uniformity of mass (2.9.5) If any of the tablets has not disintegrated, repeat the test on a
Uncoated tablets and, unless otherwise justified and further 6 tablets, replacing water R with 0.1 M hydrochloric
authorised, film-coated tablets comply with the test. If the acid. If 1 or 2 tablets fail to disintegrate, repeat the test on 12
test for uniformity of content is prescribed or justified and
additional tablets.
authorised for all the active substances, the test for
The requirements of the test are met if not fewer than 16 of
uniformity of mass is not required.
the 18 tablets tested have disintegrated.
Dissolution
Film-coated tablets comply with the disintegration test
A suitable test may be carried out to demonstrate the
prescribed above except that the apparatus is operated for
appropriate release of the active substance(s), for example
30 min, unless otherwise justified and authorised.
one of the tests described in general chapter 2.9.3. Dissolution
test for solid dosage forms. If coated tablets or film-coated tablets fail to comply because
of adherence to the discs, the results are invalid. Repeat the
test on a further 6 tablets, omitting the discs.
GASTRO-RESISTANT TABLETS TESTS

Disintegration
DEFINITION
Place 1 tablet in a beaker containing 200 mL of water R at
Gastro-resistant tablets are delayed-release tablets that are
15-25 °C; numerous bubbles of gas are evolved. When the
intended to resist the gastric fluid and to release their active
evolution of gas around the tablet or its fragments ceases the
substance(s) in the intestinal fluid. Usually they are prepared
tablet has disintegrated, being either dissolved or dispersed in
from granules or particles already covered with a gastro-
the water so that no agglomerates of particles remain. Repeat
resistant coating or in certain cases by covering tablets with a
the operation on 5 other tablets. The tablets comply with the
gastro-resistant coating (enteric-coated tablets).
test if each of the 6 tablets used disintegrates in the manner
Tablets covered with a gastro-resistant coating conform to prescribed within 5 min, unless otherwise justified and
the definition of coated tablets. authorised.
PRODUCTION
SOLUBLE TABLETS
stro-resistant coating, a suitable test is
DEFINITION
nstrate the appropriate release of the
Soluble tablets are uncoated or film-coated tablets. They are
intended to be dissolved in water before administration.
The solution produced may be slightly opalescent due to the
added excipients used in the manufacture of the tablets.
TESTS |
Disintegration (2. 9. /)
Operate the apparatus
Soluble tablets disintegrate within 3 min, using water R at
yustified and
15-25 °C as the liquid medium.
> the state of the
tablets. The time of resistance to the aci medium varies
according to the formulation of the tat DISPERSIBLE TABLETS
Itiis typically 2 h to 3 h but even with autu DEFINITION
Dispersible tablets are uncoated or film-coated tablets
intended to be dispersed in water before administration,
that would allow the escape of the contents.ne mf giving a homogeneous dispersion.
by phosphate buffer solution pH 6.8 R and add a disc t
tube. Operate the apparatus for 60 min and examine ti
state of the tablets. If the tablets fail to comply becauseof*
adherence to the discs, the results are invalid. Repeat thetest ible tablets disintegrate within 3 min, using water R at
on a further 6 tablets, omitting the discs. C as the liquid medium.
Dissolution of dispersion
For tablets prepared from granules or particles already aplets in 100 mL ofwater R and stir until
covered with a gastro-resistant coating, a suitable test is
active substance(s), for example the test described in general
chapter 2.9.3. Dissolution test for solid dosage forms.
ORODISPEK
MODIFIED-RELEASE TABLETS DEFINITION
DEFINITION
placedin the mouth where
Modified-release tablets are coated or uncoated tablets that
swallowed.
contain special excipients or are prepared by special
procedures, or both, designed to modify the rate, the place or TESTS
the time at which the active substance(s) are released. Disintegration (2. 9. /)
Modified-release tablets include prolonged-release tablets, Orodispersible tablets disintegrate within
delayed-release tablets and pulsatile-release tablets. water R as the liquid medium.
PRODUCTION
CHEWABLE TABLETS
release of the active substance(s). DEFINITION
Chewable tablets are intended to be chewed before being
swallowed.
EFFERVESCENT TABLETS
PRODUCTION
DEFINITION
Chewable tablets are prepared to ensure that they are easily
Effervescent tablets are uncoated tablets generally containing
crushed by chewing.
acid substances and carbonates or hydrogen carbonates,
which react rapidly in the presence of water to release carbon
dioxide. They are intended to be dissolved or dispersed in TABLETS FOR USE IN THE MOUTH
water before administration. DEFINITION
Tablets for use in the mouth are usually uncoated tablets.
They are formulated to effect a slow release and local action
of the active substance(s) or the release and absorption of the
active substance(s) at a defined part of the mouth. They 15 parts of non-alkalinised cocoa powder of commerce, 15
comply with the requirements of the monograph Oromucosal parts of Sucrose and 70 parts of Lactose.
preparations (1807). Content of active ingredient of tablets
The range for the content of active ingredient stated in the
ORAL LYOPHILISATES monograph is based on the requirement that 20 tablets, or
DEFINITION such other number as may be indicated in the monograph,
are used in the Assay. In circumstances where 20 tablets
Oral lyophilisates are solid preparations intended either to be
cannot be obtained, a smaller number, which must not be
placed in the mouth or to be dispersed (or dissolved) in
less than five, may be used, but to allow for sampling errors
water before administration.
the tolerances are widened in accordance with Table I.
PRODUCTION The requirements of Table I apply when the stated limits are
Oral lyophilisates are obtained by freeze-drying 90 to 110%. For limits other than 90 to 110%,
lving division into single doses, freezing, proportionately smaller or larger allowances should be made.
ng of usually aqueous, liquid or semi-
solid preparation
Disintegration
Comply with the disintegration test for tablets and capsules,
TESTS Appendix XII Al, unless otherwise stated in the individual
Disintegration monographs.
Place 1 oral lyophilisa aker containing 200 mL of For those Uncoated or Coated Tablets for which a
water R at 15-25 °C. It di tes within 3 min. Repeat requirement for Dissolution is included in the individual
the test on 5 other oral lyophy monograph, the requirement for Disintegration does not
test if all 6 have disintegrated apply.
Water (2.5.12) Uniformity of content
Oral lyophilisates comply with Details of the analytical method to be employed for
approved by the competent authority. determining the content of active ingredient may be included
in certain monographs. Unless otherwise stated in the
monograph the limits are as given in test A for Uniformity of
content, Appendix XII C3.
Any tablets that, when examined individually, show a gross
Tablets of the British Pharmacopoei deviation from the stated content are not official.
Pharmacopoeia, the following statements apply to those tablets tha
are the subject of an individual monograph in the British
Pharmacopoeia. EDICATED TAMPONS oe
DEFINITION
Tablets of the British Pharmacopoeia may contain flavouring
only when indicated in the individual monograph.
Tablets that are the subject of individual monographs in the
British Pharmacopoeia may be uncoated, compression-
coated, film-coated or sugar-coated unless otherwise
indicated in the monograph. Tablets for which the
Rectal preparations (1145,
monograph states “They are coated’ are compression-coated
or film-coated or sugar-coated. Tablets may be made gastro- Ear Preparations (0652).
resistant by enteric-coating or by other means only where this DEFINITION
is specifically indicated in the monograph.
When presented as coated formulations, where justified and
authorised, it may be necessary to remove the coating before
performing a test described in a monograph. Removal of a cellulose, collagen or silicone impregnated With en€ or more
coating is not permitted where it affects the functionality of active substances.
the product, for example in dissolution or disintegration tests.
In preparing Tablets for which Chocolate Basis is specified,
the active ingredient may be incorporated with a mixture of
Table I
Weight of active ingredients Subtract from the lower Add to the upper
in each tablet limit for samples of limit for samples of
15 10 5 15 10 5
0.12 g or less 0.2 0.7 1.6 0.3 0.8 1.8
More than 0.12 g
and less than 0.3 g 0.2 0.5 1.2 0.3 0.6 1.5
0.3 g or more 0.1 0.2 0.8 0.2 0.4 1.0
PRODUCTION detach the preparation (matrix or reservoir) or the adhesive

In the manufacture, packaging, storage and distribution of from the patch.
medicated tampons, suitable measures are taken to ensure ‘Transdermal patches are normally individually enclosed in
their microbial quality; recommendations on this aspect are sealed sachets.
provided in the text on 5.1.4. Microbiological quality of non-
PRODUCTION
sterile pharmaceutical preparations and substances for
pharmaceutical use. In the manufacture, packaging, storage and distribution of
transdermal patches suitable measures are taken to ensure
LABELLING their microbial quality; recommendations on this aspect are
The label states the quantity of active substance(s) per provided in the text on 5.1.4. Microbiological quality of non-
tampon. stertle pharmaceutical preparations and substances for
Ph Eur pharmaceutical use.
TESTS
kX
&
Transdermal patches comply with the test for uniformity of
Transderm * dosage units (2.9.40) or, where justified and authorised, with
+% +
*
w yk
the test for uniformity of content shown below. Herbal drugs
(Ph. Eur. monogt. and herbal drug preparations present in the dosage form are
Transdermal Patches not subject to the provisions of this paragraph.
European Pharmacop Uniformity of content (2.9.6)
below. Unless otherwise prescribed or justified and authorised,
Ph Eur transdermal patches comply with test C for uniformity of
content of single-dose preparations.
DEFINITION
Dissolution
of varying sizes, containing one or more get A suitable test may be required to demonstrate the
They are intended to be applied to the un appropriate release of the active substance(s), for example
one of the tests described in Dissolution test for transdermal
patches (2.9.4). The disc assembly method, the cell method
Transdermal patches normally consist of an outer ¢¢
or the rotating cylinder method may be used, as suitable,
which supports a preparation which contains the activ. according to the composition, dimensions and shape of the
substance(s). The transdermal patches are covered on patch.
of the release surface of the preparation by a protective line! ittembrane may be used. It can be of various materials,
which is removed before applying the patch to the skin. inert porous cellulose or silicones, and must not
The outer covering is a backing sheet impermeable to the e release kinetics of the active substance(s) from the
active substance(s) and normally impermeable to water, rthermore, it must be free of substances that may
designed to support and protect the preparation. The outer its performance (for example grease).
covering may have the same dimensions as the preparation or
it may be larger. In the latter case the overlapping border of
the outer covering 1s covered by pressure-sensitive adhesive
substances which assure the adhesion of the patch to the
skin.
The preparation contains the active substance(s) together authorised by the c
with excipients such as stabilisers, solubilisers or substances STORAGE
intended to modify the release rate or to enhance transdermal Store at room temperature, ur
absorption. It may be a single layer or multi-layer solid or
LABELLING
semi-solid matrix, and in this case it is the composition and
The label states, where applicabl
structure of the matrix which determines the diffusion
substance(s) per patch, the dose releag.
pattern of the active substance(s) to the skin. The matrix
the area of the releasing surface.
may contain pressure-sensitive adhesives which assure the
adhesion of the preparation to the skin. The preparation may
exist as a semi-solid reservoir one side of which is a
membrane which may control the release and the diffusion of
the active substance(s) from the preparation. The pressure-
sensitive adhesive substances may, in this case, be applied to
some or all parts of the membrane, or only around the
border of the membrane of the outer covering.
When applied to the dried, clean and unbroken skin, the
transdermal patch adheres firmly to the skin by gentle
pressure of the hand or the fingers and can be peeled off
without causing appreciable injury to the skin or detachment
of the preparation from the outer covering. The patch must
not be irritant or sensitising to the skin, even after repeated
applications.
The protective liner generally consists of a sheet of plastic or
metal material. When removed, the protective liner does not
JiI-78 General Monographs 2016
2. A statement of the active ingredients expressed

Unlicensed Medicines
Le
,
qualitatively and quantitatively per dosage unit or for a

‘
This monograph describes the minimum qualhty standards required

Faty
given volume or weight.

ae Get eye
for Unlicensed Medicines for human use. The statements in this

rigah,
eet
3. Route of administration.
monograph are intended to be read in conjunction with individual
monographs for unlicensed medicines or formulated preparations in 4. Instructions for use, including any special warnings.
:
1moe,
the Pharmacopoeia, together with relevant General Notices, 5. The pharmaceutical form.
‘e
Appendices and Supplementary Chapters.

:
6. The contents of the container by weight, volume or by

heyhey
:
Individual monographs are intended to apply throughout the number of doses.

:
ye
period for which the formulation 1s expected to be satisfactory for 7. Excipients of known effect. For injectable, topical
.
1
USE. (including inhalation products) and ophthalmic medicines, all

2
excipients.
,
DEFINITION
a!
Ge
ine is one which is prepared, at the 8. ‘Keep out of reach and sight of children’. [Note 1]
efit
ey
sd healthcare professional, to address 9. The expiry date expressed in unambiguous terms

Om
whe
4
patient medicing: irements, unmet by current licensed (dd/mm/vy).

rie,
medicines, accord tetthe Human Medicines Regulations 10. Any special storage precautions.
,
'
2012 (see Supplemerita

‘
11. The manufacturer’s MS number, where appropriate.

tte
'
manufactured under
.
:
prepared extemporaneou the supervision of a 12. The manufacturer’s name and address.
‘
'
.
tat yt,
pharmacist. 13. The batch number.

fae
‘
tn a
14. Statutory warnings required by The Human Medicines

a
SCOPE
Regulations 2012 for particular actives, e.g. paracetamol
Poefe?as a
te
tat
This general monograph applies osége forms that

PEG
(Schedule 25, Part 4 of the 2012 Regulations).

are routinely manufactured or prepa wcensed
For small containers certain details may be omitted, but the
ei,
medicines and are usually presented as ¢onv onal-release

‘o,f
formulations. These include: label should contain, as a minimum, the following

— Capsules information:
.
'
.
:
ee
— Liquids for Cutaneous Application 1. The common name of the product.

?
.
— Ear Drops and Lotions

.
2. A statement of the active ingredients expressed

.
tt
— Eye Drops qualitatively and quantitatively per dosage unit or for a

ft
.
— Preparations for Irrigation

.
ven volume or weight.

oO,
te et,
.
— Nasal Preparations
v
of administration.
— Oral Liquids
— Oral Powders
— Parenteral Preparations
— Rectal Preparations
— ‘Tablets
— Topical Semi-solid Preparations
— Vaginal Preparations x the outer packaging should
PRODUCTION ] information.
The production of unlicensed medicines should only be uirement for relevant
undertaken by competent staff, within suitable facilities and
using equipment appropriate for the scale of manufacture
and the specific dosage form. MEDICINAL SUBST
In the UK, batch manufacture should be undertaken in EXCIPIENTS
facilities holding a UK Manufacturer’s ‘Specials’ Licence in
compliance with the standards of Good Manufacturing
substance and any excipients must comp
Practice.
monograph requirements of the Pharmac
LABELLING
The following requirements are applicable to unlicensed
medicines manufactured or prepared in accordance with Pharmaceutical Use and, where appropriate, the pre’
medicines legislation. They are not intended to apply to Supplementary Chapter IV J on the Control of Impurities in
repackaging and assembly activities. The requirements were Substances for Pharmaceutical Use and the General
previously included as guidance in Supplementary Chapter V Monograph for Products with Risk of Transmitting Agents of
of the British Pharmacopoeia 2007. Animal Spongiform Encephalopathies.
Best practice guidance on the labelling and packaging of
medicines advises that certain items of information are FORMULATED PREPARATIONS
deemed critical for the safe use of the medicine (see “‘Best
Practice Guidance on the Labelling and Packaging of Unlicensed medicines must comply with the requirements of
Medicines”; MHRA, 2012). These critical items of the General Monograph for Pharmaceutical Preparations, the
information, which should be located together on the pack requirements of the General Monograph for Unlicensed
and appear in the same field of view, are: name, strength, Medicines and with the requirements of the relevant General
route of administration, dosage and warnings (highlighted in Monograph for the specific dosage form. Where a BP
bold). monograph for a formulated preparation is available, the
product must comply. In addition, where specified, they
1. The common name of the product.
must comply with the following tests.
Sterility Homogeneity of Suspension

Where the label indicates that the preparation is sterile, it Allow a suitable volume of the oral suspension being
complies with the test for sterility (Appendix XVI A). While examined to settle, undisturbed, for 24 hours. Shake the
it is expected that the formulated preparation will container for 30 seconds and accurately remove one dose
demonstrate pharmacopoeial compliance when tested, it is (usually 5 to 10 mL) at a depth of 1 cm below the meniscus
recognised that it might not be practicable to carry out the Shake the container again for 10 seconds and remove
pharmacopoeial test routinely. another dose. Repeat this procedure until 10 doses of the
suspension have been removed. Assay the 10 doses
individually according to the method specified in the
ORAL LIQUIDS
individual monograph.
PRODUCTION The preparation complies with the test if each individual
In the manufacturing, packaging and storage of oral liquids, dose is between 85% and 115% of the average dose.
The preparation fails to comply with the test if more than
armacopoeial requirements throughout one individual dose is outside these limits or if one individual
ndations for microbial limits are provided dose is outside the limits of 75% to 125% of the average
content.
VAGINAL PREPARATIONS ey
(Ph. Eur. monograph 1164) Me
minimised. Storage conditions of the f DEFINITION

prevent contamination and inhibit micr Vaginal preparations are liquid, semi-solid or solid
proliferation. The product shelf life during s preparations intended for administration to the vagina usually
should be based on the risk and probability tha the in order to obtain a local effect. They contain 1 or more
may fail to meet the requirements of Appendix XVI active substances in a suitable basis.
Acidity or alkalinity Where appropriate, containers for vaginal preparations
A test to determine the pH of the oral solution or ora comply with the requirements for materials used for the
suspension may be applied. As the pH may be formulatio mufacture of containers (3.1 and subsections) and
dependant, limits are only included in specific monographs in aers (3.2 and subsections).
cases where the stability of the active substance is affected by categories of vaginal preparations may be
pH. ished:
ORAL SUSPENSIONS
Dissolution
Carry out the test for dissolution described under dissolution
mulsions and suspensions;
test for tablets and capsules, Appendix XII B1, using Apparatus
1 solutions and suspensions;
2. Unless otherwise stated in the individual monograph use
— semi-solid vagi TP preparations;
900 mL of an appropriate dissolution medium (as suggested
— vaginal foams;
in Supplementary Chapter I E, Table 2.9.3.-5) and rotate the
— medicated vaginal tat
paddle at 50 rpm.
Shake the container containing the oral suspension being PRODUCTION |
examined for 30 seconds and accurately remove a volume During development, it must"be emenstrated that the
containing one dose at a depth of 1 cm below the meniscus. nominal contents can be withdra the container of
Introduce the dose to the medium in the dissolution vessel.
If sink conditions cannot be obtained, testing a partial dose
of the suspension (10% to 20% of the usual dose) is
preferable to using a surfactant.
Operate the apparatus at the specified rate. Within the time their microbial quality; recommendations on
interval specified, or at each of the times stated, withdraw a provided in chapter 5.1.4. Microbiological quality of
specimen from a zone midway between the surface of the pharmaceutical preparations.
dissolution medium and the top of the rotating paddle, not TESTS
less than 1 cm from the vessel wall. Where multiple sampling Uniformity of dosage units (2. 9.40)
times are specified, replace the aliquots withdrawn for Liquid and semi-solid single-dose vaginal preparations
analysis with equal volumes of fresh dissolution medium at comply with the test. Solid single-dose vaginal preparations
37° or, where it can be shown that replacement of the comply with the test or, where justified and authorised, with
medium is not necessary, correct for the volume change in the tests for uniformity of content and/or uniformity of mass
the calculation. Keep the vessel covered for the duration of shown below. Herbal drugs and herbal drug preparations
the test and verify the temperature of the medium at suitable present in the dosage form are not subject to the provisions
times. Perform the analysis using a suitable assay method. of this paragraph.
Repeat the test with a further five additional doses.
Uniformity of content (2. 9.6)
Unless otherwise specified in the individual monograph, the Unless otherwise prescribed or justified and authorised, solid
value of Q is 75% of the stated amount at 45 minutes. single-dose vaginal preparations with a content of active
substance less than 2 mg or less than 2 per cent of the total TESTS
mass comply with test A (vaginal tablets) or test B (pessaries, Disintegration (2.9. 2)
vaginal capsules). If the preparation has more than one active Unless intended for prolonged local action, they comply with
substance, the requirement applies only to those substances the test (special method for vaginal tablets). Examine the
which correspond to the above conditions. state of the tablets after 30 min, unless otherwise justified
Uniformity of mass (2.9.5) and authorised.
Solid single-dose vaginal preparations comply with the test.
If the test for uniformity of content is prescribed for all the VAGINAL CAPSULES
active substances, the test for uniformity of mass is not
required. DEFINITION
Vaginal capsules (shell pessaries) are solid, single-dose
Dissolution
preparations. They are generally similar to soft capsules as
A suitable té nay be carried out to demonstrate the
defined in the monograph Capsules (0016), differing only in
ise.@f.the active substance(s) from solid
their shape and size. Vaginal capsules have various shapes,
single-dose "Vagin
usually ovoid. They are smooth and have a uniform external
described in cha
appearance.
When:a dissolution ribed, a disintegration test PRODUCTION

may not be required. A suitable test is carried out to demonstrate the appropriate
release of the active substance(s) from vaginal capsules
intended for prolonged local action.
PESSARIES
TESTS
DEFINITION Disintegration (2. 9. 2)
Pessaries are solid, single-dose p Unless intended for prolonged local action, they comply with
the test. Examine the state of the capsules after 30 min,
suitable for insertion into the vagina. The unless otherwise justified and authorised.
active substancesdispersed or dissolved ina
VAGINAL SOLUTIONS, EMULSIONS

surface-active agents, lubricants, antimicrobial preservativee AND SUSPENSIONS
and colouring matter authorised by the competent authority EFINITION
may be added, if necessary. olutions, emulsions and suspensions are liquid
PRODUCTION
Pessaries are usually prepared by moulding. Where
appropriate in the manufacture of pessaries, measures are
taken to ensure a suitable and controlled particle size of the
active substance(s). If necessary, the active substance(s) are
previously ground and sieved through a suitable sieve.
When prepared by moulding, the medicated mass,
sufficiently liquefied by heating, is poured into suitable
moulds. The pessary solidifies on cooling. Various excipients but are readily redisper haking. Vaginal suspensions
are available for this process, such as hard fat, macrogols, may show a sediment t dily dispersed on shaking to
cocoa butter, and various gelatinous mixtures consisting, for give a suspension that re
example, of gelatin, water and glycerol. homogeneous preparation to.
release of the active substance(s) from pessaries intended for adapted to deliver the preparation to/th
prolonged local action. accompanied bya suitable applicator
TESTS PRODUCTION
Disintegration (2. 9. 2) In the manufacture of vaginal suspensions measu
Unless intended for prolonged local action, they comply with to ensure a suitable and controlled particle size witt
the test. Examine the state of the pessaries after 60 min, the intended use.
unless otherwise justified and authorised.
TABLETS FOR VAGINAL SOLUTIONS
VAGINAL TABLETS AND SUSPENSIONS
DEFINITION DEFINITION
Vaginal tablets are solid, single-dose preparations. ‘They Tablets intended for the preparation of vaginal solutions and
generally conform to the definitions of uncoated or film- suspensions are single-dose preparations that are dissolved or
coated tablets given in the monograph Tablets (0478). dispersed in water at the time of administration. They may
PRODUCTION contain excipients to facilitate dissolution or dispersion or to
prevent caking.
release of the active substance(s) from vaginal tablets Apart from the test for disintegration, tablets for vaginal
intended for prolonged local action. solutions or suspensions conform with the definition for
Tablets (0478).
After dissolution or dispersion, they comply with the

requirements for vaginal solutions or vaginal suspensions, as
ves appropriate.
oe TESTS
os Disintegration (2.9. /)
Tablets for vaginal solutions or suspensions disintegrate
within 3 min, using water R at 15-25 °C as the liquid
medium.
LABELLING
The label states:
— the method of preparation of the vaginal solution or
and duration of storage of the solution or
AGINAL PREPARATIONS
DEFINITION
Semi-solid vaginal preparafiorig are ointments, creams or gels.
They are often supplied “dose containers.
The container 1s provide
= Semi-solid vaginal preparations ¢
Sy of the monograph Semi-solid preparag
wots application (0132). |
VAGINAL FOAMS
DEFINITION
Vaginal foams comply with the requirements of t
monograph Medicated foams (1105).
MEDICATED VAGINAL TAMPONS

DEFINITION
Medicated vaginal tampons are solid, single-dose
preparations intended to be inserted in the vagina for a
limited time.
They comply with the requirements of the monograph
Medicated tampons (1155).
AROMATIC WATERS
DEFINITION
Aromatic Waters are saturated solutions of volatile oils or
other aromatic substances in water, usually employed for
their flavouring rather than their medicinal properties.
Aromatic Waters prepared as described below contain a small
amount of Ethanol.
PRODUCTION
we] Aromatic Waters are normally prepared by diluting a
soc] concentrated, ethanolic solution of the aromatic substance
: with Water.
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2016 Abacavir Preparations III-85

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FORMULATED PREPARATIONS: (6) 0.0001% w/v of abacavir impurity 1 BPCRS.

CHROMATOGRAPHIC CONDITIONS
ANw 4
SPECIFIC MONOGRAPHS (a) Use a stainless steel column (15 cm x 3.9 mm) packed |
with octadecylsilyl silica gel for chromatography (5 um) (Waters
Symmetry Shield C18 is suitable).
(b) Use gradient elution and the mobile phase described
Abacavir Oral Solution below.
Action and use (c) Use a flow rate of 0.8 mL per minute.
Nucleoside reverse transcriptase inhibitor; antiviral (HIV). (d) Use a column temperature of 30°.
(e) Use a detection wavelength of 254 nm.
(f) Inject 10 pL of each solution.
MOBILE PHASE
Mobile phase A 0.05% v/v of trifluoroacetic acid.

Mobile phase B- methanol (85%).
Time Mobile phase A Mobile phase B Comment

(Minutes) (% viv) (% viv)
dayer chromatography, 0-20 95-—»70 5-30 linear gradient

Appendix III A, using the follewing solutions in methanol 20-35 70-10 30-90 linear gradient
(50%). : 35-40 10 90 isocratic
(1) Dilute the oral solution to prodtic
40-41 10-0 90-100 column wash
the equivalent of 0.2% w/v of abacavi
41-50 0 . 100 column wash
(2) 0.23% w/v of abacavir sulfate BPCRS:
50-51 0-95 100-5 column wash
51-55 95 5 re-equilibration
(a) Use as the coating silica gel F254 (Merck silica’ ge
HPTLC plates are suitable). Before use, stand the f
SYSTEM SUITABILITY
the plate, remove and heat the plate at 105° for 1 hour. “test is not valid unless, in the chromatogram obtained
(b) Use the mobile phase described below. elution (4):
(c) Apply 1 pL of each solution. atogram closely resembles the reference
(d) Develop the plate to 7 cm. gram supplied with abacavir for peak
(e) After removal of the plate, dry in a current of warm air
and examine under ultraviolet light (254 nm).
MOBILE PHASE
LIMITS -
5 volumes of methanol, 6 volumes of 13.5M ammonia,
34 volumes of dichloromethane and 55 volumes of acetone. Identify any peak’ romatogram obtained with
sndinp to.impurity C using the
CONFIRMATION
chromatogram obtained
The principal spot in the chromatogram obtained with chromatogram supplied
solution (1) corresponds in position and colour to that in the impurity standard BPCRS. Ps
chromatogram obtained with solution (2).
In the chromatogram obtained with so
B. In the Assay, the chromatogram obtained with solution
(1) shows a peak with the same retention time as the peak
not greater than the area of the principalpeak.
due to abacavir in the chromatogram obtained with
chromatogram obtained with solution (2).47.
solution (2).
the area of any peak corresponding to abacay¥
TESTS not greater than the area of the peak in the chrématogram
Acidity obtained with solution (6) (0.5%);
pH, 3.8 to 4.5, Appendix V L.
the area of any other secondary peak is not greater than the
Related substances area of the principal peak in the chromatogram obtained with
Carry out the method for liquid chromatography, solution (3) (0.2%);
Appendix III D, using the following solutions in 0.1% v/v of the sum of the areas of all secondary peaks is not greater
orthophosphoric acid. than twice the area of the principal peak in the
(1) Dilute the oral solution to produce a solution containing chromatogram obtained with solution (2) (2.0%).
the equivalent of 0.02% w/v of abacavir and filter if Disregard any peak with an area less than 0.5 times the area
necessary. of the principal peak in the chromatogram obtained with
(2) Dilute 1 volume of solution (1) to 100 volumes. solution (3) (0.1%).
(3) Dilute 1 volume of solution (2) to 5 volumes. ASSAY
(4) Dissolve 2.5 mg of abacavir for peak identification EPCRS Carry out the method for liguid chromatography,
(containing impurities B and D) in 10.0 mL. Appendix III D, using the following solutions in 0.1% v/v of
(5) 0.02% w/v of abacavir impurity standard BPCRS. orthophosphonic acid.
IlI-86 Abacavir Preparations 2016
(1) Dilute the oral solution to produce a solution containing (b) Use the mobile phase described below.
the equivalent of 0.02% w/v of abacavir and filter if (c) Apply 10 uL of each solution.
necessary.
(d) Develop the plate to 12 cm.
(2) 0.023% wiv of abacavir sulfate BPCRS.
(e) After removal of the plate, dry it in air and immediately
(3) Dissolve 2.5 mg of abacavir for peak identification EPCRS examine under ultraviolet light (254 nm).
(containing impurities B and D) in 10.0 mL.
MOBILE PHASE
SYSTEM SUITABILITY
3 volumes of glacial acetic acid, 10 volumes of methanol and
The test is not valid unless, in the chromatogram obtained 90 volumes of dichloromethane.
with solution (3), the resolution between the peaks due to
SYSTEM SUITABILITY
abacavir and abacavir impurity D is at least 1.5.
The test 1s not valid unless the chromatogram obtained with
PHIC CONDITIONS
solution (3) shows two clearly separated spots.
CONFIRMATION
The chromatogram obtained with solution (1) shows a

principal spot corresponding in position and size to the
principal spot in the chromatogram obtained with
solution (2).
of Cr8gH36N 20> in aba
LABELLING : (1) shows a principal peak with the same retention time as
The quantity of active ingredierit. 1 the principal peak in the chromatogram obtained with
equivalent amount of abacavir. | solution (2).
IMPURITIES ‘ TESTS
The impurities limited by the requirement; Dissolution
monograph include those listed under Abaca and Comply with the dissolution test for tablets and capsules,
the following. Appendix XII Bl.
TEST CONDITIONS
(a) Use Apparatus 2 and rotate the paddle at 75 revolutions

er minute.
HN
b) Use 900 mL of 0.1m hydrochloric acid as the medium at a
NOS -N of 37°.
| »
HN NZ N
minutes withdraw a 10-mL sample of the
1. N°-cyclopropyl-1H-purine-2,6-diamine.
0.039% w/v of abacaiir,

Abacavir Tablets acid at the maximum at’
in the reference cell.
Action and use
Nucleoside reverse transcriptase inhibitor; antiviral (HIV). DETERMINATION OF CONT
Calculate the total content of aba igN,O, in the

DEFINITION medium using the declared content N,O in
Abacavir Tablets contain Abacavir Sulfate. They may be abacavir sulfate BPCRS.
coated.
LIMIT
The tablets comply with the requirements stated under Tablets and
The amount of abacavir released is not less than,
with the following requirements.
the stated amount.
Content of abacavir, C;,H;sN;O
Related substances
95.0 to 105.0% of the stated amount.
Carry out the method for liguid chromatography,
IDENTIFICATION Appendix III D, using the following solutions in 0.1% v/v of
A. Carry out the method for thin-layer chromatography, orthophosphoric acid.
Appendix III A, using the following solutions in water. (1) Shake a quantity of the powdered tablets containing the
(1) Shake a quantity of powdered tablets containing the equivalent of 0.3 g of abacavir with 70 mL for 30 minutes,
equivalent of 0.2 g of abacavir with 100 mL, filter and use mix with the aid of ultrasound for 5 minutes; dilute to
the filtrate. 100 mL and filter through a 0.45-um filter (polyvinylidene
(2) 0.23% w/v of abacavir sulfate BPCRS. fluoride is suitable). Dilute 1 volume of the filtrate to
20 volumes.
(3) 0.23% wv of abacavir sulfate BPCRS and 0.2% w/v of
zidovudine BPCRS. (2) Dilute 1 volume of solution (1) to 100 volumes and
further dilute 1 volume of the resulting solution to
5 volumes.
(a) Use precoated silica gel F254 plates (Merck silica gel 60
F454 plates are suitable).
2016 Abacavir preparations III-87
(3) Dissolve 2.5 mg of abacavir for peak identification EPCRS SYSTEM SUITABILITY
in 10.0 mL. The test is not valid unless, in the chromatogram obtained
CHROMATOGRAPHIC CONDITIONS with solution (3), the resolution between the peaks due to
abacavir and abacavir impurity D is at least 1.5.
(a) Use a stainless steel column (15 cm x 3.9 mm) packed
with octadecylsilyl silica gel for chromatography (5 um) (Waters DETERMINATION OF CONTENT
Symmetry Shield C18 is suitable). Calculate the content of C;,HigN,O in the tablets from the
(b) Use gradient elution and the mobile phase described chromatograms obtained using the declared content of
below. C,4HigN,0O in abacavir sulfate BPCRS.
(c) Use a flow rate of 0.8 mL per minute. LABELLING
(d) Use a column temperature of 30°. The quantity of active ingredient is stated in terms of the
(e) Use.a.detection wavelength of 254 nm. equivalent amount of abacavir.
IMPURITIES
The impurities limited by the requirements of this
monograph include those listed under Abacavir Sulfate.
Time Comment
(Minutes) (% viv)
Abacavir and Lamivudine Tablets
0-20 95-70 linear gradient Action and use
20-35 70-10 linear gradient Nucleoside reverse transcriptase inhibitor; antiviral (HIV).
35-40 10 isocratic
DEFINITION
40-41 100 column wash
Abacavir and Lamivudine Tablets contain Abacavir Sulfate
41-50 0 100 column wash and Lamivudine.
50-51 0-95 100-35 ' The tablets comply with the requirements stated under Tablets and
51-55 95 5 with the following requirements.
Content of abacavir, C,,HisN,<O
SYSTEM SUITABILITY 95.0 to 105.0% of the stated amount.
The test is not valid unless, in the chromatogram obtaine atent of lamivudine, C3H,,N3;0;38
with solution (3): YO to. 105.0% of the stated amount.
the chromatogram closely resembles the reference ICATION
chromatogram supplied with abacavir for peak ut the method for thin-layer chromatography,
identification EPCRS; Til_ A, using the following solutions.
the resolution between the peaks due to abacavir and abacavir
impurity D is at least 1.5.
LIMITS
In the chromatogram obtained with solution (1):

the area of any secondary peak is not greater than the area of (3) 0.1% w/v of la ditie. BPCRS in water.
the principal peak in the chromatogram obtained with CHROMATOGRAPHIC CONDITIONS
solution (2) (0.2%);
(a) Use precoated silica gel’F754 pla Merck silica gel 60
the sum of the areas of all secondary peaks is not greater than F,5,4 plates are suitable). eo
8 times the area of the principle peak in the chromatogram
(b) Use the mobile phase describ
obtained with solution (2) (1.6%).
(c) Apply 10 uL of each solution.
Disregard any peak with an area less than 0.5 times the area
of the principal peak in the chromatogram obtained with
solution (2) (0.1%). (e) After removal of the plate, dry it in air an
examine under ultraviolet hght (254 nm).
ASSAY
MOBILE PHASE
Weigh and powder 20 tablets. Carry out the method for
liquid chromatography, Appendix III D, in 0.1% v/v of 3 volumes of glacial acetic acid, 10 volumes of methanol and
orthophosphoric acid. 90 volumes of dichloromethane.
(1) Shake a quantity of the powdered tablets containing the SYSTEM SUITABILITY
equivalent of 0.1 g of abacavir with 70 mL for 30 minutes, The test is not valid unless the chromatogram obtained with
dilute to 100 mL and filter. Dilute 1 volume of the filtrate to solution (1) shows two clearly separated spots.
5 volumes.
CONFIRMATION
(2) 0.023% wv of abacauir sulfate BPCRS.
The chromatogram obtained with solution (1) shows two
(3) Dissolve 2.5 mg of abacavir for peak identification EPCRS principal spots corresponding in position, colour and size to
in 10 mL. the principal spots in the chromatograms obtained with
CHROMATOGRAPHIC CONDITIONS solutions (2) and (3).
The chromatographic conditions described under Related B. In the Assay, the chromatogram obtained with solution
substances may be used. (1) shows principal peaks with the same retention time as the
I-88 Abacavir preparations 2016
principal peaks due to abacavir and lamivudine in the MOBILE PHASE

chromatograms obtained with solutions (2) and (3) Mobile phase A 0.025M ammonium acetate, the pH adjusted
respectively. to 3.9 with glacial acetic acid.
oR!
et ne
TESTS Mobile phase B-~ methanol.

Dissolution Mobile phase C acetonitrile.
Comply with the dissolution test for tablets and capsules,
Appendix XII B1. Time Mobile Mobile phase Mobiie Comment
(Minutes) phase A B phase C
TEST CONDITIONS (% viv) (% viv) (% viv)

0-15 95 5 0 isocratic
per minute.
15-30 95-70 530 0 linear gradient
(b) Use 900..mL of 0.1m hydrochloric acid, at a temperature of 30-38 70 30 0 isocratic
38-60 70-0 30-0 0-100 change of solvent
60-65 0 0 100 washing column
65-66 0-95 055 100-0 change in solvent
66-75 95 5 0 re-equilibration
following solutions.
raw a 10 mL sample of
SYSTEM SUITABILITY
The test is not valid unless:

the chromatogram obtained with solution (4) closely
substances, to produce the sam resembles the reference chromatogram supplied with
expected for solution (1). lamivudine impurity standard BPCRS and the retention of
(3) 0.01% w/v of lamivudine impurity st@ndarg abacavir relative to lamivudine is about 2.6;
0.016% w/v of abacavir sulfate BPCRS in gi the resolution between the peaks due to lamivudine
CHROMATOGRAPHIC CONDITIONS impurity B and lamivudine is at least 2.0.
The chromatographic conditions described und LIMITS
substances may be used. Using the chromatogram obtained with solution (4) and the
DETERMINATION OF CONTENT reference chromatogram supplied with lamivudine
Calculate the total content of abacavir, Cy4H)gN,O and mpurity standard BPCRS identify any peaks in solution (1)
lamivudine, CgH,,;N303S, in the medium using the declare onding to the named lamivudine impurities.
contents of C,;,H,;sgN,O, in abacavir sulfate BPCRS and of romatogram obtained with solution (1):
CgH,,N303S in lamivudine BPCRS. any peak corresponding to lamivudine impurity A
LIMIT “r than 3 times the area of the peak due to
1e chromatogram obtained with solution (3)
The amounts of abacavir and lamivudine released are not less
than 75% (Q) of the stated amounts.
sécondary peak is not greater than
Related substances
® peak due to abacavir in the
chromatogram obtai {with solution (3) (0.2%);
Appendix III D, using the following solutions in solvent A.
the sum of the areas ndary peaks is not greater than
SOLVENT A
rR to abacavir in the |
Dissolve 1.9 g of ammonium acetate in 900 mL of water,
adjust the pH to 3.9 with glacial acetic acid and dilute to
1000 mL.
(1) Shake a quantity of the powdered tablets containing the solution (3) (0.1%).
equivalent of 0.1g of abacavir in 60 mL with the aid
ASSAY
of ultrasound for 30 minutes, dilute to 100 mL and filter.
Dilute 1 volume of the resulting solution to 5 volumes. Weigh and powder 20 tablets. Carry out t
liquid chromatography, Appendix III D, using the
(2) Dilute 1 volume of solution (1) to 100 volumes.
(3) Dilute 1 volume of solution (2) to 10 volumes. substances.
(4) 0.01% w/v of lamivudine impurity standard BPCRS and (1) Shake a quantity of the powdered tablets containing the
0.016% w/v of abacavir sulfate BPCRS in solvent A. equivalent of 0.2 g of abacavir with 60 mL of solvent A in a
CHROMATOGRAPHIC CONDITIONS 100 mL amber volumetric flask for 30 minutes, dilute to
(a) Use a stainless steel column (25 cm x 4.6 mm) packed 100 mL and filter. Dilute 1 volume to 5 volumes.
with octadecylsilyl silica gel for chromatography (5 um) (YMC (2) 0.023% w/v of abacavir sulfate BPCRS
ODS-A is suitable). (3) 0.01% w/v of lamivudine BPCRS.
(b) Use gradient elution and the mobile phase described (4) 0.01% w/v of lamivudine impurity standard BPCRS and
below. 0.016% w/v of abacavir sulfate BPCRS in solvent A.
(c) Use a flow rate of 1 mL per minute. CHROMATOGRAPHIC CONDITIONS
(d) Use a column temperature of 30°. The chromatographic conditions described under
(e) Use a detection wavelength of 270 nm. Related substances may be used.
(f) Inject 10 wL of each solution.
2016 Abacavir preparations III-89
SYSTEM SUITABILITY MOBILE PHASE

The test is not valid unless, in the chromatogram obtained 3 volumes of glacial acetic acid, 10 volumes of methanol and
with solution (4): 90 volumes of dichloromethane.
the chromatogram obtained with solution (4) closely SYSTEM SUITABILITY
resembles the reference chromatogram supplied with The test is not valid unless the chromatogram obtained with
lamivudine impurity standard BPCRS and the retention of solution (1) shows three clearly separated spots.
abacavir relative to Lamivudine is about 2.6;
CONFIRMATION
the resolution factor between the peaks due to lamivudine
impurity B and lamivudine is at least 2.0. The chromatogram obtained with solution (1) shows three
spots corresponding in position, colour and size to the spots
DETERMINATION OF CONTENT
in the chromatograms obtained with solutions (2), (3) and
ions (1) and (2), calculate the total content of (4).
(1) shows principal peaks with the same retention time as the
principal peaks due to abacavir, zidovudine and lamivudine
in the chromatograms obtained with solutions (2), (3) and
CsH,1N;038 in t (4) respectively.
obtained using
TESTS
lamivudine BPCRS.
Dissolution
IMPURITIES Comply with the dissolution test for tablets and capsules,
The impurities limited by th Appendix XII B1.
monograph include those list
TEST CONDITIONS
Sulfate and Lamivudine respective
per minute.
(b) Use 900 mL of 0.1m hydrochloric acid, at a temperature of
Abacavir, Zidovudine and Lamivu

37°, as the medium.
PROCEDURE
Tablets Carry out the method for liquid chromatography,
Appendix III D, using the following solutions.
Action and use
After 45 minutes withdraw a 10 mL sample of the
Nucleoside reverse transcriptase inhibitor; antiviral (HIV).
and filter.
DEFINITION olve suitable quantities of abacavir sulfate BPCRS,
Abacavir, Zidovudine and Lamivudine Tablets contain BPCRS and lamivudine BPCRS in solvent A,
Abacavir Sulfate, Zidovudine and Lamivudine. tder Related substances, to produce the same
Content of abacavir, C,,H,;,N;O
Content of zidovudine, C,;9H;3N;O4
CHROMATOGRAPHIE
95.0 to 105.0% of the stated amount. The chromatographi
substances may be used.
Content of lamivudine, C,H, ,N3;0;3S
IDENTIFICATION
A. Carry out the method for thin-layer chromatography,
Appendix III A, using the following solutions.
abacauir sulfate BPCRS, the declared conte [
(1) Shake a quantity of powdered tablets containing the in zidovudine BPCRS and the declared conter
equivalent of 0.2 g of abacavir with 50 mL of water, filter and CgH,1N303S in lamivudine BPCRS.
use the filtrate.
LIMIT
(2) 0.2% wiv of zidovudine BPCRS in water.
The amounts of abacavir, zidovudine and lamivudine
(3) 0.23% wv of abacavir sulfate BPCRS in water.
released are not less than 75% (Q) of the stated amounts.
(4) 0.1% w/v of lamivudine BPCRS in water.
Related substances
CHROMATOGRAPHIC CONDITIONS Carry out the method for liquid chromatography,
(a) Use precoated silica gel F254 plates (Merck silica gel 60 Appendix III D, using the following solutions in solvent A.
SOLVENT A
(b) Use the mobile phase described below.
Dissolve 1.9 g of ammonium acetate in 900 mL of water,
(c) Apply 10 uL of each solution. adjust the pH to 3.9 with glacial acetic acid and dilute to
(d) Develop the plate to 12 cm. 1000 mL.
(e) After removal of the plate, dry it in air and immediately (1) Shake a quantity of the powdered tablets containing the
examine under ultraviolet ight (254 nm). equivalent of 0.1g of abacavir in 60 mL with the aid of
ultrasound for 30 minutes, dilute to 100 mL and filter.
II-90 Abacavir preparations 2016
(2) Dilute 1 volume of solution (1) to 100 volumes. the area of any peak corresponding to zidovudine impurity G
(3) Dilute 1 volume of solution (2) to 10 volumes. (retention relative to zidovudine about 1.4) is not greater
than 0.5 times the area of the peak due to zidovudine in the
(4) 0.002% w/v of thymine.
chromatogram obtained with solution (2) (0.5%);
(5) 0.075% w/v of zidovudine and lamivudine
the area of any peak corresponding to zidovudine impurity 1
impurity standard BPCRS and 0.025% w/v of abacavir
(eluting between lamivudine impurity G and zidovudine
sulfate BPCRS in solvent A.
impurity C) is not greater than 0.4 times the area of the peak
CHROMATOGRAPHIC CONDITIONS due to zidovudine in the chromatogram obtained with
(a) Use a stainless steel column (25 cm x 4.6 mm) packed solution (2) (0.4%);
with octadecylsilyl silica gel for chromatography (5 um) (YMC the area of any peak corresponding to lamivudine impurity A
ODS-A is suitable). is not greater than 3 times the area of the peak due to
(b) Use graéitent elution and the mobile phase described lamivudine in the chromatogram obtained with solution (3)
(0.3%);
the area of any peak corresponding to a named lamivudine
impurity is not greater than 0.2 times the area of the peak
due to lamivudine in the chromatogram obtained with
(f) Inject 10 uL of eat
the area of any peak corresponding to a named zidovudine
MOBILE PHASE impurity is not greater than 0.2 times the area of the peak
Mobile phase A 0.025mM am cetate, the pH adjusted due to zidovudine in the chromatogram obtained with
to 3.9 with glacial acetic acid. solution (2) (0.2%);
Mobile phase B- methanol. the area of any other secondary peak is not greater than
Mobile phase C acetonitrile. 0.2 times the area of the peak due to abacavir in the
Time Mobile Mobile phase Mobile the sum of the areas of all the named zidovudine impurities
(Minutes) phase A
(% viv)
B
(% viv)
phase C
(% viv)
is not greater than 4 times the area of the peak due to
zidovudine in the chromatogram obtained with solution (2)
0-15 95 5 0 isocratic (4.0%);
15-30 95-70 530 0 linear gradient
the sum of the areas of all the named lamivudine impurities
30-38 70 30 0 isocratic
Js not greater than the area of the peak due to lamivudine in
38-60 70-40 30-0 0-100 change of solvent
atogram obtained with solution (2) (1.0%);
60-65 0 0 100 washing column
65-66 0-95 0-5 1000 change in solvent
other secondary peaks is not greater than the area
66-75 95 5 0 re-equilibration due to abacavir in the chromatogram obtained
SYSTEM SUITABILITY
The test is not valid unless: solution (3) “

the chromatogram obtained with solution (5) closely ASSAY
resembles the reference chromatogram supplied with Weigh and powder Carry out the method for
zidovudine and lamivudine impurity standard BPCRS and the hquid chromatography, Apperdix, III D, using the following
retention of abacavir relative to zidovudine is about 1.2; solutions dissolved in solvent;
the resolution between the peaks due to lamivudine substances.
impurity B and lamivudine is at least 2.0; (1) Shake a quantity of the powdg
the resolution between the peaks due to lamivudine and equivalent of 0.1 g of abacavir with | f solvent A in a
thymidine is at least 2.0; 100 mL amber volumetric flask for 30°thinutes, dilute to
the resolution between the peaks due to zidovudine and 100 mL and filter. Dilute 1 volume to 5'yvol
zidovudine impurity B is at least 4.0; (2) 0.023% w/v of abacavir sulfate BPCRS
the resolution between the peaks due to zidovudine and (3) 0.02% wiv of zidovudine BPCRS.
abacavir is at least 1.5. (4) 0.01% w/v of lamivudine BPCRS.
LIMITS (5) 0.075% w/v of zidovudine and lamivudine
Using the chromatogram obtained with solution (5) and the impurity standard BPCRS and 0.025% w/v of abacavir
reference chromatogram supplied with zidovudine and sulfate BPCRS in solvent A.
lamivudine impurity standard BPCRS identify any peaks in CHROMATOGRAPHIC CONDITIONS
solution (1) corresponding to the named lamivudine and
The chromatographic conditions described under Related
zidovudine impurities.
SYSTEM SUITABILITY
the area of any peak corresponding to thymine (zidovudine
impurity C) is not greater than the area of the principal peak The test is not valid unless:
in the chromatogram obtained with solution (4) (2.0%); the chromatogram obtained with solution (5) closely
the area of any peak corresponding to zidovudine impurity B resembles the reference chromatogram supplied with
is not greater than the area of the peak due to zidovudine in zidovudine and lamivudine impurity standard BPCRS and the
the chromatogram obtained with solution (2) (1.0%); retention of abacavir relative to Zidovudine is about 1.2;
2016 Acamprosate Preparations III-91
the resolution between the peaks due to lamivudine TESTS

.
oe whe Fe
impurity B and lamivudine is at least 2.0; Dissolution

.
nya
the resolution between the peaks due to lamivudine and Carry out the dissolution test for tablets and capsules,
thymidine is at least 2.0; Appendix XII B1.
Cy
the resolution between the peaks due to zidovudine and TEST CONDITIONS
zidovudine impurity B is at least 4.0; First stage
the resolution between the peaks due to zidovudine and (a) Use Apparatus 1, rotating the basket at 180 revolutions
abacavir is at least 1.5. per minute.
DETERMINATION OF CONTENT (b) Use 900 mL of 0.1m hydrochloric acid, at a temperature of
Using solutions (1) and (2), calculate the total content of 37°, as the medium.
C,4H, sNo@ in the tablets from the chromatograms obtained PROCEDURE
ed.content of C,4H;gNeOin abacavir (1) After 2 hours, withdraw a 20-mL sample of the medium,
filter through a 0.45-pm filter and dilute, if necessary, to
d (3), calculate the total content of produce a solution expected to contain 0.037% w/v of
Ci0H13N50.4 in theta s from the chromatograms obtained Acamprosate Calcium.
using the declared con f Cy0H13N504 in
(2) 0.00185% w/v of acamprosate calcium BPCRS in
zidovudine BPCRS. 0.1M hydrochloric acid.
Using solutions (1) and" te the total content
CgH,,N303S in the tablet chromatograms
obtained using the declared ca (a) Use a stainless steel column (10 cm x 4.6 mm) packed
lamivudine BPCRS. with octylsilyl silica gel for chromatography (4 um) (Synergi
Hydro RP is suitable).
IMPURITIES
(b) Use isocratic elution using the mobile phase described
below.
monograph include impurities, A, B, C,E,
(c) Use a flow rate of 1 mL per minute.
listed under Lamivudine, impurities B, C,
under Zidovudine and the following: (d) Use an ambient column temperature.
O (f) Inject 20 wL of each solution.
Me
HN
L of a solution containing 140.5 mg of sodium
and 170.95 mg of tetrabutylammonium perchlorate
of methanol R2 and dilute to 1000 mL with
OF CONTENT
A
HO NH,
1. 1-[(2R,4S,5S)-4-amino-5-(hydroxymethyl) oxolan-2-yl]-5-
methylpyrimidin-2,4(1H,3H)-dione. LIMITS
The amount of Acamprosé
than 5% of the stated amo
Final stage
Gastro-resistant Acamprosate Tablets
sufficient 0.IM citric acid to produc
Action and use to 6.8, if necessary, with 0.5m citric act
Treatment of alcoholism.
(a) Use Apparatus 1, rotating the basket at
DEFINITION per minute. ,
Gastro-resistant Acamprosate Tablets contain Acamprosate (b) Replace the 0.1m hydrochloric acid in the vessel
Calctum. They are covered with a gastro-resistant coating or 900 mL of buffer pH 6.8, previously held and maintained at
prepared from granules or particles covered with a gastro- 37°.
resistant coating. PROCEDURE
The tablets comply with the requirements stated under Tablets and (1) After 2 hours, withdraw a 20-mL sample of the medium,
with the following requirements. filter through a 0.45-um filter and dilute, if necessary, to
Content of acamprosate calcium, C; 9H 2) CaN,O,S, produce a solution expected to contain 0.037% w/v of
95.0 to 105.0% of the stated amount. Acamprosate Calcium.
(2) 0.037% w/v of acamprosate calcium BPCRS in buffer
IDENTIFICATION
pH 6.8.
A. In the Assay, the retention time of the principal peak in
the chromatogram obtained with solution (1) is similar to CHROMATOGRAPHIC CONDITIONS
that of the principal peak in the chromatogram obtained with The chromatographic conditions described under the first
solution (2). stage may be used.
B. The powdered tablets yield reaction A characteristic of
calcium salts, Appendix VI.
I-92 Acebutolol Preparations 2016
DETERMINATION OF CONTENT (2) 0.033% w/v of acamprosate calctum BPCRS in mobile

Calculate the total content of C;>)H2)>CaN»,OgS> in the phase.
medium using the declared content of C}>)H2)>CaN2OgS, in CHROMATOGRAPHIC CONDITIONS
acamprosate calcium BPCRS.
(a) Use a stainless steel column (10 cm x 4.6 mm) with a
LIMITS stainless steel pre-column (7.5 cm x 4.6 mm) both packed
The amount of Acamprosate Calcium released is not less with octadecylsilyl silica gel for chromatography (5 um)
than 75% (Q) of the stated amount. (Spherisorb ODS2 is suitable).
Impurity A (homotaurine) (b) Use isocratic elution using the mobile phase described
Carry out the method for liguid chromatography, below.
Appendix III D, using the following solutions. (c) Use a flow rate of 1 mL per minute.
(1) Remove the tablet coating from 5 tablets by stirring with (d) Use an ambient column temperature.
MOBILE PHASE
To 850 mL of a solution containing 140.5 mg of sodium

perchlorate and 342 mg of tetrabutylammonium perchlorate add
d-glass-stoppered tube. 100 mL of methanol R2 and dilute to 1000 mL with water.
Add 0.15 mL of a freshlyeg ed 0.5% w/v solution of SYSTEM SUITABILITY
fluorescamine in acetonitrile. Sk
Inject solution (2) five times. The test is not valid unless the
for 30 seconds. Place in a waté
relative standard deviation of the area of the principal peak is
at most 2.0%.
Calculate the content of C;9H2)>CaN,O¢S, in the tablets

from the chromatogram obtained and using the declared
borate buffer solution pH 10.4. Treat 3.0 mL of this content of Cjp>H2.>CaN,OgS, in acamprosate calcium BPCRS.
the same way as solution (1).
(a) Use a stainless steel column (15 cm x 4.6 mm) wit
stainless steel pre-column (7.5 cm x 4.6 mm) both packe sutolol Capsules
with octadecylsilyl silica gel for chromatography (5 wm) (Hypersil |
ODS is suitable).
below.
(d) Use an ambient column temperature.
(g) Allow the chromatography to proceed for 6 times the
retention time of impurity A.
MOBILE PHASE
10 volumes of acetonitrile, 10 mL of methanol and 80 volumes

of 0.1m phosphate buffer solution pH 6.5. Appendix II A, is concordant with the.sefe
When the chromatograms are recorded under the prescribed Acebutolol hydrochloride (RS 380).
conditions the retention time of fluorescamine is about TESTS
4 minutes and impurity A is about 8 minutes. Acamprosate Related substances
is not detected. Carry out the method for thin-layer chromatography
LIMITS Appendix III A, using the following solutions.
In the chromatogram obtained with solution (1): (1) Add to a quantity of the contents of the capsules
the area of any peak due to impurity A is not greater than containing the equivalent of 0.4 g of Acebutolol 20 mL of a
the area of the principal peak in the chromatogram obtained mixture of equal volumes of chloroform and methanol, shake
with solution (2) (0.1%). for 2 minutes, centrifuge and use the supernatant liquid.
(2) Dilute 3 volumes of solution (1) to 100 volumes with a
ASSAY
mixture of equal volumes of chloroform and methanol and
Carry out the method for liguid chromatography, further dilute 1 volume of this solution to 10 volumes with
Appendix III D, using the following solutions. the same mixture of solvents.
(1) Weigh and powder 20 tablets. Shake, with the aid of (3) Dilute 1 volume of solution (1) to 100 volumes with a
ultrasound, a quantity of the powdered tablets containing mixture of equal volumes of chloroform and methanol and
333 mg of Acamprosate Calcium with 150 mL of mobile further dilute 1 volume of this solution to 10 volumes with
phase, dilute to 200 mL and filter through a 0.45-um filter.
the same mixture of solvents.
Dilute 1 volume of the resulting solution to 5 volumes.
pe em Pe ee pe tte ee .
a 2a a Na alte wd we ee a ee
2016 Acenocoumarol Preparations III-93
CHROMATOGRAPHIC CONDITIONS mixture, shaken for 2 minutes and centrifuged. Use the
(a) Use a precoated silica gel F,5, plate (Merck silica gel 60 supernatant liquid.
F554 plates are suitable). (2) Dilute 3 volumes of solution (1) to 100 volumes with the
(b) Use the mobile phase as described below. solvent mixture. Further dilute 1 volume of the resulting
(c) Apply 10 uL of each solution. solution to 10 volumes with the solvent mixture.
(d) Develop the plate to 15 cm. (3) Dilute 1 volume of solution (1) to 100 volumes with the
solvent mixture. Further dilute 1 volume of the resulting
(e) After removal of the plate, dry in air and examine under
solution to 10 volumes with the solvent mixture.
ultraviolet light (254 nm).
MOBILE PHASE
(a) Use a precoated silica gel F254 plate (Merck silica gel 60
20 volumes of glacial acetic acid, 20 volumes of
dimethylfeymamide and 60 volumes of chloroform.
(b) Use the mobile phase as described below.
(d) Develop the plate to 15 cm. |
(e) After removal of the plate, allow it to dry in air and
MOBILE PHASE
Disregard any spot rem: 20 volumes of glacial acetic acid, 20 volumes of

dimethylformamide and 60 volumes of chloroform.
ASSAY
LIMITS
To a quantity of the mixed «
teed In the chromatogram obtained with solution (1):
any secondary spot is not more intense than the spot in the
not more than two such spots are more intense than the spot
solution add 10 mL of 0.1m hydrochloric acid a in the chromatogram obtained with solution (3) (0.1%).
water to produce 100 mL. Measure the absorbane Disregard any spot remaining on the line of application.
solution, Appendix II B, at the maximum at 233 nn’
calculate the content of C;gH2sN2O, in the capsules taking ASSAY
643 as the value of A(1%, 1 cm) at the maximum at Shake a number of whole tablets containing the equivalent of
233 nm. Acebutolol with 250 mL of water until completely
ated, add sufficient water to produce 1000 mL, filter
STORAGE
te 10 mL of the filtrate to 250 mL with water.
Acebutolol Capsules should be protected from light.
LABELLING
The quantity of active ingredient is stated in terms of the
equivalent amount of acebutolol.
maximum at 23
LABELLING
Acebutolol Tablets The quantity of acti
equivalent amount of A
Action and use
Beta-adrenoceptor antagonist.
DEFINITION
Acebutolol Tablets contain Acebutolol Hydrochloride. Acenocoumarol Tablets
Action and use :
Vitamin K epoxide reductase inhibitor; oral antoagulant.
Content of acebutolol, C,;3;H>,;N,O,4
95.0 to 105.0% of the stated amount. DEFINITION
IDENTIFICATION Acenocoumarol Tablets contain Acenocoumarol.
The infrared absorption spectrum of a 0.7% w/w dispersion of The tablets comply with the requirements stated under Tablets and
the powdered tablets in potasstum bromide, Appendix II A, is with the following requirements.
concordant with the reference spectrum of acebutolol Content of acenocoumarol, C,9H,;NO,
hydrochloride (RS 380). 92.5 to 107.5% of the stated amount.
TESTS IDENTIFICATION
Related substances A. Heat a quantity of the powdered tablets containing 50 mg
Carry out the method for thin-layer chromatography, of Acenocoumarol with 30 mL of acetone undera reflux
Appendix III A, using the following solutions in a solvent condenser for 5 minutes, filter and wash the residue with two
mixture of equal volumes of chloroform and methanol. 10 mL quantities of acetone. Evaporate the combined filtrate
(1) A quantity of the powdered tablets containing the and washings to 5 mL, add water drop wise until the solution
equivalent of 0.4 g of Acebutolol in 20 mL of the solvent becomes turbid, heat on a water bath until the solution is
IiI-94 Acetazolamide Preparations 2016
clear and allow to stand. Filter, wash the crystals with a 100 mL and measure the absorbance of the resulting solution
mixture of equal volumes of acetone and water and dry at at the maximum at 306 nm, Appendix II B. Calculate the
100° at a pressure of 2 kPa for 30 minutes. The infrared content of C;9H,;;NOg¢ taking 521 as the value of
absorption spectrum of the residue, Appendix II A, is A(1%, 1 cm) at the maximum at 306 nm.
concordant with the reference spectrum of acenocoumarol
(RS 001).
B. The light absorption, Appendix II B, of the final solution
obtained in the Assay exhibits maxima at 283 nm and
306 nm.
Acetazolamide Oral Suspension
NOTE: Acetazolamide Oral Suspension is not currently licensed in
C. Heat 25 mg of the residue obtained in test A with 2.5 mL
the United Kingdom.
of glacial acetic acid, 0.5 mL of hydrochloric acid and 0.2 g of
zinc powder o ater bath for 5 minutes, cool and filter.
Action and use
Q0%mL of sodium nitrite solution and add Carbonic anhydrase inhibitor; diuretic; treatment of
fa 1% wW solution of 2-naphthol glaucoma and ocular hypertension; treatment of mountain
um hydroxide. A bright red sickness.
precipitate is produced:
TESTS DEFINITION
Related substances Acetazolamide Oral Suspension is a suspension containing
Acetazolamide in a suitable flavoured vehicle.
The oral suspension complies with the requirements stated under
(1) Shake a quantity of the powde Oral Liquids, the requirements stated under Unlicensed Medicines
20 mg of Acenocoumarol with 5 and with the following requirements.
and use the supernatant liquid. Content of acetazolamide, C,H;N,0;3S,
(2) Dilute 1 volume of solution (1) to 200 vi 95.0 to 105.0% of the stated amount.
acetone. Shake the oral suspension vigorously before carrying out the
CHROMATOGRAPHIC CONDITIONS following tests.
(a) Use as the coating silica gel GF 254. IDENTIFICATION
(b) Use the mobile phase as described below. . In the Assay, the chromatogram obtained with solution
hows a peak with the same retention time as the
(c) Apply 20 wL of each solution.
akin the chromatogram obtained with
(e) After removal of the plate, dry in air and immediately
examine under ultraviolet light (254 nm).
MOBILE PHASE L of weak copper sulfate solution.
20 volumes of glacial acetic acid, 50 volumes of chloroform and r or precipitate is produced.
50 volumes of cyclohexane. TESTS
LIMITS Acidity
Any secondary spot in the chromatogram obtained with pH, 4.0 to 5.0, Appén
solution (1) is not more intense than the spot in the Dissolution
chromatogram obtained with solution (2) (0.5%). Complies with the requirerii
Uniformity of content Medicines, Oral Suspensions,
Tablets containing less than 2 mg and/or less than 2% w/w
of Acenocoumarol comply with the requirements stated
under Tablets using the following method of analysis. Finely volume of the oral suspension containing |
crush one tablet, add 30 mL of methanol, stir the mixture for Related substances
30 minutes and filter through sintered glass, washing the Carry out the method for thin-layer chroma
residue with three 15 mL quantities of methanol. To the Appendix III A, using the following solutions.
combined filtrate and washings add 10 mL of 1M hydrochloric (1) Shake a quantity of the oral suspension conta mg
acid and sufficient methanol to produce 100 mL. If necessary of Acetazolamide for 20 minutes with 10 mL of a mixture of
dilute further with a solvent prepared by diluting 1 volume of equal volumes of ethanol (96%) and ethyl acetate and filter.
Im hydrochloric acid to 10 volumes with methanol to produce a
(2) Dilute 1 volume of solution (1) to 100 volumes with a
solution containing about 0.001% w/v of Acenocoumarol.
mixture of equal volumes of ethanol (96%) and ethyl acetate.
Measure the absorbance of the resulting solution at the
maximum at 306 nm, Appendix II B. Calculate the content CHROMATOGRAPHIC CONDITIONS
of CyjoH,5NO,¢ taking 521 as the value of A(1%, 1 cm) at the (a) Use as the coating silica gel GF 254.
maximum at 306 nm. (b) Use the mobile phase as described below. Use the tank
ASSAY without lining the walls and allow to saturate for 1 hour
Weigh and powder 20 tablets. To a quantity of the powder before development.
containing 1 mg of Acenocoumarol add 30 mL of methanol, (c) Apply 20 uL of each solution.
stir the mixture for 30 minutes and filter through sintered (d) Develop the plate to 15 cm.
glass, washing the residue with three 15 mL quantities of (e) After removal of the plate, allow it to dry in air and
methanol. To the combined filtrate and washings add 10 mL examine under ultraviolet light (254 nm).
of 1m hydrochloric acid and sufficient methanol to produce
2016 Acetylcysteine Preparations IIJ-95
MOBILE PHASE IDENTIFICATION

A freshly prepared mixture of 20 volumes of 13.5mM ammonia, A. Shake a quantity of the powdered tablets containing 0.5 g
30 volumes of ethyl acetate and 50 volumes of propan-2-ol. of Acetazolamide with 2 mL of 1M sodium hydroxide and
LIMITS
filter. Neutralise the filtrate with glacial acetic acid, filter and
dry the resulting precipitate at 105°. The infrared absorption
Any secondary spot in the chromatogram obtained with
spectrum of the residue, Appendix II A, is concordant with
solution (1) is not more intense than the spot in the
the reference spectrum of acetazolamide (RS 002).
chromatogram obtained with solution (2) (1%).
B. Triturate a quantity of the powdered tablets containing
ASSAY 0.5 g of Acetazolamide with a mixture of 5 mL of water and
Carry out the method for liquid chromatography, 1 mL of 1M sodium hydroxide, transfer to a test tube, add
Appendix III D, using the following solutions. 0.2 g of zinc powder and 0.5 mL of hydrochloric acid and
eighed quantity of the oral suspension containing immediately place a piece of lead acetate paper over the mouth
“alamide add 50 mL of methanol and mix of the tube. The paper exhibits a brownish black colour.
trasound for 5 minutes. Add sufficient C. To a quantity of the powdered tablets containing 25 mg
ide to produce 200 mL and mix with the of Acetazolamide add 5 mL of water, 0.15 mL of 1m sodium
aid of shakitig fog inutes; dilute 10 mL of the resulting hydroxide and 0.1 mL of weak copper sulfate solution.
solution to 100 mL water and filter through a 0.45-um A greenish blue colour or precipitate is produced.
filter.
TEST
(2) To 0.25 g of acetaze idésBPCRS add 50 mL of Related substances
methanol and mix with en! Itrasound for 5 minutes.
Carry out the method for thin-layer chromatography,
Add sufficient 0.01M sodium
and mix with the aid of shal utes; dilute 10 mL
of the resulting solution to 1 ater and filter (1) Shake a quantity of the powdered tablets containing
through a 0.45-um filter. 50 mg of Acetazolamide for 20 minutes with 10 mL of a
mixture of equal volumes of ethanol (96%) and ethyl acetate
CHROMATOGRAPHIC CONDITIONS and filter.
(a) Use a stainless steel column (10 cm x (2) Dilute 1 volume of solution (1) to 100 volumes with the
with aminopropylsilyl silica gel for chromatography ( : same solvent mixture as for solution (1).
(Ascentis Express RP-Amideis suitable). tecL,
n and the mobile phase
(b) Use isocratic elutio
below. (a) Use as the coating silica gel GF54.
(c) Use a flow rate of 1 mL per minute. se a mobile phase freshly prepared as described below.
tank without lining the walls and allow to saturate
(d) Use a column temperature of 30°.
our before development.
fy 20 uL of each solution.
MOBILE PHASE
5 volumes of methanol and 95 volumes of a 0.0631% w/v
solution of ammonium formate, adjusted to pH 3.5 with formic
acid.
and 50 volumes of #
Determine the weight per mL of the oral suspension,
LIMITS
Appendix V G, and calculate the content of C,H,N,03S,,
weight in volume, using the declared content of Any secondary spot in the
C4,H.6N403S, in acetazolamide BPCRS. solution (1) is not more interise
chromatogram obtained with sol
STORAGE
ASSAY
Acetazolamide Oral Suspension should be protected from
light.
dimethylformamide and carry out Method II for ngii-
titration, Appendix VII A, using 0.1m tetrabutylammonium
hydroxide VS as titrant and determining the end point
Acetazolamide Tablets potentiometrically. Each mL of 0.1M tetrabutylammonium
hydroxide VS is equivalent to 22.22 mg of CaHgN4O3S>.
Action and use
Carbonic anhydrase inhibitor; diuretic; treatment of
glaucoma, ocular hypertension, mountain sickness.
Acetylcysteine Eye Drops
DEFINITION
Acetazolamide Tablets contain Acetazolamide. Action and use
The tablets comply with the requirements stated under Tablets and Sulfydryl donor; mucolytic; treatment of dry eye syndrome.
DEFINITION
Content of acetazolamide, C,H;N,O;S, Acetylcysteine Eye Drops are asterile solution of
95.0 to 105.0% of the stated amount. Acetylcysteine in Purified Water containing Sodium
Hydroxide.
IlI-96 Acetylcysteine Preparations 2016
The eye drops comply with the requirements stated under Eye and cystine is less than one quarter of the height of the peak
Preparations, and with the following requirements. corresponding to cysteine;
Content of acetylcysteine, C;H,NO;S in the chromatogram obtained with solution (3) a peak
95.0 to 105.0% of the stated amount. corresponding to N,N’-diacetyl-L-cystine appears which has a
retention time of about 13 minutes. The area of this peak is
IDENTIFICATION
greater than the area of any corresponding peak in the
To a volume containing 0.8 g of Acetylcysteine add
3m hydrochloric acid until the pH of the solution is 2.0. Add,
while stirring continuously, two 200-mg portions of finely LIMITS
powdered sodium chloride followed, if necessary, by further In the chromatogram obtained with solution (1):
25-mg portions of sodium chloride until a precipitate begins to the area of any peak corresponding to N,N’-diacetyl-L-cystine
appear. Allow to stand for 15 minutes, filter and dry the is not greater than twice the area of the peak corresponding
residue @t a pressure not exceeding 0.7 kPa for to acetylcysteine in the chromatogram obtained with solution
2 hours. ‘absorption spectrum of the residue, (4) (1%);
Appendix IF’ A,is ceticordant with the reference spectrum of the area of any peak corresponding to cysteine or cystine is
acetylcysteine (f .Examine as discs prepared using
not greater than the area of the corresponding peak in the
potassium bromide. :
TESTS the sum of the areas of any other secondary peaks is not
Acidity greater than the area of the peak corresponding to
pH, 5.5 to 6.5, Appendix V acetylcysteine in the chromatogram obtained with solution
Related substances (4) (1%).
Disregard any peak with an area less than 0.05 times that of
the peak corresponding to acetylcysteine in the
chromatogram obtained with solution (4) (0.05%).
immediately before use.
ASSAY
(1) Dilute a volume of the eye drops with suffi i Carry out the method for liquid chromatography,
mobile phase to produce a solution containing 0.2 Appendix III D, using the following solutions. Prepare the
Acetylcysteine. solutions immediately before use.
(2) 0.2% w/v of acetylcystenme BPCRSin the mobile oh ; (1) Dilute a volume of the eye drops with sufficient of the
(3) 0.2% w/v of acetylcystenme BPCRSin the mobile phas nobile phase to produce a solution containing 0.2% w/v of
stored at room temperature for at least 2 hours before use. teine.
(4) Dissolve 20 mg of L-cysteme and 20 mg of L-cystine in v of acetylcysteine BPCRS in the mobile phase.
10 mL of 1m hydrochloric acid, add 40 mg of
MAZOGRAPHIC CONDITIONS
acetylcysteme BPCRS and immediately dilute to 100 mL with
the mobile phase. Dilute 10 mL of the resulting solution to yromatographic conditions described under Related
200 mL with the mobile phase.
(C5H).NO3S in the eye drops using
(a) Use a stainless steel column (25 cm x 5 mm) packed
with octadecylsilyl silica gel for chromatography (5 um) a9NO3S in acetylcysteine BPCRS.
(Lichrosorb RP18 is suitable). STORAGE |
(b) Use isocratic elution and the mobile phase described Acetylcysteine Eye Drops’s:
below. stored at a temperature of 2°t
(c) Use a flow rate of 1 mL per minute. IMPURITIES
(f) Inject 20 uwL of each solution.
European Pharmacopoeia monographN rosp rely.
(g) Inject solutions (2) and (3) and allow the
chromatography to proceed for three times the retention time
of acetylcysteine.
When recorded under the prescribed conditions, the
chromatogram obtained with solution (4) shows three peaks
Acetylcysteine Injection
with retention times of about 3.6 minutes (cystine), about Action and use
4 minutes (cysteine) and about 6 minutes (acetylcysteine). Sulfydryl donor; antidote to paracetamol poisoning;
MOBILE PHASE mucolytic.
DEFINITION
solution of ammonium sulfate containing 0.02m sodium
Acetylcysteine Injection is a sterile solution in Water for
pentanesulfonate, the solution being adjusted to pH 2.0 using
Injections of acetylcysteine sodium, prepared by the
2M hydrochloric acid.
interaction of Acetylcysteine with Sodium Hydroxide.
SYSTEM SUITABILITY
The injection complies with the requirements stated under
The test is not valid unless: Parenteral Preparations and with the following requirements.
tae lb de in the chromatogram obtained with solution (4), the height Content of acetylcysteine, C;Ho»NO;S
of the trough separating the peaks corresponding to cysteine 95.0 to 105.0% of the stated amount.
2016 Acetylcysteine Preparations TII-97
IDENTIFICATION in the chromatogram obtained with solution (3), a peak due

To a volume containing the equivalent of 0.8 g of to N,N’-diacetylcystine appears which has a retention time of
acetylcysteine add 3m hydrochloric acid until the pH of the about 13 minutes. The area of this peak is greater than the
solution is 2. Add, while stirring continuously, two 200 mg area of any corresponding peak in the chromatogram
portions of finely powdered sodium chloride followed, if obtained with solution (2).
necessary, by further 25mg portions of sodium chloride until a LIMITS
precipitate begins to appear. Allow to stand for 15 minutes,
filter and dry the residue at 70° at a pressure not exceeding
0.7 kPa for 2 hours. The ifrared absorption spectrum of the the area of any peak corresponding to N,N'-diacetylcystine is
residue, Appendix II A, is concordant with the reference not greater than the area of the peak due to acetylcysteine in
spectrum of acetylcysteine (RS 003). Examine as discs the chromatogram obtained with solution (4) (1%);
prepared.using potassium bromide. the area of any peak due to cysteine or cystine is not greater
than the corresponding peak in the chromatogram obtained
with solution (4) (0.5%);
the sum of the areas of any other secondary peaks is not
greater than the area of the peak due to acetylcysteine in the
Disregard any peak with an area less than the area of the
peak due to acetylcysteine in the chromatogram obtained
exception of solution (
with solution (5) (0.1%).
Hydrogen sulfide
(1) Dilute the injection wi
solution containing the equiv Place a quantity of the injection containing the equivalent of
0.4 g of Acetylcysteine in a round-bottomed, three-necked
Acetylcysteine.
flask containing 40 mL of water. The flask is fitted with a gas
(2) 0.2% w/v solution of N-acetyl-L-cys; the mobile
inlet tube which reaches nearly to the bottom of the flask, a
phase. hag
dropping funnel containing hydrochloric acid and an outlet
(3) 0.2% w/v solution of N-acetyl-L-cysteine i tube leading to a 100 mL graduated flask containing a
phase and store at room temperature for at least mixture of 1 mL of 5M sodium hydroxide and 50 mL of water.
before use. Pass through the flask a steady current of nitrogen and add
(4) Dissolve 20 mg of L-cysteine and 20 mg of L-cystine 1 10 mL of hydrochloric acid from the dropping funnel.
10 mL of Im hydrochloric acid, add 40 mg of N-acetyl Maintain the current of nitrogen for 30 minutes and then
cysteime and immediately dilute to 100 mL with the mobile™ nect the absorption flask. Add to the flask 10 mL of a
phase. Dilute 10 mL of the resulting solution to 200 mL prepared by dissolving 0.1 g of N,N-dimethyl-p-
with the mobile phase. diamine dihydrochloride in a mixture of 45 mL of
(5) Dilute 1 volume of solution (4) to 10 volumes with ric acid and 55 mL of water decolourised with
mobile phase. oal before use, if necessary, and 5 mL ofa
in. of wron(IID chloride hexahydrate in
(a) Use a stainless steel column (25 cm x 5 mm) packed protected fro “Add sufficient water to produce 100 mL
with octadecylsilyl sihca gel for chromatography (5 wm) and measure th yce of the solution, Appendix II B, at
(Lichrosorb RP18 is suitable). 1 pathlength and using in the reference
(b) Use isocratic elution and the mobile phase described cell a solution prepared. same manner but without the
below. injection being examined
(c) Use a flow rate of 1 mL per minute. Prepare a 0.4% w/v solut sodium sulfide. Standardise
(d) Use an ambient column temperature. this solution in the following mar
(e) Use a detection wavelength of 205 nm. 0.05m iodine VS add 8 mL of hye
the sodium sulfide solution. Titra
thiosulfate solution VS using starch solutie
(g) Allow the chromatography to proceed for three times the end point, as indicator. Repeat the operat
retention time of acetylcysteine. sodium sulfide solution. The concentration a:
The retention times of cystine, cysteine and acetylcysteine are sulfide solution expressed in parts per million of’
about 3.6 minutes, 4 minutes and 6 minutes respectively. sulfide is the difference between the titrations multiplied by
MOBILE PHASE 68.16. Prepare a solution containing the equivalent of
20 ppm of hydrogen sulfide by appropriate dilution of the
10 volumes of methanol and 90 volumes of a 0.5% wiv
sodium sulfide solution with water.
solution of ammonium sulfate containing 0.02m sodium
pentanesulfonate, the mixture being adjusted to pH 2.0 using Repeat the procedure carried out on the injection using 2 mL
2M hydrochloric acid. of the 20ppm hydrogen sulfide solution in place of the
injection being examined. The absorbance of the solution
SYSTEM SUITABILITY
obtained from the injection is not greater than the
The test is not valid unless: absorbance of the solution obtained from the standard
in the chromatogram obtained with solution (4), the height (100 ppm with reference to the content of acetylcysteine).
of the trough separating the peaks due to cysteine and cystine Bacterial endotoxins
is less than one quarter of the height of the peak due to Carry out the test for bacterial endotoxins, Appendix XIV C.
cysteine; If necessary, dilute the injection with water BET to give a
solution containing 10 mg per mL (solution A).
I-98 Aciclovir Preparations 2016
The endotoxin limit concentration of solution A is not more TEST

than 0.3 IU per mL. Related substances
ASSAY Carry out the method for liquid chromatography,
Appendix III D, using the following solution, in a solvent
Add 20 mL of glacial acetic acid to a volume containing the
mixture of 1 volume of dimethyl sulfoxide and 4 volumes of
equivalent of 0.4 g of Acetylcysteine and titrate with
water unless otherwise indicated.
0.05Mm todine VS until a permanent pale yellow colour is
obtained. Each mL of 0.05 todine VS is equivalent to (1) Mix with the aid of ultrasound a quantity of the well-
16.23 mg of C5HoNO3S. mixed cream containing 25 mg of Aciclovir in 10 mL of
dimethyl sulfoxide dilute to 25 mL with the solvent mixture
STORAGE
and filter through a 0.2-um nylon filter.
Acetylcysteine Injection should be protected from light.
(2) Dilute 1 volume of solution (1) to 100 volumes and
further dilute 1 volume to 5 volumes.
The stret fed in terms of the equivalent amount of (3) Dissolve 5 mg of aciclovir for system suitability EPCRS
Acetylcysteine 1 itable dose-volume. (containing impurities A, B, J, K, N, O and P) in 1 mL of
IMPURITIES dimethyl sulfoxide and dilute to 5.0 mL with water.
The impurities limi e requirements of this (4) Dissolve the contents of a vial of aciclovir for peak
monograph include identification 1 EPCRS (containing impurities C and J) in
1. L-cystine, 200 uL of dimethyl sulfoxide and dilute to 1.0 mL with water.
Prepare the solution immediately before use.
2. L-cysteine,
(5) Dissolve the contents of a vial of aciclovir for peak
identification 2 EPCRS (containing impurities F and G) in
1.0 mL of solution (3).
with octadecylsilyl sihca gel for chromatography (5 um)
(Supelcosil LC-18-DB is suitable).
below.
Use a flow rate of 1 mL per minute.
3. N,N’-diacetyl-l-cystine. n ambient column temperature.

etection wavelength of 254 nm.
uL of each solution.
Aciclovir Cream tion pH 3.1 Dissolve 3.48 g of

dipotassium hy lophosphate in 1000 mL of water and
Action and use adjust to pH 3% hophosphoric acid.
Purine nucleoside analogue; antiviral (herpes viruses). Phosphate buffer solittio 2.5 Dissolve 3.48 g of
dipotassium hydrogen érth hate in 1000 mL of water and
DEFINITION sphoric acid.
adjust to pH 2.5 with or
Aciclovir Cream contains Aciclovir in a suitable basis.
Mobile phase A 1 volume of ac trile and 99 volumes of
The cream complies with the requirements stated under Topical phosphate buffer solution p
ne teal Semi-solid Preparations and with the following requirements.
Mobile phase B 50 volumes of aéetomeri d 50 volumes of
Content of aciclovir, Cs;H,,N;O3 phosphate buffer solution pH 2.5.
IDENTIFICATION Time Mobile phase A Mobile phase
A. Shake a quantity of the well-mixed cream containing (Minutes) (% viv) (% viv)
about 7.5 mg of Aciclovir with 50 mL of 0.5m sulfuntc acid.
0-5 100 0 5
Shake well with 50 mL of ethyl acetate, allow to separate and
5-27 100-80 0-20 linear gradient
collect the clear lower aqueous layer. Wash the organic layer
with 20 mL of 0.5m sulfuric acid and dilute the combined 27-40 80 20 isocratic
rn
washings and the aqueous layer to 100 mL with 0.5m sulfuric 40-46 80100 20-0 re-equilibration
acid. Mix well and filter (Whatman GF’F is suitable).
Discard the first few mL of the filtrate and to 10 mL of the
filtrate add sufficient water to produce 50 mL. The light SYSTEM SUITABILITY
absorption, Appendix II B, in the range 230 to 350 nm of the The test is not valid unless:
solution exhibits a maximum at 255 nm and a broad
in the chromatogram obtained with solution (4), the resolution
shoulder at about 274 nm.
between the peaks due to impurity C and aciclovir is at least
B. In the Assay, the retention time of the principal peak in 1.5.
the chromatogram obtained with solution (1) is similar to
that of the principal peak due to aciclovir in the
factor between the peaks due to impurity F and impurity A 1s
a least 1.5 and the resolution between the peaks due to
impurity K and impurity G is at least 1.5.
2016 Aciclovir Preparations III-99
LIMITS

Aciclovir Eye Ointment
multiply the area of any peak corresponding to impurity I by Action and use
a correction factor of 1.5; Purine nucleoside analogue; antiviral (herpes viruses).
the area of any peak corresponding to impurity B is not
greater than 5 times the area of the principal peak in the DEFINITION
chromatogram obtained with solution (2) (1.0%); Aciclovir Eye Ointment is a sterile preparation containing
Aciclovir in a suitable basis.
the area of any peak corresponding to impurity A is not
greater than 1.5 times the area of the principal peak in the The eye ointment complies with the requirements stated under Eye
chromatogram obtained with solution (2) (0.3%); Preparanons and with the following requirements.
the area of anyypeak corresponding to impurity O is not Content of aciclovir, CgsH,,N;O3;
‘ained with solution (2) (0.3%); IDENTIFICATION
r secondary peakis not greater than the A. Disperse a quantity of the eye ointment containing 10 mg
eak in the chromatogram obtained with of Aciclovir in 60 mL of hexane. Extract with three 30-mL
quantities of 0.1m sodium hydroxide, add sufficient
0.1M sodium hydroxide to produce 100 mL and filter.
To 15 mL of this solution add 5 mL of 2m hydrochloric acid
obtained with solution ( and sufficient water to produce 100 mL. The light absorption,
Disregard any peak with Appendix II B, in the range 230 to 350 nm exhibits a
maximum at 255 nm and a broad shoulder at about 274 nm.
solution (2) (0.1%). B. In the Assay, the retention time of the principal peak in
ASSAY sO
that of the principal peak due to aciclovir in the
Carry out the method for liquid chroma chromatogram obtained with solution (2).
Appendix III D, using the following solutié
mixture of 1 volume of dimethyl sulfoxide and 4 TEST
water unless otherwise indicated. Related substances
(1) Mix with the aid of ultrasound a quantity of the vel Carry out the method for liquid chromatography,
mixed cream containing 25 mg of Aciclovirin 10 mL & Appendix III D, using the following solutions, in a solvent
dimethyl sulfoxide dilute to 25 mL with the solvent mixture mixture of 1 volume of dimethyl sulfoxide and 4 volumes of
and filter through a 0.2-uum nylon filter. Further dilute less otherwise indicated.
1 volume to 10 volumes with the solvent mixture. erse a quantity of the eye ointment containing 25 mg
(2) Dissolve 25 mg of aciclovir BPCRS in 10 mL of dimethyl ir in 10 mL of dimethyl sulfoxide dilute to 25 mL
sulfoxide. Dilute 2 volumes to 5 volumes with the solvent the solvent mixture and filter through a 0.2-um nylon
mixture and further dilute 1 volume to 10 volumes with the
solvent mixture.
identification 1 EPCRS (aciclovir with impurities C and I) in
200 uL of dimethyl sulfoxide and dilute to 1.0 mL with water.

SYSTEM SUITABILITY
(5) Dissolve the contents of a via
The test is not valid unless, in the chromatogram obtained identification 2 EPCRS (containing impuri
with solution (3), the resolution factor between the peaks due 1.0 mL of solution (3).
to impurity C and aciclovir is at least 1.5.
(a) Use a stainless steel column (25 cm x 4.61 m) packed
Calculate the content of CgH,;Ns50O3 in the cream using the with octadecylsilyl silica gel for chromatography (5 wm)
declared content of CgH,,N5QO3 in aciclovir BPCRS. (Supelcosil LC-18-DB is suitable).
IMPURITIES (b) Use gradient elution and the mobile phase described
The impurities limited by the requirements of this below.
monograph include those listed under Aciclovir. (c) Use a flow rate of 1 mL per minute.
MOBILE PHASE
Phosphate buffer solution pH 3.1 Dissolve 3.48 g of

dipotassium hydrogen orthophosphate in 1000 mL of water and
adjust to pH 3.1 with orthophosphoric acid.
II-100 Aciclovir Preparations 2016
Phosphate buffer solution pH 2.5 Dissolve 3.48 g of CHROMATOGRAPHIC CONDITIONS

dipotassium hydrogen orthophosphate in 1000 mL of water and The chromatographic conditions described under Related
adjust to pH 2.5 with orthophosphoric acid. substances may be used.
Mobile phase A 1 volume of acetonitrile and 99 volumes of SYSTEM SUITABILITY
phosphate buffer solution pH 3.1.
The test is not valid unless, in the chromatogram obtained
Mobile phase B50 volumes of acetonitrile and 50 volumes of with solution (3), the resolution factor between the peaks due
phosphate buffer solution pH 2.5. to impurity C and aciclovir is at least 1.5.
Calculate the content of CgH,,N5O3 in the eye ointment
using the declared content of CgH,,;N5O3 in
0-5 100 0 isocratic aciclovir BPCRS.
5-27 0-20 linear gradient
IMPURITIES
27-40 20 isocratic The impurities limited by the requirements of this
40-46 20-0 re-equilibration monograph include those listed under Aciclovir.
SYSTEM SUITABILITY
The test is not valid unléés:

in the chromatogram obtained lution (4), the resolution
Aciclovir Infusion
factor between the peaks due t Aciclovir Intravenous Infusion
least 1.5;
Action and use
in the chromatogram obtained with so Purine nucleoside analogue; antiviral (herpesviruses).
a least 1.5 and the resolution factor between t DEFINITION

impurity K andG is at least 1.5. Aciclovir Infusion is a sterile solution containing aciclovir
LIMITS sodium. It is prepared by dissolving Aciclovir Sodium for
In the chromatogram obtained with solution (1): Infusion with a suitable diluent in accordance with the
manufacturer’s instructions.
multiply the area of any peak corresponding to impurity I,
a correction factor of 1.5. The infusion complies with the requirements stated under
eral Preparations and with the following requirements.
greater than 5 times the area of the principal peak in the
the area of any peak corresponding to impurity O is not test for bacterial endotoxins, Appendix XIV C.,
greater than 1.5 times the area of the principal peak in the in limit concentration of the infusion, diluted, if
area of the principal peak in the chromatogram obtained with
solution (2) (0.2%); sed within the period
the sum of the areas of any secondary peaks is not greater than r when prepared and
10 times the area of the principal peak in the chromatogram
obtained with solution (2) (2.0%). instructions.
Disregard any peak with an area less than 0.5 times the area LABELLING >
of the principal peak in the chromatogram obtained with The strength is stated in terms of th
solution (2) (0.1%). Aciclovir in a suitable dose-volume.
ASSAY
Carry out the method for liguid chromatography, ACICLOVIR SODIUM FOR INFU
Appendix III D, using the following solutions in a solvent
DEFINITION
mixture of 1 volume of dimethyl sulfoxide and 4 volumes of
water unless otherwise indicated. Aciclovir Sodium for Infusion is a sterile material prepared
from Aciclovir with the aid of a suitable alkali. It may contain
(1) Disperse a quantity of the eye ointment containing 25 mg
excipients. It is supplied in a sealed container.
of Aciclovir in 10 mL of dimethyl sulfoxide dilute to 25 mL
The contents of the sealed container comply with the requirements
with the solvent mixture and filter through a 0.2-um nylon
filter. Further dilute 1 volume to 10 volumes with the solvent for Powders for Injections or Infusions stated under Parenteral
mixture. Preparations and with the following requirements.
(2) Dissolve 25 mg of aciclovir BPCRS in 10 mL of dimethyl Content of aciclovir, CgH,,;N;O3

sulfoxide. Dilute 2 volumes to 5 volumes with the solvent 95.0 to 105.0% of the stated amount.
mixture and further dilute 1 volume to 10 volumes with the IDENTIFICATION
solvent mixture. A. Dissolve the total contents of 10 containers in sufficient
(3) Dissolve the contents of a vial of aciclovir for peak 0.1m hydrochloric acid to produce 500 mL. Dilute 3 mL of
identification 1 EPCRS (aciclovir with impurities C and I) in the resulting solution to 100 mL with 0.1m hydrochloric acid
200 uL of dimethyl sulfoxide and dilute to 1.0 mL with water. and dilute 5 mL of the resulting solution with the same
Prepare the solution immediately before use. solvent to produce a solution containing the equivalent of
0.0015% w/v of Aciclovir. The light absorption, Mobile phase B 50 volumes of acetonitrile and 50 volumes of
Appendix II B, in the range 230 to 350 nm exhibits a phosphate buffer solution pH 2.5.
maximum at 255 nm and a broad shoulder at about 274 nm.
B. In the Assay, the retention time of the principal peak in Time Mobile phase A Mobile phase B Comment
chromatogram obtained with solution (1) is similar to that of (Minutes) (% viv) (% viv)
the principal peak due to aciclovir in the chromatogram
0-5 100 0 isocratic
obtained with solution (2).
5-27 100-80 0-»20 linear gradient
C. Yield reaction A characteristic of sodium salts,
Appendix VI. 27-40 80 20 isocratic
40-46 80-100 20-0 re-equilibration
SYSTEM SUITABILITY

ciclovir (solution A). The pH of solution A
pendix V L. in the chromatogram obtained with solution (4), the resolution
between the peaks due to impurity C and aciclovir is at least
1.5;
Appendix IV A, and 1 in the chromatogram obtained with solution (5), the resolution
reference solution Yo, A between the peaks due to impurity F and impurity A is a
least 1.5 and the resolution between the peaks due to
Related substances
impurity K and G 1s at least 1.5.
LIMITS

identify any peak corresponding to impurity I using the
chromatogram obtained with solution (4) and the
chromatogram supplied with aciclovir for peak identification
1 EPCRS and multiply the area of this peak by a correction
resulting solution to 25 volumes with the solvent“i factor of 1.5;
(2) Dilute 1 volume of solution (1) to 100 volumes ‘wi the area of any peak corresponding to impurity B (guanine)
solvent mixture and further dilute 1 volume to 5 volum is not greater than 5 times the area of the principal peak in
with the solvent mixture. shromatogram obtained with solution (2) (1.0%);
(3) Dissolve 5 mg of aciclovir for system suitability EPCRS rea of any peak corresponding to impurity O is not
(containing impurities A, B, J, K, N, O and P) in 1 mL of an 1.5 times the area of the principal peak in the
dimethyl sulfoxide and dilute to 5.0 mL with water.
(4) Dissolve the contents of a vial of aciclovir for peak rea ofany other secondary peak is not greater than the
identification 1 EPCRS (containing impurities C and I) in aren: | rineipal peak in the chromatogram obtained with
200 uL of dimethyl sulfoxide and dilute to 1.0 mL with water. solution
.
. .

: Lo
identification 2 EPCRS (containing impurities F and G) in

. .
a
1.0 mL of solution (3). Disregard any peak w

Co
:
bey
CHROMATOGRAPHIC CONDITIONS of the principal peak in t

riley et Saat
.
’
solution (2) (0.05%).

tigat

ryt
!
with octadecylsilyl silica gel for chromatography (5 um) ASSAY

’ eee
ey .
(Supelcosil LC-18-DB is suitable). Determine the weight of the cont

reg
tat
(b) Use gradient elution and the mobile phase described described in the test for uniformity of
es
a
below. Appendix XII C1, Powders for Parente é

pe
(c) Use a flow rate of 1 mL per minute. method for liquid chromatography, Appendix I
foe
toe ‘
following solutions in a solvent mixture of 1 vol

’
dimethyl sulfoxide and 4 volumes of water unless otherwise

te ,

et3
rele
indicated.
nay
(f) Inject 10 pL of each solution. (1) Shake a quantity of the powder containing the equivalent
Ce tg
: abSCA
MOBILE PHASE of 25 mg of Aciclovir in 10 mL of dimethyl sulfoxide. Dilute

eye
Phosphate buffer solution pH 3.1 Dissolve 3.48 g of 2 volumes of the filtrate to 5 volumes with the solvent
Teh
.
Vy
dipotassium hydrogen orthophosphate in 1000 mL of water and mixture and further dilute 1 volume to 10 volumes with the
ve
solvent mixture.
as

ae
ye
Eaies
Phosphate buffer solution pH 2.5 Dissolve 3.48 g of (2) Dissolve 25 mg of aciclovir BPCRS in 10 mL of dimethyl
yet
Ty ae, gt
sulfoxide. Dilute 2 volumes to 5 volumes with the solvent

VE
dipotassium hydrogen orthophosphate in 1000 mL of water and

eee
,
mixture and further dilute 1 volume to 10 volumes with the

4

. ,
solvent mixture.
,
Mobile phase A 1 volume of acetonitrile and 99 volumes of

tat
ty ‘
eet wk
1
phosphate buffer solution pH 3.1. (3) Dissolve the contents of a vial of aciclovir for peak
}
gt te G Bree te
identification 1 EPCRS (aciclovir with impurities C and I) in

geg gat ‘
, tos ystale
tye ~ghe
fa yeyete
: a
. .
,
‘
ee
ey
ey
/
'
‘
fs
200 uL of dimethyl sulfoxide and dilute to 1.0 mL with water. (3) Dissolve 5 mg of aciclovir for system suitability EPCRS
Prepare the solution immediately before use. (containing impurities A, B, J, K, N, O and P) in 1 mL of
dimethyl sulfoxide and dilute to 5.0 mL with water.
The chromatographic conditions described under Related (4) Dissolve the contents of a vial of aciclovir for peak
substances may be used. identification 1 EPCRS (containing impurities C and I) in
200 uL of dimethyl sulfoxide and dilute to 1.0 mL with water.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained (5) Dissolve the contents of a vial of aciclovir for peak
with solution (3), the resolution between the peaks due to identification 2 EPCRS (containing impurities F and G) in
impurity C and aciclovir is at least 1.5. 1.0 mL of solution (3).
DETERMINATION OF CONTENT CHROMATOGRAPHIC CONDITIONS
Calculate the..content of CgH,;,N5O3 in the powder using the (a) Use a stainless steel column (25 cm x 4.6 mm) packed
H,,N503 in aciclovir BPCRS.
with octadecylsilyl sihca gel for chromatography (5 wm)
monograph inclu below.
LABELLING (c) Use a flow rate of 1 mL per minute.
The label of the sealed c (d) Use an ambient column temperature.
aciclovir sodium in terms wivalent amount of (e) Use a detection wavelength of 254 nm.
Aciclovir. (f) Inject 10 wL of each solution.
MOBILE PHASE
Phosphate buffer solution pH 3.1 Dissolve 3.48 g of

Aciclovir Oral Suspension dipotasstum hydrogen orthophosphate in 1000 mL of water and
Action and use Phosphate buffer solution pH 2.5 Dissolve 3.48 g of
Purine nucleoside analogue; antiviral (herpes viruse dipotasstum hydrogen orthophosphate in 1000 mL of water and
DEFINITION Mobile phase A 1 volume of acetonitrile and 99 volumes of
Aciclovir Oral Suspension is a suspension of Aciclovir in hosphate buffer solution pH 3.1.
suitable flavoured vehicle.
2 hase B 50 volumes of acetonitrile and 50 volumes of
The oral suspension complies with the requirements stated under é buffer solution pH 2.5.
Oral Liquids and with the following requirements.
Content of aciclovir, CgsH,;N;O3
bile phase A Mobile phase B Comment
(% viv)
IDENTIFICATION 0 | isocratic
A. The light absorption, Appendix II B, in the range 230 to
0-20 linear gradient
250 nm of the solution prepared in the Assay before the final
20 isocratic
dilution exhibits a maximum at 255 nm and a broad
shoulder at about 274 nm. 40-46 80-10 20-0 re-equilibration
B. In the Related substances test, the retention time of the

principal peak in the chromatogram obtained with solution
SYSTEM SUITABILITY
(1) is similar to that of the principal peak due to aciclovir in
the chromatogram obtained with a solution prepared as The test is not valid unless:
follows. Dissolve 25 mg of aciclovir BPCRS in 10 mL of in the chromatogram obtained with “(4), the resolution
dimethyl sulfoxide and dilute 2 volumes of the resulting factor between the peaks due to impurity and aciclovir 1s at
solution to 5 volumes with the solvent mixture used in the least 1.5.
Related substances test. in the chromatogram obtained with solution f solution
TESTS factor between the peaks due to impurity F and impurity A is
Acidity at least 1.5 and the resolution factor between the peaks due to
ee
pH, 4.0 to 7.0, Appendix V L. impurity K and G is at least 1.5.

Le eta
Related substances LIMITS

a a
Carry out the method for liquid chromatography, In the chromatogram obtained with solution (1):
ty eeeS
Appendix III D, using the following solutions, in a solvent multiply the area of any peak corresponding to impurity I by
we
mixture of 1 volume of dimethyl sulfoxide and 4 volumes of a correction factor of 1.5.

’
water unless otherwise indicated.

aan

Aa ae
(1) To a quantity of the oral suspension containing 0.5 g of greater than 5 times the area of the principal peak in the
Aciclovir add 20 mL of dimethyl sulfoxide, shake to disperse chromatogram obtained with solution (2) (1.0%);
Ia
i
and add sufficient solvent mixture to produce 100 mL and the area of any peak corresponding to impurity O is not
ae
filter through a 0.2-1m nylon filter. Dilute 1 volume of the greater than 1.5 times the area of the principal peak in the
.
filtrate to 5 volumes with the solvent mixture.

ey
ea

ae
ee ge Oy

dy Ee

egy
Oe
cy
Pa ee al a FreR PEL oe
aET : ete
So
the area of any other secondary peak is not greater than the that of the principal peak due to aciclovir in the
area of the principal peak in the chromatogram obtained with chromatogram obtained with solution (2).
TESTS
the sum of the areas of any secondary peaks is not greater than Dissolution
10 times the area of the principal peak in the chromatogram Comply with the requirements for Monographs of the British
obtained with solution (2) (2.0%). Pharmacopoeia in the dissolution test for tablets and capsules,
Disregard any peak with an area less than 0.25 times the area Appendix XII Bl.
TEST CONDITIONS
solution (2) (0.05%).
(a) Use Apparatus 2, rotating the paddle at 50 revolutions
ASSAY per minute.
taba tlie Oe
To a weighed quantity containing 0.4 g of Aciclovir add

ene
(b) Use 900 mL of 0.1M hydrochloric acid, at a temperature of

ce

pe
‘produce 500 mL. Filter the resulting PROCEDURE

first few mL of filtrate and dilute 5 mL After 45 minutes, withdraw a 25 mL sample of the medium
L with 0.05m sulfuric acid. Add 10 mL and measure the absorbance of the filtered sample, suitably
diluted with the dissolution medium if necessary, at the
d, add sufficient 0.05m sulfuric maximum at 255 nm, Appendix II B, using 0.1m hydrochloric
| measure the fluorescence, acid in the reference cell.
wavelength of 308 nm DETERMINATION OF CONTENT
m. Set the instrument
Calculate the total content of aciclovir, CgH,,;N5O3, in the
medium from the absorbance obtained and taking 560 as the
value of A(1%, 1 cm) at the maximum at 255 nm.
Related substances
by adding 10 mL of a 0.002% w/v soluti Carry out the method for liguid chromatography,
aciclovir BPCRSin 0.05M sulfuric acid an Appendix III D, using the following solutions in a solvent
words ‘... to 5 mL of a 0.01% wiv solution 6f c mixture of 1 volume of dimethyl sulfoxide and 4 volumes of
Determine the weight per mL of the oral suspensién, . water unless otherwise indicated.
Appendix V G, and calculate the content of CgH), (1) Shake a quantity of the powdered tablets containing
weight in volume, using the declared content of CgH,; 25 mg of Aciclovir with 10 mL of dimethyl sulfoxide for
in aciclovir BPCRS. inutes and filter. Dilute 2 volumes of the filtrate to
es with the solvent mixture.
IMPURITIES
The impurities limited by the requirements of this te 1 volume of solution (1) to 100 volumes with the
ixture and further dilute 1 volume to 5 volumes
monograph include those listed under Aciclovir.
Aciclovir Tablets
Action and use
Purine nucleoside analogue; antiviral (herpesviruses).
DEFINITION
Aciclovir Tablets contain Aciclovir.
with the following requirements. CHROMATOGRAPHIC CONDITIONS
Content of aciclovir, CsH,,N;O3 (a) Use a stainless steel column (25 cm :

95.0 to 105.0% of the stated amount. with octadecylsilyl silica gel for chromatography (3
IDENTIFICATION
A. To a quantity of the powdered tablets containing 0.1 g of
below.
Aciclovir add 60 mL of 0.1M sodium hydroxide and disperse
with the aid of ultrasound for 15 minutes. Adda sufficient (c) Use a flow rate of 1 mL per minute.
quantity of 0.1m sodium hydroxide to produce 100 mL, mix (d) Use an ambient column temperature.
well and filter. To 15 mL of the filtrate add 50 mL of water (e) Use a detection wavelength of 254 nm.
and 5.8 mL of 2m hydrochloric acid and sufficient water to (f) Inject 10 wL of each solution.
produce 100 mL. To 5 mL of the solution add sufficient
0.1m hydrochloric acid to produce 50 mL and mix well. The MOBILE PHASE
light absorption, Appendix II B, in the range 230 to 350 nm of Phosphate buffer solution pH 3.1 Dissolve 3.48 g of
the solution exhibits a maximum at 255 nm and a broad dipotassium hydrogen orthophosphate in 1000 mL of water and
shoulder at about 274 nm. adjust to pH 3.1 with orthophosphoric acid.
B. In the Assay, the retention time of the principal peak in Phosphate buffer solution pH 2.5 Dissolve 3.48 g of
the chromatogram obtained with solution (1) is similar to dipotassium hydrogen orthophosphate in 1000 mL of water and
adjust to pH 2.5 with orthophosphonic acid.
Mobile phase A 1 volume of acetonitrile and 99 volumes of (3) Dissolve the contents of a vial of aciclovir for peak
phosphate buffer solution pH 3.1. identification 1 EPCRS (aciclovir with impurities C and I) in
Mobile phase B 50 volumes of acetonitrile and 50 volumes of 200 uL of dimethyl sulfoxide and dilute to 1.0 mL with water.
phosphate buffer solution pH 2.5. Prepare the solution immediately before use.
Time Mobile phase A Mobile phase B Comment The chromatographic conditions described under Related
(Minutes) (% viv) (% viv) substances may be used.
0-5 100 0 isocratic SYSTEM SUITABILITY
5-27 100-80 0-20 linear gradient The test is not valid unless, in the chromatogram obtained
27-40 80 20 isocratic with solution (3), the resolution between the peaks due to
impurity C and aciclovir is at least 1.5.
40-46 . 80-100 20-0 re-equilibration
Calculate the content of CgH,,N5O3 in the tablets using the

declared content of CgH,,;N503 in aciclovir BPCRS.
IMPURITIES
between the peaks ditie monograph include those listed under Aciclovir.
1.5;
least 1.5 and the resolution betw

impurity K and G is at least 1. Dispersible Aciclovir Tablets
LIMITS Action and use
Purine nucleoside analogue; antiviral (herpesviruses).
chromatogram obtained with solution (4) and thé DEFINITION

chromatogram supplied with aciclovir for peak ident; Dispersible Aciclovir Tablets contain Aciclovir in a suitable
1 EPCRS and multiply the area of this peak by a correétion dispersible basis.
factor of 1.5; he tablets comply with the requirements stated under Tablets and
the area of any peak corresponding to impurity B is not following requirements.
greater than 5 times the area of the principal peak in the of aciclovir, CgH,,N;O3
chromatogram obtained with solution (2) (1.0%); .O% of the stated amount.
the area of any peak corresponding to impurity O is not
greater than 1.5 times the area of the principal peak in the
greater than the area of the principal peak in the
the sum of the areas of all secondary peaks is not greater than light absorption, Appendix II B
10 times the area of the principal peak in the chromatogram the final solution exhibits a maxirfruny
obtained with solution (2) (2.0%). shoulder at about 274 nm.
of the principal peak in the chromatogram obtained with (1) shows a principal peak with the same ‘Yet
solution (2) (0.05%). the peak due to aciclovir in the chromatogra
solution (2).
ASSAY
Weigh and finely powder 20 tablets. Carry out the method TESTS
for liquid chromatography, Appendix III D, using the following Related substances
solutions in a solvent mixture of 1 volume of dimethyl Carry out the method for liquid chromatography,
wn
ae aA
sulfoxide and 4 volumes of water unless otherwise indicated. Appendix III D, using the following solutions. Prepare a
solution using the following solutions in a solvent mixture of
(1) Shake a quantity of the powdered tablets containing the
1 volume of dimethyl sulfoxide and 4 volumes of water unless
equivalent of 25 mg of Aciclovir in 10 mL of dimethyl
otherwise indicated.
sulfoxide and filter. Dilute 2 volumes of the filtrate to
5 volumes with the solvent mixture and further dilute (1) Shake a quantity of the powdered tablets containing
1 volume to 10 volumes with the solvent mixture. 25 mg of Aciclovir with 10 mL of dimethyl sulfoxide for
15 minutes and filter. Dilute 2 volumes of the filtrate to
(2) Dissolve 25 mg of aciclouir BPCRS in 10 mL of dimethyl
5 volumes with the solvent mixture.
sulfoxide. Dilute 2 volumes to 5 volumes with the solvent
mixture and further dilute 1 volume to 10 volumes with the (2) Dilute 1 volume of solution (1) to 100 volumes with
solvent mixture. Solution A and further dilute 1 volume to 5 volumes with
‘2
eae
Solution A.
2016 Acitretin Preparations III-105
(3) Dissolve 5 mg of aciclovir for system suitability EPCRS the area of any other secondary peak is not greater than the
(containing impurities A, B, J, K, N, O and P) in 1 mL of area of the principal peak in the chromatogram obtained with
dimethyl sulfoxide and dilute to 5.0 mL with water. solution (2) (0.2%);
(4) Dissolve the contents of a vial of aciclovir for peak the sum of the areas of any secondary peaks is not greater than
identification 1 EPCRS (containing impurities C and I) in 10 times the area of the principal peak in the chromatogram
200 uL of dimethyl sulfoxide and dilute to 1.0 mL with water. obtained with solution (2) (2.0%).
Prepare the solution immediately before use. Disregard any peak with an area less than 0.25 times the area
(5) Dissolve the contents of a vial of aciclovir for peak of the principal peak in the chromatogram obtained with
identification 2 EPCRS (containing impurities F and G) in solution (2) (0.05%).
ASSAY
CHROMATOGRAPHIC CONDITIONS Weigh and finely powder 20 tablets. Carry out the method
(a) Useg..stainless steel column (25 cm x 4.6 mm) packed for liquid chromatography, Appendix III D, using the following
solutions in a mixture of 1 volume of dimethyl sulfoxide and
4 volumes of water, unless otherwise indicated.
(1) Shake a quantity of the powdered tablets containing
25 mg of Aciclovir in 10 mL of dimethyl sulfoxide and filter.
Dilute 2 volumes of the filtrate to 5 volumes and further
dilute 1 volume to 10 volumes.
(2) Dissolve 25 mg of aciclovir BPCRS in 10 mL of dimethyl
(e) Use a detection w
sulfoxide. Dilute 2 volumes to 5 volumes and further dilute
(f) Inject 10 wL of each | 1 volume to 10 volumes.
MOBILE PHASE (3) Dissolve the contents of a vial of aciclovir for peak
identification 1 EPCRS (containing impurities C and I) in
dipotassium hydrogen orthophosphate
in 200 uL of dimethyl sulfoxide and dilute to 1.0 mL with water.
adjust to pH 3.1 with orthophosphoric : Prepare the solution immediately before use.
Phosphate buffer solution pH 2.5. Dissolvé 3.48. CHROMATOGRAPHIC CONDITIONS
dipotassium hydrogen orthophosphate in 1000 nil. of géarer and The chromatographic conditions described under Related
adjust to pH 2.5 with orthophosphoric acid. substances may be used.
Mobile phase A 1 volume of acetonitrile and 99 vol
SYSTEM SUITABILITY
e test is not valid unless, in the chromatogram obtained
Mobile phase B 50 volumes of acetonitrile and 50 voluméses
solution (3), the resolution between the peaks due to
urity C and aciclovir is at least 1.5.
MINATION OF CONTENT
0-5 100 0 isocratic
5-27 100-80 0—»20 linear gradient
27-40 80 20 isocratic
SYSTEM SUITABILITY
The test is not valid unless: Acitretin Capsule

in the chromatogram obtained with solution (4), the resolution Action and use :
between the peaks due to impurity C and aciclovir is at least Vitamin A analogue (retinoid); treatment ¢ psoriasis;
1.5; ichthyosis; Darier’s disease.
between the peaks due to impurity F and impurity A is a DEFINITION
least 1.5 and the resolution between the peaks due to Acitretin Capsules contain Acitretin.
impurity K and impurity Gis at least 1.5. The capsules comply with the requirements stated under Capsules
LIMITS and with the following requirements.
In the chromatogram obtained with solution (1): Carry out the following tests avoiding exposure to actinic light and
using freshly prepared solutions.
tetey
identify any peak corresponding to impurity I using the

chromatogram obtained with solution (4) and the Content of acitretin, C,,H>,O3
a
tty
chromatogram supplied with aciclovir for peak identification 95.0 to 105.0% of the stated amount.
pty
1 EPCRS and multiply the area by a correction factor of 1.5; IDENTIFICATION

ake
A. Dissolve a quantity of the capsule contents containing

greater than 5 times the area of the principal peak in the 25 mg of Acitretin with sufficient methanol to produce
chromatogram obtained with solution (2) (1.0%); 250 mL, filter and dilute 1 volume of the filtrate to
.
the area of any peak corresponding to impurity O is not 20 volumes with methanol. The light absorption,
oe ot
> eee
he
Cie ae
greater than 1.5 times the area of the principal peak in the Appendix II B, in the range 230 nm to 500 nm exhibits a
chromatogram obtained with solution (2) (0.3%); maximum at 346 nm.
FG
eal
;
r
;
ye AE
IE OEE
III-106 Adapalene Preparations 2016
B. In the Assay, the chromatogram obtained with solution SYSTEM SUITABILITY

(1) shows a peak with the same retention time as the The test is not valid unless:
principal peak in the chromatogram obtained with in the chromatogram obtained with solution (3), the resolution
solution (2). factor between the peaks due to acitretin and tretinoin is at
TESTS least 3.0;
Dissolution in the chromatogram obtained with solution (4), the szgnal-to-
Comply with the dissolution test for tablets and capsules, noise ratio of the principal peak is greater than 10.
Appendix XII Bl.
LIMITS
TEST CONDITIONS In the chromatogram obtained with solution (1):
(a) Use Apparatus 1, rotating the basket at 100 revolutions the area of any secondary peak is not greater than the area of
per minute. the principal peak in the chromatogram obtained with
(b) Use 9 of a 3% w/v solution of sodium lauryl sulfate solution (2) (0.4%);
adjusted 1 ith 0.01m hydrochloric acid or 0.01mM the area of not more than one secondary peak is greater than
sodium hydroxidegat temperature of 37°, as the medium. half the area of the principal peak in the chromatogram
PROCEDURE obtained with solution (2) (0.2%);
After 45 minutes withdraw a sample of the medium, filter the sum of the areas of all the secondary peaks is not greater
through a 10-j1m filteraridgti¢asure the absorbance of the than 2.5 times the area of the principal peak in the
filtrate, suitably diluted wi fici chromatogram obtained with solution (2) (1%).
give a solution expected to Disregard any peak with an area less than the area of the
Acitretin, at the maximum at” principal peak in the chromatogram obtained with solution
(4) (0.1%).
DETERMINATION OF CONTENT ASSAY
Calculate the total content of acitretin, € Carry out the method for liquid chromatography,
medium taking 1373 as the value of A(L% Appendix III D, using the following solutions in a mixture of
maximum at 348 nm. 10 volumes of tetrahydrofuran and 13 volumes of methanol
LIMIT (solvent A).
The amount of Acitretin releasedis not lessthan775 (1) Shake a quantity of the mixed contents of 20 capsules
the stated amount. containing 25 mg of Acitretin with 8 mL of water in a water
path at 45° for 10 minutes. Mix with the aid of ultrasound
Related substances
Appendix III D, using the following solutions in a mixture of
h a 0.45-um filter (PTFE is suitable) and dilute
10 volumes of tetrahydrofuran and 13 volumes of methanol
trate to 25 mL with solvent A.
(solvent A).
of acitretin BPCKS in solvent A.
(1) Shake a quantity of the capsule contents containing
25 mg of Acitretin with 8 mL of water in a water bath at 45°
for 10 minutes. Mix with the aid of ultrasound for
15 minutes, add sufficient solvent A to produce 100 mL and
mix with the aid of ultrasound for a further 5 minutes. Filter
through a 0.45-um filter (PTFE 1s suitable). substances may be use
(2) Dilute 1 volume of solution (1) to 100 volumes with SYSTEM SUITABILITY
solvent A. Further dilute 4 volumes of this solution to
The test is not valid unless, i
10 volumes with solvent A.
with solution (3), the resolution
(3) 0.00025% w/v each of tretinoin EPCRS and to tretinoin and acitretin is at least 3s
acitretin BPCRS in solvent A.
(4) Dilute 1 volume of solution (2) to 4 volumes with solvent
A.
STORAGE
Acitretin Capsules should be protected from light.
with octadecylsilyl silica gel for chromatography (5 wm)
(Spherisorb ODS2 is suitable).
(b) Use isocratic elution and the mobile phase described
Adapalene Cream
ee
’ :
Pa
ve
~
re below.
Action and use
Vitamin A analogue (retinoid); treatment of acne.
(f) Inject 10 pL of each solution. DEFINITION
Adapalene Cream contains Adapalene in a suitable basis.
MOBILE PHASE
The cream complies with the requirements stated under Topical
0.5 volume of glacial acetic acid, 5 volumes of absolute ethanol,
Semi-solid Preparations and with the following requirements.
21 volumes of water and 74 volumes of methanol.
She Ne
par Content of adapalene, C,,H,,03
Sra
at Nee Clea
2016 Adapalene Preparations III-107
IDENTIFICATION Time Excitation wavelength § Emission wavelength

A. Carry out the method for thin-layer chromatography, (Minutes) (nm) (nm)
Appendix III A, using the following solutions. 0-44 360 380
(1) Add 10 mL of tetrahydrofuran to a quantity of cream
containing 5 mg of Adapalene and shake to disperse. 11-30 260 347
Add sufficient methanol to produce a solution containing
0.025% w/v of Adapalene and filter (a 0.2-um Dynagard PP (f) Inject 10 wL of each solution.
filter is suitable). MOBILE PHASE
(2) 0.025% w/v of adapalene BPCRS in the mobile phase. Mobile phase A 0.2 volumes of trifluoroacetic acid and
CHROMATOGRAPHIC CONDITIONS 100 volumes of water.
(a) Use as the coating octadecylsilyl silica gel F254 (Merck silica Mobile phase B40 volumes tetrahydrofuran and 60 volumes
18 F554 plates are suitable). of acetonitrile.


ultraviolet light (z. 3-30 17 83 isocratic
MOBILE PHASE . 30-31 17-+40 8360 linear gradient
18 volumes of tetrahydroft 31-40 40 60 re-equilibration
CONFIRMATION sb
The principal spot in the ch When the chromatograms are recorded under the prescribed
solution (1) corresponds in position’andolour to that in the conditions the retention times relative to adapalene (retention
chromatogram obtained with solution: time about 6.5 minutes) are: impurity A, about 0.5 and
B. In the Assay, the retention time of th al peak in impurity D, about 3.1.
the chromatogram obtained with solution (1) 48's SYSTEM SUITABILITY
that of the principal peak in the chromatogram ob The test is not valid unless the chromatogram obtained with
solution (2). : solution (3) resembles the chromatogram provided with
TESTS adapalene impurity standard BPCRS.
Acidity or alkalinity
Related substances
Carry out the method for liguid chromatography, an the area of the corresponding peak in the
Appendix III D, using the following solutions. ‘am obtained with solution (3) (0.5%);
Solvent A 2 volumes of trifluoroacetic acid and 100 volumes the
of water. 0.1 times
Solvent B 10 volumes of solvent A, 25 volumes of obtained St n (2) (0.1%);
acetonitrile, 30 volumes of propan-2-ol and 35 volumes of the sum of the in ities Is not greater than (1.0%).
tetrahydrofuran. Disregard any pea in area less than the area of the
(1) To a quantity of the cream containing 1 mg of principal peak in th
Adapalene, add 7 mL of tetrahydrofuran and mix with the aid solution (4) (0.05%).
of ultrasound. Add 6 mL of propan-2-ol, shake, add 2 mL of
ASSAY
solvent A and dilute to 20 mL with acetonitrile.
(2) Dilute 1 volume of solution (1) to 100 volumes with
solvent B.
(3) 0.005% w/v of adapalene impurity standard BPCRS in a
mixture of equal volumes of tetrahydrofuran and water.
Adapalene in 10 mL of tetrahydrofuran and sha » with the aid
solvent B.
of ultrasound for 5 minutes, dilute to 50 mL with solvent C
CHROMATOGRAPHIC CONDITIONS and filter (a 0.2-um Dynagard filter is suitable).
(a) Use a stainless steel column (25 cm x 4 mm) packed (2) Dilute 20 volumes of a 0.01% w/v of adapalene BPCRS
with end-capped octadecylsilyl silica gel for chromatography in tetrahydrofuran to 100 volumes with solvent C.
(5 um) (LiChrospher 100 RP 18 is suitable).
(a) Use a stainless steel column (25 cm x 4 mm) witha
below.
stainless steel pre-column (4 cm x 4 mm) both packed with
(c) Use a flow rate of 1.5 mL per minute. end-capped octadecylsilyl silica gel for chromatography (5 um)
(d) Use an ambient column temperature. (LiChrospher 100 RP 18 is suitable).
(e) Use a fluorimetric detector with the following (b) Use isocratic elution and the mobile phase described
programme. below.
TI-108 Adapalene Preparations 2016
(e) Use a detection wavelength of 270 nm. Related substances

(f) Inject 25 wL of each solution. Carry out the method for liquid chromatography,
MOBILE PHASE
Solvent A 2 volumes of trifluoroacetic acid and 100 volumes
0.02 volumes of trifluoroacetic acid, 21 volumes of water,
of water.
36 volumes of tetrahydrofuran and 43 volumes of acetonitrile.
Solvent B 10 volumes of solvent A, 25 volumes of
SYSTEM SUITABILITY
acetonitrile, 30 volumes of propan-2-ol and 35 volumes of
The test is not valid unless, in the chromatogram obtained tetrahydrofuran.
with solution (2), the column efficiency, determined on the (1) To a quantity of the gel containing 1 mg of Adapalene
peak due to adapalene, is at least 4500 theoretical plates per add 7 mL of tetrahydrofuran and mix with the aid of
metre. ultrasound. Add 6 mL of propan-2-ol, shake, add 2 mL of
DETERMINAZION OF CONTENT solvent A and dilute to 20 mL with acetonitrile.
solvent B.
(3) 0.005% w/v of adapalene impurity standard BPCRS in a
mixture of equal volumes of tetrahydrofuran and water.
monograph include itmpurities.A and D listed under (4) Dilute 1 volume of solution (2) to 20 volumes with
Adapalene. solvent B.

with end-capped octadecylsilyl silica gel for chromatography
Adapalene Gel (5 um) (LiChrospher 100 RP 18 is suitable).
Action and use
below.
Vitamin A analogue (retinoid); treatment of acn
(c) Use a flow rate of 1.5 mL per minute.
DEFINITION ( (d) Use an ambient column temperature.
Adapalene Gel contains Adapalene in a suitable basi (e) Use a fluorimetric detector with the following
The gel complies with the requirements stated under Topical & programme.
solid Preparations and with the following requirements.
Excitation wavelength Emission wavelength
Content of adapalene, C,,H,;03
(nm) (nm)
260 380
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, 260 347
(1) To a quantity of gel containing 5 mg of Adapalene, add
10 mL of tetrahydrofuran and shake to disperse. Add methanol
to produce a solution containing 0.025% w/v of Adapalene Mobile phase A 0%
and filter (a 0.2-1um Dynagard PP filter is suitable). 100 volumes of wate
(2) 0.025% w/v of adapalene BPCRS in the mobile phase. Mobile phase B_ 40 vol
CHROMATOGRAPHIC CONDITIONS of acetonitrile.
(a) Use as the coating octadecylsilyl silica gel F54 (Merck silica
Time Mobile phase A Comment
gel 60 RP-18 F,5, plates are suitable).
(Minutes) (% viv)
0-3 40-17 ‘linear gradient
(c) Apply 1 uwL of each solution.
3-30 17
30-31 1740
(e) After removal of the plate dry in air and examine under
31-40 40
MOBILE PHASE When the chromatograms are recorded under the prescribed
18 volumes of tetrahydrofuran and 82 volumes of methanol. conditions the retention times relative to adapalene (retention
CONFIRMATION
time about 6.5 minutes) are: impurity A, about 0.5 and
impurity D, about 3.1.
The principal spot in the chromatogram obtained with
en we
solution (1) corresponds in position and colour to that in the SYSTEM SUITABILITY
chromatogram obtained with solution (2). The test is not valid unless, the chromatogram obtained with
B. In the Assay, the retention time of the principal peak in solution (3) resembles the chromatogram provided with
the chromatogram obtained with solution (1) is similar to adapalene impunity standard BPCRS.
that of the principal peak in the chromatogram obtained with LIMITS
solution (2). In the chromatogram obtained with solution (1):
TESTS the area of any peak due to impurity A or impurity D is not
Acidity or alkalinity greater than the area of the corresponding peak in the
pH, 5.5 to 7.5, Appendix V L. chromatogram obtained with solution (3) (0.5%);
oe wy en
PLS
aPI OEE SIAL GP Ss eC
2016 Adrenaline Preparations III-109
the area of any other secondary peak is not greater than IDENTIFICATION
0.1 times the area of the principal peak in the chromatogram A. In the Assay, the retention time of the principal peak in
obtained with solution (2) (0.1%); the chromatogram obtained with solution (1) is the same as
the sum of the impurities is not greater than (1.0%). that of the principal peak in the chromatogram obtained with
Disregard any peak with an area less than the area of the solution (2).
principal peak in the chromatogram obtained with B. To 1 mL of a dilution of the eye drops containing
solution (4) (0.05%). 0.1% w/v of Adrenaline adjusted, if necessary, to a neutral or
ASSAY slightly acidic pH add, drop wise, a 0.25% w/v solution of
Carry out the method for liquid chromatography, tron (11) chloride hexahydrate until a green colour is produced.
On the gradual addition of sodium hydrogen carbonate solution,
the solution changes first to blue and then to red.
Solvent C 21 volumes of water, 36 volumes of
tetrahydrefuran and 43 volumes of acetonitrile. C. To 1 mL ofa dilution of the eye drops containing
0.1% w/v of Adrenaline add 2 mL of a 10% w/v solution of
(1) Dissolk uantity of the gel containing 1 mg of
disodium hydrogen orthophosphate and sufficient iodinated
> in LO mL of tetrahydrofuran and shake with the aid
potassium todide solution to produce a brown colour. Remove
e5 minutes, dilute to 50 mL with solvent C
excess iodine by adding 0.2m sodium thiosulfate drop wise.
ynagard PP filter is suitable).
A red colour is produced.
0.01% w/v of adapalene BPCRS
in tetrahydrofuran’ to | TESTS
CHROMATOGRAPHI
Noradrenaline
(LiChrospher 100 RP 18 is suitabl Appendix III D, using the following solutions in the mobile
phase.
(b) Use isocratic elution and the mobilé pk e described
below. (1) Dilute the eye drops to produce a solution containing
(c) Use a flow rate of 1 mL per minute. 0.10% w/v of Adrenaline.
(d) Use an ambient column temperature. (2) 0.0018% w/v of noradrenaline acid tartrate.
(e) Use a detection wavelength of 270 nm. (3) 0.0018% w/v of noradrenaline acid tartrate and
(f) Inject 25 wL of each solution. 0.0018% w/v of adrenaline acid tartrate BPCRS.
MOBILE PHASE CHROMATOGRAPHIC CONDITIONS
0.02 volumes of trifluoroacetic acid, 21 volumes of water, ‘Use a stainless steel column (10 cm x 4.6 mm) packed
36 volumes of tetrahydrofuran and 43 volumes of acetonitrile énd-capped octadecylsilyl silica gel for chromatography
Nucleosil C18 is suitable).
SYSTEM SUITABILITY
socratic elution and the mobile phase described
with solution (2), the column efficiency, determined on the per rainute.
a flow rateof 2 mL
peak due to adapalene, is at least 4500 theoretical plates per
ié
metre. (d) Use a olumn temperature.
tect
DETERMINATION OF CONTENT (e) Use a de ength of 205 nm.
Calculate the content of C2g3H».O3 in the gel using the (f) Inject 20 pL ch solution.
E
declared content of C,3H»,03 in adapalene BPCRS. MOBILE PHAS
IMPURITIES A solution containing 4 £ tetramethylammonium hydrogen
The impurities limited by the requirements of this sulfate, 1.1 g of sodium heptanesulfonate and 2 mL of
monograph include impurities A and D listed under 0.1M disodium edetate in a mixtu; 50 mL of water and
Adapalene. 50 mL of methanol, the pH of tl ire. being adjusted to
3.5 with 1M sodium hydroxide.
SYSTEM SUITABILITY
The test is not valid unless the resolution fi

Adrenaline Eye Drops two principal peaks in the chromatogram obtais
veen the
with
Epinephrine Eye Drops solution (3) is at least 2.0.
Neutral Adrenaline Eye Drops LIMITS
Neutral Epinephrine Eye Drops In the chromatogram obtained with solution (1):
the area of any peak corresponding to noradrenaline is not
Action and use
Adrenoceptor agonist; treatment of glaucoma.
DEFINITION 7 ASSAY
Adrenaline Eye Drops area sterile solution of Adrenaline in Carry out the method for liquid chromatography,
Purified Water. Appendix III D, using the following solutions in the mobile
The eye drops comply with the requirements stated under Eye phase.
Preparations and with the following requirements. (1) Dilute the eye drops with sufficient mobile phase to
Ta
Content of adrenaline, C,.H,;NO; produce a solution containing 0.1% w/v of Adrenaline.
vee id
IlI-110 Adrenaline Preparations 2016
(2) 0.2% w/v of adrenaline acid tartrate BPCRS in the mobile iodide solution to produce a brown colour and remove excess
phase. iodine by adding 0.1M sodium thiosulfate drop wise. A red
(3) 0.2% w/v of adrenaline acid tartrate BPCRS and 0.2% wiv colour is produced.
of noradrenaline acid tartrate. TESTS
CHROMATOGRAPHIC CONDITIONS Acidity
(a) Use a stainless steel column (10 cm x 4.6 mm) packed pH, 2.8 to 3.6, Appendix V L.
with end-capped octadecylsilyl silica gel for chromatography Noradrenaline
(5 um) (Nucleosil C18 is suitable). Carry out the method for liguid chromatography,
(b) Use isocratic elution and the mobile phase described Appendix III D, using the following solutions.
below. (1) Use the injection.
(c) Use a flow rate of 2 mL per minute. (2) 0.0018% w/v of noradrenaline acid tartrate in the mobile
ient column temperature. © phase.
wavelength of 205 nm. (3) 0.0018% w/v of adrenaline acid tartrate BPCRS and
0.0018% w/v of noradrenaline acid tartrate in the mobile
(f) Inject 20°u solution.
phase.
MOBILE PHASE *
A solution prepared ‘by ing 4.0 g of tetra-methylammonium
um heptanesulfonate and 2 mL of (a) Use a stainless steel column (10 cm x 4.6 mm) packed
hydrogen sulfate, 1.1 g 0
0.1m disodium edetate to a‘ “ef 950 mL of water and
(5 um) CNucleosil C18 is suitable).
50 mL of methanol, the pH « ure being adjusted to
3.5 with 1M sodium hydroxide. (b) Use isocratic elution and the mobile phase described
below.
SYSTEM SUITABILITY
The test is not valid unless the resolutiongactor between the
two principal peaks in the chromatogram a (d) Use an ambient column temperature.
solution (3) is at least 2.0. | (e) Use a detection wavelength of 205 nm.
DETERMINATION OF CONTENT (f) Inject 20 wL of each solution.
Calculate the content of C)H,3NO3 in the eye dropsai MOBILE PHASE
the declared content of CpH,3;NO3 in adrenaline acid 4.0 g of tetramethylammonium hydrogen sulfate, 1.1 g of sodium
tartrate BPCRS. eptanesulfonate and 2 mL of 0.1m disodium edetate in a
STORAGE iixture of 50 mL of methanol and 950 mL of water adjusted
Adrenaline Eye Drops should be protected from light. 5 with 1m sodium hydroxide.
TABILITY
not valid unless, in the chromatogram obtained
Adrenaline Injection
Epinephrine Injection
Adrenaline Tartrate Injection
Epinephrine Tartrate Injection
Action and use chromatogram obtained with

Adrenoceptor agonist.
ASSAY
eee
DEFINITION
Adrenaline Injection is a sterile, isotonic solution containing Appendix III D, using the following
0.18% w/v of Adrenaline Acid Tartrate in Water for phase.
Injections. (1) Dilute 1 volume of the injection to 1
The injection complies with the requirements stated under (2) 0.02% w/v of adrenaline acid tartrate BPCR,
Parenteral Preparations and with the following requirements. (3) 0.02% w/v of adrenaline acid tartrate BPCRS an
Content of adrenaline, C.H,;NO; 0.02% w/v of noradrenaline acid tartrate. 7
0.09 to 0.11% w/v. CHROMATOGRAPHIC CONDITIONS
CHARACTERISTICS The chromatographic conditions described under
A colourless solution.
svwand
Noradrenaline may be used.

IDENTIFICATION MOBILE PHASE
A. In the Assay, the principal peak in the chromatogram 4.0 g of tetramethylammonium hydrogen sulfate, 1.1 g of sodium
obtained with solution (1) has the same retention time as heptanesulfonate and 2 mL of 0.1m disodium edetate to a
that in the chromatogram obtained with solution (2). mixture of 50 mL of methanol and 950 mL of water adjusted
B. To 1 mL add a 0.25% w/v solution of tron(m) chloride to pH 3.5 with 1m sodium hydroxide.
hexahydrate drop wise until a green colour is produced.
SYSTEM SUITABILITY
the solution changes first to blue and then to red. The test is not valid unless, in the chromatogram obtained
with solution (3), the resolution factor between the two
C. To 10 mL add 2 mL of a 10% w/v solution of disodium
principal peaks is at least 2.0.
Vlg ke la
ete Lees
ta we aa
hydrogen orthophosphate and sufficient todinated potassium
a's
DETERMINATION OF CONTENT The test is not valid unless, in the chromatogram obtained
Calculate the content of C)H,3NO3 in the injection using the with solution (3), the resolution factor between the two
declared content of CgH,3NO3 in adrenaline acid principal peaks is at least 2.0.
tartrate BPCRS. In the chromatogram obtained with solution (2) the area of
wa)
STORAGE any peak corresponding to noradrenaline is not greater than

Adrenaline Injection should be protected from light. the area of the principal peak in the chromatogram obtained
with solution (1) (1%, calculated with respect to the content
LABELLING of adrenaline).
ASSAY
equivalent amount of adrenaline (epinephrine).
Adrenaline Injection contains the equivalent of adrenaline Appendix III D, using the following solutions. Solution (1)
(epinephrine), 1 in 1000 (1 mg in 1 mL). contains 0.02% w/v of adrenaline acid tartrate BPCRS in the
mobile phase. Solution (2) is the injection. Solution (3)
contains 0.02% w/w of adrenaline acid tartrate BPCRS and
0.02% w/v of noradrenaline acid tartrate in the mobile phase.
Dilute naline Injection 1 in 10,000 The chromatographic procedure may be carried out using
Dilute Epi aphrine Injection 1 in 10,000 (a) a stainless steel column (10 cm x 4.6 mm) packed with
end-capped octadecylsilyl silica gel for chromatography (5 um)
Action and use (Nucleosil C18 is suitable), (b) as the mobile phase with a
Adrenoceptor agoni flow rate of 2 mL per minute a solution prepared by adding
4.0 g of tetramethylammonium hydrogen sulfate, 1.1 g of sodium
DEFINITION heptanesulfonate and 2 mL of 0.1m disodium edetate to a
Dilute Adrenaline Injection a sterile, isotonic mixture of 950 mL of water and 50 mL of methanol and
solution containing either 0. \drenaline Acid adjusting the pH of the mixture to 3.5 with 1m sodium
Tartrate or 0.01% w/v of adrenaline h hydroxide and (c) a detection wavelength of 205 nm.
by the interaction of Adrenaline and Hy. The test is not valid unless, in the chromatogram obtained
Water for Injections. with solution (3), the resolution factor between the two
The injection complies with the requirements state’ principal peaks is at least 2.0.
Parenteral Preparations and with the following requivemes Calculate the content of Co>H,3NO3 in the injection using the
Content of adrenaline, C.H,;NO; declared content of C)H,3NO3 in adrenaline acid
0.009 to 0.011% w/v. tartrate BPCRS.
CHARACTERISTICS
A colourless or almost colourless solution.
IDENTIFICATION
A. In the Assay, the chromatogram obtained with solution
(1) shows a peak with the same retention time as the
principal peak in the chromatogram obtained with
solution (2).
adrenaline apa e), 1 in 10,000 (100 ug in 1 mL).
B. To 10 mL add 2 mL of a 10% w/v solution of disodium
hydrogen orthophosphate and sufficient iodinated potassium
todide solution to produce a brown colour and remove excess
1odine by adding 0.1M sodium thiosulfate drop wise. A red or Adrenaline Sol
pink colour is produced.
Epinephrine Solut
TESTS Adrenaline ‘Tartrate Solution *
Acidity
pH, 2.2 to 5.0, Appendix V L. Epinephrine Tartrate Solution
Noradrenaline Action and use
Carry out the method for guid chromatography, Adrenoceptor agonist.
Appendix III D, using the following solutions. Solution (1) DEFINITION :
contains 0.00018% w/v of noradrenaline acid tartrate in the Adrenaline Solution is an isotonic cutaneous solution
mobile phase. For solution (2) use the injection. Solution (3) containing 0.18% w/v of Adrenaline Acid Tartrate with a
contains 0.00018% w/v of adrenaline acid tartrate BPCRS and suitable combination of an antioxidant and an antimicrobial
0.00018% w/v of noradrenaline acid tartrate in the mobile preservative in Purified Water.
phase.
The solution complies with the requirements stated under Liquids
The chromatographic procedure may be carried out using for Cutaneous Application and with the following requirements.
(a) a stainless steel column (10 cm x 4.6 mm) packed with
Content of adrenaline, C.H,;NO;3
0.09 to 0.11% ww.
(Nucleosil C18 is suitable), (b) as the mobile phase with a
flow rate of 2 mL per minutea solution containing 4.0 g of CHARACTERISTICS
tetramethylammonium hydrogen sulfate, 1.1 g of sodium A clear, colourless solution.
heptanesulfonate and 2 mL of 0.1m disodium edetate in a IDENTIFICATION
mixture of 950 mL of water and 50 mL of methanol and A. In the Assay, the principal peak in the chromatogram
adjusting the pH to 3.5 with 1m sodium hydroxide and (c) a obtained with solution (2) has the same retention time as
detection wavelength of 205 nm. that in the chromatogram obtained with solution (1).
ITI-112 Adrenaline Preparations 2016
B. To 1 mL add a 0.25% w/v solution of iron (im) chloride (c) Use a flow rate of 2 mL per minute.
hexahydrate drop wise until a green colour is produced. (d) Use an ambient column temperature.
the solution changes first to blue and then to red.
C. To 10 mL add 2 mL of a 10% w/v solution of disodium
hydrogen orthophosphate and sufficient todinated potassium MOBILE PHASE
iodide solution to produce a brown colour and remove excess Add 4.0 g of tetramethylammonium hydrogen sulfate, 1.1 g of
iodine by adding 0.1m sodium thiosulfate drop wise. A red sodium heptanesulfonate and 2 mL of 0.1m disodium edetate to a
colour is produced. mixture of 50 mL of methanol and 950 mL of water and
adjust the pH of the mixture to 3.5 with 1M sodium hydroxide.
TESTS
SYSTEM SUITABILITY
Appendix ITI DETERMINATION OF CONTENT
phase. Calculate the content of C>H,3NQO3 in the preparation being
(1) The preparation bei examined using the declared content of CgH,3NO3 in
adrenaline acid tartrate BPCRS.
(3) 0.0018% wiv of noradrer STORAGE
0.0018% w/v of adrenaline acii Adrenaline Solution should be kept in a well-filled glass
CHROMATOGRAPHIC CONDITI ce container suitable for parenteral preparations,
Appendix XIX B, and should be protected from light.
(a) Use a stainless steel column mm) packed
with end-capped octadecylsilyl silica gel fort tography LABELLING
(5 um) (Nucleosil C18 is suitable). The label states (1) the date after which the solution is not
pha:
(b) Use isocratic elution and the mobile intended to be used; (2) the conditions under which it
below. should be stored.
(c) Use a flow rate of 2 mL per minute. The quantity of active ingredient is stated in terms of the
(d) Use an ambient column temperature. equivalent amount of adrenaline (epinephrine).
(e) Use a detection wavelength of 205 nm. he label indicates the pharmaceutical form as ‘cutaneous
9

Solution contains the equivalent of adrenaline
MOBILE PHASE e), 1 in 1000 (1 mg in 1 mL).
A solution containing 4.0 g of tetramethylammonium hydrogen ytion of adrenaline hydrochloride is prescribed or
sulfate, 1.1 g of sodium heptanesulfonate and 2 mL of lution complying with the requirements of
0.1m disodium edetate in a mixture of 950 mL of water and y be dispensed or supplied.
50 mL of methanol, the pH of the mixture being adjusted to
3.5 with 1m sodium hydroxide.
SYSTEM SUITABILITY
The test is not valid unless the resolution factor between the
two principal peaks, in the chromatogram obtained with
solution (3), is at least 2.0.
LIMITS

Solution
the area of any peak corresponding to noradrenaline is not
NOTE: Adrenaline and Cocaine Intrana
licensed 1n the United Kingdom.
ASSAY Action and use
Carry out the method for hguid chromatography, Adrenoceptor agonist + local anaesthetic.
Appendix III D, using the following solutions in the mobile
phase. : DEFINITION
Adrenaline and Cocaine Intranasal Solution contains
(1) Dilute 1 volume of the preparation being examined to
Adrenaline Acid Tartrate and Cocaine Hydrochloride in a
10 volumes.
suitable vehicle.
(2) 0.02% w/v of adrenaline acid tartrate BPCRS.
The intranasal solution complies with the requirements stated
(3) 0.02% w/v of adrenaline acid tartrate BPCRS and under Nasal Preparations, the requirements stated under
0.02% w/v of noradrenaline acid tartrate. Unlicensed Medicines and with the following requirements.
Content of adrenaline, C)H,,NO3
(a) Use a stainless steel column (10 cm x 4.6 mm) packed 95.0 to 105.0% of the stated amount.
Content of cocaine hydrochloride, C,,H,,NO,,HCI1
(5 um) (Nucleosil C18 is suitable).
below.
IDENTIFICATION (1) Dilute a suitable volume of the intranasal solution with

A. In the Assay for adrenaline, the principal peak in the sufficient mobile phase to produce a solution containing the
chromatogram obtained with solution (1) has the same equivalent of 0.011% w/v of adrenaline.
retention time as that in the chromatogram obtained with (2) 0.02% w/v of adrenaline acid tartrate BPCRS in the mobile
solution (2). phase.
B. In the Assay for cocaine hydrochloride, the principal peak (3) 0.02% wiy of adrenaline acid tartrate BPCRS and
in the chromatogram obtained with solution (1) has the same 0.02% w/v of noradrenaline acid tartrate in the mobile phase.
retention time as that in the chromatogram obtained with
CHROMATOGRAPHIC CONDITIONS.
solution (2).
C. To 10 ml of the intranasal solution add 2 mL of a
with end-capped octadecylsilyl sihca gel for chromatography
10% w/v solution of disodium hydrogen orthophosphate and
sufficientzedinated potassium iodide solution to produce a
below.
TESTS
Acidity : :
pH, 2.0 to 4.0, Appendi (f) Inject 20 wL of each solution.
Related substances (fo hydrochloride) MOBILE PHASE
Carry out the method fo rematography, Dissolve 4.0 g of tetramethylammonium hydrogen sulfate, 1.1 g
Appendix III D, using the lutions. of sodium heptanesulfonate and 2 mL of 0.1m disodium edetate
ew ard (1) Dilute a volume of the itt in a mixture of 950 mL of water and 50 mL of methanol and
mobile phase to produce a solution® adjust the pH to 3.5 with 1m sodium hydroxide.
Cocaine Hydrochloride. | SYSTEM SUITABILITY
(2) 0.0008% w/v of benzoylecgonine hydrate: The assay is not valid unless, in the chromatogram obtained
phase. with solution (3), the resolution factor between the two
(3) 0.0008% w/v of benzoic acid in the mobile phase. principal peaks is at least 2.0.
(4) 0.0008% w/v of each of benzoylecgonine hydrate DETERMINATION OF CONTENT
benzoic acid in solution (1). Calculate the content of CgH,3NOz3 in the intranasal solution
CHROMATOGRAPHIC CONDITIONS he chromatograms obtained and using the declared
(a) Use a stainless steel column (25 cm x 4.6 mm) packed of CoH,3NO3 in adrenaline acid tartrate BPCRS.
with octadecylsilyl sihca gel for chromatography (10 um) (Partisi
10 ODS is suitable). it the method for liguid chromatography,
(b) Use isocratic elution and the mobile phase described SHI D, using the following solutions.
below.
De.

ee ee
.
MOBILE PHASE
et eeTe
we,
CHROMATOGRAPHIC COR IONS

1 volume of 9m perchloric acid, 35 volumes of methanol and
age
64 volumes of water. (a) Use a stainless steel colunin (

with octadecylsilyl silica gel for chro:
ng
SYSTEM SUITABILITY
10 ODS is suitable).
The test is not valid unless, in the chromatogram obtained (b) Use isocratic elution and the mobil escribed
aos
with solution (4), the resolution factor between the peaks below.
vo
corresponding to benzoylecgonine and benzoic acid is at least

.

2.0.
.

LIMITS
the area of any peak corresponding to benzoylecgonine is not
greater than the area of the principal peak in the MOBILE PHASE
chromatogram obtained with solution (2) (2%); 1 volume of 9m perchloric acid, 35 volumes of methanol and
the area of any peak corresponding to benzoic acid is not 64 volumes of water.
greater than the area of the principal peak in the SYSTEM SUITABILITY
chromatogram obtained with solution (3) (2%). The test is not valid unless, in the chromatogram obtained
The total impurity content is not greater than 2%. with solution (3), the resolution factor between the peaks
ASSAY corresponding to benzoylecgonine and benzoic acid is at least
For adrenaline 2.0.
Carry out the method for liquid chromatography,
IiI-114 Sodium Alendronate Preparations 2016
beans
DETERMINATION OF CONTENT MOBILE PHASE

Calculate the content of C,;7H2;NO,,HCI in the intranasal 1 volume of 13.5M ammonia, 8 volumes of 2.5% v/v
solution from the chromatograms obtained and using the trichloroacetic acid and 11 volumes of methanol.
declared content of C;7H2;NO,,HC1 in cocaine CONFIRMATION
hydrochloride BPCRS.
STORAGE solution (1) corresponds in position and colour to that in the
Adrenaline and Cocaine Intranasal Solution should be chromatogram obtained with solution (2).
protected from light. B. In the Assay, the principal peak in the chromatogram
LABELLING obtained with solution (1) has the same retention time as the
The quantity of adrenaline acid tartrate is stated in terms of principal peak in the chromatogram obtained with
amount of adrenaline (epinephrine). solution (2).
TESTS
Dissolution
Appendix XII B1.
TEST CONDITIONS

per minute.
(b) Use 900 mL of water, at a temperature of 37°, as the
medium.
PROCEDURE
awa
1. Benzoylecgonine, Carry out the method for liguid chromatography,
(1) After 45 minutes, withdraw a sample of the medium and
filter (Whatman GF/C is suitable). Use the filtered
dissolution medium diluted, if necessary, to produce a
solution expected to contain the equivalent of 0.00084% w/v
of alendronic acid.
2. Benzoic acid.
11% w/v of sodium alendronate BPCRS.
OGRAPHIC CONDITIONS
tainless steel column (15 cm x 4.6 mm) packed

change resin (7 tum) (Allsep Anion is suitable).
Alendronic Acid Tablets ic elution and the mobile phase described
Sodium Alendronate Tablets
Action and use

Bisphosphonate; treatment of osteoporosis.
DEFINITION
(f) Inject 100 uL of eac
Alendronic Acid Tablets contain Sodium Alendronate
Trihydrate. MOBILE PHASE
The tablets comply with the requirements stated under Tablets and 0.02% viv offormic acid, pH a
with the following requirements. hydroxide.
Content of alendronic acid, C,H,;NO;P>, DETERMINATION OF CONTENT

95.0 to 105.0% of the stated amount. Calculate the total content of C,H,;,NO
using the declared content of C,H,;,NNaO7
IDENTIFICATION
sodium alendronate BPCRS. Each mg of
C4H,2NNaO7P>2,3H20 is equivalent to 0.7662 mg.¢
Appendix ITI A, using the following solutions.
C,H,3NO-P>.
(1) Mix a quantity of the powdered tablets containing the
LIMITS
equivalent of 76 mg of alendronic acid with 50 mL of water
Ae
oea
for 30 minutes with the aid of ultrasound and occasional The amount of alendronic acid released is not less than 75%
shaking, and filter. (Q) of the stated amount.
(2) 0.2% w/v of sodium alendronate BPCRS. Phosphate and phosphite
(a) Use as the coating cellulose.
(1) To a quantity of the powdered tablets containing the
(b) Use the mobile phase as described below. equivalent of 0.1g of alendronic acid, add 20 mL of water
(c) Apply 2 uL of each solution. and mix with the aid of ultrasound for 30 minutes.
(d) Develop the plate to 15 cm. Add sufficient water to produce 25 mL and filter (Whatman
cae ad
(e) After removal of the plate, dry in a current of warm air, GF/C is suitable).
|
spray with ninhydrin solution, heat at 100° to 105° for (2) 0.0024% w/v of orthophosphoric acid and 0.002% wiv of
15 minutes and examine. phosphorous acid.
ne
.
:
'
a?
2016 Sodium Alendronate Preparations ITI-115

vy
a's
oN
SP
.
a
CHROMATOGRAPHIC CONDITIONS (f) Inject 20 wL of each solution.

to
.
a
Use the chromatographic conditions described under

,
MOBILE PHASE
oo
ey ete
Dissolution. Allow the chromatography to proceed for twice

et Ln ee
Pt?
1
Mobile phase A 3 volumes of acetonitrile and 17 volumes of

va
the retention time of the principal peak.

buffer solution.
“4
cy
oo?
When the chromatograms are recorded under the prescribed

Y
'
Mobile phase B_ 3 volumes of buffer solution and 7 volumes

oe
aoe
conditions, the relative retentions with reference to

7
of acetonitrile.
‘
oS
1
alendronic acid (retention time, about 17 minutes) are:

phosphate, about 1.3; phosphite, about 1.6.
Time Mobile phase A% Mobile phase B% Comment
SYSTEM SUITABILITY (Minutes)
The test is not valid unless, in the chromatogram obtained 0-15 100 0 isocratic
with solution (2), the signal-to-noise ratios of the peaks due to
15-25 100-—+50 0-50 linear gradient
phosphatésand phosphite are at least 10.
The retention time of the peaks due to alendronic acid and

‘
:
‘
.
aminobutanoic acid, as their derivatives, are about 5 minutes

an
Prepare a solution conta and about 9.5 minutes respectively.

aSeet
sd
and 0.142% w/v of anhydrow SYSTEM SUITABILITY

fan
orthophosphate, adjust to pH
to

.
wees
filter (buffer solution). Carry

i abd

ey
chromatography, Appendix III D, using thé following principal peaks is at least 10.0.
vio
solutions. :
LIMITS
equivalent of 23 mg of Alendronic Acid with ¢ In the chromatogram obtained with solution (1):
solution of sodium citrate, add sufficient of a 2.94 the area of any peak corresponding to 4-aminobutanoic acid
is not greater than the area of the corresponding peak in the
(Whatman GF/C is suitable); discard the first 5 mL of chromatogram obtained with solution (2) (0.5%).
filtrate. To 5 mL of the filtrate in a screw cap centrifuge.
add 5 mL of a 1.91% w/v solution of sodium borate, 10 mL
a 0.2% w/v solution of (9-fluorenyl) methyl chloroformate in
acetonitrile, shake for 1 minute and allow to stand at room
temperature for 30 minutes, add 20 mL of dichloromethane
and shake vigorously for 1 minute; centrifuge and use the
aqueous layer.
(2) To 5 mL of a 0.0003% w/v solution of 4-aminobutanotc
acid in a 2.94% w/v solution of sodium citrate in a screw cap
centrifuge tube add 5 mL of a 1.91% w/v solution of sodium
(2) 0.2% w/v of 5 :
borate, 10 mL of a 0.2% w/v solution of (9-fluorenyl) methyl
chloroformate in acetonitrile, shake for 45 seconds and allow to CHROMATOGRAPHIG:GE IONS
stand at room temperature for 30 minutes, add 20 mL of Use the chromatographi
dichloromethane and shake vigorously for 1 minute, centrifuge Dissolution.
and use the aqueous layer.
(3) To 5 mL of a solution containing 0.06% w/v of sodium tablets using
alendronate BPCRS and 0.01% w/v 4-aminobutanoic acid in a © in sodium
2.94% w/v solution of sodium citrate in a screw cap centrifuge alendronate BPCRS. Each mg of C,H) ,.N j
tube add 5 mL of a 1.91% w/v solution of sodium borate, equivalent to 0.7662 mg of C,4H,3;NO7P2.
10 mL of a 0.2% w/v solution of (9-fluorenyl) methyl
chloroformate in acetonitrile, shake for 45 seconds and allow to LABELLING
stand at room temperature for 30 minutes, add 20 mL of The quantity of active ingredient is stated in terms of the
dichloromethane and shake vigorously for 1 minute; centrifuge equivalent amount of alendronic acid.
and use the aqueous layer. IMPURITIES
CHROMATOGRAPHIC CONDITIONS The impurities limited by the requirements of this
(a) Use a stainless steel column (25 cm x 4.1 mm) packed monograph include impurities A, B andC listed under
with styrene-divinylbenzene copolymer (10 um) (Hamilton PRP- Sodium Alendronate Trihydrate.
1 is suitable).
below.
wt ee er Be a I tk a ae ted
Ney
IWI-116 Alfuzosin Preparations 2016
Related substances
Alfuzosin Tablets Carry out the method for liquid chromatography,
Action and use Appendix III D, using the following solutions.
Alpha,-adrenoceptor antagonist. (1) Shake a quantity of powdered tablets containing 15 mg of
Alfuzosin Hydrochloride in 70 mL of methanol for
DEFINITION 30 minutes, add 10 mL of 0.01m hydrochloric acid, cool,
Alfuzosin Tablets contain Alfuzosin Hydrochloride. dilute to 100 mL with methanol and filter. Dilute 1 volume of
The tablets comply with the requirements stated under Tablets and the solution to 5 volumes with the mobile phase.
with the following requirements. (2) Dilute 1 volume of solution (1) to 200 volumes with the
Content of alfuzosin hydrochloride, C,;>H,;,N;0,,HCI mobile phase.
95.0 to 105.0% of the stated amount. (3) Dilute 2 volumes of solution (2) to 5 volumes with the
mobile phase.
(4) Dilute 1 volume of solution (2) to 5 volumes with the
ne powdered tablets containing 30 mg
sw aya
mobile phase.
oride with 50 mL of water for
just the pH of the filtrate to 12.5 (5) 0.01% w/v of alfuzosin impurity standard BPCRS in the
ith two 25-mL quantities of mobile phase.
wabined extracts with 10 mL of CHROMATOGRAPHIC CONDITIONS
infrared absorption spectrunty: with end-capped octadecylsilyl silica gel for chromatography
the reference spectrum of alfuzé (5 um) (Inertsil ODS2 is suitable).
TESTS és (b) Use isocratic elution and the mobile phase described
aeand
Dissolution below.
Comply with the dissolution test jor tablegs (c) Use a flow rate of 1.5 mL per minute.
Appendix XII B1.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 50 res (f) Inject 20 wL of each solution.
per minute. /
(g) For solution (1), allow the chromatography to proceed
(b) Use 900 mL of water, at a temperature of 37°, as for twice the retention time of the principal peak.
medium.
PROCEDURE
f tetrahydrofuran, 20 volumes of acetonitrile and
Carry out the method for liquid chromatography, of sodium perchlorate solution prepared in the
Appendix III D, using the following solutions in the mobile nner. Add 5 mL of perchlonc acid to 900 mL of
phase.
(1) After 45 minutes withdraw a sample of the medium and
filter. Use the filtered medium, diluted with mobile phase if
necessary, to produce a solution expected to contain
0.0001% w/v of Alfuzosin Hydrochloride.
(2) 0.0001% w/v of alfuzosin hydrochloride BPCRS. ith solution (5) closely
yatogram supplied with alfuzosin
(3) 0.01% w/v of alfuzosin impurity standard BPCRS.

substances may be used. Inject 100 wL of each solution.
SYSTEM SUITABILITY impurity A is at least 2.0.
The test is not valid unless: LIMITS
resembles the reference chromatogram supplied with a/fuzosin
impurity standard BPCRS; eluting peakin the chromatogram obtained ity saliition (5))
the resolution between the peaks due to impurity D and is not greater than the area of the principal peakin the
impurity E is at least 2.0; chromatogram obtained with solution (2) (0.5%);
wave
eer Ae the resolution between the peaks due to alfuzosin and the area of any peak corresponding to impurity E (the second
ne ed impurity A is at least 2.0. eluting peak in the chromatogram obtained with solution (5))
DETERMINATION OF CONTENT is not greater than the area of the principal peak in the
Calculate the total content of alfuzosin hydrochloride,
C19H27N50,4,HCI, in the medium from the chromatograms the area of any other secondary peak is not greater than the
obtained and using the declared content of Cj>H27N504,HCl area of the principal peak in the chromatogram obtained with
in alfuzosin hydrochloride BPCRS. solution (3) (0.2%);
LIMITS
greater than twice the area of the principal peak in the
The amount of alfuzosin hydrochloride released is not less
PN
vow
Nal
a
than 75% (Q) of the stated amount.
sSNA,
ee
anyway
we ae
re a
2016 Alfuzosin Preparations III-117
Disregard any peak with an area less than the area of the IDENTIFICATION
principal peak in the chromatogram obtained with Shake a quantity of the powdered tablets containing 30 mg
solution (4) (0.1%). of Alfuzosin Hydrochloride with 250 mL of water for
ASSAY 5 minutes and filter. Adjust the pH of the filtrate to pH 12.5
with 18M ammonia, extract with two 25-mL quantities of
dichloromethane, wash the combined extracts with 10 mL of
water, dry over sodium sulfate and evaporate to dryness. The
(1) Weigh and powder 20 tablets. Shake a quantity of infrared absorption spectrum, Appendix II A, is concordant with
powdered tablets containing 10 mg of Alfuzosin the reference spectrum of alfuzosin (RS 446).
Hydrochloride in 70 mL of methanol for 30 minutes, add
10 mL of 0.01m hydrochloric acid, cool, dilute to 100 mL with TESTS
methanol and filter. Dilute 1 volume of the resulting solution Related substances
to 10 volumes with the mobile phase. Carry out the method for liguid chromatography,
IX. f alfuzosin hydrochloride BPCRS in the Appendix III D, using the following solutions.
(1) Shake a quantity of powdered tablets containing 15 mg of
(3) 0.01% ifuzosin impurity standard BPCRS in the Alfuzosin Hydrochloride in 70 mL of methanol for
mobile phase. 30 minutes, add 10 mL of 0.01M hydrochloric acid, cool,
dilute to 100 mL with methanol and filter. Dilute 1 volume of
CHROMATOGRAPH QNDITIONS
the solution to 5 volumes with the mobile phase.
The chromatograph onditions described under Related (2) Dilute 1 volume of solution (1) to 200 volumes with the
substances may be mobile phase.
SYSTEM SUITABILITY (3) Dilute 2 volumes of solution (2) to 5 volumes with the
The Assay is not valid unles mobile phase.
the chromatogram obtained (4) Dilute 1 volume of solution (2) to 5 volumes with the
resembles the reference chromatogram mobile phase.
impurity standard BPCRS; ‘ (5) 0.01% w/v of alfuzosin impurity standard BPCRS in the
the resolution between the peaks due to 1m} mobile phase.
impurity E is at least 2.0; CHROMATOGRAPHIC CONDITIONS
the resolution between the peaks due to alfuzosin«and (a) Use a stainless steel column (15 cm x 4.6 mm) packed
impurity A is at least 2.0. with end-capped octadecylsilyl silica gel for chromatography
DETERMINATION OF CONTENT (5 um) (Inertsil ODS 2 is suitable).
Calculate the content of CjgH27N504,HCI in the tablets “* isocratic elution and the mobile phase described
from the chromatograms obtained and using the declared
content of Cy9H»7N50,4,HCl in alfuzosin flow rate of 1.5 mL per minute.
hydrochloride BPCRS. sé'an ambient column temperature.
IMPURITIES ion wavelength of 254 nm.
monograph include those listed under Alfuzosin
llow the chromatography to proceed
Hydrochloride.
time of the principal peak.
olumes of acetonitrile and

Prolonged-release Alfuzosin Tablets 80 volumes of sodium perchlorg solution prepared in the
following manner. Add 5 mL of oric acid to 900 mL of
Prolonged-release Alfuzosin Tablets from different manufacturers,
water, adjust to pH 3.5 with 2m godi yydroxide and add
whilst complying with the requirements of the monograph, are not
sufficient water to produce 1000 ‘al.
interchangeable unless otherwise justified and authorised.
SYSTEM SUITABILITY
Action and use The test is not valid unless:
Alpha,-adrenoceptor antagonist.
the chromatogram obtained with solution (5)
DEFINITION resembles the reference chromatogram supplied with alfuzosin
Prolonged-release Alfuzosin Tablets contain Alfuzosin impurity standard BPCRS;
Hydrochloride. They are formulated so that the medicament the resolution between the peaks due to impurity D and
is released over a period of several hours. impurity E is at least 2.0;
the resolution between the peaks due to alfuzosin and
PRODUCTION
impurity A is at least 2.0.
A suitable dissolution test is carried out to demonstrate the
appropriate release of alfuzosin hydrochloride. LIMITS
The dissolution profile reflects the in vivo performance which In the chromatogram obtained with solution (1):
in turn is compatible with the dosage schedule recommended the area of any peak corresponding to impurity D (the first
by the manufacturer. eluting peak in the chromatogram obtained with solution (5))
The tablets comply with the requirements stated under Tablets and is not greater than the area of the principal peak in the
with the following requirements. chromatogram obtained with solution (2) (0.5%);
Content of alfuzosin hydrochloride, C,)H,,N;0,,HC1
1-118 Alginate Preparations 2016
the area of any peak corresponding to impurity E (the second IDENTIFICATION

eluting peak in the chromatogram obtained with solution (5)) Evaporate to dryness on a water bath a quantity of the oral
is not greater than the area of the principal peak in the suspension containing the equivalent of 1 g of the alginate
chromatogram obtained with solution (2) (0.5%); component. The residue complies with the following tests.
the area of any other secondary peak is not greater than the A. Shake 0.2 g in 20 mL of water. To 5 mL of this solution
area of the principal peak in the chromatogram obtained with add 1 mL of calcium chloride solution. A voluminous
solution (3) (0.2%); gelatinous mass is formed.
the sum of the areas of any other secondary peaks 1s not B. To 10 mL of the solution prepared in Identification test A
greater than twice the area of the principal peak in the add 1 mL of dilute sulfurtc acid. A gelatinous mass is formed.
C. It complies with the appropriate assays (see Assay).
principal peak in the chromatogram obtained with TESTS
Alkalinity
Carry out the r liquid chromatography, Relative density

Appendix II D & ollowing solutions in the mobile 1.04 to 1.14 g/mL, Appendix V G.
phase. Raft-forming ability
(1) Weigh and powd . Shake a quantity of Introduce 150 mL of 0.1m hydrochloric acid into a 250 mL
powdered tablets containir mg.of Alfuzosin beaker having an internal diameter of 60 to 70 mm. Place in
Hydrochloride in 70 mL ofmethe r 30 minutes, add a water bath such that the volume of water in the bath is
10 mL of 0.01M hydrochloric acté dilute to 100 mL with level with the top of the acid in the beaker and allow to
methanol and filter. Dilute 1 vol sulting solution equilibrate to 36.5° to 37.5°. Using a syringe (without
to 10 volumes with the mobile p needle), remove a quantity of suspension, previously shaken,
equivalent to one dose. Where a dosage range is specified,
(2) 0.001% w/v of alfuzosin hydrochloride’ B}
use the maximum dose. Wipe the outside of the syringe and
(3) 0.01% wW of alfuzosin impurity standard E add the suspension evenly into the centre of the beaker (the
CHROMATOGRAPHIC CONDITIONS Q time taken to add the entire dose is approximately
The chromatographic conditions described under Rel: 5 seconds). After 30 minutes, remove the beaker from the
substances may be used. “ water bath, dry the outside of the beaker and examine the
SYSTEM SUITABILITY
contents. A mass is formed.
The Assay is not valid unless:

the chromatogram obtained with solution (3) closely n 30 mL of 0.1m hydrochloric acid VS is required
5 mL of the oral suspension when determined
resembles the reference chromatogram supplied with a/fuzosin
impurity standard BPCRS; ing method.
the resolution between the peaks due to impurity D and e oral suspension, accurately weighed in a
impurity E is at least 2.0; al flask, add 250 mL of 0.1m hydrochloric
. |. Place the flask in a water bath
the resolution between the peaks due to alfuzosin and
impurity A is at least 2.0.
Calculate the content of C;9H27N5O.4,HCI in the tablets

from the chromatograms obtained and using the declared expression:
content of Cy;>H»27N50,4,HCI in alfuzosin
IMPURITIES
250 Xx ©). T Xx
The impurities limited by the requirements of this 0.100
monograph include those listed under Alfuzosin
Hydrochloride.
where
C, =
moles per litre, |

Compound Alginate Antacid Oral T = the volume of 0.5m sodium hydroxide VS in mL,
C, = the concentration of 0.5m sodium hydroxide VS in
Suspension moles per litre,
DEFINITION Wa = the weight per mL of the suspension in g/mL,
Compound Alginate Antacid Oral Suspension is a suspension W = the weight of the suspension in g.
containing an alginate in a suitable flavoured vehicle. It may
ASSAY
be coloured. The suspension has an acid neutralising
For aluminium
capacity.
Dilute a quantity of the suspension containing the equivalent
The oral suspension complies with the requirements stated under of 125 mg of Al, based on the labelled amount, in water to
Oral Liquids and with the following requirements. produce 500 mL and filter. Dilute a suitable volume of the
Content of aluminium, Al; calcium, Ca; magnesium, filtrate with a solution of strontium chloride such that there is a
Mg; potassium, K; sodium, Na, as appropriate 1500- to 2000-fold excess of strontium ions in the final
84.0 to 116.0% of the requisite amount, this being calculated solution and determine by Method I for atomic emission
from the stated amounts of the relevant constituents. spectrophotometry, Appendix II D, measuring at 396 nm. Use
2016 Alginate Preparations III-119
aluminium standard solution (200 ppm Al), suitably diluted PRODUCTION

with the strontium chloride solution, for the standard The content of the active constituents in the oral suspension
solutions. is measured using suitably validated methods.
OO
For calcium IDENTIFICATION

Dilute a quantity of the suspension containing the equivalent A. Dilute a quantity of the oral suspension containing 0.25 g
of 120 mg of Ca, based on the labelled amount, in water to
co
of Sodium Alginate, accurately weighed, in sufficient water to

produce 500 mL and filter. Dilute a suitable volume of the produce 200 mL. Filter and dilute a portion of this solution
filtrate with a solution of strontium chloride such that there is a with sufficient water to produce a solution containing
1500- to 2000-fold excess of strontium ions in the final 0.0125% w/v of Sodium Alginate. To 1 mL of this solution,
solution and determine by Method I for atomic emission add 1 mL of a freshly prepared 4% w/v solution of resorcinol
spectrophotometry, Appendix II D, measuring at 393 nm. Use and 6 mL of sulfuric acid. An orange-pink colour is produced.
caletum standard solution (400 ppm Ca), suitably diluted with
B. Evaporate to dryness a quantity of the oral suspension
ide solution, for the standard solutions.
containing 1 g of Sodium Alginate on a water bath. Shake
fagetat
0.2 g of the residue with 20 mL of water. To 5 mL of this

wei
solution add 1 mL of calcium chloride solution. A voluminous

gelatinous mass is formed.
te
rite
C. Evaporate to dryness a quantity of the oral suspension

containing | g of Sodium Alginate on a water bath.
.
The residue yields the reactions characteristic of sodium,

Appendix VI.
spectrophotometry, Append
tat
peta
magnesium standard solution TESTS

Alkalinity
ees Cee
e yetoes Ce
ee
7 : wey
Ora,

Oa
solutions.
Gy
For potassium . Relative density

wee
Dilute a quantity of the suspension contain 1.03 to 1.07 g/mL, Appendix V G.

.
of 120 mg of K, based on the labelled amo Raft strength

The mean raft strength is not less than 7.5 g, determined by
the following method. Carry out the method for texture
1500- to 2000-fold excess of strontium ions in the fina analysis of semi-solds or gels, Appendix XVII F. Introduce
solution and determine by Method I for atomic emissio 150 mL of 0.1m hydrochloric acid into a 250 mL beaker
spectrophotometry, Appendix II D, measuring at 767 nm. U ng an internal diameter of 60 to 70 mm. Place in a water
potassium standard solution (600 ppm K), suitably diluted with tach that the volume of water in the bath is level with
the strontium chloride solution, for the standard solutions. f the acid in the beaker and allow to equilibrate to
For sodium 7.5°. Suspend anL-shaped probe comprising
Dilute a quantity of the suspension containing the equivalent
of 125 mg of Na, based on the labelled amount, in water to
produce 500 mL and filter. Dilute a suitable volume of the
filtrate with a solution of strontium chloride such that there is a
1500- to 2000-fold excess of strontium ions in the final lower third of th
solution and determine by Method I for atomic emission Using a syringe
spectrophotometry, Appendix II D, measuring at 589 nm. Use
sodium standard solution (200 ppm Na), suitably diluted with
the strontium chloride solution, for the standard solutions. outside of the syringe and“adé
medium (the time taken to ada thé
LABELLING
approximately 5 seconds).
The label states (1) the sodium content of the suspension
and (2) the potassium content of the suspension, as
applicable.
the raft at a speed of 5 mm/sec. Record the peal raft strength

in g.
Alginate Raft-forming Oral Suspension LABELLING
DEFINITION The label states the sodium content of the suspension.
Alginate Raft-forming Oral Suspension is a suspension
containing Sodium Alginate, Sodium Bicarbonate and
Calcium Carbonate in a suitable flavoured vehicle. It may be
coloured. The suspension formsa raft.
Content of active constituents
90.0 to 110.0 % of the stated amount of sodium alginate.
II-120 Alimemazine Preparations 2016
Paediatric Alimemazine Oral Solution Strong Paediatric Alimemazine Oral

‘
1
Solution
€ vate
oak. EN A
Action and use

re « ° ?
Histamine H, receptor antagonist; antihistamine.

oy,
Action and use

DEFINITION Histamine H, receptor antagonist; antihistamine.
Paediatric Alimemazine Oral Solution is a solution containing DEFINITION
0.15% w/v of Alimemazine Tartrate in a suitable flavoured
Strong Paediatric Alimemazine Oral Solution is a solution
vehicle.
containing 0.6% w/v of Alimemazine Tartrate in a suitable
The oral solution complies with the requirements stated under Oral flavoured vehicle.
Liquids and with the following requirements. The oral solution complies with the requirements stated under Oral
Content imemazine tartrate, C3,H,,N482,C,H,O<, Liquids and with the following requirements.
Content of alimemazine tartrate, C3,;H,,N,S,,C,H,O,
0.54 to 0.66% wiv.
IDENTIFICATION
Dilute 15 mL of the oral solution with 175 mL of water and
ether, wash the ether. add 7 mL of 1M sodium hydroxide. Extract with 100 mL of
anhydrous sodium sulfate ( ether, wash the ether layer with 15 mL of water and dry over
solution A to dryness an e residue in 0.2 mL of anhydrous sodium sulfate (solution A). Evaporate 30 mL of
dichloromethane. The infrared: n, spectrum of the solution A to dryness and dissolve the residue in 0.2 mL of
resulting solution, Appendix dichloromethane. The infrared absorption spectrum of the
reference spectrum of alimemazin resulting solution, Appendix II A, is concordant with the
TESTS reference spectrum of alimemazine (RS 005).
Related substances TESTS
Related substances
Appendix III A, using mobile phase A and the* ; Complies with the test for related substances in phenothiazines,
freshly prepared solutions. For solution (1) dilute®1. Appendix III A, using mobile phase A and the following
with an equal volume of water, add 2 mL of 1M sodisin freshly prepared solutions. For solution (1) dilute 5 mL with
hydroxide and extract with two 15-mL quantities of 15 mL of water, add 2 mL of 1m sodium hydroxide and extract
chloroform. Dry the chloroform extracts with anhydrous sodiii ith two 15 mL quantities of chloroform. Dry the chloroform
sulfate, filter and evaporate the filtrate to dryness. Dissolve xtracts..with anhydrous sodium sulfate, filter and evaporate the
the residue as completely as possible in 1 mL of a mixture of
95 volumes of methanol and 5 volumes of diethylamine.
For solution (2) dilute 1 volume of solution (1) to
50 volumes with the same solvent mixture.
ASSAY
Carry out the following procedure protected from light. To a
weighed quantity containing 15 mg of Alimemazine Tartrate ning 30 mg of Alimemazine Tartrate
add 25 mL of water and 5 mL of a 5% w/v solution of j L of a 5% w/v solution of
sodium hydroxide. Extract the mixture with two 50 mL
quantities of chloroform, shaking vigorously for 1 minute each
time, evaporate the combined extracts to dryness at about
30° at a pressure of 2 kPa and dissolve the residue in
sufficient 0.1m hydrochloric acid to produce 50 mL (solution
B). Dilute 10 mL of solution B to 50 mL with water
(solution C). To a further 10 mL of solution B add 5 mL of
peroxyacetic acid solution, allow to stand for 10 minutes and
add sufficient water to produce 50 mL (solution D). Measure sD). Measure
the absorbance of solution D at the maximum at 342 nm, the absorbance of solution D at the maximum at 3¢ :
Appendix II B, using solution C in the reference cell and
measure the absorbance of solution C at the same wavelength
using water in the reference cell. Repeat the procedure using using water in the reference cell. Repeat the procedure using
a 0.03% w/v solution of aimemazine tartrate BPCRS in a 0.03% w/v solution of alimemazine tartrate BPCRS in
0.1mM hydrochloric acid in place of solution B and beginning at 0.1m hydrochloric acid in place of solution B and beginning at
the words ‘Dilute 10 mL of ...’. Determine the weight per mL the words ‘Dilute 10 mL of ...’. Determine the weight per mL
of the oral solution, Appendix V G, and calculate the content of the oral solution, Appendix V G, and calculate the content
of C36H44N4S2,C,H,O,, weight in volume, using the of C36Ha4NuS2,C,H,O¢, weight in volume, using the
declared content of C36H44N4S2,C,H,O¢ in alimemazine declared content of C36H44N4S2,C,H,O¢ in alimemazine
tartrate BPCRS. The result is not valid if the absorbance of tartrate BPCRS. The result is not valid if the absorbance of
solution C is more than 0.10. solution C is more than 0.10.
STORAGE STORAGE
Paediatric Alimemazine Oral Solution should be protected Strong Paediatric Alimemazine Oral Solution should be
from light. protected from light.
Paediatric Alimemazine Oral Solution contains 7.5 mg of Strong Paediatric Alimemazine Oral Solution contains 30 mg
Alimemazine Tartrate in 5 mL. of Alimemazine Tartrate in 5 mL.
2016 Allopurinol Preparations TII-121
Alimemazine Tablets Allopurinol Oral Suspension

NOTE: Allopurinol Oral Suspension 1s not currently licensed in the
Action and use United Kingdom.
Action and use
DEFINITION Xanthine oxidase inhibitor; treatment of gout and
Alimemazine Tablets contain Alimemazine Tartrate. hyperuricaemia.
with the following requirements. DEFINITION
Content of alimemazine tartrate, C3,H44,N,4S,,C,H;O, Allopurinol Oral Suspension is a suspension of Allopurinol in
92.5 to 107.5% of the stated amount. a suitable flavoured vehicle.
IDENT CATION
Oral Liquids, the requirements stated under Unlicensed Medicines
and with the following requirements.
Content of allopurinol, C;H,N,O
IDENTIFICATION
methane. The infrared absorption A. The light absorption, Appendix II B, in the range 230 to
tie » Appendix II A, is 350 nm of solution (2) obtained in the Assay is concordant
with that of solution (3).
B. In the Assay, the principal peak in the chromatogram
obtained with solution (2) has the same retention time as
Alimemazine Tartrate add 1 mL'6 that in the chromatogram obtained with solution (3).
volumes offormaldehyde solution and su
TESTS
colouris produced.
Acidity
TESTS pH, 2.5 to 4.5, Appendix V L.
Related substances :
Dissolution
Comply with the test for related substances in phenothig;
Complies with the requirements stated under Unlicensed
Appendix III A, using mobile phase A and applying separately.
Medicines, Oral Suspensions, using 900 mL of
to the plate 20 pL of each of the following freshly preparext
0.01m hydrochloric acid as the dissolution medium and
solutions. For solution (1) extract a quantity of the powders
the paddle at 75 revolutions per minute. Use a
tablets containing 0.1 g of Alimemazine Tartrate with 10 m
of the oral suspension containing one dose.
of a mixture of 95 volumes of methanol and 5 volumes of
diethylamine and filter. For solution (2) dilute 1 volume of ubstances
solution (1) to 200 volumes with the same solvent mixture.
ASSAY
Carry out the following procedure protected from light.
Add 150 mL of 0.1m hydrochloric acid to 10 tablets, shake for
10 minutes, mix with the aid of ultrasound for 1 minute,
dilute with 0.1m hydrochloric acid to produce a solution Allopurinol add 38 1 solution containing 10% w/v of
containing 0.050% w/v of Alimemazine ‘Tartrate and filter sodium chloride in 0.1 hydroxide. Add 10 mL of the
(solution A). Dilute 10 mL of solution A to 100 mL with internal standard sol fficient methanol to produce
water (solution B). To a further 10 mL of solution A add 100 mL; mix andfilter t xh glass wool. Dilute
2 mL of peroxyacetic acid solution, mix, allow to stand for 100 volumes with a
5 minutes and add sufficient water to produce 100 mL
(solution C). Measure the absorbance of solution C at the sthophosphate mix and filter through
maximum at 342 nm, Appendix II B, using solution B in the filter.
reference cell and measure the absorbance of solution B at the
same wavelength using water in the reference cell. Repeat the
procedure using a 0.05% w/v solution of alimemazine hydroxide. Add 10 mL of the internal standar Segfution and
tartrate BPCRS in 0.1m hydrochloric acid in place of solution sufficient methanol to produce 100 mL; mix. Dilute 25 mL of
A, beginning at the words ‘Dilute 10 mL of solution A ...’ the resulting solution to 100 mL with a 1% w/v solution of
and calculate the content of C36H44N4S2,C4H,.O using the anhydrous potassium dihydrogen orthophosphate, mix and filter
declared content of C36H44,N4S2,C,H.O in alimemazine through a 0.45-um membrane filter.
tartrate BPCRS. The test is not valid if the absorbance of (4) Dilute 10 volumes of solution (3) to 100 volumes with
solution B is more than 0.10. the mobile phase; further dilute 10 volumes to 100 volumes
and then 5 volumes to 100 volumes with the mobile phase;
mix and filter through a 0.45-um membrane filter.
with octadecylsilyl silica gel for chromatography (5 um)
(Develosil RP-aqueous is suitable).
IWI-122 Allopurinol Preparations 2016
(b) Use isocratic elution and the mobile phase described weight in volume, using the declared content of C5H,N,O in
below. allopurinol BPCRS.
eae
(c) Use a flow rate of 1 mL per minute. Impurities
teh ete
(d) Use a column temperature of 35°. The impurities limited by the requirements of this
(e) Use a detection wavelength of 250 nm. monograph include impurities A, B, C, D andE listed under
Allopurinol.
MOBILE PHASE
2 volumes of methanol and 98 volumes of a 2% w/v solution

of anhydrous potassium dihydrogen orthophosphate.
Allopurinol Tablets
SYSTEM SUITABILITY
The chromatogram obtained with solution (3) shows a peak Action and use
Xanthine oxidase inhibitor; treatment of gout and
hyperuricaemia.
DEFINITION
LIMITS
Allopurinol Tablets contain Allopurinol.
Using the chromatog
the ratio of the area of tle peak due to allopurinol to the area
iadard (R).
Content of allopurinol, C;H,N,O
the ratio of the area of any se to.the area of the
peak due to the internal standa r than 0.04R IDENTIFICATION
(0.2%). A. The light absorption, Appendix II B, in the range 230 to
350 nm of the solution obtained in the Assay exhibits a
ASSAY |
maximum only at 250 nm.
Carry out the method for liquid chromatograph:
Appendix III D, using the following solutions. B. Shake a quantity of the powdered tablets containing 0.1 g
of Allopurinol with 5 mL of 1.25m sodium hydroxide and add
(1) 0.92% w/v solution of sulfanilamide in methanol (
3 mL of phosphomolybdotungstic reagent and 5 mL of a
standard solution).
20% w/v solution of sodium carbonate. A greyish blue colour
(2) To a weighed quantity of the oral suspension containit
0.1 g of Allopurinol add 30 mL of a solution containing
10% w/v of sodium chloride in 0.1m sodium hydroxide.
Add 10 mL of the internal standard solution and sufficient
methanol to produce 100 mL; mix and filter through glass
wool. Dilute 25 volumes of the resulting solution to
100 volumes with a 1% w/v solution of anhydrous potassium
dihydrogen orthophosphate, mix and filter through a 0.45-um
membrane filter.
(3) Dissolve 0.1 g of allopurinol BPCRS in 30 mL of a dilute to 200 mL yw
solution containing 10% w/v of sodium chloride in 0.1M sodium GF/C is suitable).
hydroxide. Add 10 mL of the internal standard solution and (2) Dilute 1 volume of.
sufficient methanol to produce 100 mL; mix. Dilute mobile phase A and furth
25 volumes of the resulting solution to 100 volumes with a with mobile phase A.
1% w/v solution of anhydrous potassium dihydrogen
orthophosphate, mix and filter through a 0.45-um membrane
filter.
of solution (1) and immediately dilute to
mobile phase A. Dilute 1 mL of the resulting’solut
100 mL with mobile phase A. 8
(Develosil RP-aqueous is suitable).
below. (a) Use a stainless steel column (25 cm x 4.6 mm) packed
tee a
(c) Use a flow rate of 1 mL per minute. with octadecylsilyl silica gel for chromatography (5 um)
mews
A (Nucleosil C18 5p is suitable).
below.
MOBILE PHASE
2 volumes of methanol and 98 volumes of a 2% w/v solution (e) Use a detection wavelength of 230 nm.
of anhydrous potassium dihydrogen orthophosphate.
HA Determine the weight per mL of the oral suspension,

oe
a al
oo eh
Appendix V G, and calculate the content of C5H,N,0O,
a
2016 Almond Oil Preparations III-123
MOBILE PHASE
Mobile phase A A mixture of 1 volume of methanol and
Almond Oil Ear Drops
9 volumes of a 0.125% w/v solution of potasstum dihydrogen DEFINITION
orthophosphate. Almond Oil Ear Drops are Virgin Almond Oil in a suitable
Mobile phase B- A mixture of 3 volumes of methanol with container.
7 volumes of a 0.125% w/v solution of potassium dihydrogen The ear drops comply with the requirements stated under Ear
orthophosphate. Preparations and with the following requirements.
ates ed
IDENTIFICATION
Time Mobile phase A% Mobile phase B% Comment Carry out the test for the zdentification offatty oils by thin-layer
(Minutes) chromatography, Appendix X N. The chromatogram obtained
0-30 100-0 0-+100 linear gradient from the oil being examined shows spots corresponding to
- 100 isocratic those in the typical chromatogram for almond oil.
TESTS
Acid value
Not more than 2.0, Appendix X B. Use 5 g dissolved in
SYSTEM SUITAB 50 mL of the prescribed mixture of solvents.
The test is not vali in solution (3) the resolution factor Peroxide value
between the peaks correspending to impurity A and Not more than 10, Appendix X F.
allopurinol is at least 3°" Relative density
Inject solution (3). When thg 0.911 to 0.920, Appendix V G.
the prescribed conditions, th Unsaponifiable matter
impurity A, about 4.2 minut Not more than 0.7% w/w, Appendix X H, Method II.
6.1 minutes; allopurinol, about 7.7 £ Use 5 g.
about 26.1 minutes; impurity E, about:
solution (1) and solution (2). Continue Apricot-kernel oil and peach-kernel oil
of solution (1) for 5 times the retention t Shake 2 mL for 5 minutes with a mixture of 1 mL of fuming
nitric acid and 1 mL of water and allow to separate. No pink
LIMITS
or brown colour develops in either layer.
Foreign fixed oils
the area of any peak corresponding to impurity A is not Carry out the test for composition offatty acids by gas
greater than the area of the corresponding peak in the matography, Appendix X N. The fatty-acid fraction of the
chromatogram obtained with solution (3) (0.2%); he following composition.
the area of any unresolved double peak corresponding to d fatty acids of chain length less than C1. Not more
impurities B andC is not greater than the area of the A
corresponding double peak in the chromatogram obtained
the area of any peaks corresponding to impurity D or
adipate, 16%3 lore than 0.6%.
impurity E is not greater than the area of the corresponding
Margaric acid sot e than 0.2%.
peak in the chromatogram obtained with solution (3) (0.1%);
the area of any other secondary peak is not greater than the Stearic acid Not mor 0%.
area of the peak due to allopurinol in the chromatogram Oleic acid (equivalent h on polyethylene glycol adipate,
obtained with solution (2) (0.1%); 18.3) 62.0 to 86.0%.
the sum of the areas of any other secondary peaks is not Linoleic acid (equivalent chaisxitength on polyethylene glycol
greater than 3 times the area of the peak due to allopurinol adipate, 18.9) 20.0 to 30.0%. @
in the chromatogram obtained with solution (2) (0.3%). Linolenic acid (equivalent chain length « ethylene glycol
Disregard any peak with an area less than 0.2 times that of adipate, 19.7) Not more than 0.4%.
the peak due to allopurinol in the chromatogram obtained Arachidic acid Not more than 0.1%.
with solution (2) (0.02%). Gadoleic acid (equivalent chain length on polyethyjen
ASSAY adipate, 20.3) Not more than 0.1%.
Weigh and powder 20 tablets. Shake a quantity of the Behenic acid Not more than 0.1%.
powder containing 0.1 g of Allopurinol with 20 mL of Erucic acid (equivalent chain length on polyethylene glycol
0.05mM sodium hydroxide for 20 minutes, add 80 mL of adipate, 22.3) Not more than 0.1%.
0.1m hydrochloric acid, shake for 10 minutes, add sufficient
Sterols
0.1m hydrochloric acid to produce 250 mL, filter and dilute
Carry out the test for sterols in fatty oils, Appendix X N.
10 mL of the filtrate to 250 mL with 0.1m hydrochlone acid.
The sterol fraction of the oil has the following composition.
maximum at 250 nm, Appendix II B, using 0.1m hydrochloric Cholesterol Not more than 0.7%.
acid in the reference cell. Calculate the content of C5H,N,O Campesterol Not more than 4.0%.
taking 563 as the value of A(1%, 1 cm) at the maximum at Stigmasterol Not more than 3.0%.
250 nm. B-Sitosterol 73.0% to 87.0%.
A°-Avenasterol At least 10.0%.
A’-Avenasterol Not more than 3.0%.
A’-Stigmastenol Not more than 3.0%.
“V
pu
se
,
ee
~
r
cee
II-124 Aloxiprin Preparations

'
2016
Fucosterol Not more than 2.0%. fluoride in 0.1M hydrochloric acid and shake for 5 minutes.
Brassicasterol Not more than 0.3%. Allow the mixture to stand for 10 minutes, shaking at
frequent intervals, extract with six 20-mL quantities of
Sesame oil
chloroform, filter the combined extracts through anhydrous
Shake 10 mL with 5 mL of a mixture of 0.5 volume of a
sodium sulfate, wash with 30 mL of chloroform and dilute to
0.35% v/v solution of furfuraldehyde in acetic anhydride and
200 mL with chloroform. Dilute 20 mL of the solution to
4.5 volumes of acetic anhydride for 1 minute, filter through a
100 mL with chloroform and measure the absorbance of the
filter paper impregnated with acetic anhydride and add
resulting solution at the maximum at 308 nm,
0.2 mL of sulfuric acid. No bluish green colour develops.
Appendix II B. Calculate the content of C7H,O3 taking 293
STORAGE as the value of A(1%, 1 cm) at the maximum at 308 nm.
Almond Oil Ear Drops should be kept in a well-filled
ASSAY
container and protected from light.
Weigh and finely powder 20 tablets. To a quantity of the
powder containing the equivalent of 0.3 g of total salicylates
add 50 mL of 1M sodium hydroxide and boil gently for
15 minutes with occasional swirling. Cool, adjust the pH of
Aloxiprin the mixture to between 2.40 and 2.50 with 1m hydrochloric
acid and dilute to 500 mL with water. Filter a portion of the
Action and use
suspension; to 5 mL of the filtrate add 35 mL of acetate buffer
Salicylate; antipyretic;
pH 2.45 and 4 mL of tron(m) chloride solution and dilute to
DEFINITION 50 mL with water. Allow to stand for 30 minutes and
measure the absorbance of the resulting solution at the
maximum at 530 nm, Appendix II B, using in the reference
cell a solution prepared by diluting 4 mL of tron(im) chloride
with the following requirements. solution to 50 mL with acetate buffer pH 2.45. Calculate the
Content of total salicylates _ : content of total salicylates as O-acetylsalicylic acid, CpHgQO,,
92.5 to 107.5% of the stated amount, calculated.as from the absorbance obtained by repeating the procedure
O-acetylsalicylic acid, CogHgQOx. : using 4 mL of a 0.05% w/v solution of salicylic acid in place
IDENTIFICATION a of the solution being examined and beginning at the words
To 0.5 g of the powdered tablets add 5 mL of hydrochlog ‘add 35 mL of acetate buffer pH 2.45 ...’. Each g of salicylic
acid is equivalent to 1.305 g of CoHgQxq.
acid, boil, cool and filter. Wash the residue with 20 mL
water and combine the filtrate and washings. The resulti
solution yields the reaction characteristic of aluminium salts ity of active ingredient is stated both as the
and, after neutralisation with 1m sodium hydroxide, yields Aloxiprin and in terms of the equivalent amount
reaction A characteristic of salicylates, Appendix VI. icylates calculated as O-acetylsalicylic acid,
TESTS
Disintegration
Maximum time, 5 minutes, Appendix XII Al.
Free salicylates
To a quantity of the powdered tablets containing the inium Paste
equivalent of 0.6 g of total salicylates add 50 mL of dry ether Baltimore Paste
|
~ |
and shake for 30 minutes. Filter rapidly through fluted filter DEFINITION
J
1
paper and wash the paper with several portions of dry ether. ins 20% w/w of
Compound Aluminium Pas
i
To the combined filtrate and washings add 10 mL of

Aluminium Powder and 40% y of Zinc Oxide in a suitable
1m sodium hydroxide, swirl to mix and evaporate the ether on
hydrophobic liquid basis.
a water bath. Cool, adjust the pH to between 2.40 and 2.50
with 1m hydrochloric acid and dilute to 100 mL with water. Extemporaneous preparation
To 20 mL of the resulting solution add 4 mL of iron(m) The following formula and directions a
chloride solution and dilute to 50 mL with acetate buffer Aluminium Powder 200 g
pH 2.45. Allow to stand for 30 minutes, filter, if necessary, Zinc Oxide 400 g
through a pair of fluted filter papers and measure the Liquid Paraffin * 400 g
absorbance of the solution at the maximum at 530 nm, Mix the Aluminium Powder and the Zinc Oxide w th the
Appendix II B, using in the reference cell a solution prepared Liquid Paraffin until smooth.
by diluting 4 mL of tron(im) chloride solution to 50 mL with The paste complies with the requirements stated under Topical
te wet
a
‘whom oy acetate buffer pH 2.45. The absorbance is not more than that Semi-solid Preparations and with the following requirements.
obtained using 5 mL of a 0.036% w/v solution of salicylic acid
Content of aluminium, Al
diluted to 20 mL with water in place of the solution being
15.8 to 20.0% wiw.
examined and beginning at the words ‘add 4 mL of zron(im)
chloride solution ...’ (1.5%, calculated with reference to the Content of zinc oxide, ZnO
content of total salicylates). 37.0 to 42.0% wiw.
Combined salicylate IDENTIFICATION
Not more than 15.0%, calculated as salicylic acid, C7H,O3, A. To 5 mL of solution A prepared in the Assay for
with reference to the content of total salicylates when aluminium add 2 mL of ammonia buffer pH 10.9, centrifuge
determined by the following method. To a quantity of the and reserve the supernatant liquid. Dissolve the residue in
finely powdered tablets containing the equivalent of 0.15 g of the minimum quantity of 2m hydrochloric acid and add
total salicylates add 40 mL of a 0.5% w/v solution of sodium 0.25 mL of ammonium acetate solution and 0.25 mL of a
2016 Aluminium Preparations TH-125
0.1% w/v solution of mordant blue 3. An intense purple on a water bath for 30 minutes. Cool, add 1 mL of 2m mitric
colour is produced. acid and 5 g of hexamine and titrate with 0.05 lead nitrate
B. Add 2 mL of sodium sulfide solution to the supernatant VS using 0.5 mL of xylenol orange solution as indicator. Each
liquid reserved in test A, centrifuge, dissolve the sediment in mL of 0.05m disodium edetate VS is equivalent to 1.349 mg of
the minimum volume of 1m sulfuric acid and add 0.05 mL of Al.
a 0.1% w/v solution of copper() sulfate and 2 mL of STORAGE
.
ammonium mercurithiocyanate reagent. A violet precipitate is Aluminium Acetate Ear Drops should be kept in a well-filled
tae . a .
produced. container.
.
:
woe
ASSAY When aluminium acetate solution or Burow’s Solution is

eT
bay
For aluminium prescribed or demanded a solution complying with the

.
tea
Disperse 1 g in a mixture of 20 mL of hydrochloric acid and requirements of this monograph shall be dispensed or
ns
Oa.
20 mL ater with the aid of gentle heat, filter, wash the supplied.
eee
re EP
rio Oey eht en

re,
gool the combined filtrate and washings and

Ce,
tata
pa OrON
Aluminium Chloride Solution

.
ve
5M lead nitrate VS, using xylenol Aluminium Chloride Cutaneous Solution

0@ purplish red colour. Add 1 g DEFINITION
olution, heat ona water
Aluminium Chloride Solution 1s a cutaneous solution.
bath for 15 minutes, coo
It contains Aluminium Chloride Hexahydrate in a suitable
purplish red colour. The vol
ethanolic vehicle.
usedin the second titration
disodium edetate liberated from thes PRODUCTION
0.05M disodium edetate VS is equivalent In making Aluminium Chloride Solution, Industrial
For zinc oxide
Methylated Spirits may be used provided that the law and
the statutory regulations governing the use of Industrial
Methylated Spirits are observed.
of 0.05m lead nitrate VS used represents the amount The solution complies with the requirements stated under Liquids
present. Each mL of 0.05m disodium edetate VS is equi for Cutaneous Apphcation and with the following requirements.
to 4.068 mg of ZnO. tent of aluminium chloride hexahydrate,
H,O
105.0% of the stated amount.
Aluminium Acetate Ear Drops

DEFINITION
Aluminium Sulfate 225 g
salts and rea aracteristic of chlorides, Appendix VI.
Calctum Carbonate 100 g
Tartaric Acid 452g TESTS
Acetic Acid (33 per cent) 250 mL Iron ‘
Purified Water 750 mL Dilute the solution being xamuned with water to produce a
solution containing 10.0% w f Aluminium Chloride
Extemporaneous preparation
Hexahydrate. 10 mL of thi lution complies with the limit
The following directions apply.
test for iron, Appendix VII (10<ppm, ermined with respect
Dissolve the Aluminium Sulfate in 600 mL of the Purified to the content of aluminium chloride hi
Water, add the Acetic Acid and then the Calcium Carbonate
Ethanol
mixed with the remainder of the Purified Water and allow to
Not less than 70.0% v/v, Appendix Vii
stand for not less than 24 hours in a cool place, stirring
occasionally. Filter, add the Tartaric Acid to the filtrate and ASSAY
mix. To a weighed quantity containing about 0.4g ofsAluminium
The ear drops comply with the requirements stated under Ear Chloride Hexahydrate add 25 mL of water and carry out the
Preparations and with the following requirements. complexometric titration of aluminium, Appendix VII D. Each
mL of 0.1m disodium edetate VS is equivalent to 24.14 mg of
Content of aluminium, Al
AIC1,,6H,0. |
1.7 to 1.9% wiv.
If the declared content is in terms of weight in volume,
CHARACTERISTICS determine the weight per mL of the solution, Appendix V G,
A clear liquid. _ and hence calculate the content of AlCl;,6H,O, weight in
Weight per mL volume.
1.06 to 1.08 g, Appendix V G. STORAGE
ASSAY Aluminium Chloride Solution should be stored upright.
Dilute 10 mL to 100 mL with water. To 10 mL of the LABELLING
resulting solution add 40 mL of 0.05m disodium edetate VS,
The label states that the solution is flammable.
90 mL of water and 0.15 mL of methyl red solution. Neutralise
by the drop wise addition of 1M sodium hydroxide and warm
II-126 Aluminium Preparations 2016
Sulfate
Aluminium Hydroxide Oral Suspension Dissolve 0.50 g in 5 mL of 2m hydrochloric acid, boil, cool,
DEFINITION dilute to 200 mL with water and filter. 12.5 mL of the
Aluminium Hydroxide Oral Suspension is an aqueous filtrate, diluted to 15 mL with 2M hydrochloric acid, complies
suspension of Dried Aluminium Oxide together with varying with the limit test for sulfates, Appendix VII (0.5%).
quantities of basic aluminium carbonate. It contains the Microbial contamination
equivalent of 4% w/w of aluminium oxide and has a Carry out a quantitative evaluation for Enterobacteria and
peppermint flavour. certain other Gram-negative bacteria, Appendix XVI B1.
The oral suspension complies with the requirements stated under 0.01 mL of the preparation gives a negative result, Table I
Oral Liquids and with the following requirements. (most probable number of bacteria per gram fewer than 107).
Content of aluminium oxide, Al,O; ASSAY
The equivalent of 3.5 to 4.4% w/w. Dissolve 5 g in 3 mL of hydrochloric acid by warming on a
CHAR# water bath, cool to below 20° and dilute to 100 mL with
A white su water. To 20 mL of this solution add 40 mL of
may separate ’o 0.05m disodium edetate VS, 80 mL of water and 0.15 mL of
properties. methyl red solution and neutralise by the drop wise addition of
1M sodium hydroxide. Heat on a water bath for 30 minutes,
IDENTIFICATIO# add 3 g of hexamine and titrate with 0.05M lead nitrate VS
A solution in 2m hydroc using 0.5 mL of xylenol orange solution as indicator. Each mL
‘
.
characteristic of aluminium®™
so
Te
of 0.05m disodium edetate VS is equivalent to 2.549 mg of

nan
ee
vy
Set
woos
ee
pena
TESTS Al,O3.
ea
ee te
ro
oo
Alkalinity
woe
.
STORAGE
ra Ee
et
‘
eeore ee we aa
a an ee
tau toe
pH, when diluted with an equa

Oe,
ae
Aluminium Hydroxide Oral Suspension should be kept at a

water, not more than 7.5, Appendix V L.
SP.
temperature not exceeding 30°. It should not be allowed to

toe
.
at
Neutralising capacity freeze.

yo,
.
.
'
es
Disperse 5 g in 100 mL of water, heat to 37

an
ee =
,
0.1m hydrochloric acid VS previously heated to 37!

continuously, maintaining the temperature at 37°. ‘he p
the solution, at 37°, after 10, 15 and 20 minutes, is not‘ les Chewable Aluminium Hydroxide Tablets
than 1.8, 2.3 and 3.0 respectively and at no time during tf
Aluminium Hydroxide Tablets
period is it more than 4.0. Add 10 mL of 0.5m hydrochloric
acid VS previously heated to 37°, stir continuously for 1 hour :
maintaining the temperature at 37° and titrate the solution
with 0.1m sodium hydroxide VS to pH 3.5. Not more than
50 mL of 0.1m sodium hydroxide VS is required.
Ammonium salts
To 25 g in an ammonia-distillation apparatus add 25 mL of
5M sodium hydroxide and 250 mL of water, distil about Content of altimiz oxide, Al,O;
100 mL, collecting the distillate in 25 mL of Not less than the®équiy ent of 0.225 g.
0.1m hydrochloric acid VS, and titrate the excess of acid with
0.1m sodium hydroxide VS using methyl red solution as
IDENTIFICATION
indicator. Not less than 20.0 mL of 0.1m sodium hydroxide VS The powdered tablets yié Feaction characteristic of
is required. alumimum salts, Appendix
Arsenic TESTS
Dissolve 2.0 g in 18 mL of brominated hydrochloric acid and Disintegration
32 mL of water. 25 mL of the resulting solution complies The requirement for Disintegration dees 4
with the limit test for arsenic, Appendix VII (1 ppm). Chewable Aluminium Hydroxide Table
Heavy metals Neutralising capacity
Dissolve 2.0 g in 20 mL of 1m hydrochloric acid and 10 mL of Pass a sufficient quantity of the powder prepare, for :
water, add 0.5 mL of mitric acid and boil for about the Assay through a sieve with a nominal mesh apef
30 seconds. Cool, add 2 g of ammonium chloride and 2 g of 150 um. Mix a quantity of the powder containing 0.5 g of
ammonium thiocyanate and extract with two 10 mL quantities Dried Aluminium Hydroxide with a small quantity of water
of a mixture of equal volumes of tsoamyl alcohol and ether. to give a smooth paste and slowly add further quantities of
To the aqueous layer add 2 g of citric acid and dilute to water to a total volume of 100 mL. Warm to 37°, add
40 mL with water. 12 mL of the resulting solution complies 100 mL of 0.1m hydrochloric acid VS previously heated to 37°
with limit test A for heavy metals, Appendix VII. Use lead and stir continuously, maintaining the temperature at 37°.
standard solution (1 ppm Pb) to prepare the standard The pH of the solution at 37° after 10, 15 and 20 minutes is
(20 ppm). not less than 1.6, 1.8 and 2.2 respectively and at no time
during this period is it more than 4.0. Add 10 mL of
Chloride
0.5m hydrochloric acid VS previously heated to 37°, stir
Dissolve 0.30 g in 2 mL of 2M nitric acid, boil, cool, dilute to
continuously for 1 hour maintaining the temperature at 37°
250 mL with water and filter. 15 mL of the filtrate complies
and titrate the solution with 0.1M sodium hydroxide VS to
with the limit test for chlorides, Appendix VII (0.3%).
pH 3.5. Subtract the volume of 0.1m sodium hydroxide VS
from 150 to obtain the number of mL of 0.1m hydrochloric
acid VS required for the neutralisation. Calculate the number
2016 Alverine Preparations III-127
of mL of 0.1m hydrochloric acid VS required for the total CHROMATOGRAPHIC CONDITIONS

weight of the tablets taken for the Assay and divide by the The chromatographic conditions described under Related
number of tablets. The result is not less than 115. substances may be used.
ASSAY DETERMINATION OF CONTENT
Weigh and powder 20 tablets, avoiding frictional heating. Calculate the total content of alverine citrate,
Dissolve a quantity of the powder containing 0.4 g of Dried C490H27N,CeHgO7, in the medium from the chromatograms
Aluminium Hydroxide as completely as possible in a mixture obtained and using the declared content of
of 3 mL of hydrochloric acid and 3 mL of water by warming C39H27N;,;C6.HgO7 in alverine citrate BPCRS.
on a water bath, cool to below 20° and dilute to 100 mL
Related substances
with water. To 20 mL of this solution add 40 mL of
0.05mM disodium edetate VS, 80 mL of water and 0.15 mL of
methyl rf solution and neutralise by the drop wise addition of
(1) Add 80 mL of methanol to a quantity of the mixed
> of hexamine and titrate with 0.05m lead contents of the capsules equivalent to 0.6 g of Alverine
ie) mL of xylenol orange solution as indicator. Citrate. Mix with the aid of ultrasound for 1 hour, allow to
cool to room temperature, add sufficient methanol to produce
100 mL, mix and filter (Whatman GF/Cis suitable).
(2) alverine citrate impurity standard solution BPCRS.
Alverine Capsules with base-deactivated end-capped octadecylsilyl silica gel for
chromatography (5 wm) (Hypersil BDS C18 is suitable).
Action and use (b) Use isocratic elution and the mobile phase described
Smooth muscle relaxant; antispasm6di below.
DEFINITION
(d) Use ambient column temperature.
Alverine Capsules contain Alverine Citrate.
(e) Use a detection wavelength of 220 nm
The capsules comply with the requirements statedtnd
Capsules and with the following requirements. (f) Inject 20 wL of each solution.
Content of alverine citrate, C,)>)H,-N,C;H;O0-7 MOBILE PHASE
95.0 to 105.0% of the stated amount. M sodium dodecyl sulfate in a mixture of 55 volumes of
IDENTIFICATION
Shake a quantity of the contents of the capsules containing
0.12 g of Alverine Citrate with 5 mL of methanol for
5 minutes, filter through a 0.45 pp PTFE filter, evaporate the
filtrate to dryness under a stream of nitrogen using a warm
water bath and dry the residue for 1 hour at 50° under alverine
vacuum. The infrared absorption spectrum of the residue,
LIMITS
Appendix II A, is concordant with the reference spectrum of
alverine citrate (RS 409).
the area of any peak.
TESTS
impurity A, is not gr
Dissolution peak in the chromatogra
Comply with the requirements for Monographs of the British
Pharmacopoeia in the dissolution test for tablets and capsules,
Appendix XII Bl.
lution (2) (0.5%);
TEST CONDITIONS
: itrate
(a) Use Apparatus 2, rotating the paddle at 50 revolutions tresponding
per minute.
ASSAY
Weigh and powder the contents of 20 capsules. Carry out the
PROCEDURE method for liquid chromatography, Appendix III D, using the
Carry out the method for liquid chromatography, following solutions.
Appendix III D, using the following solutions. (1) To a quantity of the mixed contents of the capsules
(1) After 45 minutes withdraw a 20 mL sample of the equivalent to 0.6 g Alverine Citrate add 100 mL of methanol,
medium and filter through a membrane filter with a pore size mix with the aid of ultrasound for 1 hour and add sufficient
of 0.45 um, discarding the first 10 mL of the filtrate. Dilute, methanol to produce 500 mL. Stir vigorously for 10 minutes
if necessary, with 0.1m hydrochloric acid to produce a solution and filter (Cellulose nitrate filter 0.45 um is suitable). Dilute
expected to contain about 0.006% w/v of Alverine Citrate. 10 volumes of the filtrate to 20 volumes with water.
(2) 0.006% w/v of alverine citrate BPCRS in 0.1m hydrochloric (2) Dilute 1 volume of a 0.6% w/v solution of alverine
acid. citrate BPCRS in methanol to 10 volumes with water.
(3) alverine citrate impurity standard solution BPCRS.
IlI-128 Amantadine Preparations 2016
CHROMATOGRAPHIC CONDITIONS vapour pressure hydrocarbons (type L) (ApiezonL is suitable)

The chromatographic conditions described under Related in 60 mL of toluene (dissolution requires up to 5 hours), add
substances may be used. this solution to the prepared silanised diatomaceous support
and evaporate the solvent under reduced pressure while
SYSTEM SUITABILITY
slowly rotating the mixture. Program the temperature of the
The test is not valid unless the chromatogram obtained column to increase from 100° to 200° at a constant rate of 6°
closely resembles the reference chromatogram supplied with per minute with the inlet port at 220° and the detector at
alverine citrate impurity standard solution BPCRS. 300°. Use a flow rate of 30 mL per minute for the carrier
DETERMINATION OF CONTENT gas. Record the chromatogram for at least 2.5 times the
Calculate the content of C29H27N,C.HgO7 in the capsules retention time of the principal peak.
using the declared content of C29H27N,C.HgO7 in alverine The area of any secondary peak is not greater than 0.3% and
citrate BPCRS. the sum of the areas of any secondary peaks is not greater
than 1% by normalisation.
ASSAY
and prote ed Dissolve a quantity of the mixed contents of 20 capsules
IMPURITIES containing 0.5 g of Amantadine Hydrochloride as completely
as possible in 10 mL of water by heating on a water bath
The impurities limite: requirements of this
while shaking and cool. Add 10 mL of 5m sodium hydroxide
monograph include th sted under Alverine Citrate.
and 50 mL of hexane, shake gently for 15 minutes and
centrifuge. To 10 mL of the supernatant liquid add 30 mL
of anhydrous acetic acid and carry out Method I for non-
r¥
kt
>
aqueous titration, Appendix VIII A, determining the end point

re
Ue
Amantadine Capsules
ee MARL
potentiometrically. Each mL of 0.1m perchloric acid VS is

aver
@
equivalent to 18.77 mg of C,9H;7N,HCI.

ay
ay
oe
Action and use

ae
STORAGE
.
Viral replication inhibitor (influenza A); dox mi

.
Amantadine Capsules should be kept in an airtight container

eae
>
agonist; treatment of influenza and Parkinso

and protected from light.
DEFINITION
Amantadine Capsules contain Amantadine Hydrochlo
The capsules comply with the requirements stated under Capsul.
and with the following requirements. tadine Oral Solution
Content of amantadine hydrochloride, C,;>)H,;N,HCl
IDENTIFICATION
A. Shake a quantity of the contents of the capsules
containing 200 mg of Amantadine Hydrochloride in 10 mL
of 0.1m hydrochloric acid on a water bath and filter. on is a solution of Amantadine
Add 1 mL of 5M sodium hydroxide to the filtrate, extract with ible flavoured vehicle.
5 mL of dichloromethane, filter the dichloromethane layer
through anhydrous sodium sulfate, wash the sodium sulfate
with 2 mL of dichloromethane and evaporate the solution to
dryness. The infrared absorption spectrum of the residue,
amantadine (RS 006). IDENTIFICATION
A. Acidify a volume of the oral solu
B. The contents of the capsules yield the reactions
Amantadine Hydrochloride with 1m
characteristic of chlorides, Appendix VI.
TESTS
Related substances
Carry out the method for gas chromatography, dichloromethane, filter the dichloromethane layer th fagh
Appendix III B, using 1 uwL or other suitable volume of the anhydrous sodium sulfate, evaporate the filtrate to dryness
following solution. Dissolve a quantity of the contents of the under reduced pressure and dry the residue at room
capsules containing 0.1 g of Amantadine Hydrochloride in temperature over phosphorus pentoxide at a pressure of 2 kPa
2 mL of water, add 2 mL of a 20% w/v solution of sodium for 1 hour. The infrared absorption spectrum of the dried
hydroxide and 2 mL of chloroform and shake for 10 minutes. residue, Appendix IT A, is concordant with the reference
Separate the chloroform layer, dry over anhydrous sodium spectrum of amantadine (RS 006).
sulfate and filter. B. In the Assay, the retention time of the principal peak in
The chromatographic procedure may be carried out using a the chromatogram obtained with solution (1) corresponds to
glass column (1.8 m x 2 mm) containing a packing material that of the principal peak in the chromatogram obtained with
prepared in the following manner. Mix 19.5 g of silanised solution (2).
diatomaceous support (Chromosorb G/AW/DMCS is suitable)
TESTS
with 60 mL of a 0.33% w/v solution of potassium hydroxide in
Related substances
methanol and evaporate the solvent under reduced pressure
Carry out the method described under Assay using 1 uL of
while slowly rotating the mixture. Dissolve 0.4 g of low-
the following solution. Mix, with swirling, a volume of the
2016 Amikacin Preparations III-129
oral solution containing 0.1 g of Amantadine Hydrochloride (4) 1% wiv of amikacin for system suitability EPCRS
with 4 mL of a 20% w/v solution of sodium hydroxide, add (containing impurity A) in water.
10 mL of toluene, shake the mixture for 10 minutes, allow the (5) 0.13% w/v of amikacin sulfate BPCRS in water.
layers to separate and use the upper layer.
(6) water (blank solution).
The area of any secondary peak is not greater than 0.3% and
Derivatise the solutions prior to analysis using the following
the sum of the areas of any secondary peaks is not greater than
method.
1% by normalisation.
Transfer 0.2 mL of the solution being examined to a ground
ASSAY glass stoppered vial. Add 2 mL of a 1% w/v solution of
Prepare a 0.6% w/v solution of naphthalene (internal 2,4, 6-trinitrobenzenesulfonic acid. To this solution add 3 mL of
standard) in toluene (solution A). Carry out the method for pyridine and close the vial tightly. Shake vigorously for
gas chromatography, Appendix III B, using 1 wL of each of 30 seconds and heat on a water bath at 75° for 2 hours. Cool
the following solutions. For solution (1) mix, with swirling,
a in cold water for 2 minutes and add 2 mL of glacial acetic
- f the oral solution containing 0.1 g of acid. Shake vigorously for 30 seconds. Store the derivatised
rochloride with 4 mL of a 20% w/v solution solutions at 10° prior to and during analysis.
using 0.1 g of amdiit with octadecylsilyl sihca gel for chromatography (5 wm)
water in place of the (Spherisorb ODS 2 is suitable).
below.
(g) For solution (1) allow the chromatography to proceed for
A times the retention time of amikacin.
area of the peak corresponding to Amantadine Hyd chloride MOBILE PHASE
to the area of the peak due to the internal standardin t 30 volumes of a 0.27% w/v solution of potasstum dihydrogen
chromatograms obtained with solutions (1) and (2) and & phosphate, adjusted to pH 6.5 with a 2.2% w/v solution
the declared content of C;9>H,7N,HCl in amantadine stum hydroxide, and 70 volumes of methanol.
hydrochloride BPCRS. e"chromatograms are recorded under the prescribed
Amikacin Injection
anless, in the chromatogram obtained
Action and use lution factor between the peaks due
Aminoglycoside antibacterial. to amikacin and 1
DEFINITION LIMITS Seas

Amikacin Injection is a sterile solution of Amikacin Sulfate in th solution (1):
Water for Injections. ater than 1.5 times
The injection complies with the requirements stated under the area of the principal peak in t
Parenteral Preparations and with the following requirements. with solution (3) (1.5%);
Content of amikacin, C,,H43N;0,3 the sum of the areas of all such peaks
90.0 to 110.0% of the stated amount. 3 times the area of the principal peak in
obtained with solution (3) (3%).
IDENTIFICATION
Disregard any peaks corresponding to the peaks. 4
In the test for Related substances, the principal peak in the
chromatogram obtained with solution (6), any peak eluting
chromatogram obtained with solution (2) corresponds to that
before the principal peak and any peak with an area of less
in the chromatogram obtained with solution (5).
than 0.1 times the area of the principal peak in the
Acidity chromatogram obtained with solution (3) (0.1%).
Bacterial endotoxins
TESTS Carry out the test for bacterial endotoxins, Appendix XIV C.
Related substances Dilute the injection, if necessary, with water BET to give a
Carry out the method for liquid chromatography, solution containing the equivalent of 10 mg per mL of
Appendix III D, using the following solutions. amikacin (solution A). The endotoxin limit concentration of
(1) Dilute a volume of the injection, if necessary, with solution A is 3.3 IU of endotoxin per mL.
sufficient water to produce a solution containing the ASSAY
equivalent of 1.0% w/v of amikacin. Carry out the method for liguid chromatography,
(2) Dilute 1 volume of solution (1) to 10 volumes with water. Appendix III D, using solutions (2) and (5) described under
(3) 0.013% w/v of amikacin sulfate BPCRS in water. Related substances.
IWI-130 Amiuloride Preparations 2016
CHROMATOGRAPHIC CONDITIONS (d) Use an ambient column temperature.

The chromatographic conditions described under Related (e) Use a detection wavelength of 254 nm.
substances may be used. (f) Inject 20 pL of each solution.
DETERMINATION OF CONTENT (g) Allow the chromatography to proceed for 5 times the
Calculate the content of C3.H43N5O0j3 in the injection using retention time of the peak due to amiloride.
the declared content of C2.H13N5013,2H2SOs, in amikacin MOBILE PHASE
sulfate BPCRS. Each mg of C52H43N5013,2H2SO, is
5 volumes of tetramethylammonium hydroxide solution,
equivalent to 0.7488 mg of C2.H43N5043.
250 volumes of acetonitrile and 745 volumes of water, the pH
LABELLING of the mixture being adjusted to 7.0 using a mixture of
The strength is stated in terms of the equivalent amount of 1 volume of orthophosphoric acid and 9 volumes of water.
amikacin in,a suitable dose-volume. Adjust the concentration of acetonitrile so that, in the
chromatogram obtained with solution (4), the retention time
The impuftt imited by the requirements of this of methyl 3,5-diamino-6-chloropyrazine-2-carboxylate is 5 to
monographiri those listed under Amikacin Sulfate. 6 minutes (an increase in the concentration of acetonitrile
reduces the retention time). Adjust the concentrations of
tetramethylammonium hydroxide and orthophosphoric acid
so that, in the chromatogram obtained with solution (2), the
retention time of amiloride is 9 to 12 minutes keeping the
Amiloride Tablet pH at 7.0 (an increase in the concentrations reduces the
retention time).
Action and use
SYSTEM SUITABILITY
Sodium channel blocker; potassst
reten ed
DEFINITION with solution (3), the signal-to-noise ratio of the peak due to
Amiloride Tablets contain Amiloride Hy amiloride in the chromatogram obtained is at least 5.0.
stated yi
The tablets comply with the requirements
LIMITS
with the follo wing requir ements . In the chromatogram obtained with solution (1):
Content of anhydrous amiloride hydrochlorid the sum of the areas of any secondary peaks is not greater than
C;HsCIN,-O,HCI he area of the peak due to methyl 3,5-diamino-6-
90.0 to 110.0% of the stated amount. hloropyrazine-2-carboxylate in the chromatogram obtained
IDENTIFICATION lution (4) (0.6%).
A. Extract a quantity of the powdered tablets containing the dcany peak with an area less than 0.1 times the area
equivalent of 0.5 mg of anhydrous amiloride hydrochloride due to methyl 3,5-diamino-6-chloropyrazine-2-
with 100 mL of 0.1m hydrochloric acid and filter. The hght
absorption of the filtrate, Appendix II B, in the range 230 to
380 nm exhibits two maxima, at 285 nm and at 361 nm.
B. In the test for Related substances, the principal peak in Weigh and pi *
the chromatogram obtained with solution (1) has the same containing the éqaiivales
retention time as the principal peak in the chromatogram
TEST 30 minutes and dilute t
Immediately transfer 4 mL -
Related substances
stoppered centrifuge tube and add 10. mL of 0.1M sodium
vat
1 volume of acetonitrile and 3 volumes of water.
equivalent of 17.5 mg of anhydrous amiloride hydrochloride washed tributyl orthophosphate. To the combin c
with 10 mL of a mixture of 1 volume of acetonitrile and add 2 mL of methanol and sufficient of the water-waghed
3 volumes of water, disperse with the aid of ultrasound for tributyl orthophosphate to produce 50 mL and cefitrifuge to
5 minutes and centrifuge. remove traces of water. Measure the absorbance of the
(2) Dilute 1 volume of solution (1) to 100 volumes. resulting solution at the maximum at 363 nm,
(3) Dilute 1 volume of solution (2) to 10 volumes. Appendix IT B, using in the reference cell a mixture of
(4) 0.0010% w/v of methyl 3,5-diamino-6-chloropyrazine-2- 48 volumes of the water-washed tributyl orthophosphate and
carboxylate BPCRS. 2 volumes of methanol. Calculate the content of
C.HgCIN7O,HCI taking 692 as the value of A(1%, 1 cm) at
(5) 0.175% w/v of amiloride hydrochloride BPCRS.
the maximum at 363 nm.
LABELLING
equivalent amount of anhydrous amiloride hydrochloride.
below.
elias d
2016 Aminophylline Preparations III-131
Aminophylline Injection Aminophylline Tablets

DEFINITION
Action and use
Non-selective phosphodiesterase inhibitor; treatment of Aminophylline Tablets contain Aminophylline or
reversible airways obstruction. Aminophylline Hydrate.
DEFINITION with the following requirements.
Aminophylline Injection is a solution of Aminophylline or Content of theophylline, C;H,N,O,
Aminophylline Hydrate in Water for Injections free from 81.4 to 90.0% of the stated amount of aminophylline.
carbon dioxide.
Content of ethylenediamine, C,H;N>
The injection complies with the requirements stated under 13.5 to 15.0% of the stated amount of aminophylline.
eparations and with the following requirements.
IDENTIFICATION |
A. Shake a quantity of the powdered tablets containing the
equivalent of 0.5 g of aminophylline with 20 mL of water,
filter, add to the filtrate with constant stirring 1 mL of
2M hydrochloric acid, allow to stand for a few minutes and
again filter. Reserve the filtrate for test C. Wash the residue
IDENTIFICATION with small quantities of cold water, recrystallise from hot
A. To a volume contaittir water and dry at 105°. The melting point of the residue is
aminophylline add 0.5 m about 271°, Appendix V A.
B. The ifrared absorption spectrum of the residue obtained in
old water, test A, Appendix IT A, is concordant with the reference
© The infrared spectrum of theophylline (RS 333).
C. To the filtrate reserved in test A add 0.2 mL of benzoyl
concordant with the reference spectrum o chloride, make alkaline with 5M sodium hydroxide and shake
(RS 333). vigorously. Filter, wash the residue with cold water and
recrystallise from a mixture of 1 volume of water and
Aminophylline add 2 mL of a 1% wiv solution of cop 3 volumes of ethanol (96%). The melting point of the crystals,
sulfate and shake. A purplish blue colouris produced after drying at 100°, is about 250°, Appendix V A.
C. Evaporate a volume containing the equivalent of 60°m D. Shake a quantity of the powdered tablets containing the
aminophylline to dryness in a porcelain dish. To the resi alent of 0.25 g of aminophylline with 5 mL of water and
add 1 mL of hydrochloric acid and 0.1 g of potassium chlorate 0 2 mL of the filtrate add 2 mL of a 1% w/v solution
and evaporate to dryness. A reddish residue is produced, er (1) sulfate and shake. A purplish blue colour is
which becomes purple on exposure to the vapour of
5M ammonia.
TESTS
Alkalinity
ASSAY
For theophylline
To a volume containing the equivalent of 0.1 g of
aminophylline add sufficient 0.01M sodium hydroxide to
produce 250 mL, dilute 5 mL to 250 mL with 0.01M sodium of 37°, as the medium.
hydroxide and measure the absorbance of the resulting solution
PROCEDURE
at the maximum at 275 nm, Appendix II B. Calculate the
content of C7HgN,O>, taking 650 as the value of
A(1%, 1 cm) at the maximum at 275 nm.
For ethylenediamine
To a volume containing the equivalent of 0.5 g of
aminophylline add, if necessary, sufficient water to produce
20 mL and titrate with 0.05m sulfuric acid VS, using expected to contain 0. 001% w/v theophylline.
bromocresol green solution as indicator, until the colour changes (2) 0.001% w/v solution of theophylline BPCRS in phosphate
from blue to green. Each mL of 0.05m sulfuric acid VS 1s buffer pH 7.0.
equivalent to 3.005 mg of C,;HgN>. Calculate the weight of CHROMATOGRAPHIC CONDITIONS
C,HsN> present for each g of C7HgN4O> found.
LABELLING with particles of silica the surface of which has been modified
When the injection is prepared from Aminophylline Hydrate, with chemically-bonded phenyl groups (5 um) (Apex Phenyl
Theophylline or Theophylline Hydrate the strength is stated is suitable).
in terms of the equivalent amount of aminophylline in a (b) Use isocratic elution and the mobile phase described
suitable dose-volume. below.
II-132 Aminophylline Preparations 2016
(e) Use a detection wavelength of 273 nm. Content of ethylenediamine, C,H,N,

(f) Inject 20 pL of each solution. 13.5 tol15.0% of the stated amount of aminophylline.
45 volumes of methanol and 55 volumes of water. A. Shake a quantity of the powdered tablets containing the
equivalent of 0.5 g of aminophylline with 20 mL of water,
filter, add to the filtrate with constant stirring 1 mL of
Calculate the total content of theophylline, C7HgN,O,, in 2M hydrochloric acid, allow to stand for a few minutes and
the medium using the declared content of C7HgN,O, in again filter. Reserve the filtrate for test C. Wash the residue
theophylline BPCRS. with small quantities of cold water, recrystallise from hot
ASSAY water and dry at 105°. The melting point of the residue is
For theophylline about 271°, Appendix V A.
Weigh and«pawder 20 tablets. Shake a quantity of the B. The ifrared absorption spectrum of the residue obtained in
: he equivalent of 80 mg of aminophylline test A, Appendix II A, is concordant with the reference
mL of 0.1m sodium hydroxide and spectrum of theophylline (RS 333).
minutes, add sufficient water to C. To the filtrate reserved in test A add 0.2 mL of benzoyl
d filter. Dilute 5 mL of the filtrate chloride, make alkaline with 5m sodium hydroxide and shake
hydroxide and measure the vigorously. Filter, wash the residue with cold water and
ion at the maximum at recrystallise from a mixture of 1 volume of water and
275 nm, Appendix IT B ate the content of 3 volumes of ethanol (96%). The melting point of the crystals,
C7HgN,O, taking 650 ast f Ad%, 1 cm) at the after drying at 100°, is about 250°, Appendix V A.
maximum at 275 nm.
D. Shake a quantity of the powdered tablets containing
For ethylenediamine 0.25 g of Aminophylline with 5 mL of water and filter.
Len N,
Weigh and powder 20 tablets. To 2 mL of the filtrate add 2 mL of a 1% w/v solution of
powder containing the equivalent of 0°53 g copper (1) sulfate and shake. A purplish blue colour is
with 20 mL of water, heat to 50° for 30 niin titrate produced.
with 0.05 sulfuric acid VS, using bromocresol g fHTION AS
ASSAY
indicator, until the colour changes from blue to gre
For theophylline
mL of 0.05m sulfuric acid VS is equivalent to 3.005 mé
Weigh and powder 20 tablets. Shake a quantity of the
C,HgN>. .
powder containing the equivalent of 80 mg of aminophylline
STORAGE with a mixture of 20 mL of 0.1m sodium hydroxide and
Aminophylline Tablets should be kept in an airtight f water for 10 minutes, add sufficient water to
container and protected from light. O mL, mix and filter. Dilute 5 mL of the filtrate
LABELLING with 0.01mM sodium hydroxide and measure the
the resulting solution at the maximum at
endix II B. Calculate the content of
equivalent amount of anhydrous aminophylline.
Weigh and powder 2

Prolonged-release Aminophylline Tablets powder containing th lent of 0.3 g of aminophylline
Prolonged-release Aminophylline Tablets from different with 20 mL of water, hi 50° for 30 minutes and titrate
manufacturers, whilst complying with the requirements of the with 0.05m sulfuric acid omocresol green solution as
monograph, are not interchangeable unless otherwise justified and indicator, until the colour cha: 6 from blue to green. Each
authorised. mL of 0.05m sulfuric acid VS is e to 3.005 mg of
Action and use

STORAGE
Non-selective phosphodiesterase inhibitor; treatment of
Prolonged-release Aminophylline Tablet
reversible airways obstruction.
an airtight container and protected from light;
DEFINITION LABELLING
Prolonged-release Aminophylline Tablets contain The quantity of active ingredient is stated in terms’of the
Amuinophylline or Aminophylline Hydrate. They are equivalent amount of anhydrous aminophylline.
formulated so that the medicament is released over a period
of several hours.
PRODUCTION
a a
Vaal?

appropriate release of Aminophylline. The dissolution profile
Amiodarone Infusion
Amiodarone Intravenous Infusion
reflects the im vivo performance which in turn is compatible
with the dosage schedule recommended by the manufacturer.
Action and use
The tablets comply with the requirements stated under Tablets and Potassium channel blocker; class III antiarrhythmic.
Content of theophylline, C;HsN,0, DEFINITION
wae
A
81.4 to 90.0% of the stated amount of aminophylline. Amiodarone Infusion is a sterile solution containing
Amiodarone Hydrochloride. It is prepared by diluting
a NL
2016 Amiodarone Preparations III-133
Amiodarone Sterile Concentrate with a suitable diluent in (5) 0.1%Ww/v of benzyl alcohol.
accordance with the manufacturer’s instructions. CHROMATOGRAPHIC CONDITIONS
The infusion complies with the requirements stated under (a) Use a stainless steel column (15 cm x 4.6 mm) packed
Parenteral Preparations. with end-packed octadecylsilyl silica gel for chromatography
(5 um) (Waters Symmetry C18 is suitable).
AMIODARONE STERILE CONCENTRATE (b) Use isocratic elution and the mobile phase described
below.
DEFINITION
Amiodarone Sterile Concentrate is a sterile solution of (c) Use a flow rate of 1 mL per minute.
Amiodarone Hydrochloride in a suitable diluent. (d) Use a column temperature of 30°.
The concentrate complies with the requirements for Concentrates (e) Use a detection wavelength of 240 nm.
jor Injections or Infusions stated under Parenteral Preparations (f) Inject 10 pL of each solution.
ng requirements. (g) For solution (1), allow the chromatography to proceed
darone hydrochloride, for 1.5 times the retention time of amiodarone.
MOBILE PHASE
Buffer solution pH 4.9. To 800 mL of water, add 3 mL of

glacial acetic acid, adjust to pH 4.9 with dilute ammonia R1
A. Extract a volume O and dilute to 1000 mL with water.
Amiodarone Hydrochl 30 volumes of methanol, 40 volumes of acetonitrile and
30 volumes of buffer solution pH 4.9.
conditions the retention times relative to amiodarone
(retention time about 24 minutes) are impurity D, about 0.3
evaporate to dryness. Dry the residue
and impurity E, about 0.4.
reduced pressure over phosphorus pento
SYSTEM SUITABILITY

reference spectrum of amiodarone (RS 008). with solution (4), the resolution between the peaks due to
B. In the Assay, the principal peak in the chromatog impurity D and impurity E is at least 3.5.
obtained with solution (1) has the same retention time 4 LIMITS
peak in the chromatogram obtained with solution (2).
e chromatogram obtained with solution (1):
TESTS a. of any peak corresponding to impurity D is not
Colour of solution an the area of the principal peak in the
Not more intense than reference solution BY, or GY
4, yeram obtained with solution (3) (1.6%);
Appendix IV B, Method II. fany other secondary peak is not greater than the
Iodides
SOLUTION A
1 volume of mitric acid, 20 volumes of water and 80 volumes
of methanol.
(1) Add 5.0 mL of a solution containing 0.0052% w/v of
potassium iodide to a volume of the sterile concentrate
containing 0.40 g of Amiodarone Hydrochloride and dilute
to 50 mL with solution A.
(2) Dilute 10.0 mL of a solution containing 0.0052% w/v of ASSAY
potassium iodide to 50 mL with solution A. Carry out the method for liquid ch
Titrate solutions (1) and (2) with 0.001M silver nitrate VS and Appendix III D, using the following s
determine the end point for each potentiometrically using a acetonitrile (50%).
combined silver electrode. The volume used for the titration
of solution (1) is not more than the volume required for the Amiodarone Hydrochloride to 100 mL.
titration of solution (2) (500 ppm). (2) 0.05% w/v of amiodarone hydrochloride BPCRS.
Related substances (3) 0.0005% w/v each of 2-butyl-3-(4-hydroxy-3, 5-di-
Carry out the method for liquid chromatography, todobenzoyl) benzofuran BPCRS (impurity D) and amiodarone
Appendix III D, using the following solutions in impurity E EPCRS.
acetonitrile (50%).
(1) Dilute a volume of the concentrate containing 50 mg of
Amiodarone Hydrochloride to 20 mL.
SYSTEM SUITABILITY
(3) 0.004% wiv of 2-butyl-3-(4-hydroxy-3, 5-di-
todobenzoyl) benzofuran BPCRS (impurity D).
(4) 0.0005% w/v each of 2-butyl-3-(4-hydroxy-3, 5-di- impurity D and impurity E is at least 3.5.
todobenzoyl) benzofuran BPCRS (impurity D) and amiodarone
impurity E EPCRS.
IWI-134 Amiodarone Preparations 2016
DETERMINATION OF CONTENT 10 volumes with a mixture of equal volumes of acetonitrile

Calculate the content of C25H21,NO3,HCI in the infusion and water.
using the declared content of C25H»9I,NO3,HCI in (3) Dilute 1 volume of solution (2) to 4 volumes with a
amiodarone hydrochloride BPCRS. mixture of equal volumes of acetonitrile and water.
IMPURITIES (4) Dissolve 5 mg of (2-butylbenzofuran-3-yl) (4-hydroxy-3,
5-
The impurities limited by the requirements of this duodophenyl) methanone BPCRS (impurity D) and 5 mg of
monograph include those under Amiodarone Hydrochloride. amiodarone impurity E EPCRS in methanol and dilute to
25 mL with the same solvent. Dilute 1 volume of the
STORAGE
solution to 200 volumes with a mixture of equal volumes of
Amiodarone Sterile Concentrate should be protected from acetonitrile and water.
light.
with octadecylsilyl sihca gel for chromatography (5 um) CInertsil
ODS-2 is suitable).
Amiodaren (b) Use isocratic elution and the mobile phase described
NOTE: Amiodarone below.
United Kingdom. (c) Use a flow rate of 1.0 mL per minute.
Action and use (d) Use a column temperature of 30°.
Potassium channel blocker; (e) Use a detection wavelength of 240 nm.
DEFINITION &
Amiodarone Oral Suspension is of Amiodarone
for twice the retention time of the peak due to amiodarone.
Hydrochloride in a suitable flavoured v
MOBILE PHASE
The oral suspension comples with the requireime d under
Oral Liquids, the requirements stated under Unite Aedicines 30 volumes of methanol, 40 volumes of acetonitrile and
and with the following requirements. 30 volumes of a mixture prepared in the following manner:
to 800 mL of water, add 3 mL of glacial acetic acid, adjust to
Content of amiodarone hydrochloride,
pH 4.9 with dilute ammonia R1 and dilute to 1000 mL with
C,;H29I,NO3,HCI
water.
en the chromatograms are recorded under the prescribed
IDENTIFICATION
A. Extract a volume of the oral suspension containing 0.3 g . The retention times relative to amiodarone are:
of Amiodarone Hydrochloride with three 25-mL quantities of , about 0.26; impurity D, about 0.29; impurity E,
dichloromethane. Dry the combined extracts over anhydrous
sodium sulfate, filter and evaporate to dryness. To the residue
add 2 mL of 1M sodium hydroxide and extract with 25 mL of
ether. Dry the extract over anhydrous sodium sulfate, filter and
evaporate to dryness. Dry the residue obtained under The test is ne, al| ess, in the chromatogram obtained
reduced pressure over phosphorus pentoxide for about 2 hours with solution (4) lution factor between the peaks due
and dissolve in 2 mL of dichloromethane. The infrared to impurity D and im is at least 3.5.
absorption spectrum of the resulting solution, Appendix II A, is LIMITS
concordant with the reference spectrum of amiodarone In the chromatogram obta solution (1):
(RS 008).
the area of any peak correspoidifig to impurity D is not
B. In the Assay, the retention time of the principal peak in greater than 2.5 times the area of
the chromatogram obtained with solution (1) is similar to in the chromatogram obtained with
that of the principal peak in the chromatogram obtained with
the area of any other secondary peak
solution (2).
area of the peak due to amiodarone in the
TESTS obtained with solution (2) (0.2%); ‘
Dissolution the sum of the areas of all the secondary peaks is‘not_ gr
Complies with the requirements stated under Unlicensed than 5 times the area of the peak due to amiodarofie i
Medicines, Oral Suspensions. Use a volume of the oral chromatogram obtained with solution (2) (1.0%).
suspension containing one dose.
Related substances peak due to amiodarone in the chromatogram obtained with
Carry out the method for liquid chromatography, solution (3) (0.05%).
ASSAY
(1) Add 20 mL of methanol to a quantity of the oral
Carry out the method for iguid chromatography,
suspension containing 50 mg of Amiodarone Hydrochloride;
shake for 15 minutes, cool, add sufficient methanol to
(1) Dilute a weighed quantity of the oral suspension
produce 50 mL, mix well and filter through a 0.45-um nylon
containing 10 mg of Amiodarone Hydrochloride with
filter. Dilute 1 volume of the filtrate to 2 volumes with a
sufficient mobile phase to produce 50 mL. Dilute 1 volume
mixture of equal volumes of acetonitrile and water.
of this solution to 2 volumes with the mobile phase.
(2) 0.01% w/v of amiodarone hydrochloride BPCRS in the
mobile phase.
2016 Amiodarone Preparations III-135
CHROMATOGRAPHIC CONDITIONS 10 volumes with a mixture of equal volumes of acetonitrile

(a) Use a stainless steel column (25 cm x 4.6 mm) packed and water.
with cyanosilyl silica gel for chromatography (5 um) (Spherisorb (3) Dilute 1 volume of solution (2) to 4 volumes with a
CN is suitable). mixture of equal volumes of acetonitrile and water.
(b) Use isocratic elution and the mobile phase described (4) Dissolve 10 mg each of (2-butylbenzofuran-3-
below. wb (4-hydroxy-3,5-duodophenyl) methanone BPCRS
(c) Use a flow rate of 1 mL per minute. (ampurity D) and amiodarone impurity E EPCRS in methanol
(d) Use an ambient column temperature. and dilute to 50 mL with the same solvent. Dilute 1 volume
of the solution to 200 volumes with a mixture of equal
volumes of acetonitrile and water.
MOBILE:PHASE
with octadecylsilyl sitca gel for chromatography (5 um) CInertsil
ODS(2) is suitable).
below.
(d) Use a column temperature maintained at 30°.
content of CosHoolaN P
(f) Inject 20 uL of each solution.
STORAGE &
MOBILE PHASE
Amiodarone Oral Suspensio:
30 volumes of methanol, 40 volumes of acetonitrile and
IMPURITIES |
30 volumes of a mixture prepared in the following manner:
The impurities limited by the requiremer to 800 mL of water, add 3 mL of glacial acetic acid, adjust to
monograph include impurities A to G listé pH 4.9 with dilute ammonia R1 and dilute to 1000 mL with
Amiodarone Hydrochloride. water.
SYSTEM SUITABILITY
The relative retention times with reference to amiodarone
(retention time = 24 minutes) are: impurity A = about 0.26;
Amiodarone Tablets ity D = about 0.29; impurity E = about 0.37;
Action and use B = about 0.49; impurity C = about 0.55;
Potassium channel blocker; class III antiarrhythmic. G = about 0.62; impurity F = about 0.69.
egfis not valid unless, in the chromatogram obtained
DEFINITION i0n,(4), the resolution factor between the peaks due
Amiodarone Tablets contain Amiodarone Hydrochloride. impurity E is at least 3.5.
The tablets comply with the requirements stated under Tablets and LIMITS
with the following requirements. In the chromatograx obtained with solution (1):
Content of amiodarone hydrochloride, the area of any peak corr sponding to impurity D is not
C,5H2o1,NO3,HCI1 greater than 2.5 timés..tk ea of the peak due to impurity D
95.0 to 105.0% of the stated amount. in the chromatogram obtgin ith solution (4) (0.5%);
IDENTIFICATION the area of any other secondary peak is not greater than the
Shake a quantity of the powdered tablets containing 0.3 g of peak due to amiodarone in thé chfo gram obtained with
Amiodarone Hydrochloride with 25 mL of dichloromethane, solution (2) (0.2%);
filter and evaporate the filtrate to dryness. To the residue add
2 mL of 1m sodium hydroxide and extract with 25 mL of ether.
Dry the extract over anhydrous sodium sulfate, filter and chromatogram obtained with solution (2) 1.
evaporate to dryness. Dry the residue obtained under Disregard any peak with an area less than thé are;
reduced pressure over phosphorus pentoxide and dissolve in peak due to amiodarone in the chromatogram obtained with
2.5 mL of dichloromethane. The infrared absorption spectrum of solution (3) (0.05%).
the resulting solution, Appendix II A, is concordant with the
reference spectrum of amiodarone (RS 008). ASSAY
Related substances
liquid chromatography, Appendix III D, using the following
solutions.
(1) Mix with the aid of ultrasound for 15 minutes a quantity
(1) Mix with the aid of ultrasound for 15 minutes a quantity
of the powdered tablets containing 50 mg of Amiodarone
of the powdered tablets containing 50 mg of Amiodarone
Hydrochloride with 100 mL of methanol, allow to cool and
Hydrochloride with 50 mL of methanol, allow to cool and
filter through a 0.45-um PTFE filter. Dilute 1 volume of the
filter through a 0.45-um PTFE filter. Dilute 1 volume of the
acetonitrile and water.
acetonitrile and water.
ped
a NN
IfI-136 Amiusulpride Preparations 2016
(2) Dilute 1 volume of a 0.05% w/v solution of amiodarone B. In the Assay, the retention time of the principal peak in
hydrochlonde BPCRS in methanol to 5 volumes with a mixture the chromatogram obtained with solution (1) is similar to
of equal volumes of acetonitrile and water. that of the principal peak in the chromatogram obtained with
(3) Dissolve 10 mg each of (2-butylbenzofuran-3- solution (2).
yb) (4-hydroxy-3,5-duodophenyl) methanone BPCRS and TESTS
amiodarone impurity E EPCRS in methanol and dilute to Acidity
50 mL with the same solvent. Dilute 1 mL of the solution to pH, 4.5 to 6.5, Appendix V L.
200 mL with a mixture of equal volumes of acetonitrile and
Related substances
water.
CHROMATOGRAPHIC CONDITIONS Appendix III D, using the following solutions in the mobile
The chromatographic conditions described under Related phase.
(1) Dilute a weighed quantity of the oral solution to produce
a solution containing 0.1% w/v of Amisulpride.
dilute 1 volume of this solution to 5 volumes.
(3) 0.1% w/v of amisulpride for system suitability BPCRS.
using the declared content of (a) Use a stainless steel column (15 cm x 4.6 mm) packed
amiodarone hydrochloride BPC: with end-capped octylsilyl amorphous organosilica polymer (5 \wm)
STORAGE (Waters XTerra RP8 is suitable).
below.
Amisulpride Oral Solution (e) Use a detection wavelength of 240 nm.
Action and use
)Allow the chromatography to proceed for 3 times the
Dopamine receptor antagonist; neuroleptic.
n time of amisulpride.
DEFINITION
Amisulpride Oral Solution contains Amisulpride.
The oral solution complies with the requirements stated under Oral 8% wiv of potassium dihydrogen phosphate
Liquids and with the following requirements. isted to pH 8.0 with 6M ammonia.
Content of amisulpride, C,;,H,,N3;0,S
inutes) are impurity E, about 0.2;
IDENTIFICATION
impurity B, about. ity Fl, about 0.5 and
A. Carry out the method for thin-layer chromatography, impurity F2, about 0
SYSTEM SUITABILITY
(1) Dilute a quantity of the oral solution with sufficient
methanol to produce a solution containing 0.5% w/v of The test is not valid unless, 1 chromatogram obtained
Amisulpride. with solution (3):
(2) 0.5% w/v of amisulpride BPCRS in methanol. the resolution between the peaks due.2 impurity E and
impurity Bis at least 2.0;
the resolution between the peaks due to 1
(a) Use as the coating silica gel F254 (Merck silica gel 60 Fos4 impurity F2 is at least 1.5.
plates are suitable).
LIMITS
Identify any peaks in the chromatogram obtained wit
(c) Apply 4 pL of each solution.
solution (1) corresponding to impurity B, impurity F1 and
(d) Develop the plate to 10 cm. impurity F2 using the chromatogram obtained with
(e) After removal of the plate, dry in a current of warm air solution (3) and the chromatogram supplied with amisulpnide
and examine under ultraviolet light (254 nm). for system suitability BPCRS. Multiply the area of any peak
MOBILE PHASE corresponding to impurity B by a correction factor of 0.28.
Combine the areas of the peaks corresponding to
Shake 10 volumes of 6M ammonia, 25 volumes of ethanol and
impurity Fl and impurity F2 Gmpurity F) and multiply by a
65 volumes of di-isopropyl ether, allow to separate and use the
correction factor of 1.45.
upper layer.
CONFIRMATION
the area of any peak corresponding to impurity E, impurity B
and impurity F is not greater than the area of the principal
solution (1) corresponds to that in the chromatogram
2016 Amiusulpride Preparations III-137
the area of any other secondary peak is not greater than half spectrum of the residue, Appendix II A, is concordant with
the area of the principal peak in the chromatogram obtained the reference spectrum of amisulpride (RS 462).
with solution (2) (0.1%); TESTS
the sum of the areas of any secondary peaks is not greater than Dissolution
2.5 times the area of the principal peak in the chromatogram Complies with the dissolution test for tablets and capsules,
obtained with solution (2) (0.5%). Appendix XII B1.
Disregard any peak with an area less than the area of the TEST CONDITIONS
solution (4) (0.05%).
per minute.
ASSAY (b) Use 900 mL of 0.1M hydrochloric acid, at a temperature of
Carry out the method for liguid chromatography, 37°, as the medium.
me JT D, using the following solutions.
PROCEDURE
measure the absorbance of the filtered sample, diluted with
the dissolution medium if necessary to produce a solution
containing 0.0011% w/v of Amisulpride, at the maximum at
(3) 0.1% w/v of'a about 280 nm, Appendix II B using 0.1m hydrochloric acid in
mobile phase. the reference cell.
(2) Measure the absorbance of a 0.0011% w/v solution of
The chromatographic co! amisulpride BPCRS in 0.1m hydrochloric acid using
substances may be used. 0.1m hydrochloric acid in the reference cell.
SYSTEM SUITABILITY DETERMINATION OF CONTENT
Calculate the total content of amisulpride, C;7H27N30,S, in
with solution (3): the medium from the absorbances obtained and using the
the resolution between the peaks due to im declared content of C,7H27N30.S, in amisulpride BPCRS.
impurity B is at least 2.0; LIMITS

the resolution between the peaks due to impurityF i The amount of amisulpride released is not less than 75% (Q)
and impurity F isomer 2 is at least 1.5. of the stated amount.
DETERMINATION OF CONTENT R lated substances
Determine the weight per mL of the oral solution, "yout the method for liquid chromatography,
Appendix V G, and calculate the content of C;7H»7N30,S, ridix III D, using the following solutionsin the mobile
weight in volume, using the declared content of amisulpride
in amisulpride BPCRS.
IMPURITIES
monograph include:
B. 4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-
(ethylsulfonyl)-2-hydroxybenzamide;
KE. 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid;
1
foe
F, 4-amino-N-[[(2RS)-1-ethyl-1-oxidopyrrolidin-2-yl]
: 2 ates Soy ens
*
methyl]-5-(ethylsulfonyl)-2-methoxybenzamide (observed
.
ae te ee
rte
as two peaks due to enantiomers F1 and F2).

woe
with end-capped octylsilyl amorphs

.
(Waters XTerra RP8 is suitable).

‘
.
(b) Use isocratic elution and the mobi ie*phase described

Amisulpride Tablets below.
Action and use (d) Use a column temperature of 30°.
DEFINITION (f) Inject 20 wL of each solution.
Amisulpride Tablets contain Amisulpride. (g) Allow the chromatography to proceed for 3 times the
The tablets comply with the requirements stated under Tablets and retention time of amisulpride.
with the following requirements. MOBILE PHASE
Content of amisulpride, C,,H,7N3;0,S 20 volumes of methanol and 80 volumes of a solution

95.0 to 105.0% of the stated amount. containing 0.68% w/v of potasstum dihydrogen orthophosphate
previously adjusted to pH 8.0 with 6m ammonia.
IDENTIFICATION
Extract a quantity of the powdered tablets containing 100 mg When the chromatograms are recorded under the prescribed
of Amisulpride with 10 mL of dichloromethane, mix with the conditions the retention times relative to amisulpride
aid of ultrasound and filter. Evaporate the filtrate to dryness (retention time about 10 minutes) are impurity E, about 0.2;
at a temperature not exceeding 30°. The infrared absorption
I-138 Amitriptyline Preparations 2016
impurity B, about 0.3; impurity Fl, about 0.5 and E. 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid;
impurity F2, about 0.6. F. 4-amino-N-[[(2RS)-1-ethyl-1-oxidopyrrolidin-2-yl]
SYSTEM SUITABILITY methyl]-5-(ethylsulfonyl)-2-methoxybenzamide (observed
The test is not valid unless, in the chromatogram obtained as two peaks due to enantiomers F1 and F2).
with solution (3):
the resolution between the peaks due to impurity E and
impurity B is at least 2.0;
the resolution between the peaks due to impurity F isomer 1 Amitriptyline Tablets
and impurity F isomer 2 is at least 1.5.
Action and use
LIMITS
Monoamine reuptake inhibitor; tricyclic antidepressant.
Identify any.peaks in the chromatogram obtained with
solution ( ponding to impurity B, impurity F1 and DEFINITION
impurity FQ. ‘chromatogram obtained with Amitriptyline Tablets contain Amitriptyline Hydrochloride.
solution (3) and omatogram supplied with amisulpride They are coated.
for system suitabiligy BE S. Multiply the area of any peak The tablets comply with the requirements stated under Tablets and
corresponding to im by a correction factor of 0.28. with the following requirements.
impurity Fl and impuri Content of amitriptyline hydrochloride, C,,)H.3N,HC1

correction factor of 1.45. 90.0 to 110.0% of the stated amount.
IDENTIFICATION
A. Shake a quantity of the powdered tablets containing 5 mg
and impurity F is not greater tha the prin
cipal of Amitriptyline Hydrochloride with 20 mL of methanol and
peak in the chromatogram obtained wit on (2) (0.2%); filter. To 1 mL of the filtrate add 1 mL of a 2.5% w/v
solution of sodium hydrogen carbonate, 1 mL of a 2% w/v
the area of any other secondary peak is not gré
solution of sodium periodate and 1 mL of a 0.3% w/v solution
the area of the principal peak in the chromatog:
of potassium permanganate, allow to stand for 15 minutes,
with solution (2) (0.1%); | 7
acidify with 1m sulfuric acid and extract with 10 mL of
the sum of the areas of any secondary peaks is not greg n, 2,2,4-trimethylpentane. The light absorption of the resulting
2.5 times the area of the principal peak in the chromatogra solution, Appendix II B, in the range 230 to 350 nm exhibits
obtained with solution (2) (0.5%). aximum only at 265 nm.
Disregard any peak with an area less than the area of the fate a quantity of the powdered tablets containing
principal peak in the chromatogram obtained with itriptyline Hydrochloride with 10 mL of
solution (4) (0.05%). Iter and evaporate the filtrate to a low volume.
ASSAY 1 a turbidity is produced and allow to stand.
Weigh and powder 20 tablets. Carry out the method for of the precipitate in 3 mL of water and add
solutions in mobile phase. sed within 15 minutes (distinction
(1) Shake a quantity of powdered tablets containing 0.4 g of
Amisulpride with 90 mL of the mobile phase, add sufficient
mobile phase to produce 100 mL and filter (using an ash-free
filter paper). Dilute 1 volume of filtrate to 40 volumes. TESTS
(2) 0.01% w/v of amisulprde BPCRS. Related substances
(3) 0.1% w/v of amisulpride for system suitabihty BPCRS.

SYSTEM SUITABILITY mixture of 1 volume of 2m hydrochloric acid and 9
The test is not valid unless, in the chromatogram obtained ethanol (96%), centrifuge and use the supernatanit liqy
with solution (3): (2) 0.0010% w/v of dibenzosuberone BPCRS in chloroform.
the resolution between the peaks due to impurity E and (3) 0.0040% w/v of cyclobenzaprine hydrochloride BPCRS.
impurity B is at least 2.0;
the resolution between the peaks due to impurity F isomer 1
(a) Use as the coating silica gel G.
and impurity F isomer 2 is at least 1.5.
Calculate the content of C;7H.27N30.,S in the tablets using
the declared content of amisulpride in amisulpnde BPCRS. (d) Develop the plate to 14 cm.
(e) After removal of the plate, dry in air, spray with a freshly
IMPURITIES
prepared mixture of 4 volumes offormaldehyde and
96 volumes of sulfuric acid, heat at 100° to 105° for
monograph include: 10 minutes.
B. 4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-
(ethylsulfonyl)-2-hydroxybenzamide;
2016 Ammonia Preparations III-139
MOBILE PHASE
Aromatic Ammonia Solution
3 volumes of diethylamine, 15 volumes of ethyl acetate and
te
Sal Volatile Solution

85 volumes of cyclohexane.
eyeben
wy
DEFINITION
e\ee.
LIMITS
Ammonium Bicarbonate 25 g
on
Examine the plate under ultraviolet light (365 nm):

Nutmeg Oil 0.3 mL
‘
any spot corresponding to dibenzosuberone in the Lemon Oil 0.5 mL

chromatogram obtained with solution (1) is not more intense Ethanol (90 per cent) 37.5 mL
.
than the spot in the chromatogram obtained with solution (2)

an
Strong Ammonia Solution 67.5 mL

(0.25%). Purified Water, freshly
.
Sufficient to produce 1000 mL

Examine the plate under ultraviolet ight (254 nm):
.
boiled and cooled

may
any other secondary spot in the chromatogram obtained with Extemporaneous preparation
’
is not more intense than the spot in the

woe

ent
.
Obtained with solution (3) (1%).

yey
Dissolve the Ammonium Bicarbonate in 800 mL of the

eye
wit
Purified Water. Separately dissolve the Lemon Oil and the

.
7
Nutmeg Oil in the Ethanol (90 per cent). Add the ethanolic
solution to the aqueous solution and add the Strong
Ammonia Solution and sufficient Purified Water to produce
1000 mL. Add 25 g of previously sterilised Purified Talc,
to 20 tablets, shakevig shake, allow to stand for a few hours, shaking occasionally,
op erated add 100 hanol and shake for and filter.
O mL with methanol, Content of free ammonia, NH;
1.12 to 1.25% ww.
Content of ammonium carbonate, (NH,4),CO;
with methanol (50%). ‘
2.76 to 3.24% w/v.
For sugar-coated tablets Shake a quantity
TESTS
Ethanol content
2.6 to 3.5% v/v when determined by the following method.
to 200 mL with water, centrifuge and use the supefn Carry out the method for gas chromatography,
liquid. Appendix III B, using the following solutions:
(2) Dissolve 50 mg of amitriptyline hydrochloride BPCRS iti % viv of absolute ethanol and 1.5% v/v of propan-1-ol
10 mL of methanol and dilute to 200 mL with al standard).
methanol (S0%). e a volume of the preparation being examined with
CHROMATOGRAPHIC CONDITIONS contain between 1.0% and 2.0% v/v of ethanol.
below. 4 mm) packed with porous
(c) Use a flow rate of 2 mL per minute. esh) (Porapak Q and
MOBILE PHASE (d) Use an inlet temperature of
0.03M sodium hexanesulfonate in a mixture of equal volumes of (e) Use a flame ionisation detector erature of 170°.
water and acetonitrile, adjusted to pH 4.5 by the addition of (f) Inject 1 wL of each solution.
glacial acetic acid, DETERMINATION OF CONTENT
DETERMINATION OF CONTENT Calculate the percentage content of ethanol in‘the solution
Calculate the content of C.9>H23N,HCl using the declared from the areas of the peaks due to ethanol in the
content of Cz9H23N,HCl in amitriptyline chromatograms obtained with solutions (1) and (3).
hydrochlonde BPCRS. Weight per mL
0.980 to 1.005 g, Appendix V G.
ASSAY
For free ammonia
To 20 mL add 50 mL of 1m hydrochloric acid VS, boil, cool
and titrate the excess of acid with 1m sodium hydroxide VS
using methyl red solution as indicator. Each mL of
1m hydrochloric acid VS, after subtraction of the volume of
Im sodium hydroxide VS required in the Assay for ammonium
carbonate, is equivalent to 17.03 mg of NH3.
II-140 Ammonia Preparations 2016
For ammonium carbonate Weight per mL

To 20 mL add 25 mL of 1m sodium hydroxide VS and 40 mL 0.880 to 0.893 g, Appendix V G.
of barium chloride solution, heat on a water bath for
Fee
ASSAY
vAAs
15 minutes, cool, add 10 mL offormaldehyde solution
For free ammonia
previously neutralised to thymol blue solution and titrate the
To 20 mL add 50 mL of 1m hydrochloric acid VS, boil, cool
excess of alkali with 1m hydrochloric acid VS, using thymol blue
and titrate the excess of acid with 1M sodium hydroxide VS
solution as indicator, to the grey colour indicative of pH 8.8.
using methyl red solution as indicator. Each mL of
Each mL of 1M sodium hydroxide VS is equivalent to
1m hydrochloric acid VS, after subtraction of the volume of
48.04 ng of (NH,4)2CO3.
1m sodium hydroxide VS required in the Assay for ammonium
carbonate, is equivalent to 17.03 mg of NH3.
For ammonium carbonate
aa |
Dilute A monia Solution To 20 mL add 25 mL of 1M sodium hydroxide VS and 40 mL |
of barium chloride solution, heat on a water bath for
15 minutes, cool, add 10 mL offormaldehyde solution
Dilute Ammo , ion contains 10% w/w of ammonia.
previously neutralised to thymol blue solution and titrate the
Itis prepared by trong Ammonia Solution with
excess of alkali with 1m hydrochloric acid VS, using thymol blue
freshly boiled and co i urified Water.
solution as indicator, to the grey colour indicative of pH 8.8.
Content of ammonia Each mL of 1m sodium hydroxide VS is equivalent to
9.5 to 10.5% w/w. 48.04 mg of (NH4)2CO3.
TESTS
Relative density
0.958 to 0.962, Appendix V G.
Strong Ammonium Acetate Solution

rar ors
ASSAY
Weigh 6 g into 50 mL of 1m hydrochloric act Vs ad titrate
DEFINITION
the excess of acid with 1m sodium hydroxide 81
Ammonium Bicarbonate A470 ¢g
red solution as indicator. Each mL of 1m hydroc
Glacial Acetic Acid 453 g
is equivalent to 17.03 mg of NHs3.
Strong Ammonia Solution A sufficient quantity
When ammonia solutionis prescribed or demanded, Pil Purified. Water, freshly boiled and Sufficient to produce
Ammonia Solution shall be dispensed or supplied. oled 1000 mL
emporaneous preparation
wing directions apply.
Aromatic Ammonia Spirit : Ammonium Bicarbonate by adding gradually to
Sal Volatile Spirit Acetic Acid diluted with 350 mL of Purified
Add: Strong Ammonia Solution until 0.05 mL of the
DEFINITION
diluted with 0.5 mL of water gives a full
Nutmeg Oil 3 mL
blue colour witt of bromothymol blue solution R3 and
Lemon Oil 5 mL
a full yellow c .05 mL of thymol blue solution;
Ethanol (90 per cent) 750 mL
about 100 mL o mmonia Solutionis required.
Ammonium Bicarbonate 25g
Add sufficient Purified fto produce 1000 mL.
Strong Ammonia Solution 67.5 mL
Purified Water Sufficient to produce Content of ammoniu C,H,NO,
1000 mL 55.0 to 60.0% w/v.
pane ol
Extemporaneous preparation TESTS

The following directions apply. Acidity or alkalinity
Distil a mixture of the Lemon Oil, the Nutmeg Oil, the pH of a 10% v/v solution, 7.0 to 8.0
Ethanol (90 per cent) and 375 mL of Purified Water. Weight per mL
Reserve the first 875 mL of distillate. Distil a further 55 mL 1.085 to 1.095 g, Appendix V G.
and add the Ammonium Bicarbonate and the Strong ASSAY
Ammonia Solution to the distillate. Heat on a water bath to
To 5 mL add 50 mL of water and 12 mL of formal
60° in a sealed bottle of not less than 120 mL capacity,
solution previously neutralised to phenolphthalein solution R1
shaking occasionally, until solution is complete, cool, filter
and titrate with 1m sodium hydroxide VS using phenolphthalein
through absorbent cotton, mix the filtrate with the reserved
| solution R1 as indicator. Each mL of 1m sodium hydroxide VS
distillate, add sufficient Purified Water to produce 1000 mL
ean od
is equivalent to 77.08 mg of C,H7NOs;.
and mix.
The spirit complies with the requirements stated under Spirits and STORAGE
with the following requirements. Strong Ammonium Acetate Solution should be kept in lead-
free glass containers.
Content of free ammonia, NH;
1.12 to 1.30% wv. LABELLING
When ammonium acetate solution or dilute ammonium
Content of ammonium carbonate, (NH,),CO;3
acetate solution is prescribed or demanded, Strong
2.76 to 3.24% wiv.
Ammonium Acetate Solution diluted to eight times its
TESTS volume with freshly boiled and cooled Purified Water, shall
Ethanol content be dispensed or supplied.
64 to 70% v/v, Appendix VIII F.
2016 Amoxicillin Preparations III-141

Ammonium Chloride Mixture
Ammonium Chloride Oral Solution
(e) After removal of the plate, allow it to dry in air, expose to
DEFINITION
meee
iodine vapour until spots appear and examine in daylight.

Ammonium Chloride Mixture is an oral solution containing
MOBILE PHASE
10% w/v of Ammonium Chloride in a suitable vehicle
containing Aromatic Ammonia Solution and Liquorice 10 volumes of acetone and 90 volumes of a 15.4% w/v
Liquid Extract. solution of ammonium acetate adjusted to pH 5.0 with glacial
acetic acid.
It is recently prepared according to the following formula. SYSTEM SUITABILITY
Ammonium Chloride 100 g The test is not valid unless the chromatogram obtained with
ic. Ammonia Solution 50 mL solution (3) shows two clearly separated spots.
100 mL CONFIRMATION
Sufficient to produce
1000 mL
solution (1) is similar in position, colour and size to that in
th the requirements stated under Oral the chromatogram obtained with solution (2).
ing requirements.
TESTS
Content of ammo tum chloride, NH,Cl
Related substances
9.50 to 10.66% w/
ASSAY Appendix III D, using the following solutions.
To 1 mL add 20 mL of wa swith 0.1m silver (1) Add 80 mL of mobile phase A to a quantity of the mixed
nitrate VS determining the ntiometrically. Each capsule contents contaming the equivalent of 0.15 g of
mL of 0.1m silver nitrate VS is equy ent to 5.349 mg of amoxicillin and shake for 15 minutes. Mix with the aid of
NH,Cl. ultrasound for 1 minute, add sufficient mobile phase A to
produce 100 mL, mix and filter.
mobile phase A.
Amoxicillin Capsules (3) 0.0004% w/v of cefadroxil BPCRS and 0.003% w/v of
amoxicillin trihydrate BPCRS in mobile phase A.
Action and use OMATOGRAPHIC CONDITIONS
Penicillin antibacterial.
e a stainless steel column (25 cm x 4.6 mm) packed
DEFINITION
Amoxicillin Capsules contain Amoxicillin Trihydrate.
The capsules comply with the requirements stated under Capsules
Content of amoxicillin, C,;;H,)>N3;0;S
IDENTIFICATION
'
Shake a quantity of the contents of the capsules containing

so
the equivalent of 0.5 g of amoxicillin with 5 mL of water for MOBILE PHASE

ohfe. a
ey Oe
5 minutes, filter, wash the residue first with absolute ethanol Mobile phase A 1 volu
vetfay ga
et
yty
atte
et
toe ea
and then with ether and dry at a pressure not exceeding

ten
pote
0.7 kPa for 1 hour. The residue complies with the following
ate
a
,
tests. 2M sodium hydroxide until the p

A. The infrared absorption spectrum, Appendix II A, is sufficient water to produce 1000 mL
concordant with the reference spectrum of amoxicillin Mobile phase B20 volumes of acetomtrilé olumes of
trihydrate (RS 011). the pH 5.0 buffer solution.
B. Carry out the method for thin-layer chromatography, Equilibrate the column with a mobile phase ratio A:B of
Appendix III A, using the following solutions. 92:8. Inject solutions (1) and (2) and start the elution
(1) Dissolve a quantity of the residue in sufficient sodium isocratically with the chosen mobile phase. Immediately after
hydrogen carbonate solution to produce a solution containing elution of the amoxicillin peak start a linear gradient elution
the equivalent of 0.25% w/v of amoxicillin. to reach a mobile phase ratio A:B of 1:100 over a period of
(2) 0.25% w/v of amoxicillin trihydrate BPCRS in sodium 25 minutes. Continue the chromatography with mobile
hydrogen carbonate solution. phase B for 15 minutes then equilibrate the column for
15 minutes with the mobile phase chosen originally. Inject
(3) 0.25% w/v of each of amoxicillin trihydrate BPCRS and
mobile phase A and use the same elution gradient to obtain a
ampicillin trihydrate BPCRS in sodium hydrogen carbonate
blank.
solution.
SYSTEM SUITABILITY
(a) Use a TLC silica gel silanised plate (Merck silanised silica
with solution (3), the resolution factor between the peaks due
gel 60 F54, CRP-18) plates are suitable).
WI-142 Amoxicillin Preparations 2016
to amoxicillin and cefadroxil is at least 2.0. If necessary,

adjust the composition of the mobile phase.
Amoxicillin Injection
LIMITS Action and use
In the chromatogram obtained with solution (1): Penicillin antibacterial.
the area of any secondary peak is not greater than 1.5 times
DEFINITION
the area of the principal peak in the chromatogram obtained
Amoxicillin Injection is a sterile solution of Amoxicillin
Sodium in Water for Injections. It is prepared by dissolving
the area of not more than one secondary peak is greater than Amoxicillin Sodium for Injection in the requisite amount of
the area of the principal peak in the chromatogram obtained Water for Injections immediately before use.
with solution (2) (1%);
the. area of any other secondary peak is not greater than the Parenteral Preparations.
STORAGE
Amoxicillin Injection should be used immediately after
preparation.
liquid chromatography,
owing solutions.
AMOXICILLIN SODIUM FOR INJECTION
DEFINITION
Amoxicillin Sodium for Injection is a sterile material
ultrasound for 1 minute, addsi consisting of Amoxicillin Sodium with or without excipients.
produce 100 mL, mix and filter It is supplied in a sealed container.
is suitable). | | The contents of the sealed container comply with the requirements
(2) 0.070% wiv of amoxicillin tnhydrate t ‘in. mobile for Powders for Injections or Infusions stated under Parenteral
phase A. ~ Preparations and with the following requirements.
(3) 0.0004% w/v of cefadroxil BPCRS and 0.00: Content of amoxicillin, C;;H;.N3;0;S
amoxicillin tnhydrate BPCRS in mobile phase A 90.0 to 105.0% of the stated amount.
CHROMATOGRAPHIC CONDITIONS IDENTIFICATION
(a) Use a stainless steel column (25 cm x 4.6 mm) pac ed . The infrared absorption spectrum, Appendix II A, is
with octadecylsilyl silica gel for chromatography (5 ym) (Hyper: oncordant with the reference spectrum of amoxicillin sodium
5 ODS is suitable). R& eg.
(b) Use isocratic elution and the mobile phase described t the method for thin-layer chromatography,
below. I A, using the following solutions.
(e) Use a detection wavelength of 254 nm. solution¢on
amoxicillin.
MOBILE PHASE
hydrogen carbonate soly
8 volumes of mobile phase B and 92 volumes of mobile (3) 0.25% w/v of each o lin trihydrate BPCRS and
phase A. ampicillin tnhydrate BPCRS hydrogen carbonate
Mobile phase A 1 volume of acetonitrile and 99 volumes of a solution.
‘Ne ey
25% v/v solution of 0.2m potasstum dihydrogen orthophosphate
adjusted to pH 5.0 with 2m sodium hydroxide.
(a) Use a TLC silica gel F254 silanised plate (
Mobile phase B20 volumes of acetomitrile and 80 volumes of
a 25% v/v solution of 0.2m potassium dihydrogen orthophosphate silica gel 60 F54, (RP-18) plates are
adjusted to pH 5.0 with 2m sodium hydroxide. (b) Use the mobile phase described belo
SYSTEM SUITABILITY
The Assay is not valid unless, in the chromatogram obtained
with solution (3), the resolution factor between the peaks due (e) After removal of theplate, allow it to dry in air, expose it
to amoxicillin and cefadroxil is at least 2.0. If necessary, to iodine vapour until spots appear and examine in daylight.
adjust the composition of the mobile phase to achieve the
vee
MOBILE PHASE
Meine on 3
oaw es
required resolution. 10 volumes of acetone and 90 volumes of a 15.4% w/v
DETERMINATION OF CONTENT solution of ammonium acetate adjusted to pH 5.0 with glacial
Calculate the content of C;6Hj)>.N3035S in the capsules from acetic acid.
the chromatograms obtained and from the declared content SYSTEM SUITABILITY
of Cy6Hy9N305S in amoxicillin trihydrate BPCRS. The test is not valid unless the chromatogram obtained with
LABELLING solution (3) shows two clearly separated spots.
The quantity of active ingredient is stated in terms of the CONFIRMATION
equivalent amount of amoxicillin. The principal spot in the chromatogram obtained with
the chromatogram obtained with solution (2).
2016 Amoxicillin Preparations III-143
C. Yields reaction B characteristic of sodium salts, LIMITS

Appendix VI. In the chromatogram obtained with solution (1):
TESTS the area of any peak corresponding to amoxicillin dimer is
Alkalinity not greater than 3 times the area of the principal peak in the
eS
pH of a solution containing the equivalent of 10% w/v of chromatogram obtained with solution (2) (3%);
amoxicillin, 8.0 to 10.0, Appendix V L. the area of any other secondary peak is not greater than twice
Related substances the area of the principal peak in the chromatogram obtained
Carry out the method for liguid chromatography, with solution (2) (2%);
Appendix III D, using the following solutions. the sum of the areas of all the secondary peaks is not greater
(1) Add 80 mL of mobile phase A to a quantity of the than 9 times the area of the principal peak in the
contents of a sealed container containing the equivalent of chromatogram obtained with solution (2) (9%).
“for 1 minute, add sufficient mobile phase A of the principal peak in the chromatogram obtained with
L, mix and filter. solution (2) (0.1%).
Water
Not more than 4.0% w/w, Appendix IX C. Use 0.3 g.
2 g of amoxicillin Bacterial endotoxins
deadd, dropwise, dilute sodium Carry out the test for bacterial endotoxins, Appendix XIV C.
Dissolve the contents of the sealed container in water BET to
solutionis about 8. 5) § give a solution containing the equivalent of 10 mg per mL of
temperature for 4 hours a amoxicillin (solution A). The endotoxin limit concentration
mobile phase A. of solution A is 2.5 IU of endotoxin per mL.
(4) 0.0004% w/v of cefadroxil BPC# ASSAY
amoxicillin tnhydrate BPCRS in mobile
Determine the weight of the contents of 10 containers as
CHROMATOGRAPHIC CONDITIONS described in the test for uniformity of weight,
Appendix XII C1, Powders for Parenteral Administration.
5 ODS is suitable). Appendix III D, using the following solutions.
(b) Use gradient elution and the mobile phase describs SeaAdd 80 mL ofmobile phase A to a quantity of the mixed
below.
MOBILE PHASE
Mobile phase A Mix 1 volume of acetonitrile and 99 volumes efadroxil BPCRS and 0.003% w/v of
of a pH 5.0 buffer solution prepared in the following amoxicillin trihiyd fe RS in mobile phase A.
manner. To 250 mL of 0.2m potassium dihydrogen
orthophosphate add 2m sodium hydroxide until the pH reaches
CHROMATOGRAPHIC CQNDITIONS
5.0 and add sufficient water to produce 1000 mL. (a) Use a stainless (25 cm x 4.6 mm) packed
with octadecylsilyl sitca gel. forhromatography (5 um) (Hypersil
Mobile phase B_ Mix 20 volumes of acetonitrile and
5 ODS is suitable).
80 volumes of the pH 5.0 buffer solution.
(b) Use isocratic elution and th mobi phase described
Equilibrate the column with a mobile phase ratio A:B of
below.
92:8. Inject solutions (1) and (2) and start the elution
isocratically with the chosen mobile phase. Immediately after (c) Use a flow rate of 1 mL per minute
elution of the amoxicillin peak start a linear gradient elution (d) Use an ambient column temperature,
to reach a mobile phase ratio A:B of 1:100 over a period of (e) Use a detection wavelength of 254 nm
25 minutes. Continue the chromatography with mobile (f) Inject 50 pL of each solution.
phase B for 15 minutes then equilibrate the column for
MOBILE PHASE
15 minutes with the mobile phase chosen originally. Inject
mobile phase A and use the same elution gradient to obtain a A mixture of 8 volumes of mobile phase B and 92 volumes
blank. . of mobile phase A.
Inject solution (3). The three main peaks eluted after the Mobile phase A Mix 1 volume of acetonitrile and 99 volumes
principal peak correspond to amoxicillin diketopiperazine, of a 25% v/v solution of 0.2m potassium dihydrogen
et
amoxicillin dimer and amoxicillin trimer. The retention times orthophosphate adjusted to pH 5.0 with 2m sodium hydroxide.
of these peaks relative to that of the principal peak are about Mobile phase B Mix 20 volumes of acetomitrile and
3.4, 4.1 and 4.5 respectively. 80 volumes of a 25% v/v solution of 0.2M potassium
ey
SYSTEM SUITABILITY dihydrogen orthophosphate adjusted to pH 5.0 with 2m sodium

hydroxide.
lal

with solution (4), the resolution factor between the peaks due SYSTEM SUITABILITY
tay le
PEM
SV Cpe
to amoxicillin and cefadroxil is at least 2.0. If necessary, The Assay is not valid unless, in the chromatogram obtained
oo’ veh
EVeee
pe
adjust the composition of the mobile phase. with solution (3), the resolution factor between the peaks due
yA
IiI-144 Amoxicillin Preparations 2016
to amoxicillin and cefadroxil is at least 2.0. If necessary, SYSTEM SUITABILITY

adjust the composition of the mobile phase to achieve the The test is not valid unless the chromatogram obtained with
required resolution. solution (3) shows two clearly separated spots.
DETERMINATION OF CONTENT CONFIRMATION
Calculate the content of C,;¢H, 9N30;S in a container of The principal spot in the chromatogram obtained with
average content weight from the chromatograms obtained solution (1) is similar in position, colour and size to that in
and from the declared content of C,;gH ,9N305S in amoxicillin the chromatogram obtained with solution (2).
trihydrate BPCRS.
TESTS
LABELLING Acidity or alkalinity
The label of the sealed container states the quantity of pH, 4.0 to 7.0, Appendix V L.
Amoxicillin Sodium contained in it in terms of the equivalent
ASSAY
(1) Dilute a weighed quantity of the oral suspension
containing the equivalent of 60 mg of amoxicillin with
sufficient mobile phase A to produce 100 mL, mix and filter
(Whatman GF/C filter paper is suitable).
Action and use
(2) 0.070% w/v of amoxicillin trihydrate BPCRS in mobile
phase A.
DEFINITION (3) 0.0004% w/v of cefadroxil BPCRS and 0.003% w/v of
Amoxicillin Oral Suspension isa f Amoxicillin amoxicillin tnhydrate BPCRS in mobile phase A.
Trihydrate in a suitable flavoured vehicle.It is CHROMATOGRAPHIC CONDITIONS
dispersing the dry ingredients in the specifies (a) Use a stainless steel column (25 cm x 4.6 mm) packed
Water just before issue for use. with octadecylsilyl silica gel for chromatography (5 um) (Hypersil
5 ODS is suitable).
Oral Liquids. below.
For the following tests prepare the Oral Suspension as directed o (c) Use a flow rate of 1 mL per minute.
the label. The suspension, examined immediately after prepara
an ambient column temperature.
unless otherwise indicated, complies with the requirements stated
under Oral Liquids and with the following requirements. *a detection wavelength of 254 nm.
Content of amoxicillin, C,;H;>N3;0.;S

When freshly constituted not more than 120.0% of the stated
amount. When stored at the temperature and for the period
stated on the label during which the Oral Suspension may be
expected to be satisfactory for use, not less than 80.0% of the ume of acetonitrile and 99 volumes
stated amount. of a 25% v/v solutig¢n 2M potassium dihydrogen
IDENTIFICATION orthophosphate adjusteg 69.0 with 2m sodium hydroxide.
Carry out the method for thin-layer chromatography, Mobile phase B Mix 20: yolugmes..of acetonitrile and
Appendix III A, using the following solutions. 80 volumes of a 25% v/v solution of 0.2m potassium
(1) Dilute a quantity of the oral suspension with sufficient dihydrogen orthophosphate adju 0 pH 5.0 with 2m sodium
sodium hydrogen carbonate solution to produce a solution hydroxide.
containing the equivalent of 0.25% w/v of amoxicillin. SYSTEM SUITABILITY
(2) 0.25% wiv of amoxicillin trihydrate BPCRS in sodium
hydrogen carbonate solution.
(3) 0.25% w/v of each of amoxicillin tnhydrate BPCRS and
ampicillin trihydrate BPCRS in sodium hydrogen carbonate adjust the composition of the mobile phase to ack
solution. required resolution.
CHROMATOGRAPHIC CONDITIONS DETERMINATION OF CONTENT
(a) Use a TLC silica gel silanised plate (Merck silanised silica Determine the weight per mL of the oral suspension,
gel 60 F,54, (RP-18) plates are suitable). Appendix V G, and calculate the content of C,;gH ,9>N305S,
(b) Use the mobile phase described below. weight in volume, using the declared content of
Ci6Hi9N305S in amoxicillin tnhydrate BPCRS.
Repeat the procedure using a portion of the oral suspension
that has been stored at the temperature and for the period
(e) After removal of the plate, allow it to dry in air, expose it stated on the label during which it may be expected to be
to iodine vapour until spots appear and examine in daylight. satisfactory for use.
MOBILE PHASE
STORAGE
10 volumes of acetone and 90 volumes of a 15.4% w/v The Oral Suspension should be kept at the temperature and
solution of ammonium acetate adjusted to pH 5.0 with glacial used within the period stated on the label.
acetic acid.
,
:
:
“>
2016 Amphotericin Preparations III-145

oe
LABELLING 25 volumes with solution (2) and further dilute 2 volumes to

The quantity of active ingredient is stated in terms of the 100 volumes with solution A.
equivalent amount of amoxicillin. (5) Dissolve 10 mg of amphotericin B EPCRS in 5 mL of
N-methylpyrrohdone and immediately add 35 mL of a mixture
of 1 volume of methanol and 4 volumes of absolute ethanol.
Add 0.1 mL of dilute hydrochloric acid, mix and incubate at
25° for 2.5 hours. Add 10 mL of a 1% w/v solution of
Amphotericin for Infusion ammonium acetate and mix (generation of impurities B
Amphotericin for Infusion from different manufacturers, whilst and C).
complying with the requirements of the monograph, 1s not (6) Dissolve 4 mg of amphotencin B for peak
interchangeable unless otherwise justified and authorised. identification EPCRS (containing impurities A and B) in
This monograph does not apply to formulations where 5 mL of N-methylpyrroldone and immediately dilute to
50 mL with solution A.

with base-deactivated end-capped octadecylsilyl silica gel for
chromatography (3 um) (ACE 3 C18 and YMC-Pack Pro are
suitable).
below.
for Powders for Injections or Inft (d) Use an ambient column temperature.
Preparations and with the following
(e) Use detection wavelengths of 303 nm and 383 nm.
IDENTIFICATION
A. Dissolve a quantity of the contents ofa s
containing the equivalent of 25 mg of amph MOBILE PHASE
Mobile phase A 1 volume of methanol, 3 volumes of
Dilute 0.5 mL of this solution to 50 mL with m acetomtrile and 6 volumes of a 0.42% w/v solution of citric
light absorption of the resulting solution, Appendix F acid previously adjusted to pH 4.7 using concentrated
range 300 to 450 nm exhibits three maxima, at 362, 3 ammonia.
405 nm. The ratio of the absorbance at the maximum at “*s le phase B 12 volumes of methanol, 20 volumes of a
362 nm to that at the maximum at 381 nm is 0.5 to 0.6. ‘7s, wiv solution of citric acid previously adjusted to
The ratio of the absorbance at the maximum at 381 nm to using concentrated ammonia and 68 volumes of
that at the maximum at 405 nm is about 0.9. ile,
B. In the test for Related substances, the retention time of
the principal peak in the chromatogram obtained with Mobile phase B Comment
solution (1) is the same as that of the principal peak in the (% viv)
0-3 0 isocratic
TESTS 0-30 linear gradient
Alkalinity
pH of a 0.9% w/v solution, 7.2 to 8.0, Appendix V L.
100 isocratic
Related substances
Appendix III D, using the following solutions. Protect the
solutions from light and use within 24 hours of preparation, the peaks due to impurities A and.B.
except for solution (4) which should be injected immediately chromatograms are recorded under ibed conditions
after preparation. Mix 1 volume of a 1% w/v solution of minutes.
ammonium acetate, 1 volume of N-methylpyrrolidone and
2 volumes of methanol (solution A). impurity B, about 0.75; impurity A, about 6
(1) Dissolve a quantity of the contents of a sealed container about 0.85.
containing the equivalent of 20 mg of amphotericin B in SYSTEM SUITABILITY
15 mL of N-methylpyrrolidone, immediately dilute to 50 mL The test is not valid unless, in the chromatogram obtained
with solution A and filter. Dilute 5 volumes of the filtrate to with solution (5) at 383 nm, the resolution factor between the
25 volumes with solution A. peaks due to impurity B and impurityC is at least 1.5.
(2) Dissolve 20 mg of amphotericin B EPCRS in 15 mL of LIMITS
N-methylpyrroldone and immediately dilute to 50 mL with
At a detection wavelength of 303 nm In the chromatogram
solution A. Dilute 5 volumes of the resulting solution. to
obtained with solution (1):
25 volumes with solution A.
solution A.
chromatogram obtained with solution (4) (2%);
(4) Dissolve 20 mg of nystatin EPCRS in 15 mL of
the area of any other secondary peak is not greater than
N-methylpyrrolidone and immediately dilute to 50 mL with
0.5 times the area of the principal peak in the chromatogram
solution A. Dilute 5 volumes of the resulting solution to
. 7
eats

IiI-146 Ampicillin Preparations 2016
Ampicillin Capsules
solution (4) (0.1%). Action and use
eet. |
At a detection wavelength of 383 nm In the chromatogram Penicillin antibacterial.
obtained with solution (1):
the area of any peak corresponding to impurity B is not DEFINITION
greater than 4 times the area of the principal peak in the Ampicillin Capsules contain Ampicillin or Ampicillin
chromatogram obtained with solution (3) (4%); Trihydrate.
the area of any other secondary peak is not greater than twice The capsules comply with the requirements stated under Capsules
the area of the principal peak in the chromatogram obtained and with the following requirements.
with solution (3) (2%). Content of ampicillin, C,;H,>N3;0,S
Disregard ak with an area less than 0.1 times the area 92.5 to 107.5% of the stated amount.
in the chromatogram obtained with IDENTIFICATION
303 nm and 383 nm:
(1) Shake a quantity of the capsule contents containing the
Loss on drying equivalent of 0.125 g of ampicillin with sufficient sodium
When dried over phosphot hydrogen carbonate solution to produce 50 mL and filter.
exceeding 0.7 kPa, lose n (2) 0.25% wiv of ampicillin trihydrate BPCRS in sodium
Use 0.3 g. hydrogen carbonate solution.
Bacterial endotoxins (3) 0.25% w/v of each of ampicillin trihydrate BPCRS and
amoxicillin trihydrate BPCRS in sodium hydrogen carbonate
solution.
1
amphotericin B per mL (solution A). The engdc
concentration of solution A is 50 IU per mL. (a) Use a TLC sihca gel silanised plate (Merck silanised silica
gel 60 F554, (RP-18) plates are suitable).
ASSAY
Determine the weight of the contents of 10 containers
described in the test for Uniformity of weight under ) Apply 1 wL of each solution.
Parenteral Preparations of the British Pharmacopoeia, ) Develop the plate to 15 cm.
Powders for Injections. ‘emoval of the plate, allow it to dry in air, expose it
Dissolve a quantity of the mixed contents of the 10 Vapour until spots appear and examine in daylight.
containers containing the equivalent of 50 mg of
amphotericin B in 10 mL of water for injections and dilute to
100 mL with dimethyl sulfoxide. Dilute 5 mL of this solution
to 100 mL with a phosphate buffer solution prepared by
dissolving 35 g of dipotasstum hydrogen orthophosphate in
sufficient water to produce 1000 mL and adjusting the pH, if
necessary, to 10.5 with potassium hydroxide. Carry out the
microbiological assay of antibiotics, Appendix XIV A. solution (3) shows twe
The precision of the assay is such that the fiducial limits of CONFIRMATION
view awe
error are not less than 95% and not more than 105% of the
estimated potency.
Calculate the content of amphotericin B in the infusion
taking each 1000 IU found to be equivalent to 1 mg of
B. Suspend a quantity of the capsule
amphotericin B. For a container of average content weight,
equivalent of 10 mg of ampicillin in 1 m
the upper fiducial limit of error is not less than 90.0% and
2 mL of a mixture of 2 mL of cupri-tartaric solution R1 and
the lower fiducial limit of error is not more than 115.0% of
6 mL of water. A magenta-violet colour is pro
the stated content.
immediately.
STORAGE
TESTS
Amphotericin for Infusion should be protected from light and
Related substances
stored at a temperature of 2° to 8°.
LABELLING Appendix III D, using the following solutions.
The quantity of active ingredient is stated in terms of the (1) Shake a quantity of the mixed capsule contents
equivalent amount of amphotericin B. containing the equivalent of 0.3 g of ampicillin with 80 mL
IMPURITIES of mobile phase A with the aid of ultrasound for 15 minutes,
The impurities limited by the requirements of this add sufficient mobile phase A to produce 100 mL and filter
monograph include those listed under Amphotericin. through a 0.4-um filter.
mobile phase A.
(3) 0.025% w/v of anhydrous ampicilin BPCRS and
0.002% w/v of cefradine BPCRS in mobile phase A.
2016 Ampicillin Preparations TI-147
CHROMATOGRAPHIC CONDITIONS (e) Use a detection wavelength of 254 nm.

(a) Use a stainless steel column (25 cm x 4.6 mm) packed (f) Inject 50 uwL of each solution.
MOBILE PHASE
(Nucleosil C18 is suitable).
15 volumes of solution B and 85 volumes of solution A.
below. Equilibrate the column with a mobile phase ratio A:B Solution A Dilute a mixture of 1 volume of dilute acetic acid,
of 85:15 and use this for the system suitability solution (3). 100 volumes of 0.2m potassium dihydrogen orthophosphate and
Inject solutions (1) and (2) and start the elution isocratically 100 volumes of acetonitrile to 2000 volumes with water.
with the chosen mobile phase. Immediately after elution of Solution B Dilute a mixture of 1 volume of dilute acetic acid,
the ampicillin peak start the linear gradient elution. 100 volumes of 0.2m potassium dihydrogen orthophosphate and
800 volumes of acetonitrile to 2000 volumes with water.
(d) U ambient column temperature. SYSTEM SUITABILITY
etection wavelength of 254 nm. The assay is not valid unless, in the chromatogram obtained
(e)
each solution.
to ampicillin and cefradine is at least 3.0. If necessary, adjust
the composition of the mobile phase to achieve the required
resolution.
otasstum dihydrogen orthophosphate DETERMINATION OF CONTENT
rite.to 2000 volumes with water.
Calculate the content of C;gH;9N30,S in the capsules using
the declared content of C)¢H,.N30,S in anhydrous
ampicillin BPCRS.
and 800 volumes of acetonitrile to 20 umes with water.
LABELLING
When the active ingredient is Ampicillin Trihydrate, the
Time Mobile Mobile , quantity is stated in terms of the equivalent amount of
(minutes) phase A phase B ampicillin.
(% viv) (% viv)
0 > 30 85 > 0 15 —100
30 > 45 ) 100
45 — 60 85 15
Ampicillin Injection
Inject mobile phase A and use the same elution gradient to )
obtain a blank. :
SYSTEM SUITABILITY
the composition of the mobile phase.
LIMITS
In the chromatogram obtained with solution (1): Parenteral Preparatié

the area of any secondary peak is not greater than the area of STORAGE
the principal peak in the chromatogram obtained with Ampicillin Injection sho
solution (2) (1%). preparation.
ASSAY
Carry out the method for liquid chromatography, AMPICILLIN SODIUM F
DEFINITION
(1) Shake a quantity of the mixed contents of 20 capsules
Ampicillin Sodium for Injection is a sterile m } consisting
containing the equivalent of 60 mg of ampicillin with 80 mL
of Ampicillin Sodium, with or without excipients: It is
of solution A for 15 minutes, dilute to 100 mL with the same
supplied in a sealed container.
solvent, filter and dilute 5 mL of the solution to 50 mL with
solution A. The contents of the sealed container comply with the requirements
for Powders for Injections or Infusions stated under Parenteral
(2) 0.006% w/v of anhydrous ampicillin BPCRS in solution A.
Preparations and with the following requirements.
(3) 0.025% w/v of anhydrous ampicillin BPCRS and
Content of ampicillin, C,;,H,)>N3;0,S
0.002% w/v of cefradine BPCRS in solution A.
IDENTIFICATION
A. The infrared absorption spectrum, Appendix II A, 1s
concordant with the reference spectrum of ampicillin sodium
(RS 366). If the spectra are not concordant carry out the
(b) Use isocratic elution and the mobile phase described following procedure. Dissolve a quantity of the contents of
below. the sealed container containing the equivalent of 0.25 g of
(c) Use a flow rate of 1 mL per minute. ampicillin in 5 mL of water, add 0.5 mL of 2M acetic acid,
(d) Use an ambient column temperature. mix and allow to stand for 10 minutes in ice. Filter through a
II-148 Ampicillin Preparations 2016
sintered-glass filter (ISO 4793, porosity grade 3, is suitable), CHROMATOGRAPHIC CONDITIONS

wash the residue with 2 to 3 mL of a mixture of 9 volumes (a) Use a stainless steel column (25 cm x 4.6 mm) packed
mae
of acetone and 1 volume of water, dry at 60° for 30 minutes with octadecylsilyl silica gel for chromatography (5 um)
and prepare a new spectrum of the residue. The spectrum of (Nucleosil C18 is suitable).
the residue is concordant with the reference spectrum of (b) Use gradient elution and the mobile phase described
ampicillin trihydrate (RS 013). below. Equilibrate the column with a mobile phase ratio A:B
B. Carry out the method for thin-layer chromatography, of 85:15 and use this mobile phase for the system suitability
Appendix III A, using the following solutions. solution (4). Inject solutions (1), (2) and (3) and start the
(1) Dissolve a quantity of the contents of the sealed container elution isocratically with the chosen mobile phase.
in sufficient sodium hydrogen carbonate solution to produce a Immediately after elution of the ampicillin peak start the
solution containing the equivalent of 0.25% w/v of ampicillin. linear gradient elution.
(2) 0.25% of ampicillin trihydrate BPCRS in sodium (c) Use a flow rate of 1 mL per minute.
hydrogen: ate solution. (d) Use an ambient column temperature.
(3) 0.25% Ww “each of ampicillin trihydrate BPCRS and (e) Use a detection wavelength of 254 nm.
amoxicillin tn. RS in sodium hydrogen carbonate (f) Inject 50 uwL of each solution.
solution.
MOBILE PHASE
CHROMATOGRAPH JELIONS
Mobile phase A Dilute a mixture of 1 volume of dilute acetic
mged plate (Merck silanised acid, 100 volumes of 0.2m potasstum dihydrogen orthophosphate
are. suitable). and 100 volumes of acetomtrile to 2000 volumes with water.
Mobile phase B_ Dilute a mixture of 1 volume of dilute acetic
acid, 100 volumes of 0.2m potasstum dihydrogen orthophosphate
and 800 volumes of acetomtrile to 2000 volumes with water.
to iodine vapour until spots appear and exa Time Mobile Mobile Comment
MOBILE PHASE (minutes) phase A phase B
A mixture of 10 volumes of acetone and 90 volumes « : (% viv) (% viv)
15.4% w/v solution of ammonium acetate adjusted to pH... 0 > 30 85 > 0 15 > 100 linear gradient
with glacial acetic acid. 0 > 45 0 100 isocratic
SYSTEM SUITABILITY 85 15 re-equilibration
The test is not valid unless the chromatogram obtained with
CONFIRMATION
peak due to ampicillin dimer which
Appendix VI.
TESTS with solution (4), the re
Alkalinity to ampicillin and cefrad
ane
pH of a solution containing the equivalent of 10.0% w/v of the composition of the mob
ampicillin, 8.0 to 10.0, Appendix V L, measured within LIMITS
10 minutes of preparing the solution.
Related substances
(1) Shake a quantity of the contents of the sealed container
containing the equivalent of 0.3 g of ampicillin with 80 mL the area of the principal peak in the chromatogram*obtained
of mobile phase A with the aid of ultrasound for 15 minutes,
with solution (2) (2%).
add sufficient mobile phase A to produce 100 mL and filter
through a 0.4-um filter. Water
mobile phase A. Bacterial endotoxins
Carry out the test for bacterial endotoxins, Appendix XIV C.
(3) Add 1 mL of water to 0.2 g of anhydrous
ampicillin BPCRS. Heat the solution at 60° for 1 hour and
give a solution containing the equivalent of 9.5 mg of
dilute 0.5 mL to 50 mL with mobile phase A.
ampicillin per mL (solution A). The endotoxin limit
(4) 0.025% w/v of anhydrous ampicillin BPCRS and concentration of solution A is 1.5 IU per mL.
0.002% w/v of cefradine BPCRS in mobile phase A.
ASSAY
described in the test for uniformity of weight,
heN tet 2016 Ampicillin Preparations ITI-149
Carry out the method for liquid chromatography, Content of ampicillin, C,;H,>N3;0,S
Appendix III D, using the following solutions. When freshly constituted not more than 120.0% of the stated
ame a
(1) Dissolve a quantity of the mixed contents of the 10 amount. When stored at the temperature and for the period
containers in sufficient of solution A to produce a solution stated on the label during which the Oral Suspension may be
containing the equivalent of 0.006% w/v of ampicillin. expected to be satisfactory for use, not less than 80.0% of the
stated amount.
(2) 0.006% w/v of anhydrous ampicillin BPCRS in solution A.
(3) 0.025% wy of anhydrous ampicillin BPCRS and IDENTIFICATION
0.002% w/v of cefradine BPCRS in solution A. Carry out the method for thin-layer chromatography,
(1) Dilute a quantity of the oral suspension containing the
equivalent of 0.125 g of ampicillin with sufficient sodium
hydrogen carbonate solution to produce 50 mL.
(Nug 18 is suitable).
(2) 0.25% w/v of ampicillin trihydrate BPCRS in sodium
ic elution and the mobile phase described
hydrogen carbonate solution.
(3) 0.25% w/v of each of ampicillin trihydrate BPCRS and
amoxicillin trihydrate BPCRS in sodium hydrogen carbonate
solution.
(f) Inject 50 uL of each
(a) Use a TLC silica gel silanised plate (Merck silanised silica
MOBILE PHASE gel 60 F254, (RP-18) plates are suitable).
s of solution A. (b) Use the mobile phase described below.
of dilute acetic acid, (c) Apply 1 uL of each solution.
(e) After removal of the plate, allow it to dry in air, expose it
to iodine vapour until spots appear and examine in daylight.
MOBILE PHASE
800 volumes of acetonitrile to 2000 volumeswith,
10 volumes of acetone and 90 volumes of a 15.4% w/v
SYSTEM SUITABILITY
solution of ammonium acetate adjusted to pH 5.0 with glacial
The assay is not valid unless, in the chromatogram obt acetic acid.
with solution (3), the resolution factor between the peaks du
M SUITABILITY
the composition of the mobile phase to achieve the required | St is not valid unless the chromatogram obtained with
resolution. (3) shows two clearly separated spots.
Calculate the content of C,;gH,)9.N30,S in a container of
average content weight using the declared content of
Cy6HyoN304S in anhydrous ampicillin BPCRS.
LABELLING
The label of the sealed container states the quantity of Acidity or alkalin:
Ampicillin Sodium contained in it in terms of the equivalent pH, 4.0 to 7.0, App
amount of ampicillin. ASSAY
Ampicillin Oral Suspension

sufficient solution A to produce 100 mL ¢ q
Action and use the resulting solution to 50 mL with solutio:
Penicillin antibacterial. (2) 0.006% w/v of anhydrous ampicillin BPCRS‘in solution A.
(3) 0.025% w/v of anhydrous ampicillin BPCRS and
DEFINITION
0.002% w/v of cefradine BPCRS in solution A.
Ampicillin Oral Suspension is a suspension of Ampicillin or
Ampicillin Trihydrate in a suitable flavoured vehicle. It is CHROMATOGRAPHIC CONDITIONS
prepared by dispersing the dry ingredients in the specified (a) Use a stainless steel column (25 cm x 4.6 mm) packed
volume of Water just before issue for use. with octadecylsilyl silica gel for chromatography (5 um)
The dry ingredients comply with the requirements for Powders and (Nucleosil C18 is suitable).
Granules for Oral Solutions and Oral Suspensions stated under (b) Use isocratic elution and the mobile phase described
Oral Liquids. below.
For the following tests prepare the Oral Suspension as directed on (c) Use a flow rate of 1 mL per minute.
the label. The suspension, examined immediately after preparation (d) Use an ambient column temperature.
under Oral Liquids and with the following requirements.
'
¢
II-150 Aqueous Cream 2016
MOBILE PHASE
Arachis Oil Enema
15 volumes of solution B and 85 volumes of solution A.
DEFINITION
Solution A Dilute a mixture of 1 volume of dilute acetic acid,
100 volumes of 0.2M potassium dihydrogen orthophosphate and Arachis Oil Enema is Arachis Oil in a suitable container.
100 volumes of acetonitrile to 2000 volumes with water. The enema complies with the requirements stated under Rectal
Solution B Dilute a mixture of 1 volume of dilute acetic acid, Preparations and with the following requirements.
100 volumes of 0.2m potassium dihydrogen orthophosphate and IDENTIFICATION
800 volumes of acetonitrile to 2000 volumes with water. Carry out the test for zdentification offatty oils by thin-layer
SYSTEM SUITABILITY chromatography, Appendix X N. The chromatogram obtained
from the oil being examined shows spots corresponding to
The assay is not valid unless, in the chromatogram obtained
those in the typical chromatogram for arachis oil.
to ampicilli cefradine is at least 3.0. If necessary, adjust TESTS
the comp the mobile phase to achieve the required Acid value
resolution. Not more than 0.6, Appendix X B.
Alkaline impurities
Complies with the test for alkaline impurities, Appendix X N.
Peroxide value
weight in volume, using t Not more than 5.0, Appendix X F.
C 1 6H 9N30,S8 in anhydrous
Relative density
0.912 to 0.918, Appendix V G.
mw aay Unsaponifiable matter
stated on the label during which
STAN
Not more than 1.0% w/w, Appendix X H, Method II.
satisfactory for use.
Use 5 g.
STORAGE
Foreign fixed oils
The Oral Suspension should be stored at the Carry out the test for composition offatty acids by gas
and used within the period stated on the label. chromatography, Appendix X N. The fatty-acid fraction of the
LABELLING oil has the following composition.
When the active ingredient is Ampicillin Trihydrate, the Saturated fatty acids of chain length less than C1, Not more
quantity is stated in terms of the equivalent amount of
ampicillin.
Aqueous Cream
DEFINITION
Emulsifying Ointment 300 g adipate 19.7) Net m
Phenoxyethanol 10g Arachidic acid 1.0 to
Purified Water, freshly Sufficient to produce Gadoleic acid (equivalent gth on polyethylene glycol
boiled and cooled 1000 g adipate 20.3) 0.5 to 2.19
The suitability of the Cream for use as a diluent should be Behenic acid 1.0 to 5.0%.
confirmed before use. Erucic acid (equivalent chain length.on p. hylene glycol adipate
PRODUCTION 22.3) Not more than 0.5%.
As stated in the General Notice on Antimicrobial Lignoceric acid 0.5 to 3.0%.
Preservatives, a suitable alternative antimicrobial preservative The ratio of linoleic acid to behenic acid ‘ig than
may be substituted provided that the identity and 15.
concentration are stated on the label.
Semi-drying oils
Extemporaneous preparation To 1.0 g of the oil being examined add 5 mL of a mixture of
The following directions apply. 3 volumes of 2M ethanolic potassium hydroxide and 1 volume
Dissolve the Phenoxyethanol in sufficient Purified Water at of ethanol (96%), boil under a reflux condenser for
about 60° to produce a total weight of about 700 g. Melt the 5 minutes, add 1.5 mL of 5M acetic acid and 50 mL of
Emulsifying Ointment, add the phenoxyethanol solution ethanol (70%) and heat until the solution is clear. Allow to
when both are at about 60° and mix. Stir gently until cool, cool or cool very slowly with a thermometer in the liquid.
add sufficient of the Purified Water to produce 1000 g and The temperature at which the liquid begins to become
mix. cloudy is not lower than 36°.
The cream complies with the requirements stated under Topical Sesame oil
Semi-solid Preparations. Shake 10 mL with 5 mL of a mixture of 0.5 volume of a
0.35% v/v solution offurfuraldehyde in acetic anhydride and
4.5 volumes of acetic anhydnde for 1 minute, filter the
solution througha filter paper impregnated with acetic
anhydride and add 0.2 mL of sulfuric acid. No bluish green
colour develops.
2016 Arginine Preparations III-151
Sterile Arginine Hydrochloride ASSAY

Concentrate Appendix III D, using the following solutions.
NOTE: Sterile Arginine Hydrochloride Concentrate is not currently (1) Dilute a quantity of the concentrate with sufficient water
licensed in the United Kingdom. to produce a solution containing 0.02% w/v of Arginine
Hydrochloride.
Action and use
(2) 0.02% w/v of arginine hydrochloride BPCRS in water.
Amino acid; nutrient.
DEFINITION (a) Use a stainless steel column (15 cm x 4.6 mm) packed
Sterile Arginine Hydrochloride Concentrate is a sterile with end-capped octadecylsilyl silica gel for chromatography
solution containing Arginine Hydrochloride in a suitable (5 um) (Spherisorb ODS2 is suitable).
plies with the requirements for Concentrates below. |
stons stated under Parenteral Preparations, the (c) Use a flow rate of 2 mL per minute.
requirements stéted | r Unlicensed Medicines and with the
following requirem
MOBILE PHASE
IDENTIFICATION
A. Evaporate to dryness5 tf 40 volumes of methanol R1 and 60 volumes of 0.05m sodium
gel at 40° under reduced pre dihydrogen orthophosphate containing 0.075% w/v of sodium
spectrum of the dried residue, dodecyl sulfate; adjust the pH to 3.3 with orthophosphoric acid.
with the reference spectrum of arginine h SYSTEM SUITABILITY
(RS 470). ‘ The Assay is not valid unless the symmetry factor of the
water to produce a solution containing 0.5%w Atginine solution (2) is between 0.8 and 1.5; if necessary, adjust the
Hydrochloride. The resulting solution yields react content of methanol in the mobile phase.
characteristic of chlorides. DETERMINATION OF CONTENT
TESTS Calculate the content of CgH,,N,0.2,HCI in the concentrate
Acidity g the declared content of Cg6H,4N,02,HCI in arginine
Ninhydrin-positive substances
Appendix III A, using the following solutions in water.
(1) Dilute the concentrate to contain 1.0% w/v of Arginine
Hydrochloride.
further dilute 1 volume to 4 volumes. Action and use «
‘
(3) 0.04% w/v of each of arginine hydrochloride BPCRS and Amino acid; nutrient
es
wat
on
lysine hydrochloride EPCRS.

.
.
trot
DEFINITION
.
eye,
oo
weeSop
Arginine Hydrochloride
rig gery
(a) Use as the coating silica gel.

.
containing Arginine Hydrochlori

t
Be
.
(b) Use the mobile phase as described below. to-use solution.

(e) After removal of the plate, heat it at 100° to 105° until Content of arginine hydrochloride, C;H,,
the ammonia is removed. Spray with ninhydrin solution and 95.0 to 105.0% of the stated amount. .
heat at 100° to 105° for 15 minutes.
IDENTIFICATION
MOBILE PHASE A. In the test for Ninhydrin-positive substances the spot in
30 volumes of concentrated ammonia and 70 volumes of the chromatogram obtained with solution (2) is similar in
Cee setee SY
ends
propan-2-ol. position, size and intensity to the spot in the chromatogram

SYSTEM SUITABILITY
B. Dilute a suitable volume of the infusion with sufficient
water to produce a solution containing 1.25% w/v of Arginine
Hydrochloride. To 2 mL of the resulting solution add 1 mL
LIMITS of 1-naphthol solution and 2 mL of a mixture of equal
Any secondary spot in the chromatogram obtained with volumes of sodium hypochlorite solution (3% Cl) and water.
solution (1) is not more intense than the spot in the A red colour develops.
chromatogram obtained with solution (2) (0.5%). C. Dilute a suitable volume of the infusion with sufficient
water to produce a solution containing 0.5% w/v of Arginine
IW-152 Arginine Preparations 2016
Hydrochloride. The resulting solution yields reaction A beginning at the words ‘add 5 mL of a 0.3% w/v solution of
characteristic of chlorides. potassium todide . .’. Calculate the content of
C6H,4N.0.2,HCl from the absorbances obtained using the
TESTS
declared content of Cg6H,4N40.2,HCl in arginine
Particulate contamination
When supplied in a container with a nominal volume of
more than 100 mL, complies with the test for sub-vzszble LABELLING
particles, Appendix XIII A. The label states that solutions containing visible solid
Acidity particles must not be used.
pH, 5.0 to 6.5, Appendix V L. IMPURITIES
Ninhydrin-positive substances The impurities limited by the requirements of the monograph
Carry out the method for thin-layer chromatography, include ornithine.
Append using the following solutions in water.
(1) Diluteth yn to contain 1.0% w/v of Arginine
Hydrochlori
(2) Dilute 1 voltimes lution (1) to 50 volumes. Arginine Hydrochloride Oral Solution
(3) Dilute 1 volume, of on (2) to 4 volumes. NOTE: Arginine Hydrochloride Oral Solution 1s not currently
(4) 0.02% w/v of argin chloride BPCRS. licensed in the United Kingdom.
(5) 0.04% w/v each of argis yéyochloride BPCRS and
lysine hydrochloride EPCRS iwi water. Action and use
Amino acid; nutrient.
CHROMATOGRAPHIC CONDI ah
(a) Use a TLC silica gel plate. DEFINITION

(b) Use the mobile phase as described*bel Arginine Hydrochloride Oral Solution is a solution of
Arginine Hydrochloride in a suitable flavoured vehicle.
(c) Apply 5 uL of each solution. °
The oral solution complies with the requirements stated under Oral
Liquids, the requirements stated under Unlicensed Medicines and
(e) After removal of the plate, heat it at 100° to 105° 4
the ammonia is removed. Spray with ninhydrin soluti
heat at 100° to 105° for 15 minutes. Content of arginine hydrochloride, C;H,4N,O02,HC1
MOBILE PHASE
30 volumes of concentrated ammonia and 70 volumes of
suitable volume of the oral solution with
propan-2-ol.
ater to produce a solution containing 1.25% w/v
SYSTEM SUITABILITY
LIMITS
Any secondary spot in the chromatogram obtained with tion time of the principal peak in
solution (1) is not more intense than the spot in the ed with solution (1) is similar to
solution (2).
The endotoxin limit concentration is 0.5 [TU per mL, TESTS
Appendix XIV C. Dilute infusions containing more than
5.0% w/v of Arginine Hydrochloride with water BET to
contain 5% w/v.
ASSAY
Dissolve 28 g of potassium hydroxide and 2 g of potassium
sodium (+)-tartrate in 100 mL of water, add to the cooled
solution 0.1 g of 2,4-dichloro-1-naphthol, 180 mL of and further dilute 1 volume of the resulting solution’to
ethanol (96%) and 20 mL of a solution prepared by diluting 4 volumes with water.
1 volume of sodium hypochlorite solution (3% Cl) to 6 volumes (3) 0.04% w/v each of arginine hydrochloride BPCRS and
with water and allow the mixture to stand for 1 hour lysine hydrochlonde EPCRS in water.
(solution A). Dilute a suitable volume of the infusion with
sufficient water to produce a solution containing 0.004% w/v
of Arginine Hydrochloride. To 5 mL add 5 mL ofa
0.3% w/v solution of potassium todide, mix and allow to stand (b) Use the mobile phase as described below.
for 15 minutes. Add 15 mL of solution A, mix and allow to (c) Apply 5 wL of each solution.
stand for 15 minutes. Add 5 mL of a solution prepared by (d) Develop the plate to 15 cm.
diluting 1 volume of sodium hypochlorite solution (3% Cl) to
(e) After removal of the plate, heat at 100° to 105° until the
15 volumes with water and allow to stand for 15 minutes.
ammonia is removed. Spray with ninhydrin solution and heat
at 100° to 105° for 15 minutes.
maximum at 520 nm, Appendix II B, using water in the
reference cell. Repeat the procedure using 5 mL of a
0.004% w/v solution of arginine hydrochloride BPCRS in water
2016 Ascorbic Acid Preparations III-153

50 volumes of concentrated ammonia and 50 volumes of A. Carry out the method for thin-layer chromatography,
propan-2-ol. Appendix III A, using the following solutions in water.
SYSTEM SUITABILITY (1) Dilute the injection, if necessary, to contain 0.5% w/v of
Ascorbic Acid.
solution (3) shows two clearly separated spots. (2) 0.5% w/v of ascorbic acid BPCRS.
LIMITS CHROMATOGRAPHIC CONDITIONS
Any secondary spot in the chromatogram obtained with (a) Use a silica gel F254 precoated plate (Merck silica gel 60
solution (1) is not more intense than the spot in the F454 plates are suitable).
chromatogram obtained with solution (2) (0.5%). (b) Use the mobile phase as described below.
1 ing the following solutions. (e) After removal of the plate, dry in air and examine under
: Hed quantity of the oral solution containing ultraviolet light (254 nm).
0.4 g of Arg MOBILE PHASE
(2) 0.4% wiv o 20 volumes of water and 120 volumes of ethanol (96%).
CONFIRMATION
LO cm x 4.6 mm) packed The principal spot in the chromatogram obtained with
or chromatography solution (1) corresponds in position and colour to that in the
is'suai bl
(5 um) (Spherisorb ODS2 . chromatogram obtained with solution (2).
(b) Use isocratic elution an se described B. To a volume containing 50 mg of Ascorbic Acid add
below. 0.2 mL of 2m nitric acid and 0.2 mL of 0.1M silver nitrate.
(c) Use a flow rate of 1.2 mL per min A grey precipitate is produced.
(d) Use an ambient column temperature. ° TESTS
(e) Use a detection wavelength of 210 nm. Acidity
(f) Inject 10 uwL of each solution. pH, 5.0 to 6.5, Appendix V L.
MOBILE PHASE Oxalic acid
100 volumes of methanol and 400 volumes of 0.2m sodiu Dilute a volume containing 0.25 g to 5 mL with water,
dihydrogen orthophosphate containing 0.3% w/v of sodium ze lise to litmus paper with 2M sodium hydroxide, add 1 mL
dodecyl sulfate; adjust the pH to 3.3 with orthophosphonic acid. acetic acid and 0.5 mL of calcium chloride solution and
stand for 1 hour. Any opalescence producedis not
SYSTEM SUITABILITY
ense than thatin a solution prepared at the same
The Assay is not valid unless, in the chromatogram obtained asthe following manner. Dissolve 70 mg of oxalic
with solution (2), the column efficiency is at least 1800 A of water and to 5 mL of the resulting solution
theoretical plates per metre.
DETERMINATION OF CONTENT solution (0.
Determine the weight per mL of the oral solution, ASSAY
Appendix V G, and calculate the content of To a volume cont g 2 g add5 mL of 2M sulfuric acid
C6H,4N40,,HCl, weight in volume, using the declared and titrate with 0.05ni © using starch mucilage as
content of CgH,4N,02,HCI in arginine hydrochloride BPCRS. indicator. Each mL of 0.05 igdine VSis equivalent to
STORAGE 8.806 mg of CgHgQOg.
Arginine Hydrochloride Oral Solution should be protected STORAGE
from light. Ascorbic Acid Injection should b
Ascorbic Acid Injection

Action and use
Vitamin C.
Ascorbic Acid Tablets
DEFINITION
Action and use
Ascorbic Acid Injection is a sterile solution of Ascorbic Acid
Vitamin C.
in Water for Injections containing Sodium Bicarbonate.
The injection complies with the requirements stated under DEFINITION
Parenteral Preparations and with the following requirements. Ascorbic Acid Tablets contain Ascorbic Acid.
Content of ascorbic acid, C;H,O, The tablets comply with the requirements stated under Tablets and
95.0 to 105.0% of the stated amount. with the following requirements.
CHARACTERISTICS Content of ascorbic acid, C;Hs0¢
A colourless liquid. 95.0 to 107.5% of the stated amount.
IWI-154 Ascorbic Acid Preparations 2016
IDENTIFICATION CHROMATOGRAPHIC CONDITIONS

A. Carry out the method for thin-layer chromatography, (a) Use as the coating silica gel F,54 precoated plate (Merck
Appendix III A, using the following solutions. silica gel 60 F254 plates are suitable).
(1) Shake a quantity of the powdered tablets containing (b) Use the mobile phase as described below.
50 mg of Ascorbic Acid with 10 mL of water for 15 minutes (c) Apply 2 uL of each solution.
and filter.
(2) 0.5% w/v of ascorbic acid BPCRS in water.
CHROMATOGRAPHIC CONDITIONS examine under ultraviolet light (254 nm).
(a) Use silica gel F54 precoated plate (Merck silica gel 60 MOBILE PHASE
A mixture of 20 volumes of water and 120 volumes of
(b) Use the mobile phase as described below. ethanol (96%).
CONFIRMATION
solution (1) corresponds in position and colour to that in the
MOBILE PHASE B. Shake a quantity of the powdered tablets with water and
20 volumes of water an filter. The filtrate is acidic to litmus solution, decolourises
2,6-dichlorophenolindophenol solution and reduces silver nitrate
CONFIRMATION
solution immediately at room temperature producing a black
The principal spot in the c x im, obtained with precipitate.
solution (1) corresponds in posi ‘ur to that in the
TESTS
Disintegration
The requirement for Disintegration does not apply to
Chewable Ascorbic Acid Tablets.
2,6-dichlorophenolindophenol solution and reduce
solution immediately at room temperature produc, ASSAY
precipitate. | Weigh and powder 20 tablets. Dissolve a quantity of the
ASSAY powder containing 0.15 g of Ascorbic Acid as completely as
Weigh and powder 20 tablets. Dissolve a quantity of the
ossible in a mixture of 30 mL of water and 20 mL of
iM sulfuric acid and titrate with 0.1M ammonium cerium(1v)
powder containing 0.15 g of Ascorbic Acid as completely a
using ferroin solution as indicator. Each mL of
possible in a mixture of 30 mL of water and 20 mL of
nium cerium(1v) sulfate VS is equivalent to
1m sulfuric acid and titrate with 0.1M ammonium certum(iv)
f CeHgOg.
sulfate VS using ferroin solution as indicator. Each mL of
0.1M ammonium cerium(iv) sulfate VS is equivalent to
8.806 mg of Ce6HsQO¢. ic Acid Tablets should be kept free from
protected from light and moisture.
STORAGE
Ascorbic Acid Tablets should be kept free from contact with ira e tablets are prescribed or
metal and protected from light and moisture. demanded, Chewab orbic Acid Tablets shall be
dispensed or supplied
When vitamin C tablets are prescribed or demanded,
Ascorbic Acid Tablets shall be dispensed or supplied.
Aspirin Tablets
Chewable Ascorbic Acid Tablets Acetylsalicylic Acid Tablets
Action and use Action and use

Vitamin C. Salicylate; non-selective cyclo-oxygenase inhi
antipyretic; analgesic; anti-inflammatory.
DEFINITION
Chewable Ascorbic Acid Tablets contain Ascorbic Acid. DEFINITION
Aspirin Tablets contain Aspirin.
aa
ce
Len we with the following requirements. The tablets comply with the requirements stated under Tablets and
3
Content of ascorbic acid, C;sHsO,¢
95.0 to 107.5% of the stated amount. Content of aspirin, C,H;O0O,
IDENTIFICATION .
A. Carry out the method for thin-layer chromatography, IDENTIFICATION
Appendix III A, using the following solutions. Boil 0.5 g of the powdered tablets for 2 to 3 minutes with
10 mL of 5m sodium hydroxide, cool and add an excess of
1m sulfuric acid; a crystalline precipitate is produced. To a
50 mg of Ascorbic Acid with 10 mL of water for 15 minutes
solution of the precipitate in water add iron(im) chloride
and filter.
solution R1; a deep violet colour is produced.
(2) 0.5% w/v of ascorbic acid BPCRS in water.
2016 Aspirin Preparations III-155
TESTS
Salicylic acid
Dispersible Aspirin Tablets
Shake a quantity of the powdered tablets containing 0.20 g Action and use
of Aspirin with 4 mL of ethanol (96%) and dilute to 100 mL Salicylate; non-selective cyclo-oxygenase inhibitor;
with water at a temperature not exceeding 10°. Filter antipyretic; analgesic; anti-inflammatory.
immediately, transfer 50 mL of the filtrate to a Nessler
cylinder, add 1 mL of freshly prepared ammonium tron(1) DEFINITION
sulfate solution R1, mix and allow to stand for 1 minute. Dispersible Aspirin Tablets contain Aspirin in a suitable
Any violet colour produced is not more intense than that dispersible basis.
obtained by adding 1 mL of freshly prepared ammonium The tablets comply with the requirements stated under Tablets and
1ron(Il) vat solution R1 to amixture of 3 mL of a ee with the following requirements.
Content of aspirin, C.H;0,
Dissolutio#i IDENTIFICATION
requirements for Monographs of the British Disperse a quantity of the powdered tablets containing
Pharmacopoeia e. dissolution test for tablets and capsules, 50 mg of Aspirin in 10 mL of warm water, boil and add
Appendix XII BI 0.5 mL of zron(m) chloride solution R1. A violet-red colour is
produced.
TEST CONDITIONS
(a) Use Apparatus 1, rota: basket at 50 revolutions per TESTS
minute. Salicylic acid
To a quantity of the powdered tablets containing 0.50 g of
(b) Use 500 mL of a pH 4.
Aspirin add 50 mL of dichloromethane, 2 mL of 2.5M sulfuric
acid and shake vigorously for 2 minutes. Filter the
with sufficient water to produce 10 litr
dichloromethane extract through a dry filter paper containing
1 g of anhydrous sodium sulfate and evaporate 5 mL of the
PROCEDURE filtrate to dryness at room temperature using a rotary
evaporator. Dissolve the residue in 2 mL of ethanol (96%),
transfer to a Nessler cylinder with a further 1 mL of
with the dissolution medium if necessary, at the maxim ethanol (96%), dilute to 50 mL with water at a temperature
265 nm, Appendix IT B using dissolution medium in not exceeding 10°, add 1 mL of freshly prepared ammonium
reference cell. uy) sulfate solution R1, mix and allow to stand for
(2) Measure the absorbance of a suitable solution of ate. Any violet colour producedis not more intense
aspirin BPCRS using dissolution medium in the reference t obtained by adding 1 mL of freshly prepared
cell. am tron(i) sulfate solution R1 to a mixture of 3 mL of
repared 0.050% w/v solution of salicylic acidin
DETERMINATION
OFCONTENT
% and sufficient water to produce 50 mL
Calculate the total content of aspirin, CoHgQ4,, in the
medium from the absorbances obtained and using the
declared content of CoHgQOy, in aspirin BPCRS.
ASSAY Aspirin ;in 10 mL of IM sulfuric
Weigh and powder 20 tablets. To a quantity of the powder acid and boil under a ndenser for 1 hour. Cool,
containing 0.5 g of Aspirin add 30 mL of 0.5m sodium transfer to a separating a
hydroxide VS, boil gently for 10 minutes and titrate the excess condenser with small quaritities of rand extract the
of alkali with 0.5m hydrochloric acid VS using phenol red liberated salicylic acid with fotir : . Quantities of ether.
solution as indicator. Repeat the operation without the
substance being examined. The difference between the
titrations represents the amount of sodium hydroxide temperature not exceeding 30°, disso
required. Each mL of 0.5m sodium hydroxide VS is equivalent of 0.5m sodium hydroxide VS and dilute to2
to 45.04 mg of CoHgQOag.
water. Transfer 50 mL to a stoppered flask, a
LABELLING 0.05m bromine VS and 5 mL of hydrochloric acidg
or kas
The label states that the tablets contain Aspirin, unless this solution from light, shake repeatedly for 15 minutes and
ee
att,
word appears in the name of the tablets. This requirement allow to stand for 15 minutes. Add 20 mL of dilute potassium
eee ee
todide solution, shake thoroughly and titrate with 0.1M sodium

We
does not apply in countries where exclusive proprietary rights

«$l PEG
e
fy
Fe
in the name Aspirin are claimed. thiosulfate VS, using starch mucilage, added towards the end
ooh
ae
wer
CO
point, as indicator. Each mL of 0.05m bromine VS is

equivalent to 3.003 mg of CoHgQx.
LABELLING
The label states that the tablets contain Aspirin, unless this
word appears in the name of the tablets (this requirement
in the name Aspirin are claimed).
When Dispersible Aspirin Tablets are prescribed or
demanded, no strength being stated, tablets containing
300 mg shall be dispensed or supplied.
II-156 Aspirin Preparations 2016
‘
thiosulfate VS, using starch mucilage, added towards the end

'
.
When soluble aspirin tablets are prescribed, Dispersible

te
ebé tt e ' :
’
‘
point, as indicator. Each mL of 0.05m bromine VS is

Pert!
Aspirin Tablets shall be dispensed.

+
thpoede
equivalent to 3.003 mg of CoHgQx.

woe
Tet Lay
ratty
LABELLING
oe
r
The label states that the tablets contain Aspirin, unless this
oe
t h
teas
:
Doo
Effervescent Soluble Aspirin Tablets

:
word appears in the name of the tablets (this requirement

'
to
Lt
'
1

,
>
:
Effervescent Aspirin Tablets

+
1
'
' my ‘
oat
'
in the name Aspirin are claimed).

.
1
a
-
:
Action and use When Effervescent Soluble Aspirin Tablets are prescribed or
+
1
1
e
'
.‘
‘
an
'
Salicylate; non-selective cyclo-oxygenase inhibitor; demanded, no strength being stated, tablets containing
my
'
1
ut
.
:
antipyretic; analgesic; anti-inflammatory. 300 mg shall be dispensed or supplied.

:
.
“4
‘
'
.
1
’
:
When soluble aspirin tablets are prescribed, Dispersible

+
ate.
woe
tesgor
: ef ‘ ha
ty begrtese
toriate
Aspirin Tablets shall be dispensed.

perlcesr
eget
Aspirin Tablets contain Aspirin in a

‘ e.
noe
tle
t.
fvescent basis.
.
,
:
t
‘
hoy
lf
‘
te
:
vs
'
a,
‘
-
1,
Gastro-resistant Aspirin Tablets

t
:
:
.
t
:
.
Content of aspirin,
,
.
1
a
1
'
95.0 to 105.0% of the st

oo
:
Action and use

y
role
an ?
on
3
re]
IDENTIFICATION Salicylate; non-selective cyclo-oxygenase inhibitor;

ye
,
:
tade
eet
sgt
a

ret
;
gy
a
ee
aie’
wv
re ar
wo,
Yoo ‘
root pate ve
DEFINITION
eg tyhe
spt et i letys
pytyeue
“ae
Gastro-resistant Aspirin Tablets contain Aspirin. They are

1 ’
made gastro-resistant by enteric-coating or by other means.

;
.
.
.
.
.
'
produced.
ote
‘
;.
.

:
’
ne
.
:
TESTS
'
Content of aspirin, CoH,O,

‘
:
.
.
Disintegration
:
,
.

:'
Te,
’
Comply with the requirement for Effervescent Tablets stag

.
,
.
'
‘
oa
oe
DENTIFICATION
.
under Tablets.
,
“|:
of,
reooa,
juantity of the powdered tablets containing 0.3 g of

.
.
ye ,
Salicylic acid
oot
,
2 to 3 minutes with 10 mL of 5M sodium

:
,
,

‘
ol and add an excess of 1M sulfuric acid;

:
Lo
Aspirin add 50 mL of dichloromethane, 2 mL of 2.5m sulfuric

:
-
ao
recipitate is produced. To a solution of the

, ,
ty
acid and shake vigorously for 2 minutes. Filter the

‘
'
’
ynwater add tron(1m) chloride solution R1; a deep

¢
.
‘
dichloromethane extract through a dry filter paper containing

,
oe
fe,
oe
ete
ey
1 g of anhydrous sodium sulfate and evaporate 5 mL of the

,
’
’
a
‘
rota
filtrate to dryness at room temperature using a rotary

.
-
:
’
.
.
:
evaporator. Dissolve the residue in 2 mL of ethanol (96%), Dissolution

:
.
’
Comply with the regi

:
.
transfer to a Nessler cylinder with a further 1 mL of

-
’
.
’
Pharmacopoeia in the &

.
ethanol (96%), dilute to 50 mL with water at a temperature

.
.
.
.
not exceeding 10°, add 1 mL of freshly prepared ammonium Appendix XII B1.
.
.
.
m
Cate yt le,
Tee
ay .
tron(i) sulfate solution R1, mix and allow to stand for

ar
eye
ehocle
-*
TEST CONDITIONS s
ete
eth
"3 e
1 minute. Any violet colour produced is not more intense

ge + FFL wy ees
‘
.
cet
First stage (a) Use Apparatus 1¥ro tthe basket at

se
than that obtained by adding 1 mL of freshly prepared

Ve et ee
100 revolutions per minute.

thee
vo
Ta Te
ammonium tron(1m) sulfate solution R1 to a mixture of 3 mL of

Mel ge
Tle
temperature
ws
a freshly prepared 0.050% w/v solution of salicylic acid in (b) Use 1000 mL of 0.1m hydrochloric a
.
.
ee
of 37°, as the medium.

Soe
ethanol (96%) and sufficient water to produce 50 mL

roo
oe
:
ee, oy
Poet
contained in a second Néessler cylinder (3.0%).

*
PROCEDURE
.
: .
-
3
ad
Oe
(1) After 2 hours, withdraw a sample of the mediu

-
ASSAY
tl
.
iy . le. vo
and measure the absorbance of the filtrate, Appendix II B, at

woot
.
o
.

.
.
1 mo <>
276 nm using 0.1m hydrochloric acid in the reference cell.

.
powder containing 0.3 g of Aspirin in 10 mL of 1M sulfuric

.
* OM ee
Te
to
.
acid and boil under a reflux condenser for 1 hour. Cool, (2) Measure the absorbance of a suitable solution of
ryt
fay ete Stee

Ta
>
of
_
transfer to a separating funnel, rinsing the flask and aspirin BPCRS in 0.1m hydrochloric acid.
Ac)
a et
Vise
? ‘
0@,
condenser with small quantities of water and extract the DETERMINATION

OFCONTENT
liberated salicylic acid with four 20-mL quantities of ether.
Calculate the total content of aspirin, CpHgO,, in the
Wash the combined ether extracts with two 5-mL quantities
medium using the declared content of CgHgQOy, in
of water, evaporate the ether in a current of air at a
aspirin BPCRS. The amount of aspirin released is not more
temperature not exceeding 30°, dissolve the residue in 20 mL
than 5% of the stated amount.
of 0.5m sodium hydroxide VS and dilute to 200 mL with
water. Transfer 50 mL to a stoppered flask, add 50 mL of Final stage (a) Use Apparatus 1, rotating the basket at
0.05m bromine VS and 5 mL of hydrochloric acid, protect the 100 revolutions per minute.
solution from light, shake repeatedly during 15 minutes and (b) Replace the 0.1m hydrochloric acid in the vessel with
allow to stand for 15 minutes. Add 20-mL of dilute potassium 900 mL of mixed phosphate buffer pH 6.8, previously held at
iodide solution shake thoroughly and titrate with 0.1M sodium 36.5° to 37.5°.
2016 Aspirin Preparations III-157
PROCEDURE (3) 0.075% w/v of aspirin BPCRS and 0.0015% w/v of

(1) After 45 minutes, withdraw a sample of the medium and salicylic acid in a mixture of 99 volumes of acetonitrile and
filter. Immediately measure the absorbance of the filtrate, 1 volume offormic acid.
Appendix II B, diluted with the dissolution medium, if CHROMATOGRAPHIC CONDITIONS
necessary, at 265 nm using dissolution medium in the
The chromatographic conditions described under Salicylic
reference cell.
acid may be used.
(2) Measure the absorbance of a suitable solution of
SYSTEM SUITABILITY
aspirin BPCRS in the dissolution medium.
Calculate the total content of aspirin, C>9H Ox, in the principal peaks is at least 3.0.
medium using the declared content of CpHgOy, in
Calculate the content C)>)HgQO, in the tablets using the
declared content of Cp)HgO, in aspirin BPCRS.
thod for liquid chromatography,
Appendix , the following solutions. STORAGE
Gastro-resistant Aspirin Tablets should be protected from
(1) Add 60 mL &f acetonitrile and 1 mL offormic acid to a
moisture.
quantity of powde: biets containing 0.3 g of Aspirin,
shake for 15 minutes : id_.sufficient acetonitrile to produce LABELLING
100 mL, mix and filte The label states that the tablets contain Aspirin, unless this
(2) 0.009% w/v of salicylic’agid 1 @ mixture of 99 volumes of word appears in the name of the tablets (this requirement
acetonitrile and 1 volume of foryg¢ does not apply in countries where exclusive proprietary rights
(3) 0.3% w/v of aspirin BPCRS | w/v of salicylic in the name Aspirin are claimed).
acid in a mixture of 99 volumes of déet
offormic acid.
Aspirin and Caffeine Tablets
Action and use ,
Salicylate; non-selective cyclo-oxygenase inhibitor;
below.
MOBILE PHASE
1 volume of acetonitrile and 3 volumes of 0.05m sodium
dihydrogen orthophosphate adjusted to pH 2.0 with
orthophosphonic acid.
SYSTEM SUITABILITY
with solution (3), the resolution factor between the two A. Boil 1 g of the powdered ith 10 mL of 1m sodium
principal peaks is at least 3.0. hydroxide, cool and filter. Acidé filtrate with 1m sulfuric
acid; a white precipitate is produc
LIMITS
precipitate add zron(m) chloride solutio
In the chromatogram obtained with solution (1): colour 1s produced.
the area of any peak corresponding to salicylic acid is not
greater than the area of the peak in the chromatogram
obtained with solution (2) (3%). Extract with three 30 mL quantities of dichloromethane,
ASSAY washing each extract with the same 10 mL of water. Filter
Weigh and powder 20 tablets. Carry out the method for the combined extracts through absorbent cotton and
liquid chromatography, Appendix III D, using the following evaporate the filtrate to dryness. Reserve a quantity of the
solutions. residue for test C. Dissolve 10 mg of the residue in 1 mL of
hydrochloric acid, add 0.1 g of potassium chlorate and evaporate
(1) Add 60 mL of acetonitrile and 1 mL offormic acid to a
to dryness in a porcelain dish. A reddish residue remains,
quantity of the powdered tablets containing 0.3 g of Aspirin,
which becomes purple on exposure to ammonia vapour.
shake for 15 minutes and add sufficient acetonitrile to produce
100 mL, mix and filter. Dilute 1 volume to 4 volumes with a C. The light absorption, Appendix II B, in the range 240 to
mixture of 99 volumes of acetonitrile and 1 volume offormic 350 nm of a 0.001% w/v solution of the residue reserved in
acid, test B exhibits a maximum at 273 nm.
(2) 0.075% w/v of aspirin BPCRS in a mixture of 99 volumes TESTS

of acetonitrile and 1 volume offormic acid. Salicylic acid
Aspirin add 50 mL of dichloromethane and 10 mL of water,
IiI-158 Atenolol Preparations 2016
shake well and allow to separate. Filter the dichloromethane Calculate the content of CgH,)9N,O, taking 504 as the value
layer through a dry filter paper and evaporate 10 mL of the of A(1%, 1 cm) at the maximum at 273 nm.
filtrate to dryness at room temperature using a rotary
LABELLING
evaporator. To the residue add 4 mL of ethanol (96%), stir
The label states that the tablets contain Aspirin,.unless this
well, dilute to 100 mL with water at a temperature not
word appears in the name of the tablets. This requirement
exceeding 10°, filter immediately, rapidly transfer 50 mL to a
Nessler cylinder, add 1 mL of freshly prepared ammonium
in the name Aspirin are claimed.
tron(i) sulfate solution R1, mix and allow to stand for
1 minute. Any violet colour produced is not more intense
than that obtained by adding 1 mL of freshly prepared
ammonium tron(im) sulfate solution RI toamixture of 3 mL of
Atenolol Injection
ethanol (9 nd sufficient water to produce 50 mL
contain¢ 1 Ge id Nessler cylinder (3.0%). Action and use
Beta-adrenoceptor antagonist.
Dissolution
For aspirin DEFINITION
Comply with the nts for Monographs of the British Atenolol Injection is a sterile solution of Atenolol in Water
Pharmacopoeia in it on test for tablets and capsules, for Injections containing Citric Acid Monohydrate and
Appendix XII B1. Sodium Chloride.
TEST CONDITIONS The injection complies with the requirements stated under
(a) Use Apparatus 2, rotating ite at 50 revolutions Parenteral Preparations and with the following requirements.
per minute. Content of atenolol, C,;4H2.N,03
IDENTIFICATION
To a volume of the injection containing 5 mg of Atenolol
add sufficient 1m sodium hydroxide to make it alkaline (about
PROCEDURE 0.5 mL) and extract with three 10 mL quantities of a
(1) After 45 minutes withdraw a 20 mL sample of th mixture of 1 volume of propan-2-ol and 3 volumes of
medium and measure the absorbance of the filtered sampl hloroform. Filter the combined extracts through anhydrous
suitably diluted with the dissolution medium if necessary, odium sulfate and evaporate to dryness in a current of
the maximum at 265 nm, Appendix II B, using dissolution mn. The infrared absorption spectrum of the residue,
medium in the reference cell. dix. II A, is concordant with the reference spectrum of
aspirin BPCRS in the dissolution medium using dissolution
medium in the reference cell.
DETERMINATION
OFCONTENT
Calculate the total content of aspirin, CopHgQO4,, in the
declared content of CgHgO, in aspirin BPCRS.
ASSAY
dilute 1 volume of solution
Weigh and powder 20 tablets.
mobile phase. For solution
For aspirin
To a quantity of the powder containing 0.7 g of Aspirin add
20 mL of water and 2 g of sodium citrate and boil under a phase.
reflux condenser for 30 minutes. Cool, wash the condenser The chromatographic procedure may b
with 30 mL of warm water and titrate with 0.5m sodium
hydroxide VS using phenolphthalein solution R1 as indicator.
Each mL of 0.5m sodium hydroxide VS is equivalent to
45.04 mg of CoHgQO.. a flow rate of 1.0 mL per minute a mixture of 20 volumes of
For caffeine tetrahydrofuran, 180 volumes of methanol and 800 volumes of
To a quantity of the powder containing 30 mg of Caffeine 0.025m potassium dihydrogen orthophosphate containing 1.0 g
add 200 mL of water and shake for 30 minutes. of sodium octanesulfonate and 0.4 g of tetrabutylammonium
Add sufficient water to produce 250 mL and filter. hydrogen sulfate per litre and adjusted to pH 3.0 with
To 10 mL of the filtrate add 10 mL of 1m sodium hydroxide orthophosphoric acid and (c) a detection wavelength of
and extract immediately with five 30 mL quantities of 226 nm.
chloroform, washing each extract with the same 10 mL of The test is not valid unless the chromatogram obtained with
water. Filter the combined chloroform extracts, if necessary, solution (3) resembles the reference chromatogram provided
through absorbent cotton previously moistened with with atenolol impurity standard BPCRS in that the peak due to
chloroform. Evaporate the solution to dryness and dissolve the bis ether precedes, and is separated from, that due to tertiary
residue as completely as possible in water, warming gently if amine, which is normally a doublet. If necessary, adjust the
necessary. Cool, add sufficient water to produce 100 mL, mix concentration of sodium octanesulfonate in the mobile phase;
and filter if necessary. Measure the absorbance of the resulting increasing the concentration increases the retention time of
solution at the maximum at 273 nm, Appendix II B. the tertiary amine.
2016 Atenolol Preparations II-159
In the chromatogram obtained with solution (1) the area of Related substances
any peak corresponding to blocker acid is not greater than Carry out the method for liguid chromatography,
the area of the peak in the chromatogram obtained with Appendix III D, using the following solutions.
solution (2) (0.5%) and the area of any peak corresponding (1) Dilute the oral solution with the mobile phase to produce
to either tertiary amine or bis ether is not greater than half of a solution containing 0.2% w/v of Atenolol.
the area of the peak in the chromatogram obtained with
solution (2) (0.25%).
mobile phase.
ASSAY (3) Dissolve 10 mg of atenolol impurity standard BPCRS in
Dilute a volume of the injection containing 10 mg of 0.1 mL of dimethyl sulfoxide, with the aid of gentle heat, and
Atenolol to 100 mL with methanol and measure the dilute to 20 mL with the mobile phase.
absorbance at the maximum at about 275 nm, Appendix II B.
Calculate,the content of C)4,H22N.03 taking 53.7 as the
1 cm) at the maximum at 275 nm. (a) Use a stainless steel column (15 cm x 4.6 mm) packed
(5 um) (Spherisorb ODS 2 is suitable).
ould be protected from light.
below.
Atenolol Oral So (e) Use a detection wavelength of 226 nm.
Action and use (f) Inject 20 wL of each solution.

Beta-adrenoceptor antagonis (g) Allow the chromatography to proceed for twice the
retention time of the blocker acid.
DEFINITION MOBILE PHASE
Atenolol Oral Solution is a solution ofAt a suitable
20 volumes of tetrahydrofuran, 180 volumes of methanol and
aqueous vehicle.
800 volumes of 0.025mM potassium dihydrogen orthophosphate
The oral solution complies with the requirements s containing 1.0 g of sodium octanesulfonate and 0.4 g of
Liquids and with the following requirements. tetrabutylammonium hydrogen sulfate per litre and adjusted to
Content of atenolol, C,,H2.N,03 pH 3.0 with orthophosphoric acid.
94.0 to 106.0% of the stated amount. SYSTEM SUITABILITY
IDENTIFICATION is not valid unless the chromatogram obtained with
A. Carry out the method for thin-layer chromatography, (3) resembles that of the reference chromatogram
Appendix III A, using the following solutions. with atenolol impurity standard BPCRS in that the
,
(1) Make a volume of the oral solution containing 50 mg of due to bis ether precedes, and is separated from, that
'
amine, which is normally a doublet.

:
Atenolol alkaline with 1m sodium hydroxide (about 0.5 mL),

.
my Lo ,
tala
extract with three 10-mL quantities of a mixture of 1 volume

ay
eo
of propan-2-ol and 3 volumes of chloroform, filter the n le mobile phase; increasing the
oy
ha
.
combined extracts through anhydrous sodium sulfate, evaporate concentratiori in¢reases the retention time of the tertiary
’
to dryness under reduced pressure with gentle heat and amine.

:
:
dissolve the residue in 0.5 mL of methanol. LIMITS

.
.
(2) 1.0% w/v of atenolol BPCRS in methanol.

:
Sek etket:
In the chromatogram ith solution (1):

vt
*
tet
the area of any peak correspetiding to blocker acid is not

eh tte
*
greater than the area of the peak i chromatogram

eat
(a) Use as the coating silica gel GF 254.

2
obtained with solution (2) (0.5%

te Lak
.

a ES ee,
z.
te
ee
(c) Apply 10 pL of each solution. the area of any peak correspondi ertiary amine or
Lt.
eet
PO
bis ether is not greater than half of th peak in the

oe

et
a
-
chromatogram obtained with solution (2) 4

>
-.
wo
ASSAY
a

a
of

.
a-
eee
MOBILE PHASE
oy eeey,bape ee
~

oad
1 volume of 18M ammonia and 99 volumes of methanol.

:
(1) Dilute the oral solution with the mobile phase to produce
eee
.
CONFIRMATION a solution containing 0.025% w/v of Atenolol.

RR
The principal spot in the chromatogram obtained with (2) 0.025% w/v of atenolol BPCRS in the mobile phase.
OD
solution (1) corresponds in position, size and intensity to that CHROMATOGRAPHIC CONDITIONS
in the chromatogram obtained with solution (2). Disregard
any spots due to excipients at Rf values of 0.69 and 0.80.
B. In the Assay, the principal peak in the chromatogram (5 um) (Hypersil ODS is suitable).
that in the chromatogram obtained with solution (2).
below.
TESTS
Pee: Acidity
nae
oe,
Stes
wee|
aN
IlI-160 Atenolol Preparations 2016
(e) Use a detection wavelength of 275 nm. mixture of 20 volumes of tetrahydrofuran, 180 volumes of
(f) Inject 20 uL of each solution. methanol and 800 volumes of a 0.34% w/v solution of
potassium dthydrogen orthophosphate; adjust the pH to 3.0 with
orthophosphonic acid. Inject 20 wL of each solution.
at least 30 minutes.
MOBILE PHASE
solution (3) resembles the reference chromatogram provided
1 volume of sulfuric acid (10%), 25 volumes of acetonitrile and with atenolol impurity standard BPCRS in that the peak due to
74 volumes of water containing 0.93 g per litre of sodium octyl bis ether precedes, and is separated from, that due to tertiary
sulfate adjusted to pH 3 with 2m sodium hydroxide. amine, which 1s normally a doublet. If necessary, adjust the
DETERMINATION OF CONTENT concentration of sodium octanesulfonate in the mobile phase;
Calculate the content of C,;4H22N2O3 in the oral solution increasing the concentration increases the retention time of
using the declared content of C,;4H.2»N.2O3 in the tertiary amine.
atenolol Bi In the chromatogram obtained with solution (1) the area of
any peak corresponding to blocker acid is not greater than
solution (2) (0.5%) and the area of any peak corresponding
to either tertiary amine or bis ether is not greater than half of
Atenolol Tablet the area of the peak in the chromatogram obtained with
solution (2) (0.25%).
Action and use
Beta-adrenoceptor antagonis: ASSAY
Powder 20 tablets. Transfer the powder to a 500 mL flask
DEFINITION using 300 mL of methanol, heat the resulting suspension to
Atenolol Tablets contain Aten 60° and shake for 15 minutes. Cool, dilute to 500 mL with
The tablets comply with the requirements sta Tablets and methanol, filter through a fine glass micro-fibre filter paper
with the following requirements. (Whatman GF/C is suitable) and dilute a suitable volume of
the filtrate with sufficient methanol to produce a solution
Content of atenolol, C,;,H,,N,03
containing 0.01% w/v of Atenolol. Measure the absorbance of
the resulting solution at the maximum at 275 nm,
IDENTIFICATION Appendix II B. Calculate the content of C,;,H..»N.O; taking
A. Heat a quantity of the powdered tablets containing 6.1 3.7 as the value of A(1%, 1 cm) at the maximum at
of Atenolol with 15 mL of methanol to 50°, shake for
5 minutes, filter (Whatman No. 42 paper is suitable) and
evaporate the filtrate to dryness on a water bath. Warm the
residue with 10 mL of 0.1m hydrochloric acid, shake and filter.
Add to the filtrate sufficient 1m sodium hydroxide to make it
alkaline, extract with 10 mL of chloroform, dry by shaking
with anhydrous sodium sulfate, filter, evaporate the filtrate to
dryness on a water bath and dry the residue at 105° for
1 hour. The infrared absorption spectrum of the residue,
Appendix IT A, is concordant with the reference spectrum of
atenolol (RS 015).
B. The light absorption, Appendix IT B, in the range 230 to
350 nm of the solution obtained in the Assay exhibits
maxima at 275 nm and 282 nm.
TESTS
Related substances 90.0 to 110.0% of the stated amoun
Appendix III D, using the following solutions. For IDENTIFICATION .
solution (1) shake a quantity of the powdered tablets A. Comply with test A for Identification descg |
containing 25 mg of Atenolol with 25 mL of the mobile Atropine Injection, using for the preparation of sélutign (1) a
phase, mix with the aid of ultrasound for 20 minutes, filter volume of the eye drops containing 5 mg of Atropr
(Whatman GF/C filter paper is suitable) and use the filtrate. B. In the Assay, the chromatogram obtained with
For solution (2) dilute 1 volume of solution (1) to solution (1) exhibits a peak with the same retention time as
200 volumes with the mobile phase. For solution (3) dissolve the peak due to atropine sulfate in the chromatogram
10 mg of atenolol impurity standard BPCRS in 0.1 mL of obtained with solution (2).
dimethyl sulfoxide, with the aid of gentle heat, add 10 mL of ASSAY
the mobile phase and mix.
The chromatographic procedure may be carried out using Appendix III D, using the following solutions.
For eye drops containing less than 0.1% w/v of Atropine Sulfate.
(1) Use the eye drops being examined.
(Spherisorb ODS 2 is suitable), (b) as the mobile phase with
a flow rate of 1 mL per minute a mixture prepared as (2) 0.05% w/v of atropine sulfate BPCRS and 0.05% w/v of
described below and (c) a detection wavelength of 226 nm. homatropine hydrobromide BPCRS in the mobile phase.
For the mobile phase dissolve 0.8 g of sodium octanesulfonate For eye drops containing 0.1% w/v of Atropine Sulfate or more.
and 0.4 g of tetrabutylammonium hydrogen sulfate in 1 litre of a
2016 Atropine Preparations III-161
(1) Dilute the eye drops to contain 0.1% w/v of Atropine ASSAY
Sulfate with water. Carry out the method for liquid chromatography,
(2) 0.1% w/v of atropine sulfate BPCRS and 0.1% w/v of Appendix III D, using the following solutions.
homatropine hydrobromide BPC'RS in the mobile phase. (1) Dissolve a quantity of the eye ointment containing 10 mg
CHROMATOGRAPHIC CONDITIONS of Atropine Sulfate in 10 mL of ether and extract with two
10 mL quantities of 0.01mM hydrochloric acid. Use the
combined extracts.
(5 um) (Nucleosil C18 is suitable). (2) 0.05% w/v of atropine sulfate BPCRS and 0.05% w/v of
homatropine hydrobromide BPCRS in the mobile phase.
below. CHROMATOGRAPHIC CONDITIONS
(c) Use a flow rate of 2 mL per minute. (a) Use a stainless steel column (10 cm x 4.6 mm) packed
mm wavelength of 257 nm.
eontaining less than 0.1% w/v of Atropine
below.
of each solution. For eye drops
containing 0.1% Atropine Sulfate or more inject (c) Use a flow rate of 2 mL per minute.
20 uL of each sol (d) Use an ambient column temperature.
MOBILE PHASE (e) Use a detection wavelength of 257 nm.
0.01mM sodium acetate and ! lioctyl sodium sulfosuccinate (f) Inject 100 uwL of each solution.
in methanol (60%) adjusted 1°5°5, with glacial acetic acid. MOBILE PHASE
SYSTEM SUITABILITY 0.01M sodium acetate and 0.005m dioctyl sodium sulfosuccinate
The test is not valid unless, in the chromatogram obtained in methanol (60%) adjusted to pH 5.5 with glacial acetic acid.
with solution (2), the resolution factor betweerr the peaks due SYSTEM SUITABILITY
to atropine sulfate and homatropine hydrebromgide. is at least The test is not valid unless, in the chromatogram obtained
2.5. with solution (2), the resolution factor between the peaks due
DETERMINATION OF CONTENT to atropine sulfate and homatropine hydrobromide is at least
Calculate the content of (C,;7H23NO3)2,H.SO,,H>2 2.5.
eye drops using the declared content of DETERMINATION OF CONTENT
(C,7H23NO3)2,H2SO,4,H,O in atropine sulfate BPCRS. ulate the content of (C,7H23NO3)2,H2SO,4,H2O in the
ytment using the declared content of
O3)2,H2SO,,H.O in atropine sulfate BPCRS.
Atropine Eye Ointment

Action and use
Anticholinergic.
Action and use
DEFINITION
Anticholinergic.
Atropine Eye Ointment is a sterile preparation containing
Atropine Sulfate in a suitable basis. DEFINITION
The eye ointment complies with the requirements stated under Eye Atropine Injection is a sterilesolution of Atropine Sulfate in
Preparations and with the following requirements. Water for Injections. &
Content of atropine sulfate, (C,,H,3;NO3),,H,SO,,H,O The injection complies with the regul m stated under
92.5 to 105.0% of the stated amount. Parenteral Preparations and with the fo ing Kequirements.
IDENTIFICATION Content of atropine sulfate, (C,,Hj3™
A. Complies with test A for Identification described under 90.0 to 110.0% of the stated amount.
Atropine Injection but preparing solution (1) in the following IDENTIFICATION
manner. Dissolve a quantity of the ointment containing A. Carry out the method for thin-layer chromatography,
10 mg of Atropine Sulfate as completely as possible in Appendix III A, using the following solutions.
10 mL of petroleum spint (boiling range, 40° to 60°) and
(1) Evaporate a volume of the injection containing 5 mg of
extract with two 10 mL quantities of 0.05m sulfuric acid,
Atropine Sulfate to dryness on a water bath, triturate the
washing each acid solution with the same 5 mL of petroleum
residue with 1 mL of ethanol (96%), allow to stand and use
spirit (boiling range, 40° to 60°). Mix the acid solutions, make
the supernatant liquid.
alkaline with 5M ammonia and extract with two 15 mL
quantities of chloroform. Evaporate the chloroform and (2) 0.5% w/v of atropine sulfate BPCRS in ethanol (96%).
dissolve the residue in 2 mL of ethanol (96%). CHROMATOGRAPHIC CONDITIONS
B. In the Assay, the chromatogram obtained with (a) Use as the coating silica gel.
solution (1) exhibits a peak with the same retention time as (b) Use the mobile phase as described below.
the peak due to atropine sulfate in the chromatogram
a ne ene
ey
III-162 Atropine Preparations 2016
(e) After removal of the plate, heat it at 105° for 20 minutes,

allow to cool and spray with dilute potassium 1odobismuthate
Atropine Tablets
solution. Action and use
MOBILE PHASE Anticholinergic.
10 volumes of diethylamine, 40 volumes of acetone and
DEFINITION
50 volumes of chloroform.
Atropine Tablets contain Atropine Sulfate.
CONFIRMATION
The spot in the chromatogram obtained with solution (1) with the following requirements.
corresponds to that in the chromatogram obtained with
solution (2). Content of atropine sulfate, (C,,H,3;NO3),,H,SO,,H,O
B. In the Assay, the chromatogram obtained with
ibits a peak with the same retention time IDENTIFICATION
“atropine sulfate in the chromatogram A. Carry out the method for thin-layer chromatography,
obtained Appendix III A, using the following solutions.
TESTS (1) Shaking a quantity of the powdered tablets containing
10 mg of Atropine Sulfate with 2 mL of ethanol (96%),
centrifuge and use the supernatant liquid.
(2) 0.5% w/v of atropine sulfate BPCRS in ethanol (96%).
Appendix III D, using the folldwi (a) Use as the coating silica gel G.
For injections containing less than (b) Use the mobile phase as described below.
(1) Use the injection being examined (c) Apply 5 uL of each solution.
(2) Use atropine sulfate BPCRS and homaté (d) Develop the plate to 15 cm.
hydrobromide BPCRS in the mobile phase, b same (e) After removal of the plate, heat it at 105° for 20 minutes,
concentration as the solution being examined. allow to cool and spray with dilute potassium todobismuthate
For injections containing 0.1% wiv or more of Atropine St solution.
(1) Dilute the injection, if necessary, to contain 0.1% MOBILE PHASE
Atropine Sulfate with water. 10 volumes of diethylamine, 40 volumes of acetone and
(2) 0.1% w/v of atropine sulfate BPCRS and 0.1% w/v of es of chloroform.

(5 um) (Nucleosil C18 is suitable). B. In‘the't iformity of content, the chromatogram
(b) Use isocratic elution and the mobile phase described obtained wit
below. retention timeas th k due to atropine sulfate in the
gé
(c) Use a flow rate of 2 mL per minute. chromatogram obtain ith solution (2).
:
,

soe
te

Pale ae ba
(f) For injections containing less than 0.1% w/v of Atropine e and/or less than 2% w/w
Sulfate inject 100 wL of each solution. For injections irements stated
en er
Lk
containing 0.1% w/v or more of Atropine Sulfate inject

20 uL of each solution.
a es Ve
Appendix III D, using the following sol

MOBILE PHASE
oonnn
(1) Shake 1 tablet with 2 ml of the mobile phase \ the aid

0.01M sodium acetate and 0.005mM dioctyl sodium sulfosuccinate
of ultrasound until fully disintegrated and filter. .<
1
in methanol (60%) adjusted to pH 5.5 with glacial acetic acid.

ft
(2) 0.03% w/v of atropine sulfate BPCRS and 0.03% w/v of

ye
vo
SYSTEM SUITABILITY
Ce

ri?
eG
Reet

Co
atropine sulfate and homatropine hydrobromide is at

least 2.5. with end-capped octadecylsilyl silica gel for chromatography
Calculate the content of (C;7H23NO3)2,;H2SO,4,H>,O in the
below.
injection using the declared content of
(C,7H23NO3)2,H2,SO.1,H,O in atropine sulfate BPCRS.
|
tet ated
2016 Azapropazone Preparations III-163
MOBILE PHASE CHROMATOGRAPHIC CONDITIONS

0.01mM sodium acetate and 0.005m dioctyl sodium sulfosuccinate (a) Use a stainless steel column (30 cm x 3.9 mm) packed
in methanol (60%) adjusted to pH 5.5 with glacial acetic acid. with octadecylsilyl sihca gel for chromatography (10 um)
SYSTEM SUITABILITY
(uBondapak C18 is suitable).
The test is not valid unless, in the chromatogram obtained (b) Use isocratic elution and the mobile phase described
with solution (2), the resolution factor between the peaks due below.
to atropine sulfate and homatropine hydrobromide is at least (c) Use a flow rate of 2.5 mL per minute.
2.5. (d) Use ambient column temperature.
DETERMINATION OF CONTENT (e) Use a detection wavelength of 254 nm.
Calculate the content of (C,;7H23NO3)2,;H2SO,4,H.2O in each (f) Inject 20 uL of each solution.
tablet using the declared content of MOBILE PHASE
NQ3)2,H»SO,,H.O in atropine sulfate BPCRS.
1 volume of glacial acetic acid, 36 volumes of methanol and
63 volumes of a 0.068% w/v solution of sodium
butanesulfonate in water.
SYSTEM SUITABILITY
Inject solution (7) and continue the chromatography for
5 times the retention time of the principal peak.
solution (7) closely resembles the reference chromatogram
supplied with the azapropazone impurity standard.
Action and use é If necessary adjust the proportion of methanol in the mobile
Cyclo-oxygenase inhibitor; ana phase to give the required retention times.
LIMITS
DEFINITION
the area of any peak corresponding to azapropazone
and with the following requirements. impurity A is not greater than the area of the corresponding
Content of azapropazone, C,¢,H 2 9N,02,2H,O
95.0 to 105.0% of the stated amount. the area of any peak corresponding to azapropazone
impurity B is not greater than the area of the corresponding
IDENTIFICATION ‘in the chromatogram obtained with solution (3)
A. The infrared absorption spectrum of the contents of the
capsules, Appendix II A, is concordant with the reference
any peak corresponding to azapropazone
spectrum of azapropazone (RS 016).
is not greater than the area of the corresponding
the area of
TEST area of the peak'in the chromatogram obtained with
Related substances solution (5) (0.1%:
Carry out the following operations in subdued light using Calculate the content
low-actinic glassware without delay. Carry out the method respective reference s
for liquid chromatography, Appendix III D, using the following unnamed impurities usin
solutions in a mixture of 1 volume of phosphate buffer pH 4.0
and 3 volumes of methanol.
(1) Dissolve a quantity of the contents of the capsules as principal peak in the chromatogrart
completely as possible in sufficient of a mixture of 1 volume solution (6) (0.05%).
of phosphate buffer pH 4.0 and 3 volumes of methanol to
produce a solution containing 0.10% w/v of Azapropazone
ASSAY
and filter.
low-actinic glassware without delay. Carry out tk
(2) 0.00010% w/v of azapropazone impurity A BPCRS.
for liquid chromatography, Appendix III D, using the following
(3) 0.00025% w/v of azapropazone impunity B BPCRS. solutions in a mixture of 1 volume of phosphate buffer pH 4.0
ey ees
ee Gt,
Fee Bae,
(4) 0.00025% w/v of azapropazone impurity C BPCRS. and 3 volumes of methanol.

Symeets
fob
VAD

Fh

Ce
mixture of 1 volume of phosphate buffer pH 4.0 and 3 volumes containing 20 mg of Azapropazone with 40 mL of a mixture
of methanol and further dilute 1 volume of this solution to of 1 volume of phosphate buffer pH 4.0 and 3 volumes of
10 volumes with the same solvent mixture. methanol and add sufficient solvent A to produce 100 mL.
(6) Dilute 1 volume of solution (5) to 2 volumeswith a (2) 0.02% w/v of azapropazone BPCRS.
mixture of 1 volume of phosphate buffer pH 4.0 and 3 volumes CHROMATOGRAPHIC CONDITIONS
of methanol.
(7) 0.1% wv of azapropazone impurity standard BPCRS. with octadecylsilyl sihca gel for chromatography (10 um)
(uBondapak C18 is suitable).
IlI-164 Azapropazone Preparations 2016
(b) Use isocratic elution and the mobile phase described a 0.068% w/v solution of sodium butanesulfonate in water as
below. the mobile phase with a flow rate of 2.5 mL per minute and
RN ese
(c) Use a flow rate of 2.5 mL per minute. (c) a detection wavelength of 254 nm.
(d) Use ambient column temperature. Inject solution (5) and continue the chromatography for
5 times the retention time of the principal peak. The test is
not valid unless the chromatogram obtained with solution (5)
closely resembles the reference chromatogram. If necessary
MOBILE PHASE adjust the proportion of methanol in the mobile phase to give
1 volume of glacial acetic acid, 36 volumes of methanol and the required retention times.
63 volumes of a 0.068% w/v solution of sodium In the chromatogram obtained with solution (1) the area of
butanesulfonate in water. any peaks corresponding to azapropazone impurities A and C
ION OF CONTENT are not greater than the areas of the corresponding peaks in
the chromatograms obtained with solutions (2) and (3)
ntent of C,6H29N402,;2H20 using the
(0.25% and 0.75% respectively). The area of any other
C1 6H29N,02,2H,O0 in
secondary peak other than any peak corresponding to
azapropazone impurity B is not greater than the area of the
STORAGE peak in the chromatogram obtained with solution (4) (0.1%).
Azapropazone Cap quld be protected from light. Calculate the content of impurities A and C using the
respective reference solutions and the content of any
unnamed impurities using solution (4). The total content of
impurities is not greater than 1%. Disregard any peak with
an area less than the area of the peak in the chromatogram
Azapropazone Tablet » obtained with solution (6) (0.05%).
Action and use ASSAY

Cyclo-oxygenase inhibitor; analgesic; anti; Carry out the following operations in subdued light using
low-actinic glassware without delay. Weigh and powder
DEFINITION 20 tablets. To a quantity of the powdered tablets containing
Azapropazone Tablets contain Azapropazone. 0.6 g of Azapropazone add 20 mL of water, shake for
The tablets comply with the requirements stated under Tablets 30 minutes, add 60 mL of methanol, shake for 10 minutes
with the following requirements. and dilute to 100 mL with water. Centrifuge a portion of the
solution at 3000 revolutions per minute for 10 minutes and
Content of azapropazone, C;¢H.9N,02,2H,O
! supernatant liquid through a 0.45-um membrane
95.0 to 105.0% of the stated content.
IDENTIFICATION
A. Shake a quantity of the powdered tablets containing 0.1 g re the absorbance of the resulting solution at the
of Azapropazone with 10 mL of methanol, filter (Whatman 253 nm, Appendix II B. Calculate the content
GF/C paper is suitable), evaporate the filtrate and dry the
residue at 60° for 1 hour. The ifrared absorption spectrum of
the residue, Appendix II A, is concordant with the reference
spectrum of anhydrous azapropazone (RS 017).
B. The light absorption, Appendix II B, in the range 210 to
350 nm of solution (1) obtained in the Assay is concordant
with that of solution (2).
TEST
Related substances Azathioprine Oral Su
Carry out the following operations in subdued light using It is advised that patients are monitored reguiarl
low-actinic glassware without delay. Carry out the method NOTE: Azathioprine Oral Suspension 1
for liquid chromatography, Appendix III D, using the following the Umted Kingdom.
solutions in a mixture of 1 volume of phosphate buffer pH 4.0
and 3 volumes of methanol (solvent A). For solution (1) Action and use
shake a quantity of the powdered tablets containing 0.1 g of Immunosuppressant.
Azapropazone with 70 mL of solvent A, dilute to 100 mL
and filter. Solution (2) contains 0.00025% w/v of DEFINITION
azapropazone impurity A BPCRS. Solution (3) contains Azathioprine Oral Suspension is a suspension of Azathioprine
0.00075% w/v of azapropazone impurity C BPCRS. For in a suitable flavoured vehicle.
solution (4) dilute 10 mL of solution (1) to 100 mL and The oral suspension complies with the requirements stated under
dilute 1 mL of the resulting solution to 100 mL. Solution (5) Oral Liquids, the requirements stated under Unlicensed Medicines
contains 0.1% w/v of azapropazone impurity standard BPCRS. and with the following requirements.
For solution (6) dilute 1 volume of solution (4) to Content of azathioprine, C).H;N,O,S
2 volumes. 95.0 to 105.0% of the stated amount.
The chromatographic procedure may be carried out using Shake the oral suspension vigorously before carrying out the
(a) a stainless steel column (30 cm x 3.9 mm) packed with following tests.
end-capped octadecylsilyl sihca gel for chromatography (10 um)
(uBondapak C18 is suitable), (b) a mixture of 1 volume of
glacial acetic acid, 36 volumes of methanol and 63 volumes of
2016 Azathioprine Preparations III-165
IDENTIFICATION CHROMATOGRAPHIC CONDITIONS

A. Carry out the method for thin-layer chromatography, (a) Use a stainless steel column (25 cm x 4.6 mm) packed
Appendix III A, using the following solutions prepared with octadecylsilyl silica gel for chromatography (5 wm)
immediately before use. (Kromasil is suitable).
(1) Dilute a quantity of the oral suspension containing 40 mg (b) Use gradient elution and the mobile phase described
of Azathioprine to 5 mL with water and then extract with below.
three 20-mL quantities of dichloromethane. Combine the (c) Use a flow rate of 1.0 mL per minute.
dichloromethane extracts, wash with 20 mL of water, discard
the aqueous layer and evaporate the dichloromethane under
a stream of nitrogen until about 5 mL remains. (e) Use a detection wavelength of 254 nm.
(2) Disperse 40 mg of azathioprine BPCRS in 5 mL of water (f) Inject 10 wL of each solution.
MOBILE PHASE
3
Mobile phase A 300 volumes of methanol and 700 volumes
feach of azathioprine BPCRS and 5-chloro- of a 0.01m phosphate buffer prepared by dissolving 1.36 g of
sdazole BPCRS in dichloromethane. potassium dthydrogen orthophosphate in 1000 mL of water.
Mobile phase B 600 volumes of methanol and 400 volumes
of a 0.01M phosphate buffer prepared by dissolving 1.36 g of
potasstum dihydrogen orthophosphate in 1000 mL of water.
(c) Apply 10 uL of ea
(d) Develop the plate to 1
(e) After removal of the plat
under ultraviolet ight (366 n 0-20 100 0 isocratic
MOBILE PHASE 20-30 1000 0-100 linear gradient
butan-1-ol saturated with 6M ammonia. 30-40 0 100 isocratic
SYSTEM SUITABILITY 40-41 0-100 100-0 linear gradient

CONFIRMATION
SYSTEM SUITABILITY
est is not valid unless, in the chromatogram obtained
sOlution (3):
B. In the Assay, the retention time of the principal peak in
solution (2).
TESTS
Acidity
Dissolution
Medicines, Oral Suspensions, using 900 mL of water as the the area of any peak correspwiiding
dissolution medium and rotating the paddle at 50 revolutions not greater than the area of thé*prig
per minute. Use a volume of the oral suspension containing
one dose.
Related substances 0.1 times the area of the principal peakur
Carry out the method for liguid chromatography, obtained with solution (2) (0.1%);
Appendix III D, using the following solutions. the sum of the areas of any secondary peaks 1
(1) Disperse a quantity of the oral suspension containing twice the area of the principal peak in the chroniatogram
10 mg of Azathioprine with 12.5 mL of dimethyl sulfoxide, obtained with solution (2) (2.0%).
shake for 30 minutes and add sufficient 0.1m hydrochloric acid ASSAY
to produce 25 mL. Carry out the method for liquid chromatography,
(2) Dilute 1 volume of solution (1) to 100 volumes with a Appendix III D, using the following solutions.
mixture of equal volumes of dimethyl sulfoxide and (1) Dilute a weighed quantity of the oral suspension
0.1m hydrochloric acid. containing 0.1 g of Azathioprine to 50 mL with dimethyl
(3) 0.004% w/v of each of azathioprine BPCRS, 5-chloro-1- sulfoxide, shake for 30 minutes and add sufficient
methyl-4-mtroimidazole BPCRS and 6-mercaptopurine in a 0.1m hydrochloric acid to produce 250 mL.
mixture of equal volumes of dimethyl sulfoxide and (2) Dilute 5 volumes of a 0.08% w/v solution of
0.1m hydrochloric acid. azathioprine BPCRS in dimethyl sulfoxide to 10 volumes with
0.1m hydrochlonic acid.
IWI-166 Azathioprine Preparations 2016
CHROMATOGRAPHIC CONDITIONS powder and allow to stand for 5 minutes; a yellow colour is
(a) Use a stainless steel column (25 cm x 4.6 mm) packed produced. Filter, cool in ice, add 0.1 mL of a 10% w/v
with octadecylsilyl sihca gel for chromatography (5 wm) solution of sodium nitrite and 0.1 g of sulfamic acid and shake
(Spherisorb ODS2 is suitable). until the bubbles disappear. Add 1 mL of 2-naphthol solution;
(b) Use isocratic elution and the mobile phase described a pale pink precipitate is produced.
below. TEST
(c) Use a flow rate of 1.5 mL per minute. 5-Chloro-1-methyl-4-nitroimidazole and
(d) Use an ambient column temperature. 6-mercaptopurine
(g) Wash the column with water between injections. 0.20 g of Azathioprine with 10 mL of 6M ammonia and filter
MOBILE: through a glass micro fibre filter paper (Whatman GF/C is
300 volun site anol and 700 volumes of a suitable).
0.01m phosp ffer prepared by dissolving 1.36 g of (2) 2.0% wiv of azathioprine BPCRS and 0.020% w/v of
potassium dihydrogen. hosphate in 1000 mL of water. 6-mercaptopurine in 6M ammonia.
DETERMINATION CE (3) 0.020% w/v of 6-mercaptopurine in 6M ammonia.
Determine the weight p (4) 0.020% w/v of 5-chloro-1-methyl-4-mitroimidazole BPCRS
Appendix V G, and calcula in 6M ammonia.
weight in volume, using the tc CHROMATOGRAPHIC CONDITIONS
in azathioprine BPCRS. (a) Use as the coating cellulose F54.
STORAGE : (b) Use the mobile phase as described below
Azathioprine Oral Suspension should & cted from light. (c) Apply 5 uL of each solution.
(e) After removal of the plate, dry it at 50° and examine
under ultraviolet hght (254 nm).
Azathioprine Tablets
MOBILE PHASE
Action and use butan-1-ol saturated with 6M ammonia.
Immunosuppressant
SUITABILITY
DEFINITION not valid unless the chromatogram obtained with

Azathioprine Tablets contain Azathioprine. ) shows two clearly separated spots.
Content of azathioprine, Co.H;N70,S
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, *hloro-1-methyl-4-nitroimidazole
Appendix III A, using the following solutions. in the chromatogram o} d with solution (1) is not more
intense than the spot int
(1) Shake a quantity of the powdered tablets containing 0.2 g
solution (4).
of Azathioprine with 50 mL of 6M ammonia, filter through a
glass micro fibre paper (Whatman GF/C is suitable) and use ASSAY
the filtrate.
(2) 0.4% w/v of azathioprine BPCRS in 6M ammonia.
(a) Use as the coating cellulose Fr54. Filter, dilute 25 mL of the filtrate to 1000 mL with
(b) Use the mobile phase as described below. 0.1m hydrochloric acid and measure the absorbanc
(c) Apply 5 uwL of each solution. resulting solution at the maximum at 280 nm,
(d) Develop the plate to 20 cm. Appendix II B. Calculate the content of C)jH7N7O.S taking
628 as the value of A(1%, 1 cm) at the maximum at
(e) After removal of the plate, dry it at 50° and examine
280 nm.
under ultraviolet light (254 nm).
STORAGE
MOBILE PHASE
Azathioprine Tablets should be protected from light.
butan-1-ol saturated with 6M ammonia.
CONFIRMATION
B. Heat a quantity of the powdered tablets containing 20 mg
of Azathioprine with 100 mL of water and filter. To 5 mL of
the filtrate add 1 mL of hydrochloric acid and 10 mg of zinc
2016 Baclofen Preparations III-167
MOBILE PHASE
Baclofen Oral Solution
5 g of sodium dodecyl sulfate in a mixture of 5 mL of
Action and use orthophosphoric acid and 650 mL of water and diluted to
Skeletal muscle relaxant. 1000 mL with acetonitrile R1.
SYSTEM SUITABILITY
DEFINITION
Baclofen Oral Solution is a solution of Baclofen in a suitable
aqueous vehicle.
methyl-4-hydroxybenzoate and impurity A (lactam) and
The oral solution complies with the requirements stated under Oral between the peaks due to impurity A and propyl-4-
Liquids and with the following requirements. hydroxybenzoate is at least 5.0.
Content of baclofen, C,9H,,CINO, LIMITS
.0O% of the stated amount.
ASSAY
(1) Dilute a volume
Carry out the method for hguid chromatography,
Baclofen to 100 mL
(2) 0.005% w/v of b phase.
CHROMATOGRAPHIC C (1) Dilute a weighed quantity of the oral solution containing
(a) Use as the coating silica gel. ga 5 mg of Baclofen to 50 mL.
(b) Use the mobile phase as descri (2) 0.01% w/v of baclofen BPCRS.
(c) Apply 5 uwL of each solution. (3) 0.01% w/v of baclofen BPCRS, 0.0003% w/v of propyl
(d) Develop the plate to 10 cm. 4-hydroxybenzoate and 0.0002% w/v of baclofen
wmpurity A EPCRS.
(e) After removal of the plate, dry in air.
(f) Place an evaporating dish containing 4 mL ofgi
of 7M hydrochloric acid and 0.5 g of potassium permangi (a) Use a stainless steel column (25 cm x 4.6 mm) packed
a chromatography tank, close the tank and allow to s with end-capped octadecylsilyl silica gel for chromatography
2 minutes. Place the plate in the tank, close the tank (10 um) (Nucleosil C18 is suitable).
leave the plate in contact with the vapour for 1 minute. isocratic elution and the mobile phase described
(g) After removal of the plate, place it in a current of cold air.
until an area of coating below the line of application shows flow rate of 1.5 mL per minute.
only a faint blue colour on the addition of 0.05 mL of sé an ambient column temperature.
potassium iodide and starch solution. Spray the plate with
potassium todide and starch solution and examine in daylight.
MOBILE PHASE
20 volumes of glacial acetic acid, 20 volumes of water and
80 volumes of butan-1-ol.
CONFIRMATION
1000 mL with acetont
SYSTEM SUITABILITY
with solution (3), the resolution b tweet
impurity A and propyl-4-hydroxybi
solution (1) shows a peak with the same retention time as
the principal peak in the chromatogram obtained with DETERMINATION OF CONTENT
solution (2). Determine the weight per mL of the oral sé

TEST Appendix V G, and calculate the content of ¢
weight in volume, using the declared content o
Impurity A
C1 9H) 2CINO, in baclofen BPCRS.
Appendix III D, using the following solutions in the mobile STORAGE
phase. Baclofen Oral Solution should be stored below 25° and
(1) Dilute a weighed quantity of the oral solution containing protected from light. It should not be refrigerated.
5 mg of Baclofen to 50 mL.
(2) 0.0002% w/v of baclofen impurity A EPCRS.
(3) 0.01% w/v of baclofen BPCRS, 0.0003% w/v of propyl
4-hydroxybenzoate, 0.0003% w/v of methyl 4-hydroxybenzoate
and 0.0002% w/v of baclofen impurity A EPCRS.
The chromatographic conditions described under Assay may

be used.
ad.
my
IlI-168 Baclofen Preparations 2016

Baclofen Tablets
MOBILE PHASE
Action and use 5 volumes of glacial acetic acid, 440 volumes of methanol and
Skeletal muscle relaxant. 560 volumes of water, the mixture containing 0.182% w/v of
sodium hexanesulfonate.
DEFINITION
SYSTEM SUITABILITY
Baclofen Tablets contain Baclofen.
The tablets comply with the requirements stated under Tablets and The test is not valid unless, in the chromatogram obtained
with the following requirements. with solution (3), the resolution between the peaks due to
baclofen and impurity A is at least 2.0.
Content of baclofen, C;)>H,,CINO,
LIMITS
In the chromatogram obtained with solution (1) the area of
any peak corresponding to baclofen impurity A is not greater
than the area of the peak in the chromatogram obtained with
solution (2) (2%).
Dissolution
mL of a mixture of 4 volumes of
1¢..0f glacial acetic acid for
Appendix XII B1.
(2) 0.1% w/v of baclofen BE
TEST CONDITIONS
absolute ethanol and 1 volumé.
CHROMATOGRAPHIC CONDIT
per minute.
(b) Use the mobile phase as described * 37°, as the medium.
PROCEDURE
(e) After removal of the plate, allow it to dry in dir, Appendix III D, using the following solutions.
with ninhydrin solution and heat at 100° for 10 minut
(1) After 45 minutes withdraw a 20 mL sample of the
MOBILE PHASE medium and filter through a membrane filter with a nominal
20 volumes of glacial acetic acid, 20 volumes of water and ore size not greater than 0.45 um, discarding the first
80 volumes of butan-1-ol. filtrate.
CONFIRMATION w/v of baclofen BPCRS in the mobile phase.
The principal spot in the chromatogram obtained with RAPHIC CONDITIONS
solution (1) corresponds to that in the chromatogram xaphic conditions described under Assay may
B. In the Assay, the chromatogram obtained with DETERMINA* ONTENT
solution (1) shows a peak with the same retention time as
the principal peak in the chromatogram obtained with
Calculate the total€ontent of baclofen, C,jH,2CINO,, in the
medium from the deg ntent of C;9)H,2,CINO> in
solution (2).
baclofen BPCRS.
TESTS
ASSAY
Impurity A
(1) Add a quantity of whole tablets 0.1 g of
(1) Mix with the aid of ultrasound a quantity of the
Baclofen to 25 mL of a mixture of 10
powdered tablets containing 0.10 g of Baclofen with 50 mL
1 volume of glacial acetic acid and disper
of the mobile phase for 30 minutes, shaking occasionally to
ultrasound. Dilute to 50 mL with methanol,
disperse the sample, and filter through a glass-fibre filter
filtrate.
(Whatman GF/C is suitable).
(2) 0.2% w/v of baclofen BPCRS in a mixture of 100°volumes
(2) 0.004% w/v of baclofen impurity A EPCRS in the mobile
of methanol, 100 volumes of water and 1 volume of glacial
phase.
acetic acid.
(3) 0.2% w/v of baclofen BPCRS and 0.004% w/v of baclofen
impurity A EPCRS in the mobile phase.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed (10 um) (Nucleosil C18 is suitable).
(Spherisorb ODS 1 is suitable).
below.
below.
2016 Beclometasone Preparations III-169
MOBILE PHASE (1) Disperse a quantity of the preparation being examined

0.01M sodium hexanesulfonate in a mixture of 1 volume of containing 0.5 mg of Anhydrous Beclometasone
glacial acetic acid, 100 volumes of methanol and 100 volumes Dipropionate in 20 mL of methanol (80%) by heating on a
of water. water bath until the methanol begins to boil. Shake
vigorously, cool in ice for 30 minutes and centrifuge.
Mix 10 mL of the supernatant liquid with 3 mL of water and
Calculate the content of C;>H 2CINO>, in the tablets using 5 mL of chloroform, shake vigorously, allow the layers to
the declared content of C;gH,2CINO> in baclofen BPCRS. separate, evaporate the chloroform layer to dryness in a
current of nitrogen with gentle heating and dissolve the
residue in 1 mL of chloroform.
(2) 0.025% w/v of beclometasone dipropionate BPCRS in
Barium Sulfate Oral Suspension chloroform.
(3) A mixture of equal volumes of solutions (1) and (2).
)ral Suspension is a suspension of Barium (a) Use as the coating silica gel G.
yn in a suitable aqueous vehicle. (b) Use the mobile phase as described below.
(e) After removal of the plate, allow it to dry in air until the
solvent has evaporated, heat at 105° for 5 minutes and, while
CHARACTERISTICS hot, spray with alkaline tetrazolium blue solution.
A smooth, white or creamy MOBILE PHASE
IDENTIFICATION 100 volumes of chloroform, 10 volumes of acetone and

Evaporate 1 mL to dryness and ignit 5 volumes of absolute ethanol.
The residue complies with the following te CONFIRMATION
A. To 0.2 g add 5 mL of a 50% w/v soluti The principal spot in the chromatogram obtained with
obtained with solution (2). The principal spot in the
2M hydrochloric acid. The resulting solution yieldsfg chromatogram obtained with solution (3) appears as a single
reactions characteristic of sulfates, Appendix VI. apact spot.
B. Wash the residue reserved in test A with water, add 5 ‘the Assay, the chromatogram obtained with
of 2m hydrochloric acid, mix well and filter. Add 0.3 mL of (2) shows a peak with the same retention time as
1m sulfuric acid to the filtrate. A white precipitate is produce k due to beclometasone dipropionate in the
which is insoluble in 2m hydrochloric acid.
ASSAY
cat.
a
’
Evaporate to dryness a quantity containing 0.6 g of Barium

.
eee
Sulfate in a platinum dish on a water bath and carry out the

.no
he
Assay described under Barium Sulfate for Suspension,

a
(1) Mix 10 mLof m 0%) containing 0.01% w/v of

ae GSi
beginning at the words ‘add 5 g of sodium carbonate...’.

el
CGRS and 0.0005% w/v of

St
beclometasone dipropionat
ey ese
ee
>

tte
Gee
Appendix V G, and calculate the percentage of BaSO,,

:
ee a le
Ce te
weight in volume.
va
standard) in methanol (80% anc

oo
same solvent.
Ne
aevy
:
Ce
-
tt,,
ga tae
ey
Beclometasone Cream
ve Ot.
oth,
ind filter the

A
Action and use lower layer through a small plug of absorbent cotton
fy
5
previously washed with methanol (80%). Repeat the

Coes Cr asRye ?
Glucocorticoid.
wieeUO
extraction of the trimethylpentane solution with two further

OL
THOME
DEFINITION 10 mL quantities of methanol (80%), filtering the extracts

Wyre
us
Beclometasone Cream contains Anhydrous Beclometasone through the absorbent cotton. Combine the extracts and add
wtet aa
Oe ae te a et
Dipropionate in a suitable basis.

ha
sufficient methanol (80%) to produce 50 mL. If the resulting

ce aa Sty wo
- The cream complies with the requirements stated under Topical solution is more than slightly cloudy, filter.
vo
.

re
(3) Prepare in the same manner as solution (2) but add

surah
Cpa
. >
ee
Content of beclometasone dipropionate, C,,H3;,ClO, 2 mL of a 0.05% w/v solution of the internal standard in
ee
teey
methanol (80%) before diluting to 50 mL.

‘

wy. “>* ee
a eae
For creams containing 0.5% w/w of Anhydrous

5
, yet
:
IDENTIFICATION
Beclometasone Dipropionate.
wey
Oe rid Foe
Story
ODeyteny’
fg
fen&

Dr
IiI-170 Beclometasone Preparations 2016
(1) Mix 25 mL of methanol (80%) containing 0.04% w/v of PRODUCTION

beclometasone dipropionate BPCRS and 0.002% w/v of The size of aerosol particles to be inhaled is controlled so
beclometasone 17-propionate BPCRS with 20 mL of a that a consistent portion is deposited in the lung. The fine-
0.05% w/v solution of testosterone propionate (internal particle characteristics of powders for inhalation are
standard) in methanol (80%) and dilute to 200 mL with the determined using the method described in Appendix XII C.
same solvent. 7. Preparations for Inhalation: Aerodynamic Assessment of
(2) Add 100 mL of methanol (80%) to a quantity of the Fine Particles.
preparation being examined containing 10 mg of Anhydrous Content of beclometasone dipropionate, C,,;H3;7Cl1O,
Beclometasone Dipropionate and heat on a water bath, with 80.0 to 120.0% of the stated amount.
swirling, until the preparation has dispersed. Cool, dilute to
IDENTIFICATION
200 mL with methanol (80%) and filter.
A. In the Assay, the principal peak in the chromatogram
(3) Prepare in the same manner as solution (2) but add obtained with solution (1) has the same retention time as the
e diluting to 200 mL. solution (2).
‘(CONDITIONS B. For products containing lactose; disperse 0.25 g of the
inhalation powder in 5 mL of water. Add 5 mL of
6M ammonia and heat in a water-bath at 80° for 10 minutes.
An orange-red colour is produced.
(b) Use isocratic elution TESTS
below. Related substances
(c) Use a flow rate of 2 mL per Carry out the method for guid chromatography,
(d) Use a column temperature Appendix ITI D, using the following solutions.
(1) Dissolve a quantity of the inhalation powder containing
(f) Inject 20 wL of each solution. the equivalent of 1.2 mg of beclometasone dipropionate in
the mobile phase and dilute to 5 mL with the mobile phase.
MOBILE PHASE
mobile phase.
(3) 0.0040% w/w each of beclometasone 17-propionate BPCRS
(retention time about 1.5 minutes) and beclometasone
and beclometasone 21-propionate BPCRS in the mobile phase.
dipropionate (retention time about 2 minutes) is greater th,
2.0 (a mixture of 70 volumes of methanol and 30 volumes o ) Dilute 1 volume of solution (2) to 20 volumes with the
water is usually suitable).
SYSTEM SUITABILITY
to beclometasone 17-propionate (retention time about
1.5 minutes) and beclometasone dipropionate (retention time
about 2 minutes) is greater than 2.0.
Calculate the content of C,3H37ClO, in the preparation
being examined using the declared content of C.3H37ClO, in
beclometasone dipropionate BPCRS.
STORAGE
Beclometasone Cream should be protected from light.
MOBILE PHASE
Dilute 60 volumes of acetonitrile to 100 v water.
When the chromatograms are recorded under ibed
Beclometasone Inhalation Powder conditions, the retention time for beclometasone.«
17-propionate is about 6 minutes, for beclometasong
Beclometasone Powder for Inhalation, Metered-dose Powder
21-propionate, about 7 minutes and for beclometasone
Inhaler
dipropionate, about 13 minutes.
Action and use SYSTEM SUITABILITY
Glucocorticoid. The test is not valid unless, in the chromatogram obtained
DEFINITION
to beclometasone 17-propionate and beclometasone
Beclometasone Inhalation Powder consists of Anhydrous 21-propionate is at least 1.4. If necessary adjust the
Beclometasone Dipropionate or Beclometasone Dipropionate concentration of acetonitrile in the mobile phase.
Monohydrate in microfine powder either alone or combined
LIMITS
with a suitable carrier. It is administered by a dry-powder
inhaler. In the chromatogram obtained with solution (1):
The inhalation powder complies with the requirements stated under the area of any secondary peak is not greater than twice the
Preparations for Inhalation and with the following requirements. area of the principal peak in the chromatogram obtained with
solution (2) (2%);
2016 Beclometasone Preparations III-171
not more than one such peak has an area greater than the Dipropionate Monohydrate in microfine powder either alone or
area of the principal peak in the chromatogram obtained with combined with a suitable carrier. The pre-dispensed unit is
solution (2) (1%); loaded into a dry-powder inhaler to generate an aerosol.
the sum of the areas of all the secondary peaks is not greater The inhalation powder, pre-dispensed complies with the
than 2.5 times the area of the principal peak in the requirements stated under Preparations for Inhalation and with the
chromatogram obtained with solution (2) (2.5%). following requirements.
Disregard any peak with an area less than the area of the PRODUCTION
principal peak in the chromatogram obtained with The size of aerosol particles to be inhaled is controlled so
solution (4) (0.05%). that a consistent portion is deposited in the lung. The fine-
Uniformity of delivered dose particle characteristics of powders for inhalation are
Complies with the requirements stated under Inhalation determined using the method described in Appendix XII C.
7. Preparations for Inhalation: Aerodynamic Assessment of
Fine Particles.
Content of beclometasone dipropionate, C,,H3,ClO,
When supplied as disks, 90.0 to 110.0% of the stated
amount per pre-metered unit. When supplied as capsules,
80.0 to 120.0% of the stated amount per pre-metered unit.
IDENTIFICATION
A. In the Assay, the principal peak in the chromatogram
eclometasone dipropionate.
obtained with solution (1) has the same retention time as the
(2) Dilute 10 mL of a so tionL Co ining 0.0005% wiv of principal peak in the chromatogram obtained with
beclometasone dipropionate BPGRS i solution (2).
a mixture of 45 volumes o
B. Disperse a quantity of powder, containing the equivalent
acetonitrile.
of 200 pg of beclometasone dipropionate in 5 mL of
CHROMATOGRAPHIC CONDITIONS 1M sodium hydroxide in a 25 mL conical flask. Add three
(a) Use a stainless steel column (25 cm % drops of copper sulfate solution and shake. A precipitate may
with octylsilyl silica gel for chromatography (5 sii) form which dissolves to give a clear blue solution. Heat the
60 RP-select B is suitable). solution to boiling; a red precipitate is produced.
(b) Use isocratic elution and the mobile phase deseribe C. For products containing lactose disperse 0.25 g of the
below. powder for inhalation in 5 mL of water. Add 5 mL of
(c) Use a flow rate of 1.3 mL per minute. ammonia and heat in a water-bath at 80° for 10 minutes.
(d) Use an ambient column temperature. range-red colour is produced.

MOBILE PHASE

Calculate the amount of beclometasone dipropionate,

C53H37ClO7, per delivered dose using the declared content mobile phase.
of C.3H37ClO7 in beclometasone dipropionate BPCRS. Repeat (2) Dilute 1 volume
the procedure as described for reservoir systems under mobile phase.
Inhalation Powders, Uniformity of delivered dose. 17-propionate BPCRS
ASSAY § in the mobile phase.
Use the average of the 10 individual results obtained in the (4) Dilute 1 volume of en
test for Uniformity of delivered dose. mobile phase.
LABELLING CHROMATOGRAPHIC CONDITIONS
equivalent amount of beclometasone dipropionate. with octadecylsilyl silica gel for chromatography (Bet
(Lichrosorb RP18 or Lichrospher RP18 is suitable).
below.
Beclometasone Inhalation Powder, pre- (c) Use a flow rate of 1 mL per minute.
dispensed (e) Use a detection wavelength of 254 nm.
Beclometasone Powder for Inhalation, pre-metered units
Action and use (g) For solutions (1) and (2) allow the chromatography to
Glucocorticoid. proceed for twice the retention time of the principal peak.
MOBILE PHASE
DEFINITION
Dilute 60 volumes of acetonitrile to 100 volumes with water.
Beclometasone Inhalation Powder, pre-dispensed consists of
Anhydrous Beclometasone Dipropionate or Beclometasone
IiI-172 Beclometasone Preparations 2016
When the chromatograms are recorded under the prescribed ASSAY

conditions, the retention time for beclometasone Weigh and powder the contents of 20 pre-dispensed units.
17-propionate is about 6 minutes, for beclometasone Carry out the method for liguid chromatography,
21-propionate, about 7 minutes and for beclometasone Appendix III D, using the following solutions.
dipropionate, about 13 minutes. (1) Dissolve a quantity of the mixed contents of the pre-
SYSTEM SUITABILITY dispensed unit in sufficient of the mobile phase to produce a
The test is not valid unless, in the chromatogram obtained solution containing the equivalent of 0.001% w/v of
with solution (3), the resolution factor between the peaks due beclometasone dipropionate.
to beclometasone 17-propionate and beclometasone (2) 0.001% w/v of beclometasone dipropionate BPCRS in the
21-propionate is at least 1.4. If necessary adjust the mobile phase.
concentration of acetonitrile in the mobile phase. (3) 0.001% w/v each of beclometasone 17-propionate BPCRS
LIMITS and beclometasone 21-propionate BPCRS in the mobile phase.
In the c btained with solution (1): CHROMATOGRAPHIC CONDITIONS
the area AY Se ary peak is not greater than twice the The chromatographic conditions described under Related
area of the prifici substances may be used.
SYSTEM SUITABILITY

than the area of the pri with solution (3), the resolution factor between the peaks due
obtained with solution (2 to beclometasone 17-propionate and beclometasone
21-propionate is at least 1.4. If necessary adjust the
concentration of acetonitrile in the mobile phase.
chromatogram obtained with soly DETERMINATION OF CONTENT
Disregard any peak with an area less thagi'the rea of the
Calculate the content of C,3H37ClO, using the declared
principal peakin the chromatogram obtaing :
content of C.3H37ClO, in beclometasone dipropionate BPCRS.
solution (4) (0.05%).
LABELLING
Complies with the requirements stated under Inhdlati
equivalent amount of beclometasone dipropionate.
Powders using the following method of analysis. Carry o
the method for liquid chromatography, Appendix III D, using
the following solutions. .
(1) Collect single doses of the preparation being examined
using the procedure described under Inhalation Powders, etasone Pressurised Inhalation
Uniformity of delivered dose and dissolve the collected dose
in sufficient of a mixture of 45 volumes of water and hilst complying with the requirements of the
55 volumes of acetonitrile to produce a solution containing the t necessarily be interchangeable.
equivalent of 0.00005% w/v of beclometasone dipropionate.
(2) Dilute 10 mL of a solution containing 0.0005% w/v of Action and us
beclometasone dipropionate BPCRS in methanol to 100 mL with Glucocorticoid.
a mixture of 45 volumes of water and 55 volumes of
acetomitrile. DEFINITION
Beclometasone Pressurisé d ion is a solution or
suspension of Anhydrous Bec metasone Dipropionate in a
(a) Use a stainless steel column (25 cm x 4.6 mm) packed suitable liquidin a pressurised'eefitainer fitted with a
with octylsilyl silica gel for chromatography (5 um) (Lichrospher
oe a
metering dose valve. &

60 RP-select B is suitable).
The pressurised inhalation complieswith ments stated
(b) Use isocratic elution and the mobile phase described under Preparations for Inhalation and w
below. requirements.
PRODUCTION :
(d) Use an ambient column temperature. The size of aerosol particles to be inhaled is controlle¢’so
(e) Use a detection wavelength of 240 nm. that a consistent portion is deposited in the lung. The fine-
(f) Inject 100 wL of each solution. particle characteristics of pressurised metered-dose
MOBILE PHASE
described in Appendix XII C. 7. Preparations for Inhalation:
Aerodynamic Assessment of Fine Particles.
Content of beclometasone dipropionate, C,3H37ClO,
Calculate the content of beclometasone dipropionate, 80.0 to 120.0% of the stated amount.
C23H37ClO7, per delivered dose using the declared content
IDENTIFICATION
of C53H37ClO, in beclometasone dipropionate BPCRS. Repeat
the procedure as described for pre-dispensed systems under A. The infrared absorption spectrum, Appendix II A, is
Inhalation Powders, Uniformity of delivered dose. concordant with the reference spectrum of beclometasone
dipropionate (2) (RS 379). Examine the substance as a
dispersion in potassium bromide prepared in the following
manner. Discharge the container a sufficient number of
times, under conditions of very low relative humidity (less
eons
oe gle ee
2016 Beclometasone Preparations II[I-173
than 5%), into a mortar to obtain 2 mg of Anhydrous Carry out the method for liguid chromatography,
Beclometasone Dipropionate. Heat at 110° for 2 hours at a Appendix III D, using the following solutions.
pressure of 2 kPa, cool, grind the residue thoroughly with (1) Solution A.
0.1 g of potasstum bromide, add a further 0.2 g of potassium
(2) 0.00015% w/v of beclometasone dipropionate BPCRS in the
bromide and mix thoroughly.
mobile phase.
(3) 0.00015% w/v each of testosterone propionate BPCRS and
obtained with solution (1) corresponds to the peak due to
beclometasone dipropionate BPCRS in the mobile phase.
beclometasone dipropionate in the chromatogram obtained
with solution (2). CHROMATOGRAPHIC CONDITIONS
TESTS
with octadecylsilyl silica gel for chromatography (5 tm)
Related substances
the method for thin-layer chromatography,
below.
MOBILE PHASE
70 volumes of methanol and 30 volumes of water, adjusted if
necessary so that the resolution factor between the peaks due
CHROMATOGRAPHIC CONE! to beclometasone dipropionate and testosterone propionate is
(a) Use as the coating silica gel. « at least 2.0.
(b) Use the mobile phase described béio SYSTEM SUITABILITY
(c) Apply separately to the plate the whole.¢ The test is not valid unless, in the chromatogram obtained
and 10 pL of each of solutions (2), (3) and’¢ with solution (3), the resolution factor between the two
(d) Develop the plate to 15 cm. é
(e) After removal of the plate, allow it to dry in airs y DETERMINATION OF CONTENT
with alkaline tetrazolium blue solution and heat at 50° fer’. Calculate the average content of C,3H37ClO7 delivered by a
5 minutes. Cool and spray again with alkaline tetrazohum ingle actuation of the valve using the declared content of
solution. ClO, in beclometasone dipropionate BPCRS.
MOBILE PHASE ne the content of active ingredient a second and
ae by repeating the procedure on the middle 10 and
3 volumes of methanol and 97 volumes of 1,2-dichloroethane.
0 successive combined actuations of the valve, as
LIMITS em the number of deliveries available from the
In the chromatogram obtained with solution (1): sgtatedon the label. For each of the three
any secondary spot is not more intense than the spot in the ; thesaverage content of C.3,H37ClO, delivered
chromatogram obtained with solution (2) (2%); by a single actuati f the valve is within the limits stated
not more than one such spot is more intense than the spot in under Content of: fetasone dipropionate.
the chromatogram obtained with solution (3) (1%);
in the chromatogram obtained with solution (4) (0.5%).
Disregard any spot with an Rf value of more than 0.85. Beclometasone Aquec Nasal Spray
ASSAY Beclometasone Nasal Spray
Determine the content of active ingredient delivered by the
Action and use
first 10 successive combined actuations of the valve after
Glucocorticoid.
priming. Carry out the procedure for Content of active
ingredient delivered by actuation of the valve described under
DEFINITION
Pressurised Inhalations, beginning at the words ‘Remove the
Beclometasone Aqueous Nasal Spray is an aqueous
pressurised container from the actuator ...’ and ending at the
suspension of either Anhydrous Beclometasone Dipropionate
words ‘... to the volume specified in the monograph’, using
or Beclometasone Dipropionate Monohydrate in a suitable
35 mL of methanol in the vessel. Transfer the combined
container fitted with an appropriate nasal delivery system.
solution and washings obtained from the set of 10 combined
actuations to a flask containing sufficient testosterone The liquid nasal spray complies with the requirements stated under
propionate BPCRS (internal standard) in methanol that, on Nasal Preparations and with the following requirements.
dilution to volume with appropriate amounts of water and Content of beclometasone dipropionate, C,;H;,ClO,
methanol, the final solution contains 0.00015% w/v each of 80.0 to 120.0% of the amount stated to be delivered by
testosterone propionate and beclometasone dipropionate in actuation of the valve.
the methanol-water mixture in the proportions 70:30 by IDENTIFICATION
volume (solution A). Determine the content of active
ingredient in the 10 combined actuations using the following
method of analysis.
IlI-174 Beclometasone Preparations 2016
(1) Evaporate a quantity of the nasal spray containing the (3) 0.00015% w/v each of testosterone propionate BPCRS and
equivalent of 0.5 mg of beclometasone dipropionate to beclometasone dipropionate BPCRS in the mobile phase.
dryness and dissolve the residue in 0.5 mL of acetone. CHROMATOGRAPHIC CONDITIONS
(2) 0.1% w/v of beclometasone dipropionate BPCRS in acetone. (a) Use a stainless steel column (10 cm x 4.6 mm) packed
CHROMATOGRAPHIC CONDITIONS with octadecylsilyl silica gel for chromatography (5 um)
The chromatographic conditions described under Related (Spherisorb ODS 1 is suitable).
substances may be used. | (b) Use isocratic elution and the mobile phase described
CONFIRMATION below.
The principal spot in the chromatogram obtained with (c) Use a flow rate of 2 mL per minute.
solution (1) corresponds to that in the chromatogram (d) Use a column temperature of 50°.
obtained with solution (2). (e) Use a detection wavelength of 239 nm.
Y
vs
B. In the A the principal peakin the chromatogram (f) Inject 20 pL of each solution.
~
obtained ' ti (1) corresponds to the peak due to
ad
a MOBILE PHASE
beclometasoneé dip:
with solution
SYSTEM SUITABILITY
TESTS
Related substances ° The test is not valid unless, in the chromatogram obtained
Carry out the method for: e chromatography, with solution (3), the resolution between the two principal
ings: lutions 1in acetone. peaks is at least 2.0.
equivalent of 0.5 mg of beclome Calculate the average content of C23H37ClO, delivered by a

dryness and dissolve the residue
Say
mend
Dn!
reve single actuation of the valve using the declared content of
EY
ove Evaporate the solution to a volume such*th C,3H37ClO, in beclometasone dipropionate BPCRS.
solution can be applied to the plate.
LABELLING
(2) 0.1% w/v of beclometasone dipropionate BPC The quantity of active ingredient is stated in terms of the
(3) Dilute 1 volume of solution (2) to 2 volumes equivalent amount of beclometasone dipropionate.
:
|
:i
1
(b) Use the mobile phase described below. netasone Ointment
:
(c) Apply separately to the plate the whole of solution (1)
and 10 uL of each of solutions (2), (3) and (4).
7 1
- (e) After removal of the plate, allow it to dry in air, spray
with alkaline tetrazolium blue solution and heat at 50° for
‘oe edIt
5 minutes. Cool and spray again with alkaline tetrazolium blue
solution. The ointment compliés wi
MOBILE PHASE Semi-solid Preparation
:
,
an
| 3 volumes of methanol and 97 volumes of 1,2-dichloroethane.
eae
Ss LIMITS
AY

not more than one such spot is more intense than the spot in
the chromatogram obtained with solution (3) (1%);
Shake vigorously, cool in ice for 30 minutes and filter.
Disregard any spot with an Rf value of more than 0.85. Evaporate the filtrate to dryness in a current of nitrogen with
ASSAY gentle heating and dissolve the residue in 1 mL of chloroform.
Carry out the method for liquid chromatography, (2) 0.05% w/v of beclometasone dipropionate BPCRS in
Appendix III D, using the following solutions. chloroform.
(1) Discharge the container a sufficient number of times to (3) A mixture of equal volumes of solutions (1) and (2).
obtain the equivalent of 0.5 mg of beclometasone CHROMATOGRAPHIC CONDITIONS
dipropionate, add 30 mL of mobile phase, mix with the aid
of ultrasound, dilute to 50 mL with mobile phase and filter.
Dilute 3 volumes of this solution to 20 volumes with mobile (b) Use the mobile phase as described below.
phase. (c) Apply10 uL of each solution.
(2) 0.00015% w/v of beclometasone dipropionate BPCRS in the (d) Develop the plate to 15 cm.
mobile phase.
sete
2016 Bendroflumethiazide Preparations III-175
(e) After removal of the plate, allow it to dry in air until the STORAGE
solvent has evaporated, heat at 105° for 5 minutes and, while Beclometasone Ointment should be protected from light.
hot, spray with alkaline tetrazolium blue solution.
MOBILE PHASE
5 volumes of absolute ethanol, 10 volumes of acetone and

100 volumes of chloroform. Bendroflumethiazide Oral Suspension
CONFIRMATION NOTE: Bendroflumethiazide Oral Suspension 1s not currently
The principal spot in the chromatogram obtained with licensed in the United Kingdom.
obtained with solution (2). The principal spot in the Action and use
chromatogram obtained with solution (3) appears as a single Thiazide diuretic.
DEFINITION
he chromatogram obtained with solution (2)
Bendroflumethiazide Oral Suspension is a suspension of
the same retention time as the peak due to
Bendroflumethiazide in a suitable flavoured aqueous vehicle.
pionate in the chromatogram obtained
Oral Liguids, the requirements stated under Unlicensed Medicines
Content of bendroflumethiazide, C,;H,,F3;N3;0,S,
Anhydrous Beclometas
2,2,4-trimethylpentane,
c
successive quantities of 2 Shake the oral suspension vigorously before carrying out the
methanol (80%), filtering ea following tests.
plug of absorbent cotton previously IDENTIFICATION
methanol (80%). Combine the filtrates In the Assay, the retention time of the principal peak in the
with methanol (80%). chromatogram obtained with solution (1) is similar to that of
solution (2).
beclometasone 17-propionate BPCRSwith 2 mL of a Q TESTS
solution of testosterone propionate (internal standard) ii
Acidity
methanol (80%) and dilute to 50 mL with the same
2.6 to 3.0, Appendix V L.
(3) Prepare solution (3) in the same manner as solution (1
ution
but add 2 mL of a 0.05% w/v solution of the internal
les with the requiremen's stated under Unlicensed
standard in methanol (80%) before diluting to 50 mL.
(b) Use isocratic elution and the mobile phase described solutions.
below. (1) Add 30 mL of;
(c) Use a flow rate of 2 mL per minute. suspension containin
solution through a 0.45-umnyl
MOBILE PHASE 5 mL of filtrate.
A mixture of methanol and water such that the resolution factor (2) Dilute 1 volume of solution (1) te es with
between the peaks due to beclometasone 17-propionate mobile phase A.
(retention time about 1.5 minutes) and beclometasone (3) Dilute 1 volume of solution (2) to 10 vei
dipropionate (retention time about 2 minutes) is greater than mobile phase A. :
2.0 (a mixture of 30 volumes of water and 70 volumes of
methanol is usually suitable).
SYSTEM SUITABILITY
with octadecylsilyl silica gel for chromatography (3.5 um)
The test is not valid unless, in the chromatogram obtained (Waters SunFire C18 is suitable) fitted with a stainless steel
with solution (2), the resolution factor between the peaks due guard column (4mm x 3 mm) packed with the same
to beclometasone 17-propionate (retention time about material.
1.5 minutes) and beclometasone dipropionate (retention time
about 2 minutes) is greater than 2.0.
below.
Calculate the content of C23H37ClO7 in the preparation (d) Use a column temperature of 20°.
being examined using the declared content of C,3H37ClO7 in
beclometasone dipropionate BPCRS.
re
ay
.
me
.
fo,
:
IlI-176 Bendroflumethiazide Preparations 2016

soemeOG
co nt
When the chromatograms are recorded under the prescribed (2) 0.005% w/v of bendroflumethiazide BPCRS.
conditions the retention time of bendroflumethiazide is about CHROMATOGRAPHIC CONDITIONS
16.5 minutes and the retention of impurity A [4-amino-6-
(trifluoromethyl)benzene-1,3-disulfonamide] relative to
bendroflumethiazide is about 0.33.
SYSTEM SUITABILITY
MOBILE PHASE
Mobile phase A
with solution (2), the symmetry factor of the peak
4 volumes of acetonitrile and 16 volumes of water; adjust the corresponding to bendroflumethiazide is between 0.9 and
pH of the mixture to 2.0 using orthophosphonic acid. 2.0.
Mobile phase B
4 volumes of water and 6 volumes of acetonitrile; adjust the
DH of the nitxture to 2.0 using orthophosphoric acid.
Appendix V G, and calculate the content of
Cy45Hy4F3N30,S82, weight in volume, using the declared
content of C,5H,4F3N30,S>. in bendroflumethiazide BPCRS.
STORAGE
Time Mobile phase B Comment Bendroflumethiazide Oral Suspension should be stored at a
(Minutes) temperature of 2° to 8°.
0-10 100 isocratic
IMPURITIES
10-14 100-0 linear gradient The impurities limited by the requirements of this
14-18 0 isocratic monograph include 4-amino-6-(trifluoromethyl)benzene-1
,3-
18-22 0100 disulfonamide.
22-28 100
SYSTEM SUITABILITY Bendroflumethiazide Tablets

The following test applies only if a peak due to impurity A
and a peak with a retention relative to that of Action and use
bendroflumethiazide of about 0.24 are present. hiazide diuretic.
ITION
with solution (1), the resolution between the peak due to
ar uli ethiazide Tablets contain Bendroflumethiazide.
impurity A and the peak with a retention relative to
bendroflumethiazide of about 0.24 is at least 1.5.
If co-elution of these peaks occurs, re-equilibrate the column
for at least 1 hour and repeat using freshly prepared mobile
phase.
LIMITS

the area of any peak corresponding to impurity A 1s not
ot
/
ne
te,
greater than the area of the principal peak in the (1) Shake a quantity of t
-
Oe
chromatogram obtained with solution (2) (1%); 10 mg of Bendroflumethiazi

pea Goes?
ee a
ee
the area of any other secondary peak is not greater than half 10 minutes and filter.
the area of the principal peak in the chromatogram obtained (2) 0.1% w/v of bendroflumethiazide B RS in acetone.
Ce ey
with solution (2) (0.5%); CHROMATOGRAPHIC CONDITIONS :

fe Fe
a a a!
the sum of the areas of all the secondary peaks, excluding the
ee at

peak due to impurity A, is not greater than the area of the
(b) Use the mobile phase as described belo
tt
;
solution (2) (1%). (c) Apply 5 wL of each solution.

a
eS
Disregard any peak with an area less than the area of the (d) Develop the plate to 15 cm.
ve
th
principal peak in the chromatogram obtained with (e) After removal of the plate, dry in air, examine under
Ss Ee
.
solution (3) (0.1%). ultraviolet light (254 nm) and then reveal the spots by
PAY G8 OF
Method I. :
<
ASSAY
By Hy 2
eta
Carry out the method for liguid chromatography, MOBILE PHASE

1
Appendix III D, using the following freshly prepared ethyl acetate.

solutions.
CONFIRMATION
(1) Add 30 mL of methanol to a weighed quantity of the oral By each method of visualisation the principal spot in the
suspension containing 2.5 mg of Bendroflumethiazide and chromatogram obtained with solution (1) corresponds in
shake vigorously. Add about 10 mL of a 5% w/v solution of position and colour to that in the chromatogram obtained
sodium chloride, allow to cool and add sufficient of the with solution (2).
5% wiv sodium chloride to produce 50 mL. Filter the resulting
solution through a 0.45-um nylon filter, discarding the first
5 mL of filtrate.
2016 Benorilate Preparations II-177
TESTS alkaline. A blue colour is produced which can be extracted

Related substances into butan-I1-ol.
Carry out the method for thin-layer chromatography, C. Melting point, about 179°, Appendix V A.
TESTS
Acidity
25 mg of Bendroflumethiazide with 25 mL of acetone for
10 minutes, filter, evaporate the filtrate to dryness and
dissolve the residue in 2.5 mL of acetone. Related substances
Appendix III A, using a silica gel HF,54 precoated plate
acetone.
(Analtech plates are suitable) and a mixture of 5 volumes of
CHROMATOGRAPHIC CONDITIONS glacial acetic acid, 15 volumes of ether and 80 volumes of
(a) U e coating silica gel G. dichloromethane as the mobile phase. Apply separately to the
(b) Use. le phase as described below. plate 40 pL of solution (1) and 10 uL of each of
solutions (2), (3) and (4). For solution (1) add 20 mL of
(c) Apply 4 each solution.
methanol to a quantity of the oral suspension containing
(d) Develop*the gi 15 cm.
0.40 g of Benorilate, mtx well, add 20 mL of dichloromethane,
(e) After removal, o -plate, dry in air and reveal the spots shake and filter. For solutions (2) and (3) dilute 1 volume of
by Method I. solution (1) with methanol to 25 volumes and 125 volumes
MOBILE PHASE respectively. Solution (4) contains 0.0080% w/v of
ethyl acetate.
paracetamol in methanol. After removal of the plate, allow it to
ah.
dry in air and develop in a second mobile phase consisting of
LIMIT S
a mixture of 10 volumes of formic acid, 45 volumes of ether
Any secondary spot in the chr and 45 volumes of 2,2,4-trimethylpentane. After removal of
solution (1) is not more intense than t the plate, allow it to dry in air and examine under uwiltraviolet
chromatogram obtained with solution ‘(2 light (254 nm). In the chromatogram obtained with
ASSAY solution (1) any spot corresponding to paracetamol is not
more intense than the spot obtained with solution (4) (0.2%)
and any secondary spot immediately above that of the principal
containing 15 mg of Bendroflumethiazide with 50 m]
spot [Rf value approximately 1.1 relative to benorilate] is not
0.1m sodium hydroxide with the aid of ultrasound fo
more intense than the principal spot in the chromatogram
10 minutes and dilute to 100 mL with 0.1M sodium hye
obtained with solution (2) (1%). Not more than one such
Mix, filter, dilute 10 mL of the filtrate to 100 mL with waz
more intense than the spot in the chromatogram
and measure the absorbance of the resulting solution at the ©
d with solution (3) (0.2%). Disregard any spot with
maximum at 275 nm, Appendix II B. Calculate the content |
lue higher than 1.5 relative to benorilate in the
of C,5H,4F3N30,S> taking 410 as the value of A(1%, 1 cm)
matogram obtained with solutions (1), (2) and (3).
at the maximum at 275 nm.
Benorilate Oral Suspension

Action and use
ntains 0.0010% w/v of
Salicylate-paracetamol derivative; antipyretic; analgesic; anti-
sorbic acid in methanol (80%).
inflammatory.
DEFINITION
Benorilate Oral Suspension is a suspension of Benorilate in a
Content of benorilate, C,,H,;NO,;
acetonitrile and 65 volumes of water, the mixture adjusted to
IDENTIFICATION pH 2.2 with orthophosphonc acid, and (c) a detection
To a quantity of the oral suspension containing 0.5 g of wavelength of 305 nm.
Benorilate add 10 mL of water, mix and extract with 50 mL The test is not valid unless the resolution factor between the
of dichloromethane. Wash the extract with 10 mL of water, peaks due to salicylic acid and sorbic acid in the
shake with anhydrous sodium sulfate, filter and evaporate the chromatogram obtained with solution (3) 1s at least 2.
filtrate to dryness. The residue complies with the following In the chromatogram obtained with solution (1) the area of
tests. any peak corresponding to salicylic acid is not greater than
A. The infrared absorption spectrum, Appendix II A, is the area of the peak in the chromatogram obtained with
concordant with the reference spectrum of benorilate (RS 023). solution (2) (0.1%).
B. To 10 mg add 10 mL of 6m hydrochloric acid and boil ASSAY
until completely dissolved. To 5 mL of the resulting solution To a quantity of the oral suspension containing 0.25 g of
add 0.1 mL of strong I-naphthol solution, mix and add Benorilate, add 10 mL of water, mix, extract with two 40-mL
sufficient 1M sodium hydroxide to make the solution just
IlI-178 Benorilate Preparations 2016
quantities of dichloromethane filtering each extract successively adding 0.2 mL of a 0.5% w/v solution of zron(m) chloride to a
through a plug of absorbent cotton saturated with mixture of 1 mL of a 0.025% w/v solution of salicylic acid in
dichloromethane and wash the plug with 10 mL of ethanol (96%) and sufficient water to produce 50 mL (0.5%).
dichloromethane. Combine the extracts and washings and Related substances
dilute to 100 mL with dichloromethane. Dilute 5 mL to Carry out the method for thin-layer chromatography,
50 mL with absolute ethanol and dilute 2 mL of the resulting Appendix III A, using a silica gel HF»5, precoated plate
solution to 50 mL with absolute ethanol. Measure the (Analtech plates are suitable) and a mixture of 5 volumes of
absorbance of the final solution at the maximum at 240 nm, glacial acetic acid, 15 volumes of ether and 80 volumes of
Appendix II B. Calculate the content of C;7H,;5;NOs; taking dichloromethane as the mobile phase. Apply separately to the
740 as the value of A(1%, 1 cm) at the maximum at plate 10 uL of each of the following solutions. Solution (1)
240 nm. Determine the weight per mL of the oral suspension, contains 4.0% w/v of the residue obtained in the tests for
Appendix V G, and calculate the percentage of C;7H,;NOs, Identification in a mixture of 9 volumes of chloroform and
weight in 1 volume of methanol. For solution (2) dilute 1 volume of
Neen
ee
solution (1) to 100 volumes with a mixture of 9 volumes of
chloroform and 1 volume of methanol. For solution (3) dilute
1 volume of solution (1) to 500 volumes with a mixture of
Benorilate Table 9 volumes of chloroform and 1 volume of methanol. Solution
(4) contains 0.0080% w/v of paracetamol in a mixture of
Action and use 9 volumes of chloroform and 1 volume of methanol. After
Salicylate-paracetamol deriv. yretic; analgesic; anti- removal of the plate, allow it to dry in air and develop in a
inflammatory. second mobile phase consisting of a mixture of 10 volumes of
formic acid, 45 volumes of ether and 45 volumes of
-ayial
DEFINITION . 2,2,4-trimethylpentane. After removal of the plate, allow it to
Benorilate Tablets contain Benorilate. « dry in air and examine under ultraviolet light (254 nm).
The tablets comply with the requirements state blets and Any spot corresponding to paracetamol in the chromatogram
with the following requirements. obtained with solution (1) is not more intense than the spot
in the chromatogram obtained with solution (4) (0.2%). Any
Content of benorilate, C,,H,;NO;
secondary spot in the chromatogram obtained with solution (1)
with an Rf value slightly higher than that of the principal spot
IDENTIFICATION is not more intense than the principal spot in the
Shake a quantity of the powdered tablets containing 1 g of hromatogram obtained with solution (2) (1%). Any other
Benorilate with 30 mL of a mixture of 9 volumes of spot in the chromatogram obtained with solution (1)
chloroform and 1 volume of methanol for 10 minutes, filter and — intense than the spot in the chromatogram
evaporate the filtrate to dryness. The residue complies with th solution (3) (0.2%).
the following tests.
A. The infrared absorption spectrum, Appendix II A, is
concordant with the reference spectrum of benorilate (RS 023).
B. To 10 mg add 10 mL of 6m hydrochloric acid and boil
until completely dissolved. To 5 mL of the resulting solution filtrate to 250 mL w solute ethanol and measure the
add 0.1 mL of strong 1-naphthol solution, mix and add absorbance of the resulté lution at the maximum at
sufficient 1M sodium hydroxide to make the solution just 240 nm, Appendix ITB:
alkaline. A blue colour is produced which can be extracted C,7H,;NO; taking 740'as.t
into butan-I1-ol. maximum at 240 nm.
C. Melting point, about 179°, Appendix V A.
TESTS
4-Aminophenol
Shake a quantity of the powdered tablets containing 2.5 g of Benzatropine Injection
Benorilate with 100 mL of water for 15 minutes and filter.
If the filtrate is opalescent, warm on a water bath until it Action and use
becomes clear and allow to cool. To 20 mL of the filtrate Anticholinergic.
add 0.2 mL of sodium nitroprusside-carbonate solution, mix and
allow to stand for 30 minutes. The solution is not more DEFINITION
intensely coloured than a solution prepared at the same time Benzatropine Injection is a sterile solution of Benzatropine
ee|
and in the same manner but using 2 mL of a solution of Mesilate in Water for Injections.
4-aminophenol containing 5 pg per mL and 18 mL of water in The injection complies with the requirements stated under
place of the filtrate (20 ppm). Parenteral Preparations and with the following requirements.
Salicylic acid Content of benzatropine mesilate, C,,;,H,;NO,CH,0;S
Shake a quantity of the powdered tablets contaming 0.50 g 90.0 to 110.0% of the stated amount.
of Benorilate with 100 mL of water for 15 minutes and filter.
IDENTIFICATION
If the filtrate is opalescent, warm on a water bath until it
A. Dilute a suitable volume with sufficient 2m hydrochloric
becomes clear and allow to cool. Transfer 10 mL of the
acid to producea solution containing 0.08% w/v of
filtrate to a Nessler cylinder, dilute to 50 mL with water, add
Benzatropine Mesilate. The light absorption of the resulting
0.2 mL of a 0.5% w/v solution of tron(im) chloride and allow
solution, Appendix II B, exhibits maxima at 253 nm and
to stand for 1 minute. The colour obtained is not more
258 nm and inflections at 249, 264 and 268 nm.
intense than that of a solution prepared at the same time by
2016 Benzatropine Preparations III-179
B. To a volume containing 10 mg of Benzatropine Mesilate IDENTIFICATION

add 5 mL of picric acid solution R1, mix and allow to stand A. Shake a suitable quantity of the powdered tablets with
for 1 hour. The melting point of the precipitate, after drying at 2M hydrochloric acid and filter. Dilute the filtrate with
105°, is about 185°, Appendix V A. sufficient 2m hydrochloric acid to produce a solution
TESTS containing 0.1% w/v of Benzatropine Mesilate. The light
absorption of the resulting solution, Appendix II B, in the
range 230 to 350 nm exhibits two maxima, at 253 nm and
258 nm.
Tropine
B. Extract a quantity of the powdered tablets containing
10 mg of Benzatropine Mesilate with 10 mL of
ethanol (96%) and filter. Evaporate the filtrate to about
(1)Evaporate to dryness using a rotary evaporator a volume 2 mL, pour into 5 mL of hot pucric acid solution R1 and allow
to cool. The melting point of the precipitate, after drying at
105°, is about 185°, Appendix V A.
TESTS
Tropine
Appendix ITI A, using the following solutions.
20 mg of Benzatropine Mesilate with 4 mL of acetone for
(c) Apply 20 pL of each : 5 minutes, centrifuge, evaporate 2 mL of the supernatant
liquid to dryness and dissolve the residue in 0.5 mL of
(d) Develop the plate to 15m; acetone.
(e) After removal of the plate, dry 4 airgspray with sodium
todobismuthate solution and then with a solution of
(2) 0.010% w/v of tropine in acetone.
sulfuric acid. CHROMATOGRAPHIC CONDITIONS
MOBILE PHASE (a) Use as the coating silica gel G.

15 volumes of 13.5mM ammonia and 75 volumes ¢ (b) Use the mobile phase as described below.
ethanol (96%). (c) Apply 20 uL of each solution.
LIMITS (d) Develop the plate to 15 cm.
Any spot corresponding to tropine in the chromatogram“. After removal of the plate, dry in air, spray with sodium
obtained with solution (1) is not more intense than the spot
ASSAY
To a volume containing 25 mg of Benzatropine Mesilate add
10 mL of 5m sodium hydroxide, 10 mL of water and an excess
of sodium chloride. Extract with four 25 mL quantities of ether,
combine the ether extracts and extract with four 10-mL
quantities of 2m hydrochloric acid, remove any residual ether
from the combined extracts in a current of air, dilute to
50 mL with 2m hydrochloric acid and measure the absorbance
of the resulting solution at the maximum at 258 nm,
Appendix II B. Calculate the content of C2;H2;NO,CH,03S
from the absorbance obtained by repeating the operation using
25 mg of benzatropine mesilate BPCRS beginning at the words
‘add 10 mL of 5m sodium hydroxide ...? and from the declared
content of C2;H,;NO,CH,0O3S in benzatropine
mesilate BPCRS.
liquid.
Benzatropine Tablets (2) 0.02% w/v of benzatropine mesilate BPCRS in the mobile
phase.
Action and use CHROMATOGRAPHIC CONDITIONS
Anticholinergic. (a) Use a stainless steel column ( 25 cm x 4.6 mm) packed
with end-capped octylsilyl silica gel for chromatography (10 wm)
DEFINITION
(Lichrosorb RP8 or Spherisorb C8 is suitable).
Benzatropine Tablets contain Benzatropine Mesilate.
(b) Use isocratic elution (or gradient elution) and the mobile
phase described below.
Content of benzatropine mesilate, C,,;,H,;NO,CH,0;3S
wT Ped
aceat
IlI-180 Benzoic Acid Preparations 2016
(f) Inject 20 wL of each solution. position to those in the chromatogram obtained with
MOBILE PHASE solution (2). Examine under ultraviolet light (365 nm).
The chromatogram obtained with solution (1) shows a blue
35 volumes of octylamine phosphate buffer pH 3.0 and
eae fluorescent spot corresponding in colour and position to that
65 volumes of acetonitrile.
Pees
in the chromatogram obtained with solution (2). Spray the

it
DETERMINATION OF CONTENT plate with zron(im) chloride solution R1. The chromatogram
a'
Calculate the content of C,,;H»;NO,CH,0;S in each tablet

,
obtained with solution (1) shows a purple spot corresponding

1
at
i!
using the declared content of C2,;H.;NO,CH,0O38S in in position to the blue fluorescent spot observed under
.
'
'
m
benzatropine mesilate BPCRS. ultraviolet light (365 nm) and corresponding in colour and
1
position to the spot in the chromatogram obtained with

:
7
ASSAY
’
solution (2).
it
‘
Weigh and powder 30 tablets. To a quantity of the powder

’
fr,
ASSAY
;
containing 3@.mg of Benzatropine Mesilate add 50 mL of

a Ae
water and Of<15 minutes. Add 10 mL of a 50% w/v For benzoic acid
solution of: lroxide and an excess of sodium chloride To 2 g add 150 mL of water, warm until melted and titrate
and extract with sive quantities of 50, 25, 25 and with 0.1M sodium hydroxide VS using phenolphthalein
tes
ree
e combined ether layers with solution R1 as indicator. Reserve the solution for the Assay for
:
, 25 and 15 mL of salicylic acid. After the subtraction of 1 mL for each

oo
eee
ombined extracts to 100 mL 13.81 mg of C7H,O3 found in the Assay for salicylic acid,
vo
each mL of 0.1m sodium hydroxide VS is equivalent to

.
Ft
the absorbance of the resulti 12.21 mg of C7H,O>.

:
ee tay
258 nm, Appendix II B. Ca For salicylic acid

c
se
Cool the titrated solution obtained in the Assay for benzoic

e.
soa
repeating the operation using 50:mg

Fa
tat
acid, dilute to 250 mL with water and filter. To 5 mL of the

:
mesilate BPCRS in place of the powdere: ablets and from filtrate add sufficient zron(1m) nitrate solution to produce
: wets
the declared content of C,,;H,;NO,CH,0. ezatropine 50 mL. Filter, if necessary, to remove haze and measure the
'
:
mesilate BPCRS. absorbance of the resulting solution at the maximum at

,
530 nm, Appendix II B, using zron(m) nitrate solution in the

1
i .
reference cell. Calculate the content of C7H;O3 from the

‘'
absorbance obtained by repeating the operation using 5 mL

a eet
Y‘
fa 0.024% w/v solution of salicylic acid and beginning at the

Compound Benzoic Acid Ointment yords ‘add sufficient zron(1m) nitrate solution ...’.
Whitfield’s Ointment
DEFINITION
Compound Benzoic Acid Ointment contains 6.0% w/w of
Benzoic Acid and 3.0% w/w of Salicylic Acid in a suitable
emulsifying basis.
The following formula and directions apply. 50 g
Benzoic Acid in fine powder 60 g 750 mL
Salicylic Acid in fine powder 30 g Sufficient to produce
Emulsifying Ointment 910 g 1000 mL
Triturate the Benzoic Acid and the Salicylic Acid with a

portion of the Emulsifying Ointment until smooth and
gradually incorporate the remainder of the Emulsifying e Glycol and add
Ointment.
The ointment complies with the requirements stated under Topical constant stirring, to produce 1000 m
Semi-solid Preparations and with the following requirements. Content of benzoic acid, C;H,O,
Content of benzoic acid, C;H,;O, 4.75 to 5.25% wv.
5.7 to 6.3% wiw. IDENTIFICATION
Content of salicylic acid, C;H;O3 A. To 5 mL add 30 mL of 1m sulfuric acid and extract the
2.7 to 3.3% wiw. precipitated acid with three 25-mL quantities of petroleum
spirit (boiling range, 40° to 60°). Wash the combined extracts
IDENTIFICATION
with three 25-mL quantities of water, filter through absorbent
cotton and evaporate to dryness. The infrared absorption
Appendix III A, usinga silica gel F254 precoated plate
(Merck silica gel 60 F,54 plates are suitable) and a mixture of
the reference spectrum of benzoic acid (RS 025).
80 volumes of toluene and 20 volumes of glacial acetic acid as
the mobile phase. Apply separately to the plate 2 wL of each B. Melting point of the residue obtained in test A, about 121°,
of the following solutions. For solution (1) warm 1 g of the Appendix V A.
ointment with 10 mL of chloroform, cool and filter. TESTS
Solution (2) contains 0.6% w/v of benzoic acid and 0.3% wiv Weight per mL
of salicylic acid in chloroform. After removal of the plate, allow 1.045 to 1.055 g, Appendix V G.
the solvent to evaporate in a current of air and examine
under ultraviolet hght (254 nm). The chromatogram obtained
with solution (1) shows spots corresponding in colour and
2016 Benzoyl Peroxide Preparations TII-181
ASSAY (2) Dilute 1 volume of solution (1) to 100 volumes with

.
oe
acetomitrile.
cae gp ENeeu!Ca ‘
To 10 mL add 20 mL of ethanol (96%) previously

af,
2
tr
neutralised to phenolphthalein solution R1I and titrate with

>
(3) 0.003% w/v of benzoic acid, 0.0003% w/v of ethyl benzoate

an yee!
.
to ‘ : oe ulNEARER
0.1m sodium hydroxide VS using phenolphthalein solution R1 as and 0.0003% w/v of benzaldehyde in acetonitrile.
indicator. Each mL of 0.1M sodium hydroxide VS is equivalent
od
bey
(4) 0.0025% w/v of benzoyl peroxide in acetonitrile.

of:
to 12.21 mg of C7H,.O>.
coe .
.
we
.

ces
'
‘
. . ot .
with end-capped phenyl ethyl silica gel for chromatography

an
.
(4 um) (Phenomenex Synergi Polar RP 1s suitable) fitted

Benzoyl Peroxide Cream
: :
. .
‘
with a suitable stainless steel guard column packed with

‘
.
. :
.
.
.
octadecylsilyl silica gel for chromatography.

.
:
:
gate, ta,
ute ‘
vio

os
so
, hey_
wow ee 4
rege
below.
ee
hee
hye
yg
Er
tee
.

1
1
: oa
.
'

a OO
:
-,
’
.

‘
'Soy ’ ;
:
feet '
:
te

,
ee
,
.
ou '
‘
MOBILE PHASE
:
warhol.
: , YG
rode.
pee te
’ ea oot
tees
Mobile phase A 0.00042% v/v Orthophosphonic acid.

cts '
¢
Mobile phase B acetonitrile.

on
IDENTIFICATION :
“
cee
: ms eure ,
ee,
ge
vedaae
A. Carry out the method for thin-lager nomatography

,
A
a
oe Sd.
Appendix III A, protected from light, y Time Mobile phase A Mobile phase B Comment
solutions.
Loe
eat an
:
0-5 65 35 isocratic
(1) Shake a quantity of the preparation be
:
.
5-15 6515 35-585 linear gradient

containing the equivalent of 50 mg of anhydrou
.
> :
o .
peroxide with 10 mL of dichloromethane and filt
.
.
:
:
.

..
:
.
(2) 0.5% w/w of benzoyl peroxide in dichloromethane.

: ts oa SO
:
: : : :
ps.
: . sooth .
(a) Use as the coating silica gel F254.

oe
:
Hor
e chromatograms are recorded under the prescribed

:

:
ns the retention times relative to benzoyl peroxide

. .
.tt . .
(c) Apply 5 wL of each solution. éntion time, about 14.5 minutes) are: benzoic acid, about
foe
. .
.
. .
woe

..
:.
:

:
:
.
examine under ultraviolet light (254 nm). \ nless, in the chromatogram obtained
.
u
with solution 4 ), the resolution between the peaks due to

:
MOBILE PHASE
.
.
woo
:
benzoic acid and¥j dehyde is at least 2.0.

.
1 volume of glacial acetic acid, 2 volumes of dichloromethane

. ‘
,
.
‘ ,
oo,
and 50 volumes of toluene. LIMITS

:
,
.
.
In the chromatogram obfained with solution (1):

ee
ay at ee Mee
CONFIRMATION
,
see
Ot eS oe es
WyyeWe
The principal spot in the chromatogram obtained with Identify the peaks due to Bérizoic benzaldehyde and
solution (1) corresponds to that in the chromatogram ethyl benzoate using the chrofhategram obtained with
one ee
solution (3) and multiply the are ese peaks by the

.

:
Sy
hooey whos
corresponding correction factors: benzoic acid, 1.50;

a
‘ “hoy: ets ate i
B. In the test for Related substances, the chromatogram

ay
ea te
roy
benzaldehyde, 1.74; and ethyl benzo

-
obtained with solution (1) shows a peak with the same

the area of any peak corresponding to berizo
Sete
retention time as the peak due to benzoyl peroxide in the

Po
:
. oats
chromatogram obtained with solution (4). greater than 10 times the area of the principal p
.
'
.
Tr er

'
:
TESTS
. et
te
a
feette ete
Te ait bee eb
Le a
Related substances
SAG ele
ae Seta

tae

:
solution (2) (1%). |

ELT
Appendix III D, using the following solutions. Prepare a

oe ae
Sy ey
:
mixture of 0.1 volumes of acetic acid and 999.9 volumes of ASSAY

‘
cw
acetonitrile (solvent A). Mix a quantity of the preparation being examined containing
‘ ,
.
ly
:
the equivalent of 0.25 g of anhydrous benzoyl peroxide with

So.
:
(1) Add 1 mL of solvent A to a quantity of the cream

ae
TNs ,
eT ey
containing the equivalent of 25 mg of anhydrous benzoyl 50 mL of acetone and add sufficient acetone to produce
Oe
:
peroxide. Mix using a vortex mixer until a uniform 100 mL. To 10 mL add 25 mL of a 20% w/v solution of
‘
suspension is obtained. Add three 1-mL quantities of potassium iodide, mix, stopper the flask and allow to stand for
..
oe on
15 minutes protected from light. Add 25 mL of acetone and

:
roe
vo
acetonitrile and mix using a vortex mixer between each

Oy
~
.
titrate with 0.01M sodium thiosulfate VS using starch mucilage,

te,
addition. Add a further 15 mL of acetonitrile and mix with

. eo
‘
nota,
A
added towards the end of the titration, as indicator. Repeat

,a
the aid of ultrasound for 3 minutes. Add sufficient acetonitrile

wee
fy
the operation without the substance being examined.

“etety es
to produce 100 mL. Dilute 1 volume to 10 volumes with

aesets
34
The difference between the titrations represents the amount

eer
acetonitrile.
Doe ee ee ro Se ee ee
II-182 Benzoyl Peroxide Preparations 2016
of sodium thiosulfate required. Each mL of 0.01M sodium (2) Dilute 1 volume of solution (1) to 100 volumes with
thiosulfate VS is equivalent to 1.211 mg of C,4Hj Ox. acetonitrile.
LABELLING (3) 0.003% w/v of benzoic acid, 0.0003% wiv of ethyl benzoate
The quantity of active ingredient is stated in terms of the and 0.0003% w/w of benzaldehyde in acetonitrile.
equivalent amount of anhydrous benzoyl peroxide. (4) 0.0025% w/v of benzoyl peroxide in acetonitrile.

with end-capped phenyl ethyl silica gel for chromatography
Benzoyl Peroxide Gel (4 um) (Phenomenex Synergi Polar RP is suitable) fitted
with a suitable stainless steel guard column packed with
Action and.use octadecylsilyl silica gel for chromatography.
Used toy it he treatment of acne. (b) Use gradient elution and the mobile phase described
below.
DEFINITIOD.
Benzoyl Perox solution of Hydrous Benzoyl
Peroxide in a suitable water-soluble basis. (d) Use a column temperature of 35°.
The gel complies with th. nts stated under Topical Semi-
solid Preparations and witi ing requirements. (f) Inject 10 wL of each solution.
Content of anhydrous ben MOBILE PHASE
90.0 to 110.0% of the stated Mobile phase A 0.00042% v/v of orthophosphoric acid.
IDENTIFICATION Mobile phase B_ acetonitrile.

0-5 65 35 isocratic
containing the equivalent of 50 mg of anhydrous‘e 5-15 65-15 35-85 linear gradient
peroxide with 10 mL of dichloromethane and filter. 15-18 15 85 isocratic

(2) 0.5% wiv of benzoyl peroxide in dichloromethane.
(a) Use as the coating silica gel Fo54.

hromatograms are recorded under the prescribed
he retention times relative to benzoyl peroxide
to
with solution (3),he resolut,ion between the peaks due
MOBILE PHASE
1 volume of glacial acetic acid, 2 volumes of dichloromethane benzoic acid and beng
and 50 volumes of toluene. LIMITS :
CONFIRMATION In the chromatogram obtainéd wit
The principal spot in the chromatogram obtained with Identify the peaks due to benzéie acid
solution (1) corresponds to that in the chromatogram ethyl benzoate using the chromatégrat
B. In the test for Related substances, the chromatogram
retention time as the peak due to benzoyl peroxide in the
TESTS
Related substances the area of any other secondary peak is not greater than the
Carry out the method for liquid chromatography, area of the principal peak in the chromatogram obtained with
ae eS
oe NYS
Appendix III D, using the following solutions. Prepare a solution (2) (1%).
mixture of 0.1 volumes of acetic acid and 999.9 volumes of ASSAY
acetonitrile (solvent A). Mix a quantity of the preparation being examined containing
(1) Add 1 mL of solvent A to a quantity of the gel the equivalent of 0.25 g of anhydrous benzoyl peroxide with
containing the equivalent of 25 mg of anhydrous benzoyl 50 mL of acetone and add sufficient acetone to produce
peroxide. Mix using a vortex mixer until a uniform 100 mL. To 10 mL add 25 mL of a 20% w/v solution of
suspension is obtained. Add three 1-mL quantities of potassium iodide, mix, stopper the flask and allow to stand for
acetonitrile and mix using a vortex mixer between each 15 minutes protected from light. Add 25 mL of acetone and
addition. Add a further 15 mL of acetonitrile and mix with titrate with 0.01M sodium thiosulfate VS using starch mucilage,
the aid of ultrasound for 3 minutes. Add sufficient acetonitrile added towards the end of the titration, as indicator. Repeat
to produce 100 mL. Dilute 1 volume to 10 volumes with the operation without the substance being examined.
acetonitrile. The difference between the titrations represents the amount
2016 Benzoyl Peroxide Preparations III-183
of sodium thiosulfate required. Each ml of 0.01M sodium to produce 100 mL. Dilute 1 volume to 10 volumes with
thiosulfate VS is equivalent to 1.211 mg of C,4Hj9Qq. acetomutrile.
LABELLING (2) Dilute 1 volume of solution (1) to 100 volumes with
The quantity of active ingredient is stated in terms of the acetonitrile.
equivalent amount of anhydrous benzoyl peroxide. (3) 0.003% w/v of benzoic acid, 0.0003% w/v of ethyl benzoate
and 0.0003% w/v of benzaldehyde in acetonitrile.
(4) 0.0025% w/v of benzoyl peroxide
in acetonitrile.
Benzoyl Peroxide Lotion (a) Use a stainless steel column (25 cm x 4.6 mm) packed
Benzoyl Peroxide Cutaneous Suspension with end-capped phenylethyl silica gel for chromatography (4 wm)
(Phenomenex Synergi Polar RP is suitable) fitted with a
suitable stainless steel guard column packed with octadecylsilyl
stca gel for chromatography.
below.
90.0 to 110.0% of the state MOBILE PHASE
IDENTIFICATION - Mobile phase A 0.00042% v/v Orthophosphoric acid.
Mobile phase B acetonitrile.
Appendix III A, protected from light, usin =“
solutions. Time Mobile phase A Mobile phase B Comment
(1) Shake a quantity of the preparation being ax: (Minutes) (% viv) (% viv)
containing the equivalent of 50 mg of anhydrous ‘ben 0-5 65 35 isocratic
peroxide with 10 mL of dichloromethane and filter. 5-15 65-15 35-85 linear gradient
15 85 isocratic
(2) 0.5% w/v of benzoyl peroxide in dichloromethane.
1565 8535 linear gradient
CHROMATOGRAPHIC CONDITIONS 65 35 re-equilibration
MOBILE PHASE The test is not vali
1 volume of glacial acetic acid, 2 volumes of dichloromethane with solution (3), t
and 50 volumes of toluene. benzoic acid and benz
CONFIRMATION LIMITS
The principal spot in the chromatogram obtained with In the chromatogram obtained?Wi
solution (1) corresponds to that in the chromatogram Identify the peaks due to benzoic
obtained with solution (2). ethyl benzoate using the chromatograr
B. In the test for Related substances, the chromatogram solution (3) and multiply the areas ofthe
obtained with solution (1) shows a peak with the same corresponding correction factors: benzoic aéid
retention time as the peak due to benzoyl peroxide in the benzaldehyde, 1.74; and ethyl benzoate, 1.725
chromatogram obtained with solution (A). the area of any peak corresponding to benzoic atid is not
TESTS greater than 10 times the area of the principal peak in the
Related substances chromatogram obtained with solution (2) (10%);
Carry out the method for liquid chromatography, the area of any other secondary peak is not greater than the
Appendix III D, using the following solutions. Prepare a area of the principal peak in the chromatogram obtained with
mixture of 0.1 volumes of acetic acid and 999.9 volumes of solution (2) (1%).
acetonitrile (solvent A). ASSAY
(1) Add 1 mL of solvent A to a quantity of the lotion Mix a quantity of the preparation being examined containing
containing the equivalent of 25 mg of anhydrous benzoyl the equivalent of 0.25 g of anhydrous benzoyl peroxide with
peroxide. Mix using a vortex mixer until a uniform 50 mL of acetone and add sufficient acetone to produce
suspension is obtained. Add three 1-mL quantities of 100 mL. To 10 mL add 25 mL of a 20% w/w solution of
acetomtrile and mix using a vortex mixer between each potassium iodide, mix, stopper the flask and allow to stand for
addition. Add a further 15 mL of acetonitrile and mix with 15 minutes protected from light. Add 25 mL of acetone and
the aid of ultrasound for 3 minutes. Add sufficient acetonitrile titrate with 0.01mM sodium thiosulfate VS using starch mucilage,
added towards the end of the titration, as indicator. Repeat
boy
te
woe
S2e
III-184 Benzydamine Preparations 2016
the operation without the substance being examined. ASSAY

The difference between the titrations represents the amount To a quantity of the cream containing 25 mg of
of sodium thiosulfate required. Each mL of 0.01M sodium Benzydamine Hydrochloride add 50 mL of ethanol (96%),
thiosulfate VS is equivalent to 1.211 mg of Cy4Hj9Ox. heat until the cream is completely dissolved and cool in an
LABELLING ice-bath until a white precipitate forms. Allow to warm to
20°, dilute to 100 mL with ethanol (96%) and filter. Dilute
10 mL of the filtrate to 100 mL with ethanol (96%) and
equivalent amount of anhydrous benzoyl peroxide.
measure the absorbance of the resulting solution at the
maximum at about 308 nm, Appendix II B, using
ethanol (96%) in the reference cell. Calculate the content of
C19H23N30,HCI from the absorbance obtained with a
solution containing 0.0025% w/v of benzydamine
hydrochlonde BPCRS in ethanol (96%) and using the declared
content of Cy9H23N30,HCI in benzydamine
DEFINITION
Benzydamine Crear
a suitable basis.
Benzydamine Mouthwash
The cream complies with thé" s stated under Topical
Semi-solid Preparations and ing requirements. Action and use
Content of benzydamine hy Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.
C,9H23N30,HC1
92.5 to 107.5% of the stated amount. * DEFINITION
Benzydamine Mouthwash is a solution of Benzydamine
IDENTIFICATION Hydrochloride in a suitable flavoured and coloured vehicle.
A. Heat a quantity of the cream containing 25%
The mouthwash complies with the requirements stated under
Benzydamine Hydrochloride with 50 mL of absoé
Oromucosal Preparations and with the following requirements.
until the cream is completely dissolved and place inn 1
bath until a white precipitate forms. Allow to warm to.@0° Content of benzydamine hydrochloride,
dilute to 100 mL with absolute ethanol and filter. Dilute C19H23N30,HCI
10 mL of the filtrate to 100 mL with absolute ethanol. The 92.5 to 107.5% of the stated amount.
light absorption of the resulting solution, Appendix IT B, in the : [FICATION
range 230 to 350 nm exhibits a maximum at 308 nm. ut the method for thin-layer chromatography,
B. In the test for 1-Benzyl-1H-indazol-3-ol, the principal spot A, using the following solutions.
‘in the chromatogram obtained with solution (1) corresponds mouthwash, if necessary, with absolute ethanol
to that in the chromatogram obtained with solution (2).
TESTS (2) 0.15% w
1-Benzyl-1H-indazol-3-ol absolute ethanol.
Carry out the method for thin-layer chromatography, CHROMATOGRAPH G
Appendix III A, using the following solutions in methanol.
(a) Use a TLC silica gel ated plate (Merck silica gel
(1) Extract a quantity of the cream containing 60 mg of 60 Fys54 plates are suitabi
Benzydamine Hydrochloride with 25 mL of hot methanol,
(b) Use the mobile phase a vibed below.
cool the solution in ice and filter; repeat the extraction twice,
filtering each extract and evaporate the combined extracts to (c) Apply 50 uL of each solutions
dryness using a rotary evaporator; dissolve the residue in (d) Develop the plate to 15 cm.
5 mL of methanol. (e) After removal of the plate, dry in a mine under
(2) 1.2% w/v of benzydamine hydrochloride BPCRS. ultraviolet light (254 nm).
(3) 0.0024% w/v of 1-benzyl-1H-indazol-3-ol BPCRS. MOBILE PHASE
CHROMATOGRAPHIC CONDITIONS 30 volumes of triethylamine and 80 volumes of

(a) Use as the coating silica gel GF 254. CONFIRMATION
(b) Use the mobile phase as described below. The principal spot in the chromatogram obtained with
(c) Apply 40 uL of each solution. solution (1) corresponds to that in the chromatogram
solution (1) shows a peak with the same retention time as the
ultraviolet hght (254 nm and 365 nm).
MOBILE PHASE solution (2).
30 volumes of triethylamine and 80 volumes of toluene.
TESTS
LIMITS Acidity or alkalinity
By each method of visualisation, any secondary spot in the 5.0 to 7.0, Appendix V L.
chromatogram obtained with solution (1) is not more intense 1-Benzyl-1H-indazol-3-ol
than the spot in the chromatogram obtained with solution (3) Carry out the method for thin-layer chromatography,
(0.2%). Appendix III A, using the following solutions.
2016 Benzydamine Preparations III-185
(1) Extract a quantity of the mouthwash containing 15 mg of

Benzydamine Hydrochloride with seven 90-mL quantities of
Benzydamine Oromucosal Spray
chloroform. Filter each extract through phase separating paper, Action and use
tte wd
evaporate the combined extracts to dryness and dissolve the

Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.
residue in 10 mL of methanol.
(2) 0.0015% w/v of 1-benzyl-1H-indazol-3-ol BPCRS in DEFINITION
methanol. Benzydamine Oromucosal Spray is a solution of
CHROMATOGRAPHIC CONDITIONS Benzydamine Hydrochloride in a suitable flavoured vehicle in
a suitable metered-dose container.
(a) Use a TLC silica gel F54 plate.
The oromucosal spray complies with the requirements stated under
Content of benzydamine hydrochloride,
C,9H,3N30,HC1
IDENTIFICATION
70 volumes of eye ohe? (1) Dilute the oromucosal spray, if necessary, with absolute
LIMITS ethanol to contain 0.15% w/v of Benzydamine Hydrochloride.
Any secondary spot in the c (2) 0.15% wy of benzydamine hydrochloride BPCRS in
solution (1) is not more inte absolute ethanol.
chromatogram obtained wit CHROMATOGRAPHIC CONDITIONS
ASSAY (a) Use a TLC silica gel F254 precoated plate (Merck silica gel
Carry out the method for gas chromato 60 F554 plates are suitable).
0.075% wiv solution of 1-benzyl-3-(3-diethylamjho-props (c) Apply 50 uL of each solution.
1H-indazole BPCRS (internal standard) in water (sétuti
(1) Add 10 mL of solution A, 5 mL of water, 5 mL«
1m sodium hydroxide and 20 mL of chloroform to a quanti (e) After removal of the plate, dry in air and examine under
the mouthwash containing 7.5 mg of Benzydamine ultraviolet light (254 nm).
Hydrochloride, diluted, if necessary to 5 mL with water,
shake for 5 minutes, centrifuge and use the chloroform layer. es of triethylamine and 80 volumes of toluene.
(2) Prepare solution (2) in the same manner as solution (1) SATION
except using 5 mL of a solution containing 0.15% w/v of
ypal spot in the chromatogram obtained with
benzydamine hydrochloride BPCRS in water in place of a
corresponds to that in the chromatogram
quantity of the mouthwash containing 7.5 mg of
obtained w utzon (2).
Benzydamine Hydrochloride, diluted, if necessary, to 5 mL
with water. B. In the Assaygt romatogram obtained with
solution (1) show ;.with the same retention time as
the principal peak 1 omatogram obtained with
a) Use a glass column (2 m x 2 mm) packed with acid- solution (2).
washed, diatomaceous support (80 to 100 mesh) coated with
TESTS
3% w/w of phenyl methyl silicone fluid (50% phenyl)
(OV-17 is suitable). Acidity or alkalinity
5.0 to 7.0, Appendix V L.
(b) Use nitrogen for chromatography as the carrier gas at
30 mL per minute. Uniformity of weight
Weigh one unit. Fire one shot and re it. Repeat
(c) Use isothermal conditions maintained at 260°.
four times, then repeat the entire process wi ore units
(d) Use an inlet temperature of 300°. (20 shots). Determine the average weight deli
(e) Use a flame ionisation detector at 300°. Not more than two of the individual weights deyate from the
(f) Inject 1 wL of each solution. average weight by more than 10% and none deviates by
more than 20%.
Calculate the content of C;9H23N30,HCI from the 1-Benzyl-1H-indazol-3-ol

chromatograms obtained using the declared content of Carry out the method for thin-layer chromatography,
Cj9H23N30,HCI in benzydamine hydrochloride BPCRS. Appendix III A, using the following solutions.
(1) Extract a quantity of the oromucosal spray containing
LABELLING
15 mg of Benzydamine Hydrochloride with seven 90-mL
The label states, where appropriate, that the preparation is
quantities of chloroform. Filter each extract through phase
also suitable for use as a gargle.
separating paper, evaporate the combined extracts to dryness
and dissolve the residue in 10 mL of methanol.
(2) 0.0015% w/v of 1-benzyl-1H-indazol-3-ol BPCRS in
methanol.
IlI-186 Benzyl Benzoate Preparations 2016
CHROMATOGRAPHIC CONDITIONS Melt the Emulsifying Wax, add the Benzyl Benzoate and
(a) Use a TLC silica gel F254 plate. mix. Pour the mixture into sufficient warm Purified Water to
(b) Use the mobile phase as described below. produce 1000 mL and stir thoroughly until cold.
The application complies with the requirements stated under
awed

Liguids for Cutaneous Application and with the following
requirements.
Content of benzyl benzoate, C,,H,,0>
23.1 to 26.9% wy.
MOBILE PHASE
ASSAY
10 volumes of glacial acetic acid, 20 volumes of chloroform and
Appendix ITI D, using the following solutions.
LIMITS
(1) Dissolve 1 g of the application in sufficient of the mobile
.the chromatogram obtained with phase to produce 100 mL and dilute 1 volume of the
ore intense than the spot in the resulting solution to 50 volumes with the mobile phase.
(2) 0.0050% w/v of benzyl benzoate BPCRS in the mobile
phase.
hromatography, Appendix III B CHROMATOGRAPHIC CONDITIONS
using the following sol repare a 0.075% w/v solution
of 1-benzyl-3-(3-diethylami with end-capped octadecylsilyl silica gel for chromatography
(1) Add 10 mL of solution A,
1m sodium hydroxide and 20 mI
below.
the oromucosal spray containing 7.5 m
Hydrochloride, diluted, if necessary to 5 : (c) Use a flow rate of 1.5 mL per minute.
but using 5 mL of solution containing 0.15% w/v of (f) Inject 20 wL of each solution.
benzydamine hydrochloride BPCRS in water in place of az
MOBILE PHASE
quantity of the oromucosal spray containing 7.5 mg of
30 volumes of water and 70 volumes of acetonitrile.
Benzydamine Hydrochloride, diluted, if necessary, to 5 m:
with water. EMMINATION OF CONTENT
CHROMATOGRAPHIC CONDITIONS the weight per mL of the application,

V G, and calculate the content of C,,H,,.O,,
(a) Use a glass column (2 m x 2 mm) packed with acid-
ume, using the declared content of C,4H,20O> in
washed, diatomaceous support (80 to 100 mesh) coated with
3% wiw of phenyl methyl silicone fluid (50% phenyl)
(OV-17 is suitable).
(b) Use mitrogen for chromatography as the carrier gas at
30 mL per minute.
(d) Use an inlet temperature of 300°.
Action and use
(e) Use a flame ionisation detector at 300°. Penicillin antibacterial.
DEFINITION
Calculate the content of C;9H.3N30,HCI from the

chromatograms obtained using the declared content of
Water for Injections. It is prepared by dis:
C190H23N30,HCI in benzydamine hydrochloride BPCRS.
Benzylpenicillin for Injection in the requisite*
Water for Injections.
Parenteral Preparations.
Benzyl Benzoate Application STORAGE |
Benzyl Benzoate Cutaneous Emulsion Benzylpenicillin Injection should be used immediately after
DEFINITION preparation but, in any case, within the period recommended
Benzyl Benzoate Application is a cutaneous emulsion. by the manufacturer when prepared and stored strictly in
It contains 25% w/v of Benzyl Benzoate in a suitable oil-in- accordance with the manufacturer’s instructions.
water emulsified basis.
Extemporaneous preparation BENZYLPENICILLIN FOR INJECTION
The following formula and directions apply. DEFINITION
Benzyl Benzoate 250 g
Benzylpenicillin for Injection is a sterile material consisting of
Emulsifying Wax 20 g
Benzylpenicillin Potassium or Benzylpenicillin Sodium with
Purified Water, freshly Sufficient to produce 1000 mL
or without excipients. It is supplied in a sealed container.
boiled and cooled
2016 Benzylpenicillin Preparations III-187
The contents of the sealed container comply with the requirements mobile phase B. Inject 20 uL of solution (1) and elute
for Powders for Injections or Infusions stated under Parenteral isocratically with a mixture of 70 volumes of mobile phase A
Preparations and with the following requirements. and 30 volumes of mobile phase B. Immediately after elution
Content of penicillins, calculated as C,;H,;N,O,S of the benzylpenicillin peak start the following linear gradient.
95.0 to 105.0% of the content of benzylpenicillin stated on
the label. Time Mobile phase A Mobile phase B Comment
(main) fper cent VIPS (per cent VI)
IDENTIFICATION
A. The infrared absorption spectrum, Appendix II A, is 0-20 7D 30-»100 linear gradient
concordant with the spectrum of benzylpenicillin 20-35 0 100 isocratic
potassium EPCRS or benzylpenicillin sodium EPCRS as 35-30 79 30 re-equilibration
appropriate.
Inject water and use the same elution pattern to obtain a

blank.
LIMITS
the area of any secondary peak is not greater than the area of
solution (2) (1%).
benzylpenicillin potassium EPGRS, asa: Loss on drying
0.5% w/v of phenoxymethylpenicill pe When dried to constant weight at 105°, lose not more than
CHROMATOGRAPHIC CONDI 10 | 1.0% of their weight. Use 1 g.
(a) Use a TLC silica gel silanised plate(Me#ck-silanised silica Bacterial endotoxins
gel 60 plates are suitable). Carry out the test for bacterial endotoxins, Appendix XIV C.
(b) Use the mobile phase as described belo Dissolve the contents of the sealed container in water BET to
(c) Apply 1 wL of each solution. give a solution containing the equivalent of 10 mg of
benzylpenicillin per mL (solution A). The endotoxin limit of
solution A is 1.6 IU per mL.
(e) After removal of the plate allow it to dry in air, exp
iodine vapour until spots appear and examine in daylight. ASSAY
ine the weight of the contents of 10 containers as
MOBILE PHASE
in the test for uniformity of weight,
30 volumes of acetone and 70 volumes of a 15.4% w/v XII C1, Powders for Parenteral Administration.
solution of ammonium acetate adjusted to pH 5.0 with glacial
acetic acid.
SYSTEM SUITABILITY
CONFIRMATION
C. Yield reaction A characteristic of potassium salts or
reaction A characteristic of sodium salts, Appendix VI, as
appropriate.
TESTS with end-capped octadecylsilyl silica gel fo
Acidity or alkalinity (5 um) (Hypersil ODS is suitable).
pH of a solution containing the equivalent of 10.0% w/v of
benzylpenicillin, 5.5 to 7.5, Appendix V L. below.
Related substances (c) Use a flow rate of 1 mL per minute.
Carry out the method for liquid chromatography, (d) Use an ambient column temperature.
Appendix III D, using the following solutions prepared (e) Use a detection wavelength of 225 nm.
(1) Dissolve a quantity of the contents of a sealed container
MOBILE PHASE
containing the equivalent of 80 mg of benzylpenicillin in
20 mL of water, mix, filter and use the filtrate. 70 volumes of mobile phase A and 30 volumes of mobile
(2) 0.0040% w/v of benzylpenicillin sodium EPCRS in water. phase B.
Mobile phase A Mix 10 volumes of a 6.8% w/v solution of
potassium dihydrogen orthophosphate, adjusted to pH 3.5 with a
The chromatographic conditions described under Assay may 50% w/v solution of dilute orthophosphoric acid, 30 volumes of
be used. methanol and 60 volumes of water.
Inject 20 pL of solution (2) and elute isocratically with a Mobile phase B_ Mix 10 volumes of a 6.8% w/v solution of
mixture of 70 volumes of mobile phase A and 30 volumes of potasstum dihydrogen orthophosphate, adjusted to pH 3.5 with a
IiI-188 Betahistine Preparations 2016
50% w/v solution of dilute orthophosphoric acid, 40 volumes of (3) 0.00064% w/v of N-methyl-2-(pyridin-2-yl)-N-[2-(pyridine-
water and 50 volumes of methanol. 2-yl) ethyl/ethanamine trihydrochloride BPCRS in the mobile
yea,
Equilibrate the column with the mobile phase. phase.
(4) 0.000032% w/v of 2-vinylpyridine in acetonitrile.
Na
SYSTEM SUITABILITY
wets 708
The test is not valid unless, in the chromatogram obtained (5) 0.00064% w/v each of N-methyl-2-(pyridin-2-yl)-N-[2-
with solution (3), the resolution factor between the two (pyridine-2-yl) ethyl/ethanamine trihydrochloride BPCRS and
principal peaks is at least 6.0 (if necessary adjust the ratio betahistine dihydrochloride BPCRS in the mobile phase.
A:B of the mobile phase). CHROMATOGRAPHIC CONDITIONS
DETERMINATION OF CONTENT (a) Use a stainless steel column (25 cm x 4.6 mm) packed
Calculate the content of penicillins, as C;gsH;gN2O,S, in a with octadecylsilyl silica gel for chromatography (5 um) (Zorbax
container of average content weight using the declared XDB Eclipse is suitable).
tweed content o Hy7N2Na0as |in benzylpenicillin (b) Use isocratic elution and the mobile phase described
Lan
veh
4
eA
sodium § ach mg of C;g6H,7N2Na0O,5Sis equivalent to below.
exceeding 30°. (f) Inject 20 wL of each solution.
LABELLING (g) Allow the chromatography to proceed for four times the
retention time of betahistine (retention time of betahistine,
about 5 minutes).
MOBILE PHASE
Benzylpenicillin Sodium contai ms of the
Dissolve 0.4 g of hexylamine in 600 mL of a solution
equivalent amount of benzylpenicillins
containing 0.46% w/v of sodium dihydrogen orthophosphate
monohydrate and 0.27% w/v of sodium dodecyl sulfate, add
400 mL of acetonitrile, mix and adjust the pH to 3.5 using
Betahistine Dihydrochloride Tablets SYSTEM SUITABILITY
Action and use
ith solution (5), the resolution factor between the two
fincipal peaksis at least 3.0.
DEFINITION
Betahistine Dihydrochloride Tablets contain Betahistine atogram obtained with solution (1):
Dihydrochloride. y, peak corresponding to N-methyl-bis[B-
The tablets comply with the requirements stated under Tablets and nine is not greater than the area of the
with the following requirements. he Ghromatogram obtained with
Content of betahistine dihydrochloride, CgH,,N>,2HCl
greater than twice ie
IDENTIFICATION
chromatogram obtaine
A. Extract a quantity of the powdered tablets containing
5 mg of Betahistine Dihydrochloride with 100 mL of water
and filter. The light absorption, Appendix II B, in the range
230 to 350 nm exhibits a maximum at about 260 nm, a less solution (2) (0.2%);
well-defined maximum at about 267 nm and a shoulder at the sum of the areas of the peaks Cc
about 256 nm. bis[f$-(2-pyridyl)ethyl]amine, 2-viny
B. In the Assay, the chromatogram obtained with secondary peaks is not greater than 10 tir
solution (1) shows a peak with the same retention time as principal peak in the chromatogram obtained
the principal peak in the chromatogram obtained with solution (2) (2%).
solution (2). Disregard any peak with an area less than 0.05% ;
TESTS
solution (1) (0.05%).
mM aay
enw
Related substances
Carry out the method for liquid chromatography, ASSAY
Appendix III D, using the following solutions. Weigh and powder 20 tablets. Carry out the method for
(1) Add 50 mL of the mobile phase to a quantity of the liquid chromatography, Appendix III D, using the following
powdered tablets containing 32 mg of Betahistine solutions.
Dihydrochloride, shake for 10 minutes, add sufficient mobile (1) Add 50 mL of the mobile phase to a quantity of the
phase to produce 100 mL, mix, centrifuge and use the powdered tablets containing 32 mg of Betahistine
supernatant liquid. Dihydrochloride, shake for 10 minutes, add sufficient mobile
(2) Dilute 1 volume of solution (1) to 500 volumes with the phase to produce 100 mL, mix, centrifuge and use the
mobile phase. supernatant liquid.
wane
nee ad
(2) 0.032% w/v of betahistine dihydrochloride BPCRS in the
aoa
~we eee
mobile phase.
aA
2016 Betamethasone Preparations IHI-189
(3) 0.00064% w/v each of N-methyl-2-(pyridin-2-yl)-N-[2- (4) A mixture of equal volumes of solution (2) and a
(pyridine-2-yl) ethyl]ethanamine trihydrochloride BPCRS and 0.1% w/v solution of prednisolone sodium phosphate BPCRS.
eae 4
betahistine dihydrochloride BPCRS in the mobile phase. CHROMATOGRAPHIC CONDITIONS
CHROMATOGRAPHIC CONDITIONS (a) Use as the coating silica gel GF254.
The chromatographic conditions described under Related (b) Use the mobile phase as described below.
SYSTEM SUITABILITY (d) Develop the plate to 15 cm.
The test is not valid unless, in the chromatogram obtained (e) After removal of the plate, dry in air, heat at 110° for
with solution (3), the resolution factor between the two 10 minutes and examine under ultraviolet light (254 nm).
MOBILE PHASE
20 volumes of acetic anhydride, 20 volumes of water and

60 volumes of butan-1-ol, prepared immediately before use.
Pe as
SYSTEM SUITABILITY

solution (4) shows two principal spots with almost
identical Rf values.
CONFIRMATION
The chromatograms obtained with solutions (1), (2) and (3)
show single principal spots with similar Rf values.
peak due to betamethasone sodium phosphate in the
C. To a volume containing 0.2 mg of Betamethasone
Sodium Phosphate, add slowly 1 mL of sulfuric acid and
allow to stand for 2 minutes. A brownish yellow colour but
no red colour or yellowish green fluorescence is produced.
TESTS
or alkalinity
to 8.5, Appendix V L.
ubstances
the method for liquid chromatography,
: protected from light and using the following
ps if necessary to give a solution

of Betamethasone Sodium Phosphate.
3. N-methyl-2-(pyridin-2-yl)-N-[2-(pyridin-2-yl)ethy]]
ethanamine.
Betamethasone Eye Drops

with octadecylsilyl silica gel for chro natogr ky (10 um)
Action and use (Spherisorb ODS 1 is suitable).
Glucocorticoid. (b) Use isocratic elution and the mob
below.
DEFINITION
Betamethasone Eye Drops area sterile solution of
Betamethasone Sodium Phosphate in Purified Water.
The eye drops comply with the requirements stated under Eye
Preparations and with the following requirements. (f) Inject 20 wL of each solution.
Content of betamethasone sodium phosphate, (g) For solutions (1) and (2) record the chromatogram for
C,,H,,;FNa,O;P three times the retention time of the principal peak.
90.0 to 110.0% of the stated amount. MOBILE PHASE
IDENTIFICATION 40 volumes of methanol and 60 volumes of citro-phosphate
A. Carry out the method for thin-layer chromatography, buffer pH 5.0.
Appendix III A, using the following solutions. SYSTEM SUITABILITY
(1) Use the eye drops, diluted if necessary with water, to The test is not valid unless in the chromatogram obtained
contain 0.1% w/v of Betamethasone Sodium Phosphate. with solution (3) the resolution factor between the peaks due
(2) 0.1% w/v of betamethasone sodium phosphate BPCRS. to betamethasone sodium phosphate and betamethasone is at
(3) A mixture of equal volumes of solutions (1) and (2). least 3.5.
IlI-190 Betamethasone Preparations 2016
LIMITS The injection complies with the requirements stated under

In the chromatogram obtained with solution (1): Parenteral Preparations and with the following requirements.
the area of any peak corresponding to betamethasone is not Content of betamethasone, C,,H> .FO;
greater than 1.3 times the area of the principal peak in the 92.5 to 107.5% of the stated amount.
IDENTIFICATION
the area of any other secondary peak is not greater than A. To a volume of the injection containing the equivalent of
1.5 tumes the area of the principal peak in the chromatogram 4 mg of betamethasone add 1 mL of water and sufficient
obtained with solution (2) (3%); absolute ethanol to produce 40 mL. Place 2 mL of the
the sum of the areas of all the secondary peaks is not greater solution in a stoppered tube, add 10 mL of phenylhydrazine-
than 2.5 times the area of the principal peak in the sulfuric acid solution, mix, warm in a water bath at 60° for
chromatogram obtained with solution (2) (5%). 20 minutes and cool immediately. The absorbance of the
resulting solution at the maximum at 450 nm is not more
than 0.1, Appendix II B.
B. Carry out the method for thin-layer chromatography,
quid chromatography, (1) Dilute the injection, if necessary, with sufficient water to
llewing solutions. produce a solution containing the equivalent of 2 mg of
betamethasone per mL.
ps Containing 5 mg of
ith 10 mL of methanol (2) 0.25% w/v solution of betamethasone sodium
phosphate BPCRS in water.
(4) A mixture of equal volumes of solution (1) and a
0.25% w/v solution of prednisolone sodium phosphate BPCRS
in water.
(3) Prepare in the same manner as solution (fe Dut, CHROMATOGRAPHIC CONDITIONS
10 mL of the internal standard solution in place éf th (a) Use as the coating silica gel GF 254.
methanol.
(b) Use the mobile phase as described below and prepare
CHROMATOGRAPHIC CONDITIONS immediately before use.
with octadecylsilyl silica gel for chromatography (10 pm)
(Spherisorb ODS1is suitable).
moval of the plate, allow it to dry in air, heat at
aminutes and examine under ultraviolet light
below.
MOBIEE
20 vol
MOBILE PHASE
45 volumes of methanol and 55 volumes of citro-phosphate show single spots with si
buffer pH 5.0. the chromatogram obtained
Calculate the content of C.,H23FNa,OgP in solution A by

measuring the absorbance, Appendix II B, of an aliquot
diluted with water to contain 0.002% w/v of Betamethasone
Sodium Phosphate at the maximum at 241 nm and taking
297 as the value of A(1%, 1 cm) at the maximum at residue in 2 mL of sulfurc acid and allow to stand'to
241 nm. Calculate the content of Co,H2gFNa2OeP in the eye 2 minutes. No red colour is produced.
drops using peak areas.
TESTS
STORAGE Alkalinity
Betamethasone Eye Drops should be protected from light. pH, 8.0 to 9.0, Appendix V L.
Colour
The injection, diluted if necessary with water to contain the
equivalent of 2 mg of betamethasone per mL, is not more
Betamethasone Injection intensely coloured than reference solution BY,, Appendix IV B,
Method I.
Action and use Related substances
Glucocorticoid. Carry out the method for liquid chromatography,
Appendix III D, protected from light, using the following
DEFINITION solutions.
Betamethasone Injection is a sterile solution of
Betamethasone Sodium Phosphate in Water for Injections.
2016 Betamethasone Preparations HI-191
(1) Dilute the injection with mobile phase, if necessary, to MOBILE PHASE
give a solution containing the equivalent of 0.10% w/v of 45 volumes of methanol and 55 volumes of citro-phosphate
betamethasone. buffer pH 5.0.
(2) Dilute 1 volume of solution (1) to 50 volumes with DETERMINATION OF CONTENT
mobile phase.
Calculate the content of C,H»9.FOs in the injection,
(3) 0.0060% w/v each of betamethasone sodium determining the exact strength of C22H29FOs in solution (2)
phosphate BPCRS and betamethasone in mobile phase. as follows. Dilute 3 mL of solution A to 50 mL with water
CHROMATOGRAPHIC CONDITIONS and measure the absorbance, Appendix II B, of the resulting
(a) Use a stainless steel column (25 cm x 4.6 mm) packed solution at the maximum at 241 nm, taking 391 as the value
with octadecylsilyl silica gel for chromatography (10 um) of A(1%, 1 cm) for betamethasone.
(Spherisorb ODS1is suitable). STORAGE
Betamethasone Injection should be stored at a temperature
not exceeding 30° and protected from light.
LABELLING
equivalent amount of betamethasone in a suitable dose-
(f) Inject 20 pL of tion. For solutions (1) and (2) volume.
record the chromatogr times the retention time
of the principal peak.
MOBILE PHASE
40 volumes of methanol and citro-phosphate Betamethasone Tablets
buffer pH 5.0.
Action and use
SYSTEM SUITABILITY Glucocorticoid.
The test is not valid unless, in the chromati
with solution (3), the resolution factor betwee DEFINITION
betamethasor
betamethasone sodium phosphate and
Betamethasone Tablets contain Betamethasone.
to
least 3.5. The tablets comply with the requirements stated under Tablets and
LIMITS
In the chromatogram obtained with solution (1): tent of betamethasone, C,,H,.FO;
» 110.0% of the stated amount.
the area of any peak corresponding to betamethasone is not
greater than 1.3 times the area of the principal peak in the FICATION
chromatogram obtained with solution (2)(2.6%); auannty of the powdered tablets containing
obtained with solution (2)(3%); ‘winsulfate, evaporate the solution to
the sum of the areas of all the secondary peaks is not greater i esidue at 105° for 2 hours. The ifrared
than 2.5 times the area of the principal peak in the absorption spectri
chromatogram obtained with solution (2)(5%). concordant with
(RS 029).
Disregard any peak the area of which is less than 0.05 times
with solution (2)(0.1%).
ASSAY
Appendix III D, using the following solutions protected from of 9 volumes of chloroform and 1 volum ethanol.
light. The chromatogram obtained with this s | ws two
(1) Dilute a volume of the injection containing the equivalent
of 8 mg of betamethasone to 50 mL with methanol (50%). C. In the Assay, the chromatogram obtained witt
(2) Dilute 5 mL of a 0.045% w/v solution of betamethasone (1) shows a peak with the same retention time as the peak
sodium phosphate BPCRS in water (solution A) to 10 mL with due to betamethasone in the chromatogram obtained with
methanol. solution (2).
CHROMATOGRAPHIC CONDITIONS TESTS
(a) Use a stainless steel column (25 cm x 4.6 mm) packed Uniformity of content
with octadecylsilyl sihca gel for chromatography (10 um) Tablets containing less than 2 mg and/or less than 2% w/w
(Spherisorb ODS 1 is suitable). of Betamethasone comply with the requirements stated under
(b) Use isocratic elution and the mobile phase described Tablets using the following method of analysis. Carry out the
below. method for liquid chromatography, Appendix III D, using the
(1) Finely crush one tablet, add 20 mL of a 0.002% w/v
solution of hydrocortisone in methanol (50%), shake for
(e) Use a detection wavelength of 241 nm. 10 minutes and filter through a glass-fibre filter paper
(f) Inject 20 wL of each solution. (Whatman GF/Cis suitable).
IWI-192 Betamethasone Preparations 2016
(2) 0.0025% w/v of betamethasone BPCRS and 0.002% w/v of Content of clioquinol, C,.H;CIINO
hydrocortisone (internal standard) in methanol (50%). 90.0 to 110.0% of the stated amount.
(a) Use a stainless steel column (25 cm x 5 mm) packed A. Carry out the method for thin-layer chromatography,
with octadecylsilyl sihca gel for chromatography (10 um) Appendix III A, using the following solutions.
(Spherisorb ODS1 is suitable). (1) Disperse a quantity of the preparation being examined
(b) Use isocratic elution and the mobile phase described containing the equivalent of 0.5 mg of betamethasone in
below. 20 mL of methanol (80%) by heating on a water bath until
(c) Use a flow rate of 1.4 mL per minute. the methanol begins to boil. Shake vigorously, cool in ice and
(d) Use an ambient column temperature. centrifuge. Transfer 10 mL of the supernatant liquid to a
separating funnel, add 3 mL of water and 5 mL of chloroform,
(e) Use a de
shake vigorously, allow the layers to separate and evaporate
the chloroform layer to dryness in a current of nitrogen with
MOBILE PHS gentle heating. Dissolve the residue in 1 mL of chloroform.
47 volumes of / and 53 volumes of water. (2) 0.03% w/v of betamethasone valerate BPCRS in chloroform.
DETERMINATION CHROMATOGRAPHIC CONDITIONS |
Calculate the conterit: E 29FOsiin each tablet using the (a) Use as the coating silica gel G.
ratios of the peak areas and ? declared content of (b) Use the mobile phase as described below.
C32H»9FOs in betametha (c) Apply 10 uL of each solution.
ASSAY (d) Develop the plate to 15 cm.
For tablets containing less t id/or less than (e) After removal of the plate, allow it to dry in air, heat at
2% w/w of Betamethasone
105° for 5 minutes and spray while hot with alkaline
Use the average of the 10 individual re Its.
tetrazolium blue solution.
test for Uniformity of content.
MOBILE PHASE
For Tablets containing 2 mg or more ari
more of Betamethasone < 5 volumes of absolute ethanol, 10 volumes of acetone and
Weigh and powder 20 tablets. Carry out the method¢fo1 100 volumes of chloroform.
liquid chromatography, Appendix II D, using the follow, CONFIRMATION
solutions. . he principal spot in the chromatogram obtained with
(1) To a quantity of the powder containing 2.5 mg of 1 (1) correspondsin position and colour to thatin the
Betamethasone add 20 mL of methanol (50%), shake for gmategram obtained with solution (2).
10 minutes and filter through a glass-fibre filter paper ssay for betamethasone the chromatogram
(Whatman GF/C is suitable). th solution (1) shows a peak with the same
(2) 0.0125% w/v of betamethasone BPCRS and 0.010% w/v of
hydrocortisone (internal standard) in methanol (50%).
(3) Prepare the solution in the same manner as solution (1)
but use 20 mL of a 0.01% w/v solution of hydrocortisone in ": a peak with the same retention time
methanol (50%) in place of the 20 mL of methanol (50%). juinolin the chromatogram obtained
CHROMATOGRAPHIC CONDITIONS with solution (2).
The chromatographic conditions described under Uniformity ASSAY
of content may be used. For betamethasone
mone all
ven e
Appendix III D, using the followings

Calculate the content of C,H» .FOs in the tablets using the
ratios of the peak areas and the declared content of (1) Shake a quantity of the cream ci
s NAR,
C22H29FOs in betamethasone BPCRS.

STORAGE
Betamethasone Tablets should be protected from light.
cotton
wn previously washed with ethanol (75%)."Re eatthe
extraction of the hexane mixture with two 10-mL quantities
of ethanol (75%), filtering each extract in turn through the
absorbent cotton and dilute the combined filtrates to 50 mL
Betamethasone and Clioquinol Cream with ethanol (75%).
i
Action and use (2) Prepared in the same manner as solution (1) but add
Glucocorticoid. 5 mL of a 0.072% w/v solution of beclometasone
dipropionate BPCRS (internal standard) in ethanol (80%)
oe.
DEFINITION before diluting to 50 mL.

.
awe,
Betamethasone and Clioquinol Cream contains (3) Mix 2 volumes of a solution containing 0.024% w/v of
“oat
Betamethasone Valerate and Clioquinol, the latter in very fine betamethasone valerate BPCRS and 0.0012% w/v of
a!
powder, in a suitable basis.

pos
betamethasone 21-valerate BPCRS in ethanol (80%) with

:
et? rr

wt?
1 volume of a 0.072% w/v solution of the internal standard

Semi-solid Preparations and with the following requirements. in ethanol (80%) and dilute to 10 volumes with the same
solvent.
2a
Content of betamethasone, C,,H>,FO;

retesy

"¢
2016 Betamethasone Preparations III-193
CHROMATOGRAPHIC CONDITIONS LABELLING

(a) Use a stainless steel column (10 cm x 5 mm) packed The quantity of active ingredient with respect to
with octadecylsilyl silica gel for chromatography (5 wm) Betamethasone Valerate is stated in terms of the equivalent
(Spherisorb ODS 1 is suitable). amount of betamethasone.
below.
(d) Use a column temperature of 60°. Betamethasone and Clioquinol Ointment
Action and use
Glucocorticoid.
MOBILE PHASE
DEFINITION
Betamethasone and Clioquinol Ointment contains
Betamethasone Valerate and Clioquinol, the latter in very fine
powder, in a suitable basis.
solution factor between the peaks due
The ointment complies with the requirements stated under Topical
retention time about 5 minutes)
Sem1-solid Preparations and with the following requirements.
Content of betamethasone, C,,H>.FO;
DETERMINATION OF CONT Content of clioquinol, C7H;CIINO
Calculate the content of C,H |
declared content of C,.H,,FO, in £ IDENTIFICATION
valerate BPCRS. | A. Carry out the method for thin-layer chromatography,
For choquinol Appendix III A, using the following solutions.
Carry out the method for liquid chromatogr (1) Disperse a quantity of the ointment containing the
Appendix III D, using the following solutions: equivalent of 1 mg of betamethasone with 10 mL of methanol
(1) Add 80 mL of a hot 80% v/v solution of 2-meéth by heating on a water bath until the methanol begins to boil.
to a quantity of the cream containing 30 mg of Clioqui Shake vigorously, cool in ice and filter. Evaporate the filtrate
and heat on a water bath for 5 minutes, swirling vigor to dryness in a current of nitrogen and dissolve the residue in
Cool to room temperature, dilute to 100 mL with the sa mL of chloroform.
solvent, mix and filter. To 5 mL of the filtrate add 1 mL of 24% wiv of betamethasone valerate BPCRS in chloroform.
solution containing 1% w/v of nickel(m) chloride hexahydrate OGRAPHIC CONDITIONS
and dilute to 50 mL with the mobile phase.
the coating stlica gel Ge
(2) Mix 5 mL ofa solution containing 0.024% w/v of
choquinol BPCRS in an 80% v/v solution of 2-methoxyethanol
and 1 mL of a solution containing 1% w/v of nickel(m)
chloride hexahydrate in water and dilute to 50 mL with the
mobile phase.
tetrazolium blue soluti
with phenyl silica gel for chromatography (5 um) (Spherisorb MOBILE PHASE
Pheny] is suitable). 5 volumes of absolute ethanol, 10 volumes of acetone and
(b) Use isocratic elution and the mobile phase described 100 volumes of chloroform. :
below. CONFIRMATION
(c) Use a flow rate of 1.5 mL per minute. The principal spot in the chromatogr
(d) Use an ambient column temperature. solution (1) corresponds in position and
(e) Use a detection wavelength of 273 nm. chromatogram obtained with solution (2).
(f) Inject 20 uL of each solution. B. In the Assay for betamethasone the chromatég
MOBILE PHASE
retention time as the peak due to betamethasone valerate in
0.024% w/v of nickel() chloride hexahydrate in a mixture of the chromatogram obtained with solution (3).
C. In the Assay for clioquinol the chromatogram obtained
5 volumes of water.
with solution (1) shows a peak with the same retention time
DETERMINATION OF CONTENT as the peak due to clioquinol in the chromatogram obtained
Calculate the content of Cp)H5CIINO in the cream using the with solution (2).
declared content of C)JH;CIINO in choquinol BPCRS. ASSAY
STORAGE For betamethasone
Betamethasone and Clioquinol Cream should be protected Carry out the method for liquid chromatography,
from light. Appendix III D, using the following solutions.
(1) Disperse a quantity of the ointment containing the
equivalent of 2 mg of betamethasone in 100 mL of hot
III-194 Betamethasone Preparations 2016
hexane, cool, extract with 20 mL of ethanol (65%) and filter modified with chemically bonded phenyl groups (5 pum)
the lower, ethanolic layer through absorbent cotton (Spherisorb Phenyl is suitable).
previously washed with ethanol (65%); repeat the extraction (b) Use isocratic elution and the mobile phase described
of the hexane mixture with two 10-mL quantities of ethanol below.
(65%), filtering each extract in turn through the absorbent
cotton. To the combined extracts, add 5 mL ofa
0.072% w/v solution of beclometasone dipropionate BPCRS
(internal standard) in ethanol (65%) and dilute the combined (e) Use a detection wavelength of 273 nm.
filtrates to 50 mL with ethanol (65%). (f) Inject 20 wL of each solution.
(2) Prepare in the same manner as solution (1) but do not MOBILE PHASE
add the internal standard before diluting to 50 mL. A solution containing 0.024% w/v of nickel(1) chloride
(3) Mix 10 of a solution containing 0.024% w/v of hexahydrate in a mixture of 2 volumes of methanol, 3 volumes
rate BPCRS and 0.0012% w/v of of acetonitrile and 5 volumes of water.
ite BPCRS in ethanol (65%) with 5 mL
n of beclometasone dipropionate BPCRS
(internal standard ol (65%) and dilute to 50 mL Calculate the content of C)H5CIINO in the cream using the
with ethanol (65%). declared content of CgH5CIINO in choguinol BPCRS.
CHROMATOGRAPHI NS STORAGE
Betamethasone and Clioquinol Ointment should be protected
from light.
(Spherisorb ODS1is suitable).°s, LABELLING
(b) Use isocratic elution and the The quantity of active ingredient with respect to
below. Betamethasone Valerate is stated in terms of the equivalent
(c) Use a flow rate of 2 mL per minute. amount of betamethasone.
(d) Use a column temperature of 60°C.
MOBILE PHASE
Betamethasone Sodium Phosphate
A mixture of absolute ethanol and water adjusted so that th
resolution factor between the peaks due to betamethasone
valerate (retention time about 5 minutes) and betamethasone
21-valerate (retention time about 7 minutes) is greater than
1.0 (a mixture of 42 volumes of absolute ethanol and
58 volumes of water is usually suitable).
SYSTEM SUITABILITY
to betamethasone valerate and betamethasone 21-valerate is
greater than 1.0. |
90.0 to 110.0% ofthest
IDENTIFICATION
Calculate the content of C2,H2 FO; in the ointment using
the declared content of C,,H FO; in betamethasone
valerate BPCRS and using peak areas.
(1) Dissolve a quantity of the powder
For choquinol the equivalent of 2 mg of betamethas
Carry out the method for liquid chromatography, add 2.5 g of sodium chloride and 1 mL of hy
Appendix III D, using the following solutions. extract with 25 mL of chloroform and discard tk J
(1) Add 80 mL of a hot 80% v/v solution of 2-methoxyethanol layer. Extract with 25 mL of tnbutyl orthophosphaté
to a quantity of the cream containing 30 mg of Clioquinol discard the aqueous layer.
and heat on a water bath for 5 minutes, swirling vigorously. (2) Prepare in the same manner as solution (1) but using
Cool to room temperature, dilute to 100 mL with the same 2.5 mg of betamethasone sodium phosphate BPCRS in place of
solvent, mix and filter. To 5 mL of the filtrate add 1 mL ofa the powdered tablets.
solution containing 1% w/v of nickel(u) chloride hexahydrate
(3) Mix equal volumes of solutions (1) and (2).
and dilute to 50 mL with the mobile phase.
(4) Mix equal volumes of solution (1) and a solution
(2) Mix 5 mL of a solution containing 0.024% w/v of
prepared in the same manner as solution (1) but using
choquinol BPCRS in an 80% v/v solution of 2-methoxyethanol
2.5 mg of prednisolone sodium phosphate BPCRS in place of
and 1 mL ofa solution containing 1% w/v of nickel(i)
the powdered tablets.
chloride hexahydrate in water and dilute to 50 mL with the
mobile phase. CHROMATOGRAPHIC CONDITIONS
CHROMATOGRAPHIC CONDITIONS (a) Use as the coating silica gel G.

(a) Use a stainless steel column (25 cm x 4.6 mm) packed (b) Use the mobile phase as described below prepared
with particles of silica, the surface of which has been immediately before use.
mle UP eee te .
oh ee a a
2016 Betamethasone Preparations JTII-195
(d) Develop the plate to 15 cm. (1) Shake a quantity of the powdered tablets containing
(e) After removal of the plate, dry in air, heat at 110° for 2.5 mg of betamethasone for 20 minutes with 25 mL of
10 minutes, spray the hot plate with ethanolic sulfuric acid water, dilute to 50 mL with methanol, mix and filter through
(20%) and again heat at 110° for 10 minutes. a glass fibre filter (Whatman GF/C is suitable).
MOBILE PHASE (2) Dilute 5 mL of a 0.014% w/v solution of betamethasone
sodium phosphate BPCRS in water (solution A) to 10 mL with
20 volumes of acetic anhydride, 20 volumes of water and
methanol.
60 volumes of butan-1-ol prepared immediately before use.
SYSTEM SUITABILITY
The chromatographic procedure described under Uniformity
of content may be used.
solution (4) shows two principal spots with almost
identical Rf values. DETERMINATION OF CONTENT
Calculate the content of C,,H29FOs, in the tablets,

determining the exact strength of C,H»)FOs in solution (2)
as follows. Dilute 5 mL of solution A to 25 mL with water
and measure the absorbance, Appendix II B, of the resulting
B. Mix a quantity solution at the maximum at 241 nm, taking 391 as the value
equivalent of 0.4 of A(1%, 1 cm) for betamethasone.
acid and allow to stan inutes. A pale yellow colour is
produced (distinction fre Fusolone sodium phosphate STORAGE
tablets). Betamethasone Sodium Phosphate Tablets should be
protected from light.
TESTS
Disintegration LABELLING
Maximum time, 5 minutes,Appendix é The quantity of active ingredient is stated in terms of the
equivalent amount of betamethasone.
Uniformity of content ‘
Tablets containing less than the equivalent:
less than 2% w/w of betamethasone complywi
requirements stated under Tablets using the followi
method of analysis. Carry out the procedure protect Betamethasone Valerate Scalp
light. Carry out the method for liquid chromatography,
Appendix III D, using the following solutions. Application
(1) Dissolve one tablet as completely as possible in 5 mL
water, add 5 mL of methanol and filter. Add sufficient
methanol (50%) to produce a solution expected to contain
0.00325% w/v of betamethasone sodium phosphate.
(2) 0.0065% w/v of betamethasone sodium phosphate BPCRS in
water. Dilute 1 volume of this solution to 2 volumes with
methanol.
CHROMATOGRAPHIC CONDITIONS The application co up ith the requirements stated under
(a) Use a stainless steel column (20 cm x 4.6 mm) packed Liquids for Cutaneous: ion and with the following
with octadecylsilyl silica gel for chromatography (10 um) requirements. .
(Spherisorb ODS 1 is suitable). Content of betameth
(b) Use isocratic elution and the mobile phase described 90.0 to 115.0% of the stat
below. IDENTIFICATION
.

at
atte
ee

7

feet
te

es
we
0.04% w/v of betamethasone.

et
MOBILE PHASE B. In the Assay, the chromatogram obtained with.

et
ele
45 volumes of methanol and 55 volumes of citro-phosphate solution (2) shows a peak with the same retention time as the
ey
ge
te
buffer pH 5.0. peak due to betamethasone valerate in the chromatogram

te
v5
DETERMINATION OF CONTENT obtained with solution (1).

FSHS
eee
Calculate the content of Cz.H.9FOs in each tablet, ASSAY

o
determining the exact strength of the solution of Carry out the Assay described under Betamethasone Valerate
a
betamethasone sodium phosphate BPCRS as described in the Lotion, preparing solutions (2) and (3) in the following
ee
Assay. manner. For solution (2) dilute a quantity of the application

eS
containing the equivalent of 3 mg of betamethasone to

Fee
ASSAY
25 mL with ethanol (65%). For solution (3) add 5 mL of a
Weigh and powder 20 tablets. Carry out the procedure
a
0.11% w/v solution of the internal standard to a quantity of

get
protected from light. Carry out the method for liquid

the application containing the equivalent of 3 mg of
chromatography, Appendix III D, using the following
Lo)
betamethasone and dilute to 25 mL with ethanol (65%).

og
solutions.
VASA
III-196 Betamethasone Preparations 2016
STORAGE (1) Shake a quantity of the cream containing the equivalent

Betamethasone Valerate Scalp Application should be of 2 mg of betamethasone with 100 mL of hot hexane for
protected from light. 2 minutes, cool, extract the mixture with 20 mL of ethanol
(96%) and filter the lower, ethanolic layer through absorbent
LABELLING
cotton previously washed with ethanol (75%). Repeat the
The label indicates the pharmaceutical form as ‘cutaneous absorbent cotton. Combine the filtrates, add 5 mL ofa
solution’. 0.072% w/v solution of beclometasone dipropionate BPCRS
(internal standard) and dilute to 50 mL with ethanol (75%).
(2) Shake a quantity of the cream containing the equivalent
of 2 mg of betamethasone with 100 mL of hot hexane for
2 minutes, cool, extract the mixture with 20 mL of ethanol
(96%) and filter the lower, ethanolic layer through absorbent
cotton previously washed with ethanol (75%). Repeat the
DEFINITION absorbent cotton and dilute the combined filtrates to 50 mL
Betamethasone Valerate mm contains Betamethasone with ethanol (75%).
Valerate in a suitable ba (3) Mix 10 mL of a solution containing 0.024% w/v of
The cream complies with the v nts stated under Topical betamethasone valerate BPCRS and 0.0012% w/v of
Sem1-solid Preparations and witit. ollowing requirements. betamethasone 21-valerate BPCRS in ethanol (80%) with 5 mL
Content of betamethasone, ©;3Hhao. of a 0.072% w/v solution of beclometasone dipropionate BPCRS
90.0 to 110.0% of the stated amount. (internal standard) in ethanol (80%) and dilute to 50 mL
with the same solvent.
IDENTIFICATION
A. Carry out the method for thin-layer chromat
Appendix IIT A, using the following solutions. (a) Use a stainless steel column (10 cm x 5 mm) packed
(1) Disperse a quantity of the cream containing the.é
equivalent of 0.5 mg of betamethasone in 20 mL of m
(80%) by heating on a water bath until the methanol be (b) Use isocratic elution and the mobile phase described
to boil. Shake vigorously, cool in ice for 30 minutes and
centrifuge. Mix 10 mL of the supernatant liquid with 3 mL Sa flow rate of 2 mL per minute.
of water and 5 mL of chloroform, shake vigorously, allow the a.column temperature of 60°.
layers to separate and evaporate the chloroform layer to letection wavelength of 238 nm.
dryness in a current of nitrogen with gentle heating. Dissolve
the residue in 1 mL of chloroform.
(2) 0.03% w/v of betamethasone valerate BPCRS in chloroform.
SYSTEM SUITABIEIT
(a) Use as the coating silica gel G. The test is not validé
with solution (1), the *
to betamethasone valer
(e) After removal of the plate, dry in air until the solvent has phase.
evaporated, heat at 105° for 5 minutes and spray while hot DETERMINATION OF CONTENT
with alkaline tetrazolium blue solution.
Calculate the content of C,,H» 9FOs in
MOBILE PHASE declared content of C22.H» 9FOs, in betame X
5 volumes of absolute ethanol, 10 volumes of acetone and valerate BPCRS.
100 volumes of chloroform. STORAGE
CONFIRMATION Betamethasone Valerate Cream should be protected from
The principal spot in the chromatogram obtained with light.
solution (1) corresponds in position and colour to that in the LABELLING
chromatogram obtained with solution (2). The spot in the The quantity of active ingredient is stated in terms of the
chromatogram obtained with solution (3) appears as a single equivalent amount of betamethasone.
compact spot.
peak due to betamethasone valerate in the chromatogram
og ASSAY
se Carry out the method for liguid chromatography,
or Appendix ITI D, using the following solutions.
2016 Betamethasone Preparations ITII-197
of ethanol (65%) and 50 mL of hexane, shake for 2 minutes

Betamethasone Valerate Lotion and filter the lower, ethanolic layer through absorbent cotton
"Nw Ay
Betamethasone Valerate Cutaneous Solution previously washed with ethanol (65%). Repeat the extraction
of the hexane mixture with two 5-mL quantities of ethanol
Action and use
(65%), filtering the ethanol extracts through the absorbent
Glucocorticoid.
cotton, add 5 mL of ethanol (65%) to the combined filtrates
DEFINITION
and mix.
Betamethasone Valerate Lotion is a cutaneous solution. (3) Mix 20 mL of a solution containing 0.018% w/v of
It contains Betamethasone Valerate in a suitable vehicle. betamethasone valerate BPCRS and 0.0010% w/v of
betamethasone 21-valerate BPCRS in ethanol (65%) with 5 mL
The lotion complies with the requirements stated under Liquids for
of a 0.11% w/v solution of beclometasone dipropionate BPCRS
Cutaneous Application and with the following requirements.
(internal standard) in ethanol (65%).
ae are) tof
:
eo ten
eS ge
a¢

with octadecylsilyl sihca gel for chromatography (5 ym)
(Spherisorb ODS1is suitable).
llowing solutions.
(1) Disperse aqu: ie preparation being examined below.
containing the equiva % of betamethasone with
g on a water bath until the
1g ‘ously, cool 1in ice and (d) Use a column temperature of 60°.
allow the layers to separate and use *t
MOBILE PHASE
(2) 0.05% w/v of betamethasone valerat. n chloroform.
42 volumes of absolute ethanol and 58 volumes of water.
(3) A mixture of equal volumes of solution
SYSTEM SUITABILITY
(a) Use as the coating silica gel G. with solution (1), the resolution factor between the peaks due
(b) Use the mobile phase as described below. to betamethasone valerate (retention time about 5 minutes)
(c) Apply 10 wL of each solution. d betamethasone 21-valerate (retention time about
(d) Develop the plate to 15 cm. fiutes) is greater than 1.0. If necessary, adjust the mobile
(e) After removal of the plate, dry in air until the solvent has
evaporated, heat at 105° for 5 minutes and spray while hot TERMINATION OF CONTENT
with alkaline tetrazolium blue solution. . content of C,H» .FOs in the lotion using the
MOBILE PHASE at ot Co2H2oFOs;1in betamethasone
5 volumes of absolute ethanol, 10 volumes of acetone and
CONFIRMATION
Betamethasone Val tion should be protected from
light.
solution (1) corresponds in position and colour to that in the LABELLING
chromatogram obtained with solution (2). The spot in the The quantity of active in it is stated in terms of the
chromatogram obtained with solution (3) appears as a single equivalent amount of betam thason
compact spot.
peak due to betamethasone valerate in the chromatogram Betamethasone Valerate
Action and use
ASSAY Glucocorticoid.
Carry out the method for guid chromatography,
Appendix IIT D, using the following solutions. DEFINITION
Betamethasone Valerate Ointment contains Betamethasone
(1) Disperse a quantity of the lotion containing the
equivalent of 3 mg of betamethasone in a mixture of 10 mL Valerate in a suitable basis.
of ethanol (65%) and 50 mL of hexane, shake for 2 minutes The ointment complies with the requirements stated under Topical
and filter the lower, ethanolic layer through absorbent cotton Semi-solid Preparations and with the following requirements.
previously washed with ethanol (65%). Repeat the extraction Content of betamethasone, C,H,.>FO;
of the hexane mixture with two 5-mL quantities of ethanol 90.0 to 110.0% of the stated amount.
(65%), filtering the ethanol extracts through the absorbent
IDENTIFICATION
cotton, add 5 mL of a 0.11% w/v solution of beclometasone
A. Complies with test A for Identification described under
dipropionate BPCRS (internal standard)to the combined
Betamethasone Valerate Lotion preparing solution (1) in the
filtrates and mix.
following manner. Disperse a quantity of the ointment
Va,
Cw 2 Or
(2) Disperse a quantity of the lotion containing the

containing the equivalent of 1 mg of betamethasone in
equivalent of 3 mg of betamethasone in a mixture of 10 mL
10 mL of methanol by heating on a water bath until the
III-198 Betaxolol Preparations 2016
methanol begins to boil, shake vigorously, cool in ice for IDENTIFICATION

30 minutes and filter. Evaporate the filtrate to dryness in a A. Carry out the method for thin-layer chromatography,
current of nitrogen with gentle heating and dissolve the Appendix III A, using the following solutions.
residue in 0.5 mL of chloroform. Solution (2) contains (1) Dilute the eye drops with water to produce a solution
0.24% w/v of betamethasone valerate BPCRS in chloroform. containing the equivalent of 0.1% w/v of betaxolol. Shake
B. In the Assay, the chromatogram obtained with solution 1 mL of the solution with 4 mL of water, 0.1 mL of
(2) shows a peak with the same retention time as the peak 13.5M ammonia and 2 mL of chloroform, centrifuge and use
due to betamethasone valerate in the chromatogram obtained the chloroform layer.
with solution (1). (2) Prepare solution (2) in the same manner as solution (1)
ASSAY but using a 0.1% w/v solution of betaxolol
Carry out the method for liguid chromatography, hydrochloride BPCRS in place of the eye drops.
using the following solutions. For solution (3) A mixture of equal volumes of solution (1) and
(1) mix 1Q glution containing 0.024% w/v of solution (2).
betamethasone 3PCRS and 0.0012% w/v of CHROMATOGRAPHIC CONDITIONS
betamethasone 24> BPCRS in ethanol (65%) with 5 mL
(a) Use as the coating silica gel (Merck silica gel 60 plates are
of a 0.072% wiv & g f beclometasone dipropionate BPCRS
suitable).
(internal standard) in eth 65%) and dilute to 50 mL
with ethanol (65%). (2) disperse a quantity of (b) Use the mobile phase as described below.
the ointment containing thi quivalent of 2 mg of (c) Apply 5 uwL of each solution.
betamethasonein 100 mL of é, cool, extract with (d) Develop the plate to 15 cm.
20 mL of ethanol (65%) and fil er, ethanolic layer (e) After removal of the plate, dry in air, spray with a
through absorbent cotton previo with ethanol solution prepared by dissolving 5 g of zodine and 10 g of
(65%); repeat the extraction of the’he ture with two potassium todide in sufficient water to produce 100 mL and
10-mL quantities of ethanol (65%), filte mixing 20 mL of the resulting solution with 30 mL of water
turn through the absorbent cotton anddilut and 50 mL of 2M acetic acid. Examine the plate immediately;
spots due to betaxolol appear brown.
the same manner as solution (2) but add 5m
MOBILE PHASE
0.072% w/v solution of the internal standardin eilianol :
(65%) before diluting to 50 mL. ‘ 30 volumes of a solution prepared by diluting 1 volume of
The chromatographic procedure may be carried out using _13.5M ammonia to 50 volumes with propan-2-ol immediately
(a) a stainless steel column (10 cm x 5 mm) packed with fore use and 70 volumes of chloroform.
octadecylsilyl silica gel for chromatography (5 um) (Spherisorb ITABILITY
ODS 1 is suitable) and maintained at 60°, (b) as the mobile ot valid unless the chromatogram obtained with
phase with a flow rate of 2 mL per minute a mixture of
absolute ethanol and water adjusted so that the resolution factor
between the peaks due to betamethasone valerate (retention
time about 5 minutes) and betamethasone 21 valerate
(retention time about 7 minutes) is more than 1.0 (a mixture
of 42 volumes of absolute ethanol and 58 volumes of water is
usually suitable) and (c) a detection wavelength of 238 nm.
Calculate the content of C2.H. FO; in the ointment using (1) showsa principal p
yea the same retention time as
the principal peakin the
‘ ram obtained with
fe
the declared content of C,H» .FOs in betamethasone

solution (2).
.
valerate BPCRS.
eae
.
ae,
STORAGE TESTS
.
Betamethasone Valerate Ointment should be protected from Acidity or alkalinity

light. pH, 6.0 to 7.8, Appendix V L.
a
ca
LABELLING Related substances

.

Appendix III D, using the following solutions 1
:

wee
phase.
toe
(1) Dilute a suitable volume of the eye drops to prod cea

. Nt,
solution containing the equivalent of 0.02% w/v of betaxolol.

ele le
vo

Betaxolol Eye Drops, Solution
Seay he
yey
’
Action and use (a) Use a stainless steel column (25 cm x 4.6 mm) packed
Beta-adrenoceptor antagonist. with octadecylsilyl silica gel for chromatography (10 um)
(Spherisorb ODS-2 is suitable).
DEFINITION
Betaxolol Eye Drops, Solution area sterile solution of below.
Betaxolol Hydrochloride in Purified Water.
Content of betaxolol, C,;;H,,.NO;
90.0 to 110.0% of the stated amount. (f) Inject 20 wL of each solution.
2016 Betaxolol Preparations III-199
MOBILE PHASE
Dissolve 3 g of sodium dodecyl sulfate in 450 mL of the
Betaxolol Eye Drops, Suspension
following solution. 45 volumes of a buffer solution prepared Action and use
as described below and 55 volumes of acetomtrile. To prepare Beta-adrenoceptor antagonist.
the buffer solution add 5 mL of orthophosphoric acid to
990 mL of water, adjust the pH to 3.0 with 2m ammonia and DEFINITION
add sufficient water to produce 1000 mL. Betaxolol Eye Drops, Suspension are a sterile suspension of
SYSTEM SUITABILITY Betaxolol Hydrochloride in Purified Water containing
suitable binding and suspending agents.
with solution (2), the column efficiency, determined on the The eye drops comply with the requirements stated under Eye
peak due to betaxolol is at least 8000 theoretical plates per Preparations and with the following requirements.
e symmetry factor of the principal peak is not The eye drops should be shaken vigorously before carrying out the
following tests.
Content of betaxolol, C;3;H,.NO;
obtained with solution (1): 90.0 to 110.0% of the stated amount.
peak is not greater than the area of IDENTIFICATION
x omatogram obtained with Comply with the tests described under Betaxolol Eye Drops,
Solution.
the area of not more tha dary peak is greater than TESTS
0.3 times the area of the ak in the chromatogram Particle size
obtained with solution (2) a Examine using an automated light obscuration instrument
ASSAY such as that described in Appendix XIII A. Not less than
99.5% of the particles are less than 25 um, not less than
Appendix III D, using the following sof 7 99.95% are less than 50 um and none exceeds 75 Lum.
phase. Acidity or alkalinity
(1) Dilute the eye drops to produce a solution: pH, 6.5 to 7.5, Appendix V L.
equivalent of 0.01% w/v of betaxolol. Related substances
(2) 0.012% w/v of betaxolol hydrochlonde BPCRS. Comply with the test described under Betaxolol Eye Drops,
(3) 0.012% w/v of betaxolol hydrochlonde BPCRS and Solution, but preparing solution (1)in the following manner.
0.006% w/v of pilocarpine nitrate BPCRS. a suitable volume of the eye drops with sufficient of
ile phase to produce a solution containing the
nt of 0.02% w/v of betaxolol, centrifuge and use the
(Spherisorb ODS-2 is suitable).
below.
(e) Use a detection wavelength of 220 nm. suspension containin
betaxolol, mix with
MOBILE PHASE
45 volumes of acetonitrile and 55 volumes of water containing

0.71% w/v of anhydrous disodium hydrogen orthophosphate and and dilute a
0.91% w/v of dimethylamine hydrochloride, adjusted to pH 3.0 | sufficient of
with orthophosphonic acid. the mobile phase to produce a solution’ o contain
SYSTEM SUITABILITY
the equivalent of 0.01% w/v of betaxolol. Soluggon
contains 0.012% w/v of betaxolol hydrochloride*BPGRS in the
mobile phase. |
to betaxolol and pilocarpine is at least 1.5. The chromatographic conditions described under Assay may
be used.
Determine the weight per mL of the eye drops,
Calculate the content of C;gH..NO3 in the eye drops using Appendix V G, and calculate the content of C;3H2903,
the declared content of C);gH..NO3 in betaxolol weight in volume, in solutions (1) and (2) using the declared
hydrochloride BPCRS. content of C,;gH» O03 in betaxolol hydrochloride BPCRS.
STORAGE Calculate the content of bound betaxolol from the difference
Betaxolol Eye Drops, Solution should be protected from between the contents of betaxolol found in solutions (1) and
light. (2).
LABELLING ASSAY
The quantity of active ingredient is stated in terms of the Carry out the method for liquid chromatography,
equivalent amount of betaxolol. Appendix III D, using the following solutions. For solution
(1) dilute a weighed quantity of the eye drops with sufficient
IMI-200 Bezafibrate Preparations
AN eH
2016
of the mobile phase to produce a suspension containing the (b) Use as the medium, at a temperature of 37°, 900 mL of
equivalent of 0.01% w/v of betaxolol, mix thoroughly, a pH 6.5 buffer solution prepared by dissolving 0.608 g of
centrifuge and use the supernatant liquid. Solution (2) sodium hydroxide and 6.805 g of potassium dihydrogen
contains 0.012% w/v of betaxolol hydrochloride BPCRS in the orthophosphate in sufficient water to produce 1000 mL and
mobile phase. Solution (3) contains 0.012% w/w of betaxolol adjusting the pH to 6.5 + 0.05 using sodium hydroxide
hydrochloride BPCRS and 0.006% w/v of pilocarpine solution or orthophosphoric acid.
nitrate BPCRS in the mobile phase. PROCEDURE
The chromatographic procedure may be carried out using (1) After 45 minutes withdraw a 10 mL sample of the
(a) a stainless steel column (25 cm x 4.6 mm) packed with medium, filter and dilute 1 volume of the filtrate to
octadecylsilyl silica gel for chromatography (10 um) (Spherisorb 20 volumes with the dissolution medium and measure the
ODS-2 is suitable), (b) as the mobile phase with a flow rate absorbance at the maximum at 229 nm, Appendix II B, using
of 1 mL per minute a mixture of 45 volumes of acetonitrile dissolution medium in the reference cell.
of water containing 0.71% w/v of anhydrous
n<orthophosphate and 0.91% w/v of
bezafibrate BPCRS in the dissolution medium using
dissolution medium in the reference cell.
orthophosphoric
220 nm. : DETERMINATION OF CONTENT
Inject 10 uL of each: Calculate the total content of bezafibrate, C;o>H
2 9CINOs,, in
in the chromatogram obj the medium from the absorbances obtained and using the
factor between the peaks& declared content of CyoH29CINO, in bezafibrate BPCRS.
at least 1.5. Related substances
Determine the weight per mL Carry out the method for liquid chromatography,
Appendix V G, and calculate the’ce Appendix III D, using the following solutions.
weight in volume, using the declared c¢ (1) Mix with the aid of ultrasound a quantity of the
in betaxolol hydrochloride BPCRS. | powdered tablets containing 100 mg of Bezafibrate with
STORAGE 15 mL of methanol for 2 minutes, shake for a further
Betaxolol Eye Drops, Suspension should be proteé 10 mimutes, cool, add sufficient of the mobile phase to
light and stored in accordance with the manufacturer’: produce 100 mL, mix and filter, discarding the first 20 mL
instructions. : of filtrate.
LABELLING
mobile phase.
equivalent amount of betaxolol. 1 volume of solution (2) to 10 volumes with the
se.
Bezafibrate Tablets contaifing

0.0002% w
Action and use
Fibrate; lipid-regulating drug.
(a) Usea stainless stéelsco an (15 cm x 3.9 mm) packed
DEFINITION with octadecylsilyl silica | chromatography (4 um)
Bezafibrate Tablets contain Bezafibrate. (Novapak C18 is suitab
The tablets comply with the requirements stated under Tablets and (b) Use isocratic elution an mobile phase described
with the following requirements. below.
Content of bezafibrate, C;)>H 2 >CINO, (c) Use a flow rate of 1 mL per miriute.
95.0 to 105.0% of the stated amount. (d) Use an ambient column temperatur
IDENTIFICATION (e) Use a detection wavelength of 239 n
Shake a quantity of the powdered tablets containing 0.2 g of (f) Inject 20 wL of each solution.
Bezafibrate with two 10-mL quantities of acetone for (g) The retention time of bezafibrate is about in
10 minutes, combine and filter the extracts (a Whatman Allow the chromatography to proceed for four times the
GF/C is suitable) and evaporate the filtrate to dryness. retention time of the principal peak.
The infrared absorption spectrum of the residue,
MOBILE PHASE
bezafibrate (RS 419). 3.9 volumes of 40% w/v of tetrabutylammonium hydroxide,
400 volumes of acetonitrile and 600 volumes of water and
TESTS adjusting the final pH to 4.0 with 10% v/v orthophosphoric
Dissolution acid,
SYSTEM SUITABILITY
Appendix XII Bl. The test is not valid unless, in the chromatogram obtained
TEST CONDITIONS
to bezafibrate and chlorobenzoyltyramine is at least 7.0.
(a) Use Apparatus 2, rotating the paddle at 50 revolutions If necessary, adjust the content of tetrabutylammonium
ee
per minute. hydroxide to obtain the required resolution.
2016 Bezafibrate Preparations IT-201
LIMITS 10 minutes, filter the combined extracts (Whatman GF/C is

In the chromatogram obtained with solution (1): suitable) and evaporate the filtrate to dryness. The infrared
the area of any secondary peak is not greater than the area of absorption spectrum of the residue, Appendix II A, is
the principal peak in the chromatogram obtained with concordant with the reference spectrum of Bezafibrate
solution (2) (0.5%); (RS 419).
the total area of any such peaks is not greater than 1.5 times TESTS
the area of the principal peak in the chromatogram obtained Related substances
with solution (2) (0.75%). Carry out the method for liquid chromatography,
Disregard any peak with an area less than that of the Appendix III D, using the following solutions.
principal peak in the chromatogram obtained with solution (1) Mix with the aid of ultrasound a quantity of the
(4) (0.05%). powdered tablets containing 100 mg of Bezafibrate with
15 mL of methanol for 2 minutes, shake for a further
10 minutes, cool, add sufficient mobile phase to produce
er 20 tablets. For solution (1) mix with the
100 mL, mix and filter, discarding the first 20 mL of filtrate.
quantity of the powdered tablets
containing f Bezafibrate with 70 mL of methanol for (2) Dilute 1 volume of solution (1) to 200 volumes with the
2 minutes, sha rther 10 minutes, cool, add mobile phase.
ce 100 mL, mix and filter (3) Dissolve sufficient quantities of bezafibrate BPCRS and
discarding the first 0 m f.filtrate; dilute 1 volume of the chlorobenzoyltyramine BPCRS in the minimum quantity of
filtrate to 100 volumes® nol. Solution (2) contains methanol and dilute with mobile phase to produce a solution
0.001% w/v of bezafibr n methanol. containing 0.0002% w/v of bezafibrate BPCRS and
Measure the absorbance at sat 229 nm,
0.0002% w/v of chlorobenzoyltyramine BPCRS.
Appendix II B. Calculate th 11929 CINO4 in the (4) Dilute 1 volume of solution (2) to 10 volumes with the
tablets from the absorbances obtair from the declared mobile phase.
content of C,;9Hz >CINO, in bezafibra: CHROMATOGRAPHIC CONDITIONS
IMPURITIES (a) Use a stainless steel column (15 cm x 3.9 mm) packed
The impurities limited by the requirements«& with octadecylsilyl sitca gel for chromatography (4 um)
monograph include, (Novapak C18 is suitable).
OH below.
LY
O
se a flow rate of 1 mL per minute.

N e ambient column temperature.
H
a detection wavelength of 230 nm.
Cl
4-chloro-N-[2-(4-hydroxyphenyl) ethy!|benzamide
(chlorobenzoyltyramine).
A mixture of 3.9°v@ium
Prolonged-release Bezafibrate Tablets tetrabutylammonium hy
Prolonged-release Bezafibrate Tablets from different manufacturers, 600 volumes of water,
whilst complying with the requirements of the monograph, are not 10% v/v orthophosphonic ae,
interchangeable unless otherwise justified and authorised. SYSTEM SUITABILITY
The test is not valid unless, in the chr
Action and use
with solution (3), the resolution facto
Fibrate; lipid-regulating drug.
DEFINITION If necessary adjust the content of tetrabu

Prolonged-release Bezafibrate Tablets contain Bezafibrate. hydroxide to obtain the required resolution«
They are formulated so that the medicament is released over LIMITS
a period of several hours. In the chromatogram obtained with solution (1):
PRODUCTION the area of any secondary peak is not greater than the area of
A suitable dissolution test is carried out to demonstrate the the principal peak in the chromatogram obtained with
appropriate release of bezafibrate. The dissolution profile solution (2) (0.5%);
reflects the in vivo performance which in turn is compatible the total area of any such peaks is not greater than 1.5 times
with the dosage schedule recommended by the manufacturer. the area of the principal peak in the chromatogram obtained
The tablets comply with the requirements stated under Tablets and with solution (2) (0.75%).
with the following requirements. Disregard any peak with an area less than that of the
Content of bezafibrate, C,;,H,)CINO, principal peak in the chromatogram obtained with solution
95.0 to 105.0% of the stated amount. (4) (0.01%).
IDENTIFICATION ASSAY
went, Shake a quantity of the powdered tablets containing 0.2 g of Weigh and powder 20 tablets. For solution (1) mix with the
Bezafibrate with two 10-mL quantities of acetone for aid of ultrasound a quantity of the powdered tablets
IlI-202 Bicalutamide Preparations 2016
containing 0.1 g of Bezafibrate with 70 mL of methanol for maximum at 272 nm, Appendix IIT B using the dissolution
2 minutes, shake for a further 10 minutes, cool, add medium in the reference cell.
sufficient methanol to produce 100 mL, mix and filter (2) Measure the absorbance of a 0.0056% w/v solution of
discarding the first 20 mL of filtrate. Dilute 1 volume to bicalutamide BPCRS using the dissolution medium in the
100 volumes with methanol. Solution (2) is a 0.001% w/v reference cell.
solution of bezafibrate BPCRS in methanol.
Measure the absorbance of the resulting solutions at the
Calculate the total content of bicalutamide, C;3H,4Fi1N,0.S
maximum at about 230 nm, Appendix IJ B. Calculate the
in the medium from the absorbances obtained and using the
content of Cyj>H»z oCINO, from the declared content of
declared content of C,;3H,4F,4N20,S in bicalutamide BPCRS.
Cy9H29CINO, in bezafibrate BPCRS.
LIMITS
The amount of bicalutamide released is not less than 75%
(Q) of the stated amount.
Related substances
Prepare a mixture of 0.5 volumes orthophosphoric acid,
500 volumes of acetonitrile R1 and 500 volumes of water
(solvent A).
(1) Dissolve a quantity of the powdered tablets containing
25 mg of Bicalutamide in solvent A with the aid of
4-chloro-N-[2-(4-hydroxyphenyl
ultrasound. Add sufficient solvent A to produce a solution
(chlorobenzoyltyramine).
containing 0.1% w/v of Bicalutamide and filter.
solvent A. Dilute 1 volume of this solution to 10 volumes.
(3) Dissolve 5 mg of bicalutamide for system suitability EPCRS
Bicalutamide Tablets (containing impurities B and C) in solvent A and dilute to
5.0 mL.
Action and use
0.001% w/v of bicalutamide impurity D BPCRS in
Antiandrogen; treatment of prostate cancer.
DEFINITION
Bicalutamide Tablets contain Bicalutamide.
Content of bicalutamide, C,3H,,F,N,0,S
IDENTIFICATION
A. To a quantity of the powdered tablets containing 0.1 g of
Bicalutamide add 10 mL of acetone, shake and centrifuge.
Filter the supernatant liquid (Whatman GF/C filter is (f) Inject 10 pL of each S
suitable) and evaporate to dryness under a stream of nitrogen
MOBILE PHASE
at 40° for 30 minutes. The infrared absorption spectrum of the
residue, Appendix IIA, is concordant with the reference Mobile phase A 1.9 volumes of ortho
spectrum of bicalutamide (RS 466). 100 volumes of acetonitrile R1 and 19!
that of principal peak in the chromatogram obtained with
solution (2).
Time Mobile phase A Mobile phase B
TESTS (Minutes) (% viv) (% viv)
Dissolution 0-3 92 8 isocratic
Comply with the requirements in the dissolution test for tablets 3-23 92-67 833 linear gradient
and capsules, Appendix XII B1.
TEST CONDITIONS
55-56 50-92 508 ~ finear gradient
per minute. | |
(b) Use 900 mL of a 1.0% w/v solution of sodium dodecyl
sulfate, at a temperature of 37°, as the medium.
PROCEDURE Use the chromatogram supplied with bicalutamide for system
suitability EPCRS and the chromatogram obtained with
solution (3) to identify the peaks due to impurities B and C.
medium and measure the absorbance of the filtered sample,
suitably diluted with water if necessary, to produce a solution Use the chromatogram obtained with solution (4) to identify
expected to contain 0.0056% w/v of Bicalutamide, at the the peak due to impurity D.
2016 Bisacodyl Preparations IJI-203
When the chromatograms are recorded under the prescribed DETERMINATION OF CONTENT
conditions, the relative retentions with reference to Calculate the content of CjgH ,4F,N20,S in the tablets using
wae
bicalutamide (retention time = about 38 minutes) are: the declared content of C,;gH,4F4,N.20,S in
impurity B = about 0.98; impurity C = about 1.1; bicalutamide BPCRS.
impurity D = about 0.68.
IMPURITIES |
SYSTEM SUITABILITY The impurities limited by the requirements of this
The test is not valid unless, in the chromatogram obtained monograph include those listed under Bicalutamide.
with solution (3), the peak to valley ratio is at least 2.5,
where H, is the height above the baseline of the peak due to
impurity B and H, is the height above the baseline of the
lowest point of the curve separating this peak from the peak Bisacodyl Suppositories
dueto ‘bicalutamide.
LIM : Action and use
Stimulant laxative.
In the chre gram obtained with solution (1):
the area of any .corresponding to impurity D is not DEFINITION
greater than twice the area of the principal peak in the Bisacodyl Suppositories contain Bisacodyl in a suitable
chromatogram ob dvaith solution (2) (0.2%); suppository basis.
the area of any peak pending to impurity C is not The suppositories comply with the requirements stated under Rectal
greater than 1.5 times th fthe principal peak in the Preparations and with the following requirements.
chromatogram obtained with solkition (2) (0.15%);
Content of bisacodyl, C,.H,;».NO,
with solution (2) (0.2%); IDENTIFICATION

the sum of the areas of any secondary ped A. Carry out the method described under Related substances
7 times the area of the principal peak int applying to the plate 2 wL of each solution and using as
obtained with solution (2) (0.7%). é : solution (2) a 1% w/v solution of bisacodyl BPCRS in acetone.
Disregard any peak with an area less than the aréa
principal peak in the chromatogram obtained wi
solution (2) (0.1%).
B. Dissolve a quantity of the suppositories containing 0.15 g
ASSAY sisacodyl as completely as possible in 150 mL of petroleum
Weigh and powder 20 tablets. Carry out the method for t (boiling range, 40° to 60°), filter, wash the residue with
liquid chromatography, Appendix III D, using the following spirit (boiling range, 40° to 60°) until free from fatty
solutions. and dry at about 100°. Wash with a very small
Prepare a mixture of 40 volumes of water and 60 volumes of .<of warm chloroform and dissolve the residue in
acetonitrile (solvent B).
(1) To a quantity of the powdered tablets containing 0.25 g
of Bicalutamide, add 40 mL of water and mix with the aid of
ultrasound, add sufficient acetonitrile to produce 100 mL and
mix. Centrifuge and dilute 1 volume of the supernatant
liquid to 25 volumes with solvent B. D. Boil 2 mL of the
(2) 0.01% w/v of bicalutamide BPCRS in solvent B. nitric acid; a yellow colo
with octadecylsilyl silica gel for chromatography (4 um) Carry out the method for thin-l
(Novapak C18 is suitable). Appendix HI A, using siica gel GFo5
substance and a mixture of equal vol
below.
(d) Use a column temperature of 30°. Bisacodyl with 20 mL of petroleum spint (boiling range, 40° to
(e) Use a detection wavelength of 270 nm. 60°), filter, wash the residue with petroleum spirit (botling
(f) Inject 10 wL of each solution. range, 40° to 60°) until free from fat and dissolve in 2 mL of
acetone. For solution (2) dilute 3.volumes of solution (1) to
MOBILE PHASE
100 volumes with acetone. After removal of the plate, allow it
1 volume of trifluoroacetic acid, 350 volumes of acetonitrile and to dry in air and examine under ultraviolet light (254 nm).
650 volumes of water. Any secondary spot in the chromatogram obtained with
SYSTEM SUITABILITY solution (1) is not more intense than the spot in the
The test is not valid unless, in the chromatogram obtained chromatogram obtained with solution (2).
with solution (2), the column efficiency determined on the ASSAY
peak due to bicalutamide is at least 2000 theoretical plates. To a quantity of the suppositories containing 0.1 g of
Bisacodyl add 80 mL of anhydrous acetic acid previously
neutralised with 0.02m perchloric acid VS to 1-naphthol-benzein
solution, warm gently until solution is complete and
II-204 Bisacodyl Preparations 2016
immediately carry out Method I for non-aqueous titration, LIMITS

Appendix VIII A, using 0.02m perchloric acid VS and The amount of bisacodyl released is not more than 5% of the
determining the end point potentiometrically. Each mL of
hee eet
stated amount.
“Awa
ae.
0.02m perchloric acid VS is equivalent to 7.228 mg of Final stage Dissolve 1.56 g of sodium hydroxide and 7.80 g of
C32H);9.NO,. Calculate the average content of bisacodyl, sodium dihydrogen orthophosphate in sufficient water to produce
C,2H;9NOz, in the suppositories. 1000 mL. Add 5.00 g of sodium dodecyl sulfate, heat to
dissolve and adjust the pH to 7.4, if necessary (phosphate
buffer pH 7.4).
Gastro-resistant Bisacody! Tablets per minute.
Bisacodyl Tablets (b) Replace the 0.1m hydrochloric acid in the vessel with
900 mL of phosphate buffer pH 7.4, previously held and
Action a: maintained at 36.5° to 37.5°.
Strmulant PROCEDURE
DEFINITION * (1) After 45 minutes, withdraw a 10 mL sample of the

Gastro-resistant Bisacod medium and filter through a 5-um filter.
ablets contain Bisacodyl. They
are covered with a gastr istant coating. (2) 0.00056% w/v of bisacodyl BPCRS in phosphate buffer
The tablets comply with theve s stated under Tablets and
pH 7.4.
with the following requirements CHROMATOGRAPHIC CONDITIONS
Content of bisacodyl, C,H; es The chromatographic conditions described under Related
95.0 to 105.0% of the stated am substances may be used.
IDENTIFICATION . SYSTEM SUITABILITY
A. In the Assay, the chromatogram obtainéd The test is not valid unless the chromatogram obtained with
(1) is similar to that of the principal peak in 1 solution (3) closely resembles the reference chromatogram
chromatogram obtained with solution (2). supplied with bisacodyl for system suitability EPCRS.
B. Extract a quantity of the powdered tablets containy DETERMINATION OF CONTENT
50 mg of Bisacodyl with 20 mL of dichloromethane, filters Calculate the total content of C,,H,),NOy, in the medium
evaporate the filtrate to dryness and dissolve the residue i sing the declared content of Cz2H,9NO, in
10 mL of a 0.5% v/v solution of sulfuric acid. To 2 mLo BPCRS.
the solution obtained add sulfuric acid. A reddish violet colour
is produced on addition of the concentrated acid.
t of bisacodyl released is not less than 75% (Q)
C. Boil 2 mL of the solution obtained in test B withalittle
nitric acid; a yellow colour is produced. Cool and add
5M sodium hydroxide; the colour becomes yellowish brown.
TESTS
Dissolution
Appendix XII Bl.
TEST CONDITIONS
yee ny
First stage (a) Use Apparatus 2, rotating the paddle at (1) Shake a quantity of the powder
100 revolutions per minute. 25 mg of Bisacodyl with 40 mf solvent A, dilute to
(b) Use 500 mL of 0.1m hydrochloric acid, at a temperature of 50 mL with solvent A and filter. «
solvent A and further dilute 1 volume o
PROCEDURE
solution to 10 volumes with solvent A.
(3) Dissolve the contents of a vial of bisacodyl for sy
suitability EPCRS in 1 mL of acetonitrile and mix “Wi
(1) After 2 hours, withdraw a 10 mL sample of the medium of solvent A. :
and filter through a 5-um filter.
(4) Dissolve 5 mg of bisacodyl for peak identification EPCRS in
(2) 0.001% w/v of bisacodyl BPCRS in 0.1m hydrochloric acid. 2.5 mL of acetonitrile and dilute to 5 mL with solvent A.
The chromatographic conditions described under Related (a) Use a stainless steel column (25 cm x 4.6 mm) packed
substances may be used. with base-deactivated octadecylsilyl silica gel for chromatography
SYSTEM SUITABILITY (5 um) (Waters Symmetry C18 is suitable).
The test 1s not valid unless the chromatogram obtained with (b) Use isocratic elution using the mobile phase described
solution (3) closely resembles the reference chromatogram below.
supplied with bisacodyl for system suitability EPCRS. (c) Use a flow rate of 1.5 mL per minute.
DETERMINATION OF CONTENT (d) Use ambient column temperature.
Calculate the total content of C,.H ,)>NO, in the medium (e) Use a detection wavelength of 265 nm.
ney
using the declared content of C,H, >9NOz, in
bisacodyl BPCRS.
2016 Bisoprolol Preparations III-205
(f) Inject 50 wL of each solution. Allow the chromatography

to proceed for 3.5 times the retention time of the principal
Bisoprolol Tablets
peak. Action and use
MOBILE PHASE Beta-adrenoceptor antagonist.
A mixture of 45 volumes of acetonitrile and 55 volumes of
DEFINITION
0.025mM ammonium formate previously adjusted to pH 5.0 with
anhydrous formic acid. Bisoprolol Tablets contain Bisoprolol Fumarate.
SYSTEM SUITABILITY
solution (3) closely resembles the reference chromatogram Content of bisoprolol fumarate, (C,3H3,;NO,)2,C,H,O,
with bisacodyl for system suitability EPCRS. 95.0 to 105.0% of the stated amount.
IDENTIFICATION |
10 mg of Bisoprolol] Fumarate in methanol, dilute to 10 mL
with the same solvent, mix and filter (a 0.45-um nylon
syringe filter is suitable).
(2) 0.1% w/v of bisoprolol fumarate BPCRS in methanol.
the area of any peak corres}
greater than the area of thes (a) Use as the coating silica gel F254.
|

greater than twice the area of the principal peak in;
MOBILE PHASE
the area of any peak corresponding to impurity Fis not 20 volumes of methanol and 80 volumes of ethyl acetate.
greater than 3 times the area of the principal peakinthe” the bottom of the chromatography tank, place a beaker
chromatogram obtained with solution (2) (0.3%); taining 15 mL of concentrated ammonia.
the area of any other impurity is not greater than the area o
solution (2) (0.1%); -orresponds 1 in position and colour to thatin the
the sum of the impurities is not more than 1.0%. obtained with solution (2).
solution (2) (0.05%). jak in the chromatogram obtained with
solution (2).
ASSAY
Weigh and powder 20 tablets. Carry out the method for TESTS
liquid chromatography, Appendix III D, using the following Dissolution
solutions. Comply with the requirements 1 dissolution test for tablets
and capsules, Appendix XII Bl.:
10 mg of Bisacodyl with 40 mL of solvent A, dilute to TEST CONDITIONS
50 mL and filter. Dilute further 1 volume to 4 volumes with (a) Use Apparatus 2, rotating the pad revolutions
solvent A. per minute.
(2) 0.005% w/v of bisacodyl BPCRS in solvent A. (b) Use 900 mL of water, at a temperature*
CHROMATOGRAPHIC PROCEDURE medium.
The chromatographic procedure described under the test for PROCEDURE
Related substances may be used. Prepare a solution containing 2.5 volumes of orthophosphoric
Aw A
eh tee
SYSTEM SUITABILITY acid, 5 volumes of triethylamine, 35 volumes of water and
160 volumes of methanol (solvent A).
solution (3) closely resembles the reference chromatogram Carry out the method for liguid chromatography,
supplied with bisacodyl for system suitability EPCRS. Appendix III D, using the following solutions.
(1) After 45 minutes withdraw a sample of the medium, filter
and dilute with an equal volume of solvent A.
Calculate the total content of bisacodyl, C22H,>NOux, in the
tablets using the chromatogram obtained and the declared (2) Dissolve a quantity of bisoprolol fumarate BPCRS in water
content of C..H;9NO, in bisacodyl BPCRS. to obtain a solution with a concentration of about twice the
concentration of bisoprolol fumarate in solution (1). Dilute
1 volume of this solution to 2 volumes with solvent A.
poo
aS
ve ence
III-206 Bisoprolol Preparations 2016
CHROMATOGRAPHIC CONDITIONS Time Mobile phase A% Mobile phase B% Comment
(a) Use a stainless steel column (3.3 cm x 4.6 mm) packed (Minutes)
with octasilyl silica gel for chromatography (3 um) (Pecosphere 0-4 95 5 isocratic
3CR C8 is suitable). 4-8 95-»80 520 linear gradient
(b) Use isocratic elution and the mobile phase described 8-15 80 20 ‘socratic
below. , .
. 15-34 80-20 20-80 linear gradient
. 34-36 20 80 isocratic
(d) Use an ambient column temperature. 5
. 36-37 20-95 8055 linear gradient
(e) Use a detection wavelength of 227 nm. g
MOBILE PHASE
Use the chromatogram supplied with bzsoprolol for peak
identification EPCRS and the chromatogram obtained with
solution (3) to identify the peaks due to fumaric acid and
impurities A and E; use the chromatogram supplied with
bisoprolol for system suitability EPCRS and the chromatogram
bisoprolol fumarate, obtained with solution (4) to identify the peak due to
medium from the impurity G.
chromatograms obtained e declared content of When the chromatograms are recorded under the prescribed
(Cy gH3;NO4)2,C4H4Os,, in 62 marate BPCRS.
conditions, the relative retentions with reference to bisoprolol
LIMITS (retention time = about 22 minutes) are: impurity A = about
The amount of bisoprolol fuma 0.49; impurity L = about 0.55; impurity G = about 1.03;
75% (Q) of the stated amount. impurity K = about 1.05; impurity E = about 1.10.
Related substances : SYSTEM SUITABILITY
Carry out the method for liquid chromatographys The test is not valid unless, in the chromatogram obtained
Appendix TI D, using the following solutions. ~ ¢ with solution (4), the peak to valley ratio is at least 2.5,
Prepare a mixture of 2 volumes of acetonitrile and 8 velu where H, is the height above the baseline of the peak due to
of water for chromatography (solvent B). impurity G and H,, is the height above the baseline of the
(1) Mix with the aid of ultrasound a quantity of the owest point of the curve separating this peak from the peak
powdered tablets containing 10 mg of Bisoprolol Fumarate i bisoprolol.
solvent B. Add sufficient solvent B to produce a 0.1% w/v
solution of Bisoprolol Fumarate. Mix and filter (0.45-um atogram obtained with solution (1):
nylon syringe filter is suitable).
solvent B. Dilute 1 volume of this solution to 5 volumes with btai
solvent B.
ik co: esponding to impurity A is not
(3) Dissolve the contents of a vial of bisoprolol for peak * area of the principal peak in the
identification EPCRS (containing impurities A and E) in
1.0 mL of solvent B.
ponding to impurity E is not
(4) Dissolve the contents of a vial of bisoprolol for system greater than the area of t srisitipal peak in the
suitability EPCRS (containing impurity G) in 1.0 mL of chromatogram obtained with
solvent B.
the area of any other secondary
CHROMATOGRAPHIC CONDITIONS area of the principal peak in the chi
(a) Use a stainless steel column (25 cm x 4.6 mm) packed solution (2) (0.2%).
with monolithic octadecylsilyl silica gel for chromatography the sum of the areas of any secondary pea
(5 um) (Ace C18 is suitable). 10 times the area of the principal peak in
(b) Use gradient elution and the mobile phase described obtained with solution (2) (2.0%).
below.
(c) Use a flow rate of 1 mL per minute. principal peak in the chromatogram obtained with solution
(d) Use a column temperature of 20°. (2) (0.1%); disregard the peak due to fumaric acid.
(e) Use a detection wavelength of 225 nm. Uniformity of content

of Bisoprolol Fumarate comply with the requirement stated
MOBILE PHASE under Tablets using the following method of analysis. Carry
Mobile phase A 1% w/v solution of orthophosphonic acid. out the method for liquid chromatography, Appendix HI D,
Mobile phase B 1% wW solution of orthophosphoric acid in using the following solutions in the mobile phase.
acetonitrile R1. (1) Add 20 mL of mobile phase to one tablet and mix with
the aid of ultrasound. Dilute with sufficient mobile phase to
produce a solution containing 0.005% w/v of Bisoprolol
Fumarate and filter (0.45-1m nylon syringe filter is suitable).
(2) 0.005% w/v of bisoprolol fumarate BPCRS.
2016 Bleomycin Preparations III-207
Bleomycin Injection
be used. Action and use
DETERMINATION OF CONTENT Cytotoxic antibacterial.
Calculate the content of (C;3H3;NO,4)2,C4,H4O, in each
DEFINITION
tablet using the declared content of (CygH3,NO,)2,C,H,O,
Bleomycin Injection is a sterile solution of Bleomycin Sulfate
in bisoprolol fumarate BPCRS.
in a suitable liquid. It is prepared by dissolving Bleomycin
ASSAY Sulfate for Injection in the requisite amount of the liquid
For tablets containing less than 2 mg and/or less than stated on the label before use.
2% wlw of Bisoprolol Fumarate The injection complies with the requirements stated under
Use thesaverage of the 10 individual results obtainedin the Parenteral Preparations.
of content.
STORAGE
taining 2 mg or more and 2% wiw or
Bleomycin Injection should be used immediately after
5 6lol Fumarate
preparation but, in any case, within the period recommended
Weigh and p wdér'2Q tablets. Carry out the method for
by the manufacturer when prepared and stored strictly in
liquid chromatogra ndix HI D, using the following
accordance with the manufacturer’s instructions.
d tablets containing 25 mg
L of the mobile phase and BLEOMYCIN SULFATE FOR INJECTION
mix with the aid of ultrasots Bleomycin Sulphate for Injection
phase to produce a solution | DEFINITION
Bleomycin Sulfate for Injection is a sterile material consisting
is suitable).
of Bleomycin Sulfate with or without excipients. It is
(2) 0.005% w/v of bisoprolol fumarate supplied in a sealed container.
CHROMATOGRAPHIC CONDITIONS The contents of the sealed container comply with the requirements
(a) Use a stainless steel column (25 cm x 4.0 mr for Powders for Injections or Infusions stated under Parenteral
with octyldecylsilyl silica gel for chromatography (5 jim) Preparations and with the following requirements.
(LiChrospher RP-Select B is suitable). IDENTIFICATION
(b) Use isocratic elution and the mobile phase describ A. The infrared absorption spectrum, Appendix II A, is
below. cerdant with the reference spectrum of bleomycin sulfate
MOBILE PHASE
0.5 volumes of glacial acetic acid and 1000 volumes of

0.136% sodium acetate trihydrate in methanol (50%).
conditions, the retention time of bisoprolol is about
5 minutes.
produce a solution containing”
SYSTEM SUITABILITY mL. The pH of the resulting. solu
The assay is not valid unless, in the chromatogram obtained Appendix V L.
with solution (2), the symmetry factor of the peak due to Colour of solution
bisoprolol is between 0.8 and 1.6. Dissolve a quantity in sufficient waterteg
DETERMINATION OF CONTENT containing 40,000 IU of bleomycin per mi
Calculate the content of (C;3H3,;NO,4)2,C4H40O, in the of the solution at 430 nm is not greater thanJ.
tablets using the declared content of (C;gH3;,NO,)2,C4,H4O,4 Appendix IT B.
in bisoprolol fumarate BPCRS. Loss on drying
When dried at 60° at a pressure not exceeding 0.7 kPa for
IMPURITIES
3 hours, lose not more than 6.0% of their weight. Use the
combined contents of two containers.
monograph include those listed under Bisoprolol Fumarate.
Composition
in sufficient water to produce a solution containing 1000 IU
of bleomycin per mL.
(2) 0.05% w/v of bleomycin sulfate BPCRS in water.
II-208 Bretylium Preparations 2016
CHROMATOGRAPHIC CONDITIONS LABELLING

(a) Use a stainless steel column (25 cm x 4.6 mm) packed The label of the sealed container states the total number
with end-capped octadecylsilyl silica gel for chromatography of IU (Units) contained 1n it.
below.
(c) Use a flow rate of 1.2 mL per minute. Bretylium Injection
(e) Use a detection wavelength of 254 nm. Action and use
Antiarrhythmic.
(f) Inject 20 pL of each ‘solution.
MOBILE PHASE DEFINITION
eA
Use as sbile phase a mixture of 10 volumes of Bretylium Injection is a sterile solution of Bretylium Tosilate
in Water for Injections.
Parenteral Preparations and with the following requirements.
Content of bretylium tosilate, C,;3H,,BrNO;S
40 volumes over 60 minutes CHARACTERISTICS

phase until demethylbleomycin A clear, colourless solution.
20 minutes; retention time 1.5 te IDENTIFICATION
bleomycin A,). A. Dry a quantity of the injection containing 50 mg of
SYSTEM SUITABILITY Bretylium Tosilate over phosphorus pentoxide at a pressure not
exceeding 0.7 kPa for 16 hours. The infrared absorption
with solution (2), the resolution factor betwee spectrum of the residue, Appendix ITI A, is concordant with
principal peaksis at least 5. the reference spectrum of bretylium tosilate (RS 030). If the
spectra are not concordant, dissolve a sufficient quantity of
LIMITS
the residue in the minimum volume of acetone by heating on
Using the chromatogram obtained with solution (1), calcul ce a water bath at 50°, evaporate to dryness at room
the percentage content of bleomycin components by ture under a current of nitrogen and prepare a new
normalisation. The proportions are within the followinglimits
bleomycin A, (first principal peak), between 55% and 70%;
bleomycin B,, between 25% and 32%;
the sum of the contents of bleomycin A, and bleomycin B, 1s
not less than 85%;
demethylbleomycin A, (retention time 1.5 to 2.5, relative to
bleomycin A,), not greater than 8%;
the total content of other related substances is not greater
than 9.5%.
Disregard any impurity present at less than 0.1%.
Dissolve the contents of the sealed container in water BET to (e) After removal of the plate, drysit urrent of air and
produce a solution containing 15,000 IU of bleomycin per examine under ultraviolet light (254
mL (solution A). The endotoxin limit concentration of MOBILE PHASE
solution A is 50 IU of endotoxin per mL. 15 volumes of glacial acetic acid, 30 volu
ASSAY 75 volumes of butan-1-ol.
Determine the weight of the contents of 10 containers as SYSTEM SUITABILITY
described in the test for uniformity of weight, The test is not valid unless the chromatogram obtained with
Appendix XII C1, Powders for Parenteral Administration. solution (1) shows two clearly separated spots.
Mix the contents of the containers and carry out the
CONFIRMATION
microbiological assay of antibiotics, Appendix XIV A,
The two principal spots in the chromatogram obtained with
Method A. The precision of the assay is such that the
solution (1) correspond in position and colour to those in the
fiducial limits of error are not less than 95% and not more
than 105% of the estimated potency.
For a container of average content weight, the upper fiducial TESTS
limit of error is not less than 90.0% and the lower fiducial Acidity or alkalinity
limit of error is not more than 120.0% of the stated number pH, 5.0 to 7.0, Appendix V L.
of IU. Related substances
STORAGE Carry out the method for liquid chromatography,
The sealed container should be protected from light. Appendix III D, using the following solutions in mobile
phase.
2016 Bromocriptine Preparations III-209
(1) Dilute the injection with sufficient of the mobile phase to IMPURITIES
produce a solution containing 0.2% w/v of Bretylium The impurities limited by the requirements of this
Tosilate. monograph include those listed in the monograph for
(2) Dilute 1 volume of solution (1) to 100 volumes. Bretylium Tosilate.
(3) 0.05% w/v of bretylium tosilate BPCRS and 0.05% w/v of
2-bromobenzyldimethylamine hydrochloride BPCRS.
CHROMATOGRAPHIC CONDITIONS Bromocriptine Capsules
Action and use
with phenyl silica gel (5 um) (Spherisorb Pheny] is suitable).
Dopamine receptor agonist.
atic elution and the mobile phase described
DEFINITION
Bromocriptine Capsules contain Bromocriptine Mesilate.
umn temperature. The capsules comply with the requirements stated under Capsules
elength of 265 nm. and with the following requirements.
(f) Inject 20 pL o Content of bromocriptine, C3,H,)BrN;O;
MOBILE PHASE
IDENTIFICATION
19 volumes of acetonitrile an A. Shake a quantity of the contents of the capsules
octanesulfonate. containing the equivalent of 10 mg of bromocriptine with
50 mL of methanol for 30 minutes, centrifuge and dilute
er ow ad
SYSTEM SUITABILITY
5 mL of the supernatant liquid to 20 mL with methanol. The
light absorption of the resulting solution, Appendix II B, in the
range 230 to 380 nm exhibits a maximum at 305 nm and a
principal peaks is at least 6.0. minimum at 270 nm.
LIMITS B. In the test for Related substances, the principal band in
In the chromatogram obtained with solution (1): the chromatogram obtained with solution (2) corresponds to
the area of any secondary peak is not greater than half ti that in the chromatogram obtained with solution (6).
of the peak in the chromatogram obtained with solution {Q).. In the Assay, the retention time of the principal peak in
(0.5%) omatogram obtained with solution (1) is the same as
the sum of the areas of any such peaks is not greater than th
area of the peak in the chromatogram obtained with
solution (2) (1%).
Disregard any peak due to tosilate (retention time, about
2 minutes) and any peak with an area less than the area of Carry out. for thin-layer chromatography,
the peak in the chromatogram obtained with solution (4) Appendix IE ig the following solutions, prepare the
(0.05%). it and immediately before use. Apply
ASSAY solution and develop the
latelytn an unsaturated tank.
Appendix III D, using the following solutions in mobile atents of the capsules
phase.
(1) Dilute the injection to produce a solution containing
0.05% w/v of Bretylium Tosilate. (2) Dilute 1 volume of solution (
methanol.
(2) 0.05% w/v of bretylium tosilate BPCRS.
(3) Dilute 3 volumes of solution (1) to
(3) 0.05% w/v of bretylium tosilate BPCRS and 0.05% w/v of
methanol.
2-bromobenzyldimethylamine hydrochloride BPCRS.
methanol.
methanol.
SYSTEM SUITABILITY (6) 0.023% w/v of bromocriptine mesilate BPCRS in methanol.
(c) Apply 50 uL of each solution as 10-mm bands.
Calculate the content of C;gH»,BrNO3S in the injection
using the declared content of C;gH24BrNO38S in bretylhum (d) Develop the plate to 15 cm.
tosilate BPCRS. (e) After removal of the plate, dry it in a current of cold air
for 2 minutes, spray with ammonium molybdate solution R3
STORAGE
if 2.4 and heat at 100° until bands appear (about 10 minutes).
Bretylium Injection should be protected from light.
vt tbl
~ X
ee
IWI-210 Bromocriptine Preparations 2016
MOBILE PHASE
0.1 volumes of 13.5M ammonia, 1.5 volumes of water,

Bromocriptine Tablets
3 volumes of propan-2-ol, 88 volumes of dichloromethane and Action and use
100 volumes of ether. Dopamine receptor agonist.
LIMITS
DEFINITION
Bromocriptine Tablets contain Bromocriptine Mesilate.
any secondary band is not more intense than the band in the
not more than one such band is more intense than the band
in the chromatogram obtained with solution (4) (1%); Content of bromocriptine, C3,H,)>BrN;O;
further two such bands are more intense
.chromatogram obtained with IDENTIFICATION
thin 20 mm of the line of application. equivalent of 10 mg of bromocriptine with 50 mL of
methanol for 30 minutes, centrifuge and dilute 5 mL of the
tued light. Weigh and pow supernatant liquid to 20 mL with methanol. The light
der absorption of the resulting solution, Appendix II B, in the
ss y out the met
the contents of 20 capsu hod for liqu
id range 230 to 380 nm exhibits a maximum at 305 nm and a
chromatography, Appendi sing the following
minimum at 270 nm.
solutions.
B. In the test for Related substances, the principal band in
the chromatogram obtained with solution (2) corresponds to
methanol (50%) with the aid of ultrasowiid fo: minutes,
C. In the Assay, the chromatogram obtained with solution
filter and dilute to 100 mL with the sam
(2) 0.011% w/v of bromocriptine mesilate B principal peak in the chromatogram obtained with
methanol (50%). solution (2).
(3) Heat a 0.011% w/v solution of bromocriptine :
TESTS
mesilate BPCRS in a mixture of 1 volume of 1M acetic a,
Related substances
and 9 volumes of methanol at 60° for 90 minutes and coo
arry out the method for thin-layer chromatography,
room temperature.
pe III A, using the following solutions.
quantity of the powdered tablets containing the
(a) Use a stainless steel column (10 cm x 4 mm) packed f 10 mg of bromocriptine with 25 mL ofa
with octadecylsilyl sihca gel for chromatography (5 um) squal volumes of chloroform and methanol for
below.
(c) Use a flow rate of 1 mL per minute. i t 25° at a pressure of 2 kPa,
dissolve the residtie i L of the solvent mixture and
centrifuge.
MOBILE PHASE ; volumes with a
45 volumes of a 0.08% w/v solution of ammonium carbonate mixture of equal volumes of chloréfor#i’and methanol.
and 55 volumes of acetonitrile. (4) Dilute 1 volume of solution (2) |
SYSTEM SUITABILITY
The assay is not valid unless the resolution factor between the (5) Dilute 1 volume of solution (2) to 20 V6
two peaks obtained with solution (3) is not less than 3.0. mixture of equal volumes of chloroform and
DETERMINATION OF CONTENT (6) 0.055% w/v of bromocriptine mesilate BPCRS in
of equal volumes of chloroform and methanol.
Calculate the content of C3.H,4)BrN5O; using the declared
content of C3,H4 .BrNs5Os5 in bromocriptine mesilate BPCRS. CHROMATOGRAPHIC CONDITIONS
STORAGE (a) Use as the coating silica gel G.

Bromocriptine Capsules should be Kept in an airtight (b) Use the mobile phase as described below.
container and protected from light. (c) Apply 20 uL of each solution as 10-mm bands.
LABELLING (d) Develop the plate to 15 cm.
The quantity of active ingredient is stated in terms of the (e) After removal of the plate, dry in air for 2 minutes, spray
equivalent amount of bromocriptine. with ammonium molybdate solution R3 and heat at 100° until
bands appear (about 10 minutes).
MOBILE PHASE
0.1 volumes of 13.5mM ammonia, 1.5 volumes of water,
3 volumes of propan-2-ol, 88 volumes of dichloromethane and
100 volumes of ether.
Ce pe
2016 Brompheniramine Preparations III-211
LIMITS LABELLING
In the chromatogram obtained with solution (1): The quantity of active ingredient is stated in terms of the
any secondary band is not more intense than the band in the equivalent amount of bromocriptine.
not more than one such band is more intense than the band
in the chromatogram obtained with solution (4) (1%);
not more than a further two such bands are more intense
Brompheniramine Tablets
than the band in the chromatogram obtained with Action and use
solution (5) (0.5%). Histamine H, receptor antagonist; antihistamine.
Disregard any band within 20 mm of the line of application.
DEFINITION
ty of content
Brompheniramine Tablets contain Brompheniramine
Maleate.
under Tablets using the following The tablets comply with the requirements stated under Tablets and
method of analy: ix one tablet with 50 mL of ethanol with the following requirements.
(50%) with th Content of brompheniramine maleate,
for 30 minutes ge. Measure the absorbance of the C;¢6H,oBrN2,C,H,0,4
aximum at 305 nm, 95.0 to 105.0% of the stated amount.
IDENTIFICATION
C3.H 4 .BrN5O5 taking
In the test for Related substances the retention time of the
ASSAY (2) is similar to that of the principal peak in the
Prepare the solutions in subdued light chromatogram obtained with solution (3).
20 tablets. Carry out the method for lig Related substances
Carry out the method for gas chromatography,
Appendix III B.
equivalent of 10 mg of bromocriptine with 70 miL o: (1) Shake a quantity of the powdered tablets containing
methanol (50%) with the aid of ultrasound for 5 minutes,” 20 mg of Brompheniramine Maleate with 5 mL of water for
shake for 30 minutes, filter and dilute to 100 mL with’ th:
5 minutes, make the resulting suspension alkaline by adding
same solvent. ammonia drop wise, add 2.5 mL of toluene, shake for a
(2) 0.011% wv of bromocriptine mesilate BPCRS in 5 minutes, centrifuge and use the upper, toluene
methanol (50%).
(3) Heat a 0.011% w/v solution of bromocriptine iuite I volume of solution (1) to 50 volumes with
mesilate BPCRS in a mixture of 1 volume of 1M acetic acid
and 9 volumes of methanol at 60° for 90 minutes and cool to
room temperature.
CHROMATOGRAPHIC CONDITIONS phentramine maleate EPCRS and
(a) Use a stainless steel column (10 cm x 4 mm) packed ine maleate BPCRS in
(Spherisorb ODS1is suitable). ONS
below.
(c) Use a flow rate of 1 mL per minute. 175 um) (Chromosorb W AW-
(d) Use an ambient column temperature. impregnated with 3% w/w of po
(e) Use a detection wavelength of 300 nm. phenyl) (OV 17 is suitable).
(f) Inject 20 wL of each solution. (b) Use helium as the carrier gas at 1.7 m
MOBILE PHASE
(c) Use isothermal conditions maintained at
45 volumes of a 0.08% w/v solution of ammonium carbonate (d) Use an inlet temperature of 250°.
and 55 volumes of acetonitrile. (e) Use a flame ionisation detector at a temperature of 250°.
ater ete] SYSTEM SUITABILITY

4.3
wand
The assay is not valid unless the resolution factor between the (g) For solution (1), continue the chromatography for at least
two peaks obtained with solution (3) is not less than 3.0. 2.5 times the retention time of the principal peak.
SYSTEM SUITABILITY
Calculate the content of C3,H,)BrNs5Os in the tablets using The test is not valid unless, in the chromatogram obtained
the declared content of C3,H4 )BrN5Os5 in bromocriptine with solution (4), the resolution factor between the peaks
mesilate BPCRS. corresponding to brompheniramine and chlorpheniramine is
at least 1.5.
STORAGE
LIMITS
Bromocriptine Tablets should be kept in an airtight container
we Ae
als,
and protected from light. In the chromatogram obtained with solution (1):
no secondary peak has an area greater than 0.4% of the area
of the principal peak;
top anw ad
II-212 Budesonide Preparations 2016
the sum of the areas of any secondary peaks is not greater than (4) Dilute 1 volume of solution (2) to 20 volumes with
Veen 1% of the area of the principal peak. solvent A.
rN we
Disregard any peak with an area less than 0.1% of that of the CHROMATOGRAPHIC CONDITIONS
|

solution (1). with end-capped octadecylsilyl silica gel for chromatography
ASSAY (3 um) (Spherisorb ODS2 is suitable).
Weigh and powder 20 tablets. Shake a quantity of the (b) Use gradient elution and the mobile phase described
powder containing 4 mg of Brompheniramine Maleate with below.
50 mL of water for 10 minutes, adjust the pH to 11.0 with (c) Use a flow rate of 1 mL per minute.
0.1m sodium hydroxide and cool to room temperature. Extract
MOBILE PHASE
Mobile phase A 2 volumes of ethanol, 34 volumes of

acetonitrile and 66 volumes of phosphate buffer solution pH 3.2.
Mobile phase B- Equal volumes of acetonitrile and phosphate
buffer solution pH 3.2.
STORAGE :
Brompheniramine Tablets sh Time Mobile phase A Mobile phase B Comment
Budesonide Aqueous Nasal 4 38-50 100-0 0—100 linear gradient

Action and use
Glucocorticoid.
DEFINITION
Budesonide Aqueous Nasal Sprayis an aqueous suspensi on en the© chromatograms are recorded underthe prescribed
of Budesonidein a suitable container fitted with an
appropriate nasal delivery system. ‘time about 17 minutes) is epimer A, about 1.1.
The nasal spray complies with the requirements stated under Nasal TABILITY
Content of budesonide, C,;H3,0,
IDENTIFICATION
A. Dilute a quantity of the nasal spray with sufficient water to the chromatogram*6btaitied with solution (3) closely
produce a solution containing 0.002% w/v of Budesonide resembles the chromat mesupplied with budesonide
and filter. The light absorption of the resulting solution, impurity standard BPCR
Appendix II B, in the range 200 nm to 350 nm exhibits a in the chromatogram obtain with solution (4), the signal-to-
maximum only at 247 nm. noise ratio of each of the pea to epimer A and epimer B
B. In the Assay, the retention time of the principal peak in is at least 10.
the chromatogram obtained with solution (1) is similar to LIMITS
Identify any peaks (2 epimer peaks) due impurity D in the
solution (2).
chromatogram obtained with solution (1) “tg: 2
TESTS chromatogram obtained with solution (3) andem
Acidity sum of the areas of these peaks by 1.8.
pH, 4.0 to 5.0, Appendix V L. In the chromatogram obtained with solution (1):
Related substances the area of any peak due to Impurity D is not greater than
Carry out the method for guid chromatography, the sum of the areas of the epimer peaks in the
Appendix III D, using the following solutions, protected from chromatogram obtained with solution (2) (2%);
light. the sum of the areas of any secondary peaks is not greater than
Solvent A 34 volumes of acetonitrile and 66 volumes of 1.5 times the sum of the areas of the epimer peaks in the
phosphate buffer solution pH 3.2. chromatogram obtained with solution (2) (3%).
(1) To a quantity of the nasal spray containing 2 mg of Disregard any peak with an area less than the sum of the
Budesonide add 3.4 mL of acetonitrile. Mix with the aid of areas of the epimer peaks in the chromatogram obtained with
ultrasound and add sufficient phosphate buffer solution pH 3.2 solution (4) (0.1%).
to produce 10 mL and filter.
Epimer A
(2) Dilute 1 volume of solution (1) to 50 volumes in In the chromatogram obtained with solution (1), as described
solvent A. under Assay, the content of epimer A (second peak) is 40.0%
(3) 0.01% w/v of budesonide impurity standard BPCRS in to 51.0% of the sum of the areas of the two epimer peaks of
solvent A. budesonide.
2016 Budesonide Preparations III-213
ASSAY | IDENTIFICATION
Carry out the method for liquid chromatography, A. Dilute a quantity of the nebuliser suspension being
Appendix III D, using the following solutions, protected from examined with sufficient water to produce a solution
light. containing 0.002% w/v of Budesonide and filter. The light
(1) To a quantity of the nasal spray containing 1 mg of absorption of the resulting solution, Appendix II B, in the
Budesonide add 3.4 mL of acetonitrile. Mix with the aid of range 200 nm to 350 nm exhibits a maximum only at
ultrasound, add sufficient phosphate buffer solution pH 3.2 to 247 nm.
produce 10 mL and filter. B. In the Assay, the retention time of the principal peak in
(2) 0.01% w/v of budesonide BPCRS in solvent A (as the chromatogram obtained with solution (1) is similar to
described under Related substances). that of the principal peak in the chromatogram obtained with
solution (2).
ss steel column (15 cm x 4.6 mm) packed TESTS
octadecylsilyl silica gel for chromatography Acidity
sxb ODS2 is suitable). pH, 4.0 to 5.0, Appendix V L.
Related substances
Appendix III D, using the following solutions, protected from
light.
Solvent A 34 volumes of acetonitrile and 66 volumes of
(1) To a quantity of the nebuliser suspension containing
2 mg of Budesonide add 3.4 mL of acetonitrile. Mix with the
aid of ultrasound, add sufficient phosphate buffer solution
66 volumes of phosphate buffer solution pH 3.2 to produce 10 mL, centrifuge and use the
SYSTEM SUITABILITY supernatant liquid.
The test is not valid unless, in the chromatogra (2) Dilute 1 volume of solution (1) to 200 volumes with
with solution (2), the resolution between the peaks solvent A.
epimer B and epimerAis at least 1.5. (3) Dilute 1 volume of solution (2) to 10 volumes with
DETERMINATION OF CONTENT solvent A.
Calculate the content of C,5;H34,0¢ in the nasal spray fro OMATOGRAPHIC CONDITIONS
the sum of the areas of the two budesonide epimer peaks a a stainless steel column (15 cm x 4.6 mm) packed
using the declared content of C25H340¢ in capped octadecylsilyl silica gelior chromatography
budesonide BPCRS.
IMPURITIES
monograph include those listed under Budesonide. 1 mL per minute.
(d) Use a cole n erature of 50°.
(e) Use a detect
Budesonide Nebuliser Suspension (f) Inject 100 uL of

MOBILE PHASE
Tete Nad
Action and use
Glucocorticoid.
DEFINITION Mobile phase B- Equal volumes

Budesonide Nebuliser Suspension is a suspension of buffer solution pH 3.2.
Budesonide in a suitable vehicle.
The nebuliser suspension complies with the requirements stated Time Mobile phase A Mobile phase B
under Preparations for Inhalation and with the following (Minutes) (% viv) (% viv)
requirements. 0-38 100 0 isocratic
PRODUCTION 38-50 100-0 0-100 linear gradient
The active substance delivery rate and the total active
substance delivered are determined using the methods
described in Appendix XII C. 8. Preparations for 60-61 0100 1000 linear gradient
Nebulisation: Characterisation. Where justified and 61-70 100 0 re-equilibration

authorised, a different apparatus and procedure may be used.
The particle-size distribution is determined using an
apparatus and procedure described in Appendix XII C. When the chromatograms are recorded under the prescribed
8. Preparations for Nebulisation: Characterisation. Where conditions the retention time relative to budesonide epimer B
justified and authorised, a different apparatus and procedure (retention time about 17 minutes) is epimer A, about 1.1.
may be used. SYSTEM SUITABILITY
Content of budesonide, C,;H3,0, The test is not valid unless:

II-214 Budesonide Preparations 2016

between the peaks due to epimer B and epimerAis at least
Budesonide Inhalation Powder
wet tel
FAN eed 1.5; Budesonide Powder for Inhalation, metered dose powder
Nw Aye
inhaler
in the chromatogram obtained with solution (3), the signal-to-
noise ratio of each of the peaks due to epimer A and epimer B Action and use
is at least 10. Glucocorticoid.
LIMITS
In the chromatogram obtained with solution (1): DEFINITION

Budesonide Inhalation Powder consists of Budesonide in
the area of any secondary peak is not greater than the sum of
muicrofine powder either alone or combined with a suitable
the areas of the epimer peaks in the chromatogram obtained
carrier. It is administered by a dry-powder inhaler.
a(2) (0.5%);
The inhalation powder complies with the requirements stated under
tw and
Preparations for Inhalation and with the following requirements.
PRODUCTION
area less than the sum of the The size of aerosol particles to be inhaled is controlled so
areas of the epimer'pea 1.the chromatogram obtained with that a consistent portion is deposited in the lung. The fine-
solution (3) (0.05%). particle characteristics of powders for inhalation are
determined using the method described in Appendix XII C.
Epimer A
7. Preparations for Inhalation: Aerodynamic Assessment of
In the chromatogram obtainéd"wi tion (1), as described
Fine Particles.
under Assay, the content of e ond peak) is 40.0%
to 51.0% of the sum of the area: pimer peaks of Content of budesonide, C,;H34,0,
budesonide. 80.0 to 120.0% of the stated amount.
ASSAY IDENTIFICATION
Carry out the method for liquid chromatography A. Dilute a quantity of the inhalation powder with sufficient
Appendix III D, using the following solutions, water to produce a solution containing 0.002% w/v of
light. Budesonide and filter. The light absorption of the resulting
solution, Appendix II B, in the range 200 nm to 350 nm
(1) To a quantity of the nebuliser suspension containing®
exhibits a maximum only at 247 nm.
1 mg of Budesonide add 3.4 mL of acetonitrile. Mix with
aid of ultrasound, add sufficient phosphate buffer solution 3. In the Assay, the retention time of the principal peak in
ye"Chrematogram obtained with solution (1) is similar to
pH 3.2 to produce 10 mL and filter.
(2) 0.01% w/v of budesonide BPCRS in solvent A (as
described under Related substances).
ts containing lactose disperse 0.25 g of the
weler in 5 mL of water. Add 5 mL of
(a) Use a stainless steel column (15 cm x 4.6 mm) packed at in a water bath at 80° for 10 minutes.
(3 um) (Spherisorb ODS2 is suitable).
below.
Carry out the method f
(c) Use a flow rate of 1.5 mL per minute. Appendix III D, using
(d) Use a column temperature of 50°. light.
: containing
MOBILE PHASE
2 volumes of ethanol, 34 volumes of acetonitrile and

66 volumes of phosphate buffer solution pH 3.2.
SYSTEM SUITABILITY
(2) Dilute 1 volume of solution (1) to 200 volumesawith
The test is not valid unless, in the chromatogram obtained solvent A.
epimer B and epimerA is at least 1.5.
owe
a
solvent A.
_ DETERMINATION OF CONTENT
eae ay
Calculate the content of C,5H34,0,¢ in the nebuliser
suspension from the sum of the areas of the two budesonide
epimer peaks and using the declared content of C35H34,0¢ in
budesonide BPCRS.
STORAGE below.
Budesonide Nebuliser Suspension should be protected from (c) Use a flow rate of 1 mL per minute.
light.
IMPURITIES (e) Use a detection wavelength of 240 nm.
monograph include those listed under Budesonide.
wy
\
-
MOBILE PHASE (c) Use a flow rate of 1.5 mL per minute.

Mobile phase A 2 volumes of ethanol, 34 volumes of (d) Use a column temperature of 50°.
NN ett
acetonitrile and 66 volumes of phosphate buffer solution pH 3.2. (e) Use a detection wavelength of 240 nm.
Mobile phase B Equal volumes of acetonitrile and phosphate (f) Inject 200 nL of each solution.
MOBILE PHASE
2 volumes of ethanol, 34 volumes of acetomitrile and

66 volumes of phosphate buffer solution pH 3.2.
SYSTEM SUITABILITY
38-50 100-0 0100 linear gradient with solution (2), the resolution between the peaks due to
100 isocratic epimer B and epimerA is at least 1.5.
100-0 linear gradient DETERMINATION OF CONTENT
= 0 re-equilibration Calculate the amount of budesonide, C,5;H340.¢, per

delivered dose using the declared content of C,5H34O0¢ in
budesonide BPCRS. Repeat the procedure as described for
reservoir systems under Inhalation Powders, Uniformity of
conditions the re ne relative to budesonide epimer B delivered dose.
(retention time abou i ) is epimer A, about 1.1.
ASSAY
SYSTEM SUITABILITY
Use the average of the 10 individual results obtained in the
The test is not valid unless test for Uniformity of delivered dose.
in the chromatogram obtai olution (2), the resolution
Pree
IMPURITIES
between the peaks due to epimer B’and.¢pimer Ais at least
1.5;
monograph include those listed under Budesonide.
in the chromatogram obtained with sol io the signal-to-
noise ratio of each of the peaks due to epim <epimer B
is at least 10.
LIMITS

Budesonide Inhalation Powder, pre-
the area of any secondary peak is not greater than the sum spensed
the areas of the epimer peaks in the chromatogram obtaine eSonide Powder for Inhalation, pre-metered units
3 times the sum of the areas of the epimer peaks in the
Disregard any peak with an area less than the sum of the
areas of the epimer peaks in the chromatogram obtained with
solution (3) (0.05%).
Epimer A
In the chromatogram obtained with solution (1), as described The inhalation powder, ispensed complies with the
under Uniformity of delivered dose, the content of epimer A requirements stated under yations for Inhalation and with the
(second peak) is 40.0% to 51.0% of the sum of the areas of following requirements.
the two epimer peaks of budesonide.
PRODUCTION
The size of aerosol particles to bet
Complies with the requirements stated under Inhalation
that a consistent portion is deposite
Powders using the following method of analysis. Carry out
particle characteristics of powders for 1
the method for liguid chromatography, Appendix III D, using
the following solutions, protected from light.
7. Preparations for Inhalation: Aerodynamic As
Solvent A 34 volumes of acetonitrile and 66 volumes of Fine Particles.
Content of budesonide, C,;H340¢
waved
vee aw
(1) Collect single doses of the preparation being examined When supplied as disks, 90.0 to 110.0% of the stated
wae od
cee eA
using the procedure described under Inhalation Powders, amount per pre-metered unit. When supplied as capsules,
Uniformity of delivered dose and dissolve the collected dose 80.0 to 120.0% of the stated amount per pre-metered unt.
in sufficient solvent A to produce a solution containing
0.001% w/v of Budesonide. | IDENTIFICATION
A. Dilute a quantity of the powder, with sufficient water to
(2) 0.001% w/v of budesonide BPCRS in solvent A.
wrk a
produce a solution containing 0.002% w/v of Budesonide
CHROMATOGRAPHIC CONDITIONS and filter. The light absorption of the resulting solution,
(a) Use a stainless steel column (15 cm x 4.6 mm) packed Appendix II B, in the range 200 nm to 350 nm exhibits a
with end-capped octadecylsilyl silica gel for chromatography maximum only at 247 nm.
(3 um) (Spherisorb ODS2 is suitable). B. In the Assay, the retention time of the principal peak in
PAN aA
4A an
(b) Use isocratic elution and the mobile phase described the chromatogram obtained with solution (1) is similar to
awn e|
below.
ate NTE
eos a
IJI-216 Budesonide Preparations 2016
that of the principal peak in the chromatogram obtained with the sum of the areas of any secondary peaks is not greater than
solution (2). 3 times the sum of the areas of the epimer peaks in the
C. For products containing lactose disperse 0.25 g of the chromatogram obtained with solution (2) (1.5%).
powder for inhalation in 5 mL of water. Add 5 mL of Disregard any peak with an area less than the sum of the
6M ammonia and heat in a water bath at 80° for 10 minutes. areas of the epimer peaks in the chromatogram obtained with
An orange-red colour is produced. solution (3) (0.05%).
TESTS Epimer A
Related substances In the chromatogram obtained with solution (1), as described
Carry out the method for liquid chromatography, under Uniformity of delivered dose, the content of epimer A
Appendix III D, using the following solutions, protected from (second peak) is 40.0% to 51.0% of the sum of the areas of
light. the two epimer peaks of budesonide.
e of 34 volumes of acetonitrile and Uniformity of delivered dose
esphate buffer solution pH 3.2 (solvent A). Complies with the requirements stated under Inhalation
Powders using the following method of analysis. Carry out
the method for liguid chromatography, Appendix III D, using
the following solutions, protected from light.
solvent A. (1) Collect single doses of the preparation being examined
(3) Dilute 1 volume of soluti using the procedure described under Inhalation Powders,
solvent A. Uniformity of delivered dose and dissolve the collected dose
in sufficient solvent A to produce a solution containing
0.001% w/v of Budesonide.
with end-capped octadecylsilyl silica gel for chroyiittt
(3 um) (Spherisorb ODS2 is suitable). 4 CHROMATOGRAPHIC CONDITIONS
(b) Use gradient elution and the mobile phase described : (a) Use a stainless steel column (15 cm x 4.6 mm) packed
below. with end-capped octadecylsilyl silica gel for chromatography
) Use isocratic elution and the mobile phase described
MOBILE PHASE

Mobile phase B_- Equal volumes of acetonitrile and phosphate


two budesonide epimer peaks and using
of C45H340¢ in budesonide BPCRS. Repeat t
described for pre-dispensed systems under Inhalati
When the chromatograms are recorded under the prescribed Powders, Uniformity of delivered dose. .
conditions the retention time relative to budesonide epimer B ASSAY
(retention time about 17 minutes) is epimer A, about 1.1. Use the average of the individual results obtained in the test
SYSTEM SUITABILITY for Uniformity of delivered dose.
The test is not valid unless: IMPURITIES
in the chromatogram obtained with solution (2), the resolution The impurities limited by the requirements of this
between the peaks due to epimer B and epimer Ais at least monograph include those listed under Budesonide.
1.5;
LIMITS

the area of any secondary peak is not greater than the sum of
the areas of the epimer peaks in the chromatogram obtained
Mobile phase B Equal volumes of acetonitrile and phosphate

Budesonide Pressurised Inhalation buffer solution pH 3.2.
eee oe ee
Cer Gey,
Action and use

Glucocorticoid. Time Mobile phase A Mobile phase B Comment
DEFINITION
:
Budesonide Pressurised Inhalation is a suspension of 0-38 100 0 isocratic

Budesonide in a suitable liquid in a pressurised container 38-50 100-0 0—100 linear gradient
fitted with a metering dose valve.
The pressurised inhalation complies with the requirements stated
under Preparations for Inhalation and with the following
requirements. 61-70 100 0 re-equilibration

conditions the retention time relative to budesonide epimer B
particle char (retention time about 17 minutes) is epimer A, about 1.1.
preparations fe are determined using the method
SYSTEM SUITABILITY
7. Preparations for Inhalation:
Content of budesonid
between the peaks due to epimer B and epimerAis at least
80.0 to 120.0% of the amot
1.5;
actuation of the valve.
in the chromatogram obtained with solution (3), the signal-to-
IDENTIFICATION : noise ratio of each of the peaks due to epimer A and epimer B
A. Dilute a quantity of the pressurised: is at least 10.
sufficient water to produce a solution cortair:
LIMITS
of Budesonide and filter. The light absorption
solution, Appendix II B, in the range 200 nm to In the chromatogram obtained with solution (1):
exhibits a maximum only at 247 nm. the area of any secondary peak is not greater than the sum of
B. In the Assay, the retention time of the principal peak'in the areas of the epimer peaks in the chromatogram obtained
the chromatogram obtained with solution (1) is simil with solution (2) (0.5%);
that of the principal peakin the chromatogram obtained We um of the areas of any secondary peaks is not greater than
solution (2). | the sum of the areas of the epimer peaks in the
ogram obtained with solution (2) (1.5%).
TESTS
Related substances d any peak with an area less than the sum of the
Carry out the method for guid chromatography, © epimer peaksin the chromatogram obtained with
Appendix II D, using the following solutions, protected from
light.
to 51.0% of the sur
(1) Freeze the pressurised container and carefully open the
canister. Dissolve a quantity of the frozen contents containing budesonide.
ree
aN we
2 mg of Budesonide in 3.4 mL of acetonitrile. Mix with the ASSAY
aid of ultrasound and add sufficient phosphate buffer solution
solvent A.
solvent A.
pressurised container from the actuator ...’ and.¢nding at the
words *... to the volume specified in the monograph’, using
(a) Use a stainless steel column (15 cm x 4.6 mm) packed 32 mL of acetonitrile in the vessel. Transfer the combined
with end-capped octadecylsilyl silica gel for chromatography solution and washings obtained from the set of 10 combined
a ek
actuations to a flask so that, on dilution to volume with

eee A
L
PON gt
we ae
(b) Use gradient elution and the mobile phase described appropriate amounts of acetonitrile and phosphate buffer solution
below. pH 3.2, the final solution contains 0.002% w/v of Budesonide
(c) Use a flow rate of 1 mL per minute. in solvent A, as described under Related substances (solution
(d) Use a column temperature of 50°. A). Determine the content of active ingredient in the 10
combined actuations using the following method of analysis.
Appendix II D, using the following solutions.
MOBILE PHASE
(1) Solution A.
CA
way es
ere eves
Te
An.
Ae
rte
oe Aw A
mae Ne oD
IW-218 Buffered Cream 2016
CHROMATOGRAPHIC CONDITIONS The cream complies with the requirements stated under Topical
(a) Use a stainless steel column (15 cm x 4.6 mm) packed Semi-solid Preparations and with the following requirements.
tN
aw an!
with end-capped octadecylsilyl silica gel for chromatography TESTS
(3 um) (Spherisorb ODS2 is suitable). Acidity
(b) Use isocratic elution and the mobile phase described pH, 5.7 to 6.3, determined directly on the cream,
below. Appendix V L.
(c) Use a flow rate of 1.5 mL per minute. STORAGE
(d) Use a column temperature of 50°. If Buffered Cream is kept in aluminium tubes, their inner
(e) Use a detection wavelength of 240 nm. surfaces should be coated with a suitable lacquer.
MOBILE PHASE
34 volumes of acetonitrile and
tate buffer solution pH 3.2. Bumetanide Injection
Action and use
Loop diuretic.
epimer B and epimer DEFINITION

DETERMINATION OF CO Bumetanide Injection is a sterile solution of Bumetanide in
Calculate the content of C;Hs, Water for Injections.
inhalation from the sum of the The injection complies with the requirements stated under
epimer peaks and using the deckire Parenteral Preparations and with the following requirements.
budesonide BPCRS. Content of bumetanide, C,7H,)N,0;S
IDENTIFICATION
on the last 10 successive combined actuations
A. Shake a quantity of the injection containing 10 mg of
estimated from the number of deliveries available frony th Bumetanide with 20 mL of ether, filter the ether layer
container as stated on the label. For each of the three
through anhydrous sodium sulfate and evaporate to dryness
determinations the average content of C.5H340,¢ delivere
sing a rotary evaporator. The infrared absorption spectrum of
a single actuation of the valve is within the limits stated
due, Appendix II A, is concordant with the reference
under Content of budesonide.
af bumetanide (RS 033).
IMPURITIES ssay, the retention time of the principal peak in
The impurities limited by the requirements of this togram obtained with solution (1) 1s similar to
monograph include those listed under Budesonide. ncipal peak in the chromatogram obtained with
Buffered Cream pH,6.0 to 7.8, App

DEFINITION Related substance
Emulsifying Ointment 300 g Carry out the method fc ay chromatography,
Disodium Hydrogen Phosphate 25g Appendix III A, using the fo owl, solutions.
Dodecahydrate
Citric Acid Monohydrate 5g
Chlorocresol lg.
Purified Water, freshly Sufficient to produce
boiled and cooled 1000 g
If another antimicrobial preservative replaces Chlorocresol in
this formulation, the suitability of the Cream as a diluent
dryness using a rotary evaporator. Dissolve the residue in
should be confirmed before use.
5 mL of methanol and centrifuge. Evaporate the supernatant
Extemporaneous preparation liquid to dryness using a rotary evaporator and dissolve the
Melt the Emulsifying Ointment with the aid of gentle heat. residue in 0.5 mL of methanol. ,
In a vessel that can be closed, heat about 650 g of Purified
Water to about 60°; add the Chlorocresol and, when it melts,
methanol and further dilute 1 volume of this solution to
vigorously shake the closed vessel to effect dissolution.
30 volumes with methanol.
Dissolve the Disodium Hydrogen Phosphate Dodecahydrate
and the Citric Acid Monohydrate in the chlorocresol (3) Dilute 1 volume of solution (2) to 3 volumes with
solution. Add the aqueous phase to the melted ointment methanol.
when both are at about 60°. Stir gently until cool, add (4) 0.005% w/v of 3-amino-4-phenoxy-5-sulfamoylbenzotc
sufficient Purified Water to produce 1000 g and mix. acid BPCRS in methanol.
(a) Use as the coating silica gel F254 (Merck silica gel 60 Fo5q4
ters
2016 Bumetanide Preparations JII-219

Bumetanide Oral Solution
(d) Develop the plate to 15 cm. Action and use
(e) After removal of the plate, dry in air and examine under Loop diuretic.
DEFINITION
MOBILE PHASE Bumetanide Oral Solution is a solution of Bumetanide in a
2.5 volumes of methanol, 10 volumes of glacial acetic acid, suitable flavoured vehicle.
10 volumes of cyclohexane and 80 volumes of chloroform. The oral solution complies with the requirements stated under Oral
LIMITS Liguids and with the following requirements.
In the chromatogram obtained with solution (1): Content of bumetanide, C,;Hj)N,0-;S
acid is not more intense than the spot in IDENTIFICATION
btained with solution (4) (0.5%); A. In the test for Related substances, the principal spot in the
eyspot is not more intense than the spot in chromatogram obtained with solution (2) corresponds to that
than the spot in the ci the chromatogram obtained with solution (1) is similar to
(0.1%). that of the peak in the chromatogram obtained with
ASSAY solution (2).
TESTS
Related substances
Bumetanide to 20 mL using a mixture o: Appendix III A, using a silica gel F254 precoated plate
acetic acid, 5 volumes of tetrahydrofuran a (Merck silica gel 60 F,54 plates are suitable) and a mixture of
methanol. 2.5 volumes of methanol, 10 volumes of glacial acetic acid,
(2) Dilute 10 mL of a 0.025% w/v solution of é 10 volumes of cyclohexane and 80 volumes of chloroform as
bumetanide BPCRS in a mixture of 2 volumes of glaéial aéetic. the mobile phase. Apply separately to the plate 25 uL of each
acid, 5 volumes of tetrahydrofuran and 45 volumes of miethe of the following solutions. For solution (1) mix a quantity of
to 20 mL with water. al solution containing 2 mg of Bumetanide with 10 mL
and 0.6 mL of 1m hydrochloric acid, add 5 mL of
(3) 0.0125% w/v of 3-amino-4-phenoxy-5-sulfamoylbenzotc
tate, shake for 15 minutes, centrifuge and decant the
acid BPCRS in solution (2).
ate. Add a further 5 mL of ethyl acetate to the
CHROMATOGRAPHIC CONDITIONS hake for 15 minutes, centrifuge and decant the ethyl
(a) Use a stainless steel column (30 cm x 3.9 mm) packed : ate the combined ethyl acetate extracts to
(10 um) (uBondapak ODS is suitable).
(b) Use isocratic elution and the mobile phase described solution (1) tod
below. dilute 1 volume
with methanol. For soleti
(d) Use an ambient column temperature. (2) to 100 volumes with etha;
(e) Use a detection wavelength of 254 nm. 0.040% w/v of bumetanide BPCRS in methanol. Solution (6)
(f) Inject 20 wL of each solution. contains 0.002% w/v of 3-amitio-4 “y-5-sulfamoylbenzoic
acid BPCRS in methanol. After r
MOBILE PHASE
to dry in air and examine under
2 volumes of glacial acetic acid, 5 volumes of tetrahydrofuran,
SYSTEM SUITABILITY
The Assay is not valid unless, in the chromatogram obtained the chromatogram obtained with solution (6) (Q:5%), any
with solution (3), the resolution factor between the two other secondary spot is not more intense than the spot in the
principal peaks is at least 15. chromatogram obtained with solution (3) (0.3%) and not
more than two other such spots are more intense than the
spot in the chromatogram obtained with solution (4) (0.1%).
Calculate the content of C;7H.>N2O5S using the declared
content of C,;7H»)9N20sS in bumetanide BPCRS. ASSAY
Appendix III D, using the following solutions. For solution
(1) mix a quantity of the oral solution containing 2.5 mg of
Bumetanide with 12.5 mL of water and 0.8 mL of
Im hydrochloric acid, add 10 mL of ethyl acetate, shake for
15 minutes, centrifuge and decant the ethyl acetate. Repeat
the extraction procedure twice using a further two 10-mL
quantities of ethyl acetate and beginning at the words ‘add
10 mL of ... ’. Evaporate the combined ethyl acetate extracts
a rn)
II-220 Bumetanide Preparations 2016
to dryness using a rotary evaporator, dissolve the residue in (2) Dilute 1 volume of solution (1) to 100 volumes with
vewaend
10 mL of a mixture of 2 volumes of glacial acetic acid, methanol and further dilute 3 volumes of this solution to
we ae ft 5 volumes of tetrahydrofuran and 45 volumes of methanol and 10 volumes with methanol.
dilute to 20 mL with water. For solution (2) dilute 5 mL of a (3) Dilute 1 volume of solution (1) to 10 volumes with
0.025% w/v solution of bumetanide BPCRS in a mixture of methanol and further dilute 1 volume of this solution to
2 volumes of glacial acetic acid, 5 volumes of tetrahydrofuran 100 volumes with methanol.
and 45 volumes of methanol and dilute to 10 mL with water.
Inject 20 pL of each solution. Solution (3) contains
0.0125% w/v of 3-amino-4-phenoxy-5-sulfamoyl-benzotc (a) Use a precoated TLC silica gel F254 plate (Merck silica gel
acid BPCRS in solution (2). 60 F454 plates are suitable).
The chromatographic procedure may be carried out using (b) Use the mobile phase as described below.
s. steel column (30 cm x 4 mm) packed with (c) Apply 10 uwL of each solution.
ilyl silica gel for chromatography (10 um) (d) Develop the plate to 15 cm.
; suitable), (b) a mixture of 2 volumes of (e) After removal of the plate, allow it to dry in air and
volumes of tetrahydrofuran, 45 volumes of examine under ultraviolet light (254 nm).
.methanol as the mobile phase with a
flow rate of 1 mL MOBILE PHASE
of 254 nm. 2.5 volumes of methanol, 10 volumes ofglacial acetic acid,
chromatogram obtained 10 volumes of cyclohexane and 80 volumes of chloroform.
- between the two LIMITS
principal peaks is at least 15. Any secondary spot in the chromatogram obtained with
Determine the weight per mL o solution (1):
is not more intense than the spot in the chromatogram
weight in volume, using the declared con obtained with solution (2) (0.3%);
C17H29N205S in bumetanide BPCRS.
and not more than three such spots are more intense than
the spot in the chromatogram obtained with solution (3)
(0.1%).
Uniformity of content
Bumetanide Tablets Tablets containing less than 2 mg and/or less than 2% w/w
f Bumetanide comply with the requirements stated under
Action and use ~using the following method of analysis. Carry out the
Loop diuretic. or liquid chromatography, Appendix III D, using the
olutions.
DEFINITION
solve one tablet in 10 mL of a mixture of 2 volumes
Bumetanide Tablets contain Bumetanide.
eneeacid, 5 volumes of tetrahydrofuran and
The tablets comply with the requirements stated under Tablets and f{ methanol, shake with the aid of ultrasound for
with the following requirements. 5 minutes, » 2 mL with water, filter and use the
Content of bumetanide, C,,H2)>N,0;S filtrate. .
95.0 to 105.0% of the stated amount. (2) Dilute 10 mL of 0% w/v solution of
IDENTIFICATION bumetanide BPCRS ixtiire of 2 volumes of glacial acetic
A. Shake a quantity of the powdered tablets containing acid, 5 volumes of tetraitydr d 45 volumes of methanol
50 mg of Bumetanide with 25 mL of ether, filter through to 20 mL with water.
anhydrous sodium sulfate and evaporate the filtrate to dryness
using a rotary evaporator. The infrared absorption spectrum of
the residue, Appendix IJ A, is concordant with the reference be used.
spectrum of bumetanide (RS 033).
that of the peak in the chromatogram obtained with
solution (2). ASSAY
TESTS Carry out the method for liquid chromatography,
Related substances
Carry out the method for thin-layer chromatography, (1) Dissolve a quantity of the powdered tablets containing
Appendix III A, using the following solutions. 2.5 mg of Bumetanide in 10 mL of a mixture of 2 volumes
of glacial acetic acid, 5 volumes of tetrahydrofuran and
(1) Shake mechanically a quantity of the powdered tablets
45 volumes of methanol, shake with the aid of ultrasound for
containing 12.5 mg of Bumetanide with 20 mL of a mixture
5 minutes, dilute to 20 mL with water, filter and use the
of equal volumes of acetonitrile and methanol for 20 minutes,
filtrate.
centrifuge for 10 minutes, decant and reserve the supernatant
liquid. Extract the residue with 5 mL of a mixture of equal (2) Dilute 10 mL of a 0.025% w/v solution of
volumes of acetonitrile and methanol, shaking mechanically for bumetanide BPCRS in a mixture of 2 volumes of glacial acetic
30 seconds, centrifuge for 10 minutes, decant and combine acid, 5 volumes of tetrahydrofuran and 45 volumes of methanol
the extracts. Evaporate the combined extracts to dryness to 20 mL with water.
ate 72
tea
a8 we mnt under reduced pressure, dissolve the residue in 0.5 mL of (3) 0.0125% w/v of 3-amino-4-phenoxy-5-sulfamoylbenzoic
methanol and centrifuge for 10 minutes. acid BPCRS in solution (2).
een
2016 Bumetanide Preparations III-221
CHROMATOGRAPHIC CONDITIONS 2 mL of water and filter. The filtrate yields reaction A

(a) Use a stainless steel column (30 cm x 3.9 mm) packed characteristic of potassium salts, Appendix VI.
with end-capped octadecylsilyl silica gel for chromatography D. Dissolve a quantity of the powdered tablets containing
(10 um) (uBondapak ODS 1s suitable). 0.02 g of Potassium Chloride as completely as possible in
(b) Use isocratic elution and the mobile phase described 2 mL of water and filter. The filtrate yields reaction A
below. characteristic of chlorides, Appendix VI.
(c) Use a flow rate of 1 mL per minute. TESTS
(d) Use an ambient column temperature. Dissolution
(e) Use a detection wavelength of 254 nm. For bumetanide
(f) Inject 20 pL of each solution. Comply with the requirements for Monographs of the British
Appendix XII B1, using Apparatus 2. Use as the medium
900 mL of water and rotate the paddle at 100 revolutions per
minute. Withdraw a sample of 10 mL of the medium, filter
and measure the fluorescence, Appendix IIT E, using an
excitation wavelength of 350 nm and an emission wavelength
of 445 nm and water in the reference cell. Measure the
fluorescence of a 0.04% w/v solution of bumetanide BPCRS in
ethanol (96%) diluted to a suitable concentration with water
under the same conditions and calculate the total content of
C,7H29N205S in the medium from the fluorescences
obtained and from the declared content of C,7H2)N20;S in
bumetanide BPCRS.
Related substances
Bumetanide and Prolonged- Appendix III A, using a high-performance silica gel F5,4
plate (Merck 5629 plates are suitable) and a mixture of
Potassium Tablets 2.5 volumes of methanol, 10 volumes of glacial acetic acid,
Bumetanide and Prolonged-release Potassium Tablets fro 10 volumes of cyclohexane and 80 volumes of chloroform as
the mobile phase but allowing the solvent front to ascend
the monograph, are not interchangeable unless otherwise justifie a.above the line of application. Apply separately to the
and authonised. 10 uL of each of solutions (1) and (2) and 5 pL of
(3). For solution (1) add 10 mL of
a 0.1% wiv
Action and use
Loop diuretic.
d tle. cores, extract the solution with two 20-mL
DEFINITION
, evaporate the combined extracts to
Bumetanide and Prolonged-release Potassium ‘Tablets
: ed pressure and dissolve the residue in
contain Bumetanide and Potassium Chloride. They are
Vi ite. For solution (2) add 2 mL ofa
formulated so that the Potasstum Chloride is released over a
0.20% w/v solutié:
period of several hours.
10 mL of a 0.1%
PRODUCTION : the ethyl acetate layer.
A suitable dissolution test is carried out to demonstrate the a 0.20% w/v solution of
appropriate release of Potasstum Chloride. The dissolution 0 acid BPCRS in ethyl
profile reflects the 1m vivo performance which in turn is acetate and 1 mL of a 0.20% w/v solution of
compatible with the dosage schedule recommended by the bumetanide BPCRS in ethyl acetat
manufacturer. to produce 100 mL, add 2 mL of thi
The tablets comply with the requirements stated under Tablets and 0.1% w/v solution of citric acid, shake fe
with the following requirements. the ethyl acetate layer. After removal of t
Content of bumetanide, C,;,H2).N,0-;S
corresponding to 3-amino-4-phenoxy-5-sulfamoylbenzoic acid
Content of potassium chloride, KCl is not more intense than the corresponding spot in the
95.0 to 105.0% of the stated amount. chromatogram obtained with solution (3) (0.5%) and any
IDENTIFICATION other secondary spot is not more intense than the spot due to
A. In the test for Related substances the spot in the bumetanide in the chromatogram obtained with solution (3)
chromatogram obtained with solution (1) is similar in (0.5%).
position, size and intensity to the spot in the chromatogram Uniformity of content
obtained with solution (2). Tablets containing less than 2 mg of Bumetanide comply
B. Examine the filtrate obtained in the test for Uniformity of with the requirements stated below. Carry out the method
content by fluorescence spectrophotometry, Appendix II E, using for liquid chromatography, Appendix II D, using the following
an excitation wavelength of 350 nm. The solution emits light solutions. For solution (1) shake one tablet in 0.5 mL of
at 445 nm. methanol for 3 minutes, add 9 mL of the mobile phase and
shake for 30 minutes. Filter to remove the tablet core, add
C. Dissolve a quantity of the powdered tablets containing
sufficient of the mobile phase to produce 10 mL, centrifuge
0.1 g of Potasstum Chloride as completely as possible in
II-222 Bupivacaine Preparations 2016
a
..
a8 ees
for 15 minutes and use the supernatant liquid. If the

Bupivacaine Injection
.
supernatant liquid is cloudy, filter through a 0.45-ym

ae he
TINE ‘ ysee
.
ee
hh
membrane filter (Millipore Millex is suitable), discarding the Action and use
bled
first 2 mL of filtrate. For solution (2) dilute 5 mL ofa Local anaesthetic.

to
0.1% w/v solution of bumetanide BPCRS in methanol to

100 mL with the mobile phase. DEFINITION
The chromatographic procedure described under Assay may Bupivacaine Injection is a sterile solution of Bupivacaine
be used. Hydrochloride in Water for Injections.
Calculate the content of C;7H2)>N2O;S in each tablet using The injection complies with the requirements stated under
the declared content of C;7H2)N205S in bumetanide BPCRS. Parenteral Preparations and with the following requirements.
The tablets comply with the test if not more than one of the Content of anhydrous bupivacaine hydrochloride,
individual es is outside the range 85% to 115% of the CisH.,N,O,HCl
average | d.ffene is outside the limits 75% to 125% of 92.5 to 107.5% of the stated amount.
the average é. If two or three individual values are
outside the 1 to 115% of the average value and CHARACTERISTICS
none is outside'the Jimits,75% to 125%, repeat the A colourless or almost colourless solution.
determination on a further 20 tablets taken at random. IDENTIFICATION
The tablets comply w t if in the total number of A. To a volume of the injection containing the equivalent of
tablets tested not more thanhrée.individual values are 25 mg of anhydrous bupivacaine hydrochloride add 2 mL of
outside the limits 85% to 1 5% none is outside the 13.5m ammonia, shake and filter. Wash the precipitate with
limits 75% to 125% of the aver. water and dry at 60° at a pressure of 2 kPa for 16 hours. The
ASSAY infrared absorption spectrum of the dried residue,
For bumetanide é Appendix IT A, is concordant with the reference spectrum of
Carry out the method for liquid chromatog: bupivacaine (RS 034).
Appendix III D, using the following solutio B. To a volume of the injection containing the equivalent of
(1) shake a number of whole tablets containitig 50 mg of anhydrous bupivacaine hydrochloride add 2 mL of
Bumetanide in 5 mL of methanol for 3 minutes, a 10% w/v solution of disodium hydrogen orthophosphate and
of the mobile phase and shake for 30 minutes. Filtef’to_ sufficient iodinated potassium todide solution to produce a
remove the tablet cores, add sufficient of the mobile pha: distinct brown colour. Remove the excess iodine by adding
produce 100 mL, centrifuge for 15 minutes and use the 0.1m sodium thiosulfate. No pink colour is produced.
supernatant liquid. If the supernatant liquid is cloudy, filte
through a 0.45-um membrane filter (Millipore Muillex is
suitable), discarding the first 2 mL of filtrate. For solution
(2) dilute 5 mL of a 0.1% w/v solution of bumetanide BPC'RS
in methanol to 100 mL with the mobile phase. Solution (3)
contains 0.005% w/v of 3-amino-4-phenoxy-5-sulfamoylbenzotic
acid BPCRS in solution (2).
water, if neceé
The chromatographic procedure may be carried out using
hydroxide unt 3 n is just alkaline and extract with
(a) a stainless steel column (12.5 cm x 4 mm) packed with
three 5 mL quantiti «ehloromethane. Dry the combined
octadecylsilyl silica gel for chromatography (5 um) (Lichrospher
100 RP-18 is suitable), (b) a mixture of 2 volumes of glacial
acetic acid, 5 volumes of tetrahydrofuran, 45 volumes of water
and 50 volumes of methanol as the mobile phase with a flow
residue in 2 mL of methanol, #dé€@°1 mL of a 1% w/v solution
rate of 1 mL per minute and (c) a detection wavelength of
of 4-dimethylaminobenzaldehyde inemetianeal and 2 mL of
254 nm. Inject separately 20 uL of each solution.
glacial acetic acid and allow to stand at roo
The Assay is not valid unless, in the chromatogram obtained 10 minutes. The yellow colour prod more intense
with solution (3), the resolution factor between the two fon using
than the colour produced by repeating the
principal peaks is at least 15. 10 mL of a solution in water containing 1 jg,
Calculate the content of C;7H.)N2OsS in the tablets using 2,6-dimethylaniline per mL in place of the injecti
the declared content of C;7H2)N205S in bumetanide BPCRS. (400 ppm). |
For potassium chloride Bupivacaine-related bases
Shake 20 whole tablets with 800 mL of water for 15 minutes, Carry out the method for thin-layer chromatography,
aaa
heating on a water bath if necessary, and allow to stand for Appendix III A, using silica gel G as the coating substance
wea ws
24 hours. Add sufficient water to produce 1000 mL, filter and a mixture of 0.1 volume of 13.5mM ammonia and
and dilute a portion of the filtrate to a suitable concentration. 100 volumes of methanol as the mobile phase but allowing
Carry out the method for atomic emission spectrophotometry, the solvent front to ascend 10 cm above the line of
Appendix IIT D, measuring at 766.5 nm and using potassium application. Apply separately to the plate 10 wL of each of
standard solution (600 ppm K), suitably diluted with water, to the following solutions. For solution (1) evaporate a volume
prepare the standard solutions. Each mg of potassium is of the injection containing the equivalent of 0.1 g of
equivalent to 1.908 mg of KCI. anhydrous bupivacaine hydrochloride using a rotary
evaporator, add sufficient methanol to the residue to produce
2 mL, mix, centrifuge and use the supernatant liquid.
Lea a
ne ns For solution (2) dilute 1 volume of solution (1) to
100 volumes with methanol. After removal of the plate, allow
it to dry in air and spray with dilute potassium iodobismuthate
2
:
any
“oy
2016 Bupivacaine Preparations III-223

.
.
a
.
solution. Any secondary spot in the chromatogram obtained evaporate the filtrate to dryness using a rotary evaporator and
:
with solution (1) is not more intense than the spot in the dry at 60° at a pressure of 2 kPa for 16 hours. The infrared
‘
bee ee
‘
ree
chromatogram obtained with solution (2) (1%). absorption spectrum of the dried residue, Appendix IT A, is
a
concordant with the reference spectrum of bupivacaine

Or
ASSAY
say
4
(RS 034).
’
Appendix III D, using the following solutions. For solution B. Dip, for 1 second, a suitable stick with a reactive pad
(1) dilute a quantity of the injection with sufficient of the containing glucose-oxidase, peroxidase and a hydrogen-
mobile phase to produce a solution containing 0.0025% w/v donating substance, such as tetramethylbenzidine, in the
of anhydrous bupivacaine hydrochloride. Solution (2) injection. Observe the colour of the reactive pad; within
contains 0.0025% w/v of bupivacaine hydrochloride BPCRS in 60 seconds the colour changes from yellow to green or blue.
the mobile phase. For solution (3) prepare a 0.1% w/v C. In the Assay for bupivacaine, the chromatogram obtained
6-dimethylanilinein acetonitrile, dilute 10 volumes with solution (1) shows a peak with the same retention time
th the mobile phase and then dilute as the principal peak in the chromatogram obtained with
solution (2).
D. When heated with cupri-tartaric solution R1, a copious
precipitate of copper(/) oxide is produced.
(30 cm x 3.9 mm) packed with TESTS
: gel Jor chromatography (10 pm)
Acidity
“€b) a mixture of 40 volumes of
1 60 volumes of acetonitrile
rat®of 1mL per minute and 2,6-Dimethylaniline
(c) a detection wavelength i To 27.6g of sodium dihydrogen phosphate monohydrate add
solution. 7 mL of a solution containing 8.9% of disodium hydrogen
orthophosphate dihydrate and add sufficient water to produce
The test is not valid unless in the chr
1000 mL, if necessary adjust the pH to 5.0 using
with solution (3) the resolution factor b
1m orthophosphoric acid or 1M sodium hydroxide (buffer
principal peaksis at least 8.
solution).
hydrochlonde BPCRS.
phase.
LABELLING 1 Dilute a volume of the injection with mobile phase if
The strength is stated in terms of the equivalent amount Sssary to contain 0.5% w/v of Bupivacaine Hydrochloride
anhydrous bupivacaine hydrochloride in a suitable dose-
04% w/v of 2,6-dimethylaniline.
volume.
2% w/v of 2,6-dimethylaniline and 0.0002% w/v
Bupivacaine Heavy Injection

Bupivacaine and Dextrose Injection; Bupivacaine and
Glucose Injection
(b) Use isocratic
below.
Action and use
Local anaesthetic.
DEFINITION
Bupivacaine Heavy Injection is a sterile solution of ilver-silver chloride
Bupivacaine Hydrochloride and either Anhydrous Glucose or reference electrode, held at + 0.9 Vv tential, and
Glucose in Water for Injections. No preservative is added. a detector sensitivity of 20 nA/V.
The inclusion of glucose in the formulation assists the
(f) Inject volume of 20 pL of each solution
gravitational flow of the injection when administered.
Under the prescribed conditions the retention e
2,6-dimethylaniline is about 6.5 minutes.
MOBILE PHASE
Content of bupivacaine hydrochloride,
C,3H2sN,0,HC1,H,O A mixture of 4 volumes of acetonitrile and 6 volumes of buffer
95.0 to 105.0% of the stated amount. solution containing 0.006% w/v disodium edetate and
0.055% w/v tetrabutylammonium hydrogen sulfate R1.
Content of glucose monohydrate, C;H;.0¢,H,O
72.0 to 88.0 mg per mL. SYSTEM SUITABILITY
CHARACTERISTICS
with solution (3), the resolution factor between the peaks
A clear, colourless solution.
corresponding to 2,6-dimethylaniline and 4-chloroaniline is at
IDENTIFICATION least 1.5.
A. To a volume of the injection containing 50 mg of
CHROMATOGRAPHY
Bupivacaine Hydrochloride add sufficient 2M sodium hydroxide
to obtain a pH of 11 and extract with 25 mL of n-heptane. In the chromatogram obtained with solution (1):
Dry the heptane extract over anhydrous sodium sulfate, filter,
IWI-224 Bupivacaine Preparations 2016
the area of any peak corresponding to 2,6-dimethylaniline is DETERMINATION OF CONTENT

not greater than the area of any corresponding peak in the Calculate the content of C;3H23;N,O,HCI,H.O in the
chromatogram obtained with solution (2) (800 ppm). injection using the declared content of C;gH»3N,O,HCI,H,O
5-Hydroxymethylfurfural and light absorbing in bupivacaine hydrochloride BPCRS.
impurities For glucose
Dilute a volume of the injection containing 1.0 g of Glucose To a quantity containing the equivalent of 2 to 5 g of
Monohydrate to 250 mL with water. The absorbance of the glucose, CgH)20,, add 0.2 mL of 5M ammonia and
resulting solution at the maximum at 284 nm is not more sufficient water to produce 100 mL. Mix well, allow to stand
than 0.25, Appendix II B. for 30 minutes and measure the optical rotation in a 2-dm
Related substances tube, Appendix V F. The observed rotation in degrees
To 0.18g of sodium dihydrogen phosphate monohydrate and multiplied by 0.9477 represents the weight in g of glucose,
iy hydrogen orthophosphate dihydrate add C.5H,20¢, in the quantity of the injection taken for assay.
..fiFaduce 1000 mL, if necessary adjust the LABELLING
The strength is stated in terms of the equivalent amount of
bupivacaine hydrochloride and in terms of the equivalent
amount of glucose, CgH 20, in a suitable dose-volume.
IMPURITIES
(1) Dilute a volume of the injeetign if necessary to contain
0.5% w/v of Bupivacaine E ride. CH;
(2) Dilute 1 volume of solutic NH
(3) Dilute 1 volume of solution
CH;
(a) Use a stainless steel column (15 cm x packed
with octadecylsilyl sihca gel for chromatograp
A. 2,6-Dimethylaniline,
(uBondapak is suitable).
B. 5-hydroxymethylfurfural.
below.
(c) Flow rate of 1.5 mL per minute.
vacaine and Adrenaline Injection
(e) Use a detection wavelength 240nm.
acaine and Epinephrine Injection
MOBILE PHASE
A mixture of 4 volumes of buffer solution and 6 volumes of
acetonitrile.
LIMITS
In the chromatogram obtained with solution (1): Bupivacaine Hydre :

the area of any secondary peak is not greater than the area of Water for Injections.
the total area of any secondary peaks is not greater than twice Content of anhydrous bupivac e hydrochloride,
the area of the principal peak in the chromatogram obtained C ishhosN30 sHCl1 ae
with solution (2) (1.0%); 92.5 to 107.5% of the stated amoun:
Disregard any peak with an area less than that of the Content of adrenaline, Co)H,;NO3
principal peak in the chromatogram obtained with solution 80.0 to 120.0% of the stated amount.
(3) (0.05%) and any peak corresponding to
2,6-dimethylaniline. CHARACTERISTICS
ASSAY
For bupivacaine hydrochloride IDENTIFICATION
Carry out the method for liquid chromatography, A. Carry out the method for thin-layer chromatography,
Appendix III D, using the following solutions in the mobile Appendix III A, using a silica gel precoated plate (Merck
phase. silica gel G60 plates are suitable) and a mixture of 5 volumes
of methanol and 95 volumes of dichloromethane as the mobile
(1) Dilute a volume of the injection if necessary to contain
phase. Apply separately to the plate 5 wL of each of the
0.05% w/v of Bupivacaine Hydrochloride.
following solutions. For solution (1) dilute a quantity of the
(2) 0.05% w/v of bupivacaine hydrochloride BPCRS.
injection, if necessary, with water to produce a solution
CHROMATOGRAPHIC CONDITIONS containing 0.2% w/v of Bupivacaine Hydrochloride. Solution
The chromatographic conditions described under Related (2) contains 0.2% w/v of bupivacaine hydrochloride BPCRS in
substances may be used. water. Solution (3) contains 0.2% w/v of bupivacaine
hydrochloride BPCRS and 0.2% w/v of lidocaine
hydrochloride BPCRS in water. After removal of the plate, dry
it in a current of cold air, heat at 110° for 1 hour, place the
hot plate in a tank of chlorine gas prepared by the addition
2016 Bupivacaine Preparations ITI-225
of hydrochloric acid to a 5% w/v solution of potassium LABELLING

ae al\
permanganate contained in a beaker placed in the tank and The quantities of the active ingredients are stated in terms of
we AS
allow to stand for 2 minutes. Dry the plate in a current of the equivalent amounts of anhydrous bupivacaine
cold air until an area of the plate below the line of hydrochloride and adrenaline (epinephrine).
application gives at most a very faint blue colour with a
0.5% w/v solution of potassium todide in starch mucilage; avoid
prolonged exposure to cold air. Spray the plate with a
0.5% w/v solution of potasstum todide in starch mucilage.
The principal spot in the chromatogram obtained with Bupivacaine and Diamorphine Injection
solution (1) corresponds to that in the chromatogram NOTE: Bupivacaine and Diamorphine Injection 1s not currently
obtained with solution (2). The test is not valid unless the licensed in the United Kingdom.
chromategram obtained with solution (3) shows two clearly
incipal spots. Action and use
Spinal anaesthetic; analgesic.
DEFINITION
the chromatogram obtained with
Bupivacaine and Diamorphine Injection is a sterile solution
solution (1).
of Bupivacaine Hydrochloride and Diamorphine
TESTS Hydrochloride, made isotonic with Sodium Chloride, in
Acidity Water for Injections.
pH, 3.0 to 5.5, Append: The injection complies with the requirements stated under
2,6-Dimethylaniline; Related bases Parenteral Preparations, the requirements stated under Unlicensed
Complies with the requireménts..st: der Bupivacaine Medicines and with the following requirements.
Injection. Content of anhydrous bupivacaine hydrochloride,
ASSAY . C,3sH23sN,O0,HCI
For anhydrous bupivacaine hydrochiag 95.0 to 105.0% of the stated amount.
Carry out the Assay described under Bupiv Content of diamorphine hydrochloride,
For adrenaline C,,H2,3NO;,HCI1,H,O
Dissolve 8.0 g of tetramethylammonium hydrogen sulfate
of sodium heptanesulfonate and 2 mL of 0.1M disodium *®: IDENTIFICATION
in a mixture of 900 mL of water and 100 mL of methan In the Assay, the retention times of the two principal
adjust the pH to 3.5 with 1M sodium hydroxide and filter eaks:.in the chromatogram obtained with solution (1)
through glass micro fibre paper under reduced pressure espond to those in the chromatogram obtained with
(solution A). Carry out the method for liguid chromatography, (4).
(1) dilute 5 mL of a 0.001% w/v solution of adrenaline acid
tartrate BPCRS to 10 mL with solution A. For solution (2)
dilute the injection, if necessary, to produce a solution
containing the equivalent of 0.0005% w/v of adrenaline and
dilute 5 mL of the resulting solution to 10 mL with solution
A. For solution (3) mix 5 mL of solution (1) with 5 mL ofa Carry out the method f
0.001% w/v solution of noradrenaline acid tartrate in the Appendix III D, using
mobile phase. solution of sodium chlor
The chromatographic procedure may be carried out using (1) Dilute a quantity of the sto produce a solution
(a) a stainless steel column (10 cm x 4.6 mm) packed with containing the equivalent of 0.0: v of anhydrous
end-capped octadecylsilyl silica gel for chromatography (5 um) bupivacaine hydrochloride.
(Nucleosil C18 is suitable), (b) as the mobile phase with a
flow rate of 2 mL per minute a solution prepared by adding
4.0 g of tetramethylammonium hydrogen sulfate, 1.1 g of sodium
heptanesulfonate and 2 mL of 0.1M disodium edetate to a
mixture of 950 mL of water and 50 mL of methanol and (3) and add sufficient of a 0.9% w/v solution of sodium
adjusting the pH of the mixture to 3.5 with 1m sodium chloride to produce 25 volumes.
hydroxide and (c) a detection wavelength of 205 nm. CHROMATOGRAPHIC CONDITIONS
The test is not valid unless the resolution factor between the (a) Use a stainless steel column (25 cm x 4.6 mm) packed
two principal peaks in the chromatogram obtained with with end-capped octadecylsilyl silica gel for chromatography
solution (3) is at least 2.0. (5 um) (Spherisorb ODS2 is suitable).
Calculate the content of Cp)H,;3NO3 1n the injection using the (b) Use isocratic elution and the mobile phase described
declared content of C9H,3NO3 in adrenaline acid below.
tartrate BPCRS. (c) Use a flow rate of 1 mL per minute.
STORAGE (d) Use a column temperature of 30°.
Bupivacaine and Adrenaline Injection should be protected (e) Use a detection wavelength of 260 nm.
from light. (f) Inject 10 wL of each solution.
conditions, the retention time of diamorphine hydrochloride
IWI-226 Bupivacaine Preparations 2016
is about 3.5 minutes and the retention time of bupivacaine CHROMATOGRAPHIC CONDITIONS
hydrochloride is about 5.5 minutes. (a) Use a stainless steel column (15 cm x 4.6 mm) packed
MOBILE PHASE with base-deactivated octadecylsilyl silica gel for chromatography
(5 um) (ProntoSIL C18 EPS is suitable).
45 volumes of acetonitrile and 55 volumes of 0.01M sodium
heptanesulfonate, containing 0.0075mM N,N-dimethyloctylamine, (b) Use isocratic elution and the mobile phase described
which has been adjusted to pH 3.0 with orthophosphoric acid. below.
DETERMINATION OF CONTENT (c) Use a flow rate of 1.5 mL per minute.

Calculate the content of C;gH»3N,O,HC!I and of (d) Use an ambient column temperature.
C,,H»3NO;,HCI,H,O in the injection using the declared (e) Use a detection wavelength of 206 nm.
content of CygH»sN.O,HCl in bupivacaine (f) Inject 10 wL of each solution.
hydrochloride BPCRS and the declared content of
MOBILE PHASE
0.4 volumes of orthophosphoric acid, 30 volumes of acetonitrile

R1 and 70 volumes of water.
Bupivacaine an
LIMITS
from light. |
LABELLING
the area of any secondary peak 1s not greater than 0.3% by
The label states that the } nsis intended for epidural
normalisation;
administration. The quanti ivacaine Hydrochloride is
stated in terms of the equiv t of anhydrous the sum of the areas of any such peaks is not greater than
1.0% by normalisation.
bupivacaine hydrochloride.
Disregard any peak corresponding to the principal peak in
ASSAY
Bupivacaine and Fentanyl Injec For anhydrous bupivacaine hydrochloride

Dilute a quantity of the injection to contain the equivalent of
Action and use 0.005% w/v of anhydrous bupivacaine hydrochloride with
Spinal anaesthetic; analgesic. 0.01m hydrochloric acid. Measure the absorbance of the
esulting solution at the maximum at 263 nm,
DEFINITION Appendix II B. Calculate the content of C}gH»sN.O,HCl
Bupivacaine and Fentanyl Injection is a sterile solution of K s the value of A(1%, 1 cm) at the maximum at
Bupivacaine Hydrochloride and Fentanyl Citrate, made
isotonic with Sodium Chloride, in Water for Injections. l
The injection complies with the requirements stated under ie method for liquid chromatography,
Content of anhydrous bupivacaine hydrochloride,
C,3H23N,0,HCI1 sufficient of a
95.0 to 105.0% of the stated amount. a solution containsfig
fentanyl.
Content of fentanyl, C,,H,,;N,O
IDENTIFICATION
een
aw
350 nm of the solution obtained in the Assay for anhydrous
bupivacaine hydrochloride exhibits two maxima, at 263 nm
and at 271 nm. CN is suitable).
B. In the Assay for fentanyl, the chromatogram obtained with (b) Use isocratic elution and the mobile p
solution (1) shows a peak with the same retention time as the below.
principal peak in the chromatogram obtained with (c) Use a flow rate of 1 mL per minute.
solution (2). (d) Use an ambient column temperature.
C. Yields reaction A characteristic of chlorides and reaction B (e) Use a detection wavelength of 206 nm.
characteristic of cztrates, Appendix VI.
TESTS MOBILE PHASE
Acidity
7 volumes of 0.1M sodium heptanesulfonate containing
0.011% w/v of N,N-dimethyloctylamine, adjusted to pH 3.0
Related substances (anhydrous bupivacaine with orthophosphoric acid, 30 volumes of acetonitrile R1 and
hydrochloride) 63 volumes of water.
Calculate the content of C,,H»3N,O in the injection using
(1) Use the injection being examined.
the declared content of C2.H.3N.O in fentanyl
(2) 0.0004% w/v of fentanyl citrate BPCRS in a 0.9% wiv citrate BPCRS.
solution of sodium chloride.
rT wm
2016 Buprenorphine Preparations TI-227
LABELLING Time Mobile phase A _—- Mobile phase B Comment

The quantities of the active ingredients are stated in terms of (Minutes) (% viv) (% viv)
ven
the equivalent amounts of anhydrous bupivacaine 0-2 89 44 isocratic
hydrochloride and fentanyl. 2-12 89-364 11-36 linear gradient
Sante!
12-15 6441 36-59 isocratic
Buprenorphine Injection |
" . " 20-21 39-89 6111 linear gradient
Action and use

Opioid receptor partial agonist; analgesic.
SYSTEM SUITABILITY
wets el
nection is a sterile solution containing with solution (3), the resolution factor between the peaks due
iydrochloride. to buprenorphine and buprenorphine impurity J is at least
The inyjection’co twith the requirements stated under 3.0.
Parenteral Prep with the following requirements. LIMITS
Content of bupren Identify any peak corresponding to impurity G using solution
95.0 to 105.0% of th (3) and multiply the area of this peak by a correction factor
IDENTIFICATION of 0.3.
0.3 mg of buprenorphine ade the area of any secondary peak is not greater than the area of
dilute hydrochloric acid to turn litmus’ p the principal peak in the chromatogram obtained with
of potassium todobismuthate solution. An. solution (2) (0.5%);
is formed. the sum of the areas of any other secondary peaks is not
solution (2). principal peak in the chromatogram obtained with
TESTS solution (4) (0.1%).
Acidity
pH 3.5 to 5.5, Appendix V L. ut the method for liguid chromatography,
Related substances ix III D, using the following solutions.
(1) Dilute a quantity of the injection, if necessary, with
sufficient methanol to produce a solution containing the (2) 0.01%
equivalent of 0.03% w/v of buprenorphine and filter. methanol.
(2) Dilute 1 volume of solution (1) to 100 volumes with (3) 0.05% wiv o
methanol, further dilute 1 volume of this solution to methanol.
2 volumes with methanol.
(3) 0.05% w/v of buprenorphine for system suitability EPCRS in
methanol.
SYSTEM SUITABILITY
methanol.
The test is not valid unless, in the c tog
with solution (3), the resolution factor between
(a) Use a stainless steel column (50 mm x 4.6 mm) packed
with octadecylsilyl sihca gel for chromatography (3.5 wm) 3.0.
(Waters SunFire C18 is suitable).
Calculate the content of C.9H4,;NO, 1n the injection using
below.
the declared content of C29H4;NO,,HCI in buprenorphine
(c) Use a flow rate of 1.3 mL per minute. hydrochloride BPCRS. Each mg of Cx9H4,NO4,HCl1 is
(d) Use a column temperature of 30°. equivalent to 0.9276 mg of C59H4,;NQOx,.
LABELLING
(f) Inject 20 uwL of each solution. The quantity of the active ingredient is stated in terms of the
MOBILE PHASE equivalent amount of buprenorphine.
a 0.544% w/v solution of potassium dihydrogen orthophosphate
previously adjusted to pH 4.5 with dilute orthophosphoric acid.
veto
nA a
a Mobile phase B acetonitrile
eee
we aed
ee al
IWI-228 Buprenorphine Preparations 2016
Buprenorphine
|
Transdermal Patches Minutes)
Time
mata
Mobile phase A
ata
Mobile phase B Comment
Ne,
Action and use 0-2 89 11 isocratic

Opioid receptor partial agonist; analgesic. 2-12 89-64 11336 linear gradient
Buprenorphine Transdermal Patches contain Buprenorphine 18-20 41-939 59461 linear gradient
in a suitable matrix or reservoir presentation. 20-21 39-89 6111 linear gradient
PRODUCTION 21-30 89 14 re-equilibration
release of buprenorphine.
SYSTEM SUITABILITY
al, patches comply with the requirements stated
al. Patches and with the following requirements. The test is not valid unless, in the chromatogram obtained
to buprenorphine and buprenorphine impurity J is at least
3.0.
IDENTIFICATIO. LIMITS
A. Evaporate 10 mL'6
Identify any peak corresponding to impurity G using solution
of potasstum todobismuthate s (3) and multiply the area of this peak by a correction factor
is formed. of 0.3.
B. In the Assay, the retention tit the area of any secondary peak is not greater than the area of
the chromatogram obtained with solutién the principal peak in the chromatogram obtained with
that of the principal peak in the chromatopr: solution (2) (1%);
solution (2). | the sum of the areas of any other secondary peaks is not
greater than three times the area of the principal peak in the
TESTS
Related substances
(1) Remove the release liners from the patches. Mix, with the:
aid of ultrasound, a quantity of whole patches with sufficient
methanol to produce a solution containing 0.1% w/v of
Buprenorphine.
ntent of each dosage unit and using the
fod. of analysis.
methanol.
d fer hgqud chromatography,
(3) 0.1% w/v of buprenorphine for system suitability EPCRS in
: the following solutions.
methanol.
(1) Remove the réleas from the patch. Place the patch
in a flask containing suf it, methanol to produce a solution
methanol.
containing 0.1% w/v of |] hine, mix with the aid of
CHROMATOGRAPHIC CONDITIONS ultrasound and filter.
(a) Use a stainless steel column (50 mm x 4.6 mm) packed (2) 0.01% w/v of buprenorphitie:sdrochloride BPCRS in
with octadecylsilyl silica gel for chromatography (3.5 um) methanol. :
(Waters Sunfire C18 is suitable). (3) 0.1% wy of buprenorphine for sysi
(b) Use gradient elution and the mobile phase described methanol.
below.
The chromatographic conditions described urider
(d) Use a column temperature of 30°. substances may be used.
SYSTEM SUITABILITY
(f) Inject 10 wL of each solution. The test is not valid unless, in the chromatogram obtained
MOBILE PHASE with solution (3), the resolution factor between the peaks due
Mobile phase A 10 volumes of acetonitrile and 90 volumes of to buprenorphine and buprenorphine impurity J is at least
a 0.544% w/v solution of potassium dihydrogen orthophosphate 3.0.
previously adjusted to pH 4.5 with dilute orthophosphonic acid. DETERMINATION OF CONTENT
Mobile phase B_ acetonitrile Calculate the content of Cz9H,4,;NO, in the transdermal
patch using the declared content of C.9H4,;NO,4,HCl in
buprenorphine hydrochloride BPCRS. Each mg of
C49H4,NO,4,HCI is equivalent to 0.9276 mg of CooH4;NOx.
ASSAY
Use the average of the 10 results obtained in the test for
se! 90"70"rl Uniformity of content.
2016 Buprenorphine Preparations II-229
Buprenorphine Sublingual Tablets SYSTEM SUITABILITY

Action and use with solution (3), the resolution factor between the peaks due
Opioid receptor partial agonist; analgesic. to buprenorphine and buprenorphine impurity J is at least
3.0.
DEFINITION LIMITS
Buprenorphine Sublingual Tablets contain Buprenorphine
Hydrochloride. They may be flavoured.
Identify any peak corresponding to impurity G using solution
The tablets comply with the requirements stated under Oromucosal
(3) and multiply the area of this peak by a correction factor
of 0.3.
Content of buprenorphine, C,5H,,;,NO,
90.0 toxiQ5.0% of the stated amount. the principal peak in the chromatogram obtained with
solution (2) (2%);
the area of not more than one secondary peak is greater than
half the area of the principal peak in the chromatogram
obtained with solution (2) (1%);
is formed. three times the area of the principal peak in the
B. In the Assay, the chromatogram obtained with solution (2) (6%).
the chromatogram obtaii Disregard any peak with an area less than the area of the
that of the principal peak 1 principal peak in the chromatogram obtained with
Pe et
solution (2). solution (4) (0.1%).
TESTS
eee AN
Related substances Tablets containing less than 2 mg and/or 2% w/v of
Carry out the method for liquid chromatégr Buprenorphine Hydrochloride comply with the requirements
Appendix III D, using the following soluti stated under Tablets using the following method of analysis.
(1) Mix, with the aid of ultrasound, a quantity ofthe Carry out the method for liquid chromatography,
powdered tablets containing the equivalent of 4 mg. Appendix III D, using the following solutions.
buprenorphine with 4 mL of methanol and filter. — (1) To one tablet add 1 mL of methanol, mix with the aid of
(2) Dilute 2 volumes of solution (1) to 100 volumes wi rasound and add sufficient mobile phase to produce a
methanol.
(3) 0.1% w/v of buprenorphine for system suitability EPCRS in orphine.
methanol. 4% wiv of buprenorphine hydrochloride BPCRS in
methanol.
(a) Use a stainless steel column (50 mm x 4.6 mm) packed

with octadecylsilyl sihca gel for chromatography (3.5 wm) cedure described under Related
(Waters Sunfire C18 is suitable). nject 25 uL of each solution.
(b) Use gradient elution and the mobile phase described SYSTEM SUITABILIT
below.
Nee
The test is not valid unl
“Newey
(d) Use a column temperature of 30°. to buprenorphine and buprenor

(e) Use a detection wavelength of 240 nm. 3.0.
(f) Inject 10 pL of each solution. DETERMINATION OF CONTENT
MOBILE PHASE Calculate the content of C,9H4,NO, in e&

ht
Mobile phase A 10 volumes of acetonitrile and 90 volumes of declared content of C29H4;,NO,4,HCI in bup;
a 0.544% w/v solution of potassium dihydrogen orthophosphate hydrochloride BPCRS. Each mg of Cz9H4;NOsHICl i
equivalent to 0.9276 mg of Cy9H4,;NOxq.
previously adjusted to pH 4.5 with dilute orthophosphoric acid.
SPA LS
Mobile phase B acetonitrile ASSAY
For tablets containing less than 2 mg and/or 2% w/v of
awn
rheteS ate
Buprenorphine Hydrochloride
«wen
wl
ne

0-2 89 11 isocratic
For tablets containing 2 mg or more, or 2% w/v or
2-12 89-64 1136 linear gradient more of Buprenorphine Hydrochloride
12-15 64-41 3659 isocratic Carry out the method for liquid chromatography,

Tepe els
tw ANS
aw yee Aw
ay eat
oe powdered tablets containing the equivalent of 2 mg of
wn we
Pet a
A 21-30 89 11 re-equilibration
NW
.e moe
wl
swe we
II-230 Busulfan Preparations 2016
buprenorphine with 10 mL of methanol, add sufficient shake vigorously for 1 minute and allow to separate. Use the
methanol to produce 20 mL and filter. hexane layer.
(2) 0.01% w/v of buprenorphine hydrochloride BPCRS in (2) Prepare solution (2) in the same manner as solution (3)
methanol. but using 10 mL of acetone in place of solution A.
(3) 0.1% w/v of buprenorphine for system suitability EPCRS in (3) Add 1 mL of water to one tablet in a 50 mL graduated
methanol. flask and mix with the aid of ultrasound until completely
dispersed. Add 30 mL of acetone, shake for 15 minutes and
dilute to 50 mL with acetone. Centrifuge and dilute a
The chromatographic procedure described under Related
quantity of the supernatant liquid with acetone to produce a
solution containing 0.0001% w/v of Busulfan. To 5 mL of
SYSTEM SUITABILITY the resulting solution add 5 mL of a 30% w/v solution of
The test is not valid unless,
iin the chromatogram obtained sodium todide in acetone, stopper the flask lightly and heat in a
water bath at 50° for 90 minutes. Cool, add 10 mL of
solution A, mix, add 10 mL of water and 20 mL of hexane,
shake vigorously for 1 minute and allow to separate. Use the
hexane layer.
sHC]in buprenorphine (a) Use a glass column (1.5 m x 4 mm) packed with acid-
Ee a9H4,;NO,,HCl is washed, diatomaceous support (80 to 100 mesh) coated with
O4. 3% w/w of phenyl methyl silicone fluid (50% phenyl) (OV-
17 is suitable).
(b) Use helium as the carrier gas at 1.7 mL per minute.
znwal
equivalent amount of buprenorphine. (c) Use isothermal conditions maintained at 140°.
(e) Use an electron capture detector.
Busulfan Tablets DETERMINATION OF CONTENT
Action and use Calculate the content of CsH,,0,¢S, using the declared
ontent of CgH,40¢S> in busulfan BPCRS.
Cytotoxic alkylating agent.
DEFINITION powder 20 tablets. Carry out the method for gas

Busulfan Tablets contain Busulfan. They are coated. phy, Appendix III B, using the following
The tablets comply with the requirements stated under Tablets and gepare a 0.0001% w/v solution of
Content of busulfan, C;H,,0,S>,
5 stopper the flask lightly and heat
IDENTIFICATION
90 minutes. Cool, add 10 mL of
A. Shake a quantity of the powdered tablets containing
10 mg of Busulfan with 10 mL of hot acetone, filter and
evaporate the filtrate to dryness. Dry the residue at 60° at a
hexane layer.
pressure not exceeding 0.7 kPa for 1 hour. The infrared
absorption spectrum of the residue, Appendix II A, is (2) Prepare solution (2) in
concordant with the reference spectrum of busulfan (RS 035). but using 10 mL of acetone in place

ultrasound until completely dispersed. Add
solution (1). acetone, shake for 15minutes and dilute to 25:
TESTS liquidtto 100 mL with acetone. To 5 mL of the vesufting
Disintegration solution add 5 mL of a 30% w/v solution of sodium todide in
re
acetone, stopper the flask lightly and heat in a water bath at

Uniformity of content 50° for 90 minutes. Cool, add 10 mL of solution A, mix, add
Tablets containing less than 2 mg and/or less than 2% w/w 10 mL of water and 20 mL of hexane, shake vigorously for
of Busulfan comply with the requirements stated under 1 minute and allow to separate. Use the hexane layer.
Tablets using the following method of analysis. Carry out the CHROMATOGRAPHIC CONDITIONS
method for gas chromatography, Appendix III B, using the
The chromatographic conditions described under Uniformity
following solutions. Prepare a 0.0001% w/v solution of
1,5-di-todopentane (internal standard) in acetone (solution A).
(1) Add 5 mL of a 30% w/v solution of sodium iodide in
acetone to 5 mL of a 0.0001% w/v solution of Calculate the content of CsH,,0,S. using the declared
busulfan BPCRS in acetone, stopper the flask lightly and heat content of CgH,40.S>, in busulfan BPCRS.
in a water bath at 50° for 90 minutes. Cool, add 10 mL of
solution A, mix, add 10 mL of water and 20 mL of hexane,
2016 Caffeine Preparations III-231
LABELLING
Caffeine Citrate Injection The label states the quantity of active ingredient in terms of
Action and use the amount of caffeine citrate and the equivalent amount of
caffeine.
Ne NG
Central nervous system stimulant.
DEFINITION
Caffeine Citrate Injection is a sterile solution of caffeine
citrate, prepared by the interaction of Caffeine and Citric
Acid Monohydrate, in Water for Injections.
Caffeine Citrate Oral Solution
The injection complies with the requirements stated under Action and use
Parenteral Preparations and with the following requirements. Central nervous system stimulant.
DEFINITION
Caffeine Citrate Oral Solution is a solution of caffeine citrate,
prepared by the interaction of Caffeine and Citric Acid
Monohydrate, in a suitable aqueous vehicle.
Liquids and with the following requirements.
(1) shows a principal ps the same retention time as
Content of caffeine citrate, CsH,)N,O02,C;HsO,
the principal peak in th fSindtegram obtained with 95.0 to 105.0% of the stated amount.
solution (2).
IDENTIFICATION
B. Yields the reaction chara ates, Appendix VI.
san aad
TESTS (1) shows a principal peak with the same retention time as
Acidity the principal peak in the chromatogram obtained with
pH, 4.2 to 5.2, Appendix V L. solution (2).
ASSAY B. Yields the reaction characteristic of citrates, Appendix VI.
Carry out the method for liquid chromatography, é ASSAY
Appendix III D, using the following solutions. Carry out the method for liguid chromatography,
(1) To a volume of the injection containing the equiva! Appendix III D, using the following solutions.
50 mg of caffetne add 250 mL of water and filter througi ilute a weighed quantity of the oral solution containing
0.45-um filter. ivalent of 50 mg of caffeine to 250 mL with water and
(2) 0.02% w/v of caffeine BPCRS in water. ough a 0.45-um filter.
(3) 0.02% w/v of caffeine BPCRS and 0.0004% w/v of % wiv of caffeine BPCRS in water.
theophylline in water.
(a) Use a stainless steel column (15 cm x 4.6 mm) packed CONDITIONS
with octadecylsilyl sihca gel for chromatography (5 um) el column (15 cm x 4.6 mm) packed
(Supelcosil LC-18-DB is suitable). gei.for chromatography (5 wm)
(b) Use isocratic elution and the mobile phase described (Supelcosil LC-18- : ble).
below. tic elu tio e mobile phase described
(b) Use isocra
(c) Use a flow rate of 1 mL per minute. below.
(f) Inject 10 wL of each solution. (e) Use a detection wavelength of 2
MOBILE PHASE (f) Inject 10 wL of each solution.
4 volumes of tetrahydrofuran, 5 volumes of acetonitrile and MOBILE PHASE
191 volumes of 0.01M sodium acetate, adjusted to pH 4.5 with 4 volumes of tetrahydrofuran, 5 volumes of aceténitri
glacial acetic acid. 191 volumes of 0.01M sodium acetate, adjusted to pH 4.5 with
SYSTEM SUITABILITY glacial acetic acid.
The assay is not valid unless, in the chromatogram obtained SYSTEM SUITABILITY
with solution (3), the resolution factor between the peaks due The assay is not valid unless, in the chromatogram obtained
to caffeine and theophylline is at least 6.0. with solution (3), the resolution factor between the peaks due
DETERMINATION OF CONTENT to caffeine and theophylline is at least 6.0.
Calculate the content of CgH;9N4O02,C¢HgO7 in the DETERMINATION OF CONTENT
injection using the declared content of CgH,)N,O, in Determine the weight per mL of the oral solution,
caffene BPCRS. Each mg of CgH;9N4Oz is equivalent to Appendix V G, and calculate the content of
2 mg of CgH,oN4O2,Ce6Hg07, CgH i 9N402,;C.HgO-7, weight in volume, using the declared
content of CgH;)N4O> in caffeine BPCRS. Each mg of
CgHi9N4O> 1S equivalent to 2 mg of CgH)9N402,C6Hg07,
IWI-232 Calamine Preparations 2016
LABELLING Triturate the Calamine, the Zinc Oxide and the Bentonite
The quantity of active ingredient is stated in terms of the with a solution of the Sodium Citrate in about 700 mL of
amount of caffeine citrate and the equivalent amount of the Purified Water and add the Liquefied Phenol, the
ee ee!
caffeine. Glycerol and sufficient Purified Water to produce 1000 mL.
Cutaneous Application and with the following requirements.
IDENTIFICATION
Aqueous Calamine Cream A. To 2 mL add 2 mL of pertodic acid reagent, shake,
DEFINITION centrifuge and add 0.5 mL of the supernatant liquid to 2 mL
of ammomiacal silver nitrate solution in a test tube. Heat on a
Aqueous Calamine Cream contains 4% w/w of Calamine and
water bath at 70° for 5 minutes. A silver mirror is produced
3% wiw of 44nc Oxide in a suitable oil-in-water emulsified
on the side of the tube.
B. Mix 2 mL with 50 mL of water, centrifuge and decant the
supernatant liquid. Suspend the residue in 20 mL of water,
add 1 mL of hydrochloric acid, mix and filter. 5 mL of the
Calamine 40g
filtrate, after neutralisation by drop wise addition of
Zinc Oxide 30g
2M sodium hydroxide, yields the reaction characteristic of zinc
Liquid Paraffin 200 g
salts, Appendix VI.
Self-emulsifying Glycery 50 g
Monostearate Residue on ignition
Cetomacrogol Emulsifying 14.5 to 18.0% w/w when determined by the following
Wax ots. method. Evaporate 5 g to dryness and ignite until, after
Phenoxyethanol | further ignition, two successive weighings do not differ by
Purified Water, freshly more than 0.2% of the weight of the residue.
boiled and cooled
emulsifying Glyceryl Monostearate, add the Liqus |

and heat to about 60°. Dissolve the Phenoxyethanol., Calamine Ointment
620 g of Purified Water at about 60°, add the oily phase’
DEFINITION
the phenoxyethanol solution and mix. Stir until cool, add
sufficient Purified Water to produce 930 g and mix. Tritu calamine Ointment contains 15% w/w of Calamine in a
the Calamine and the Zinc Oxide and incorporate in the ydrophobic basis.
cream. aneous preparation
Semi-solid Preparations and with the following requirements. 150 ¢g
850 g
Content of zinc, Zn
4.3 to 5.2% wiw.
IDENTIFICATION
White SoftParat
The residue obtained in the Assay is yellow when hot and
The ointment complies requirements stated under Topical
white when cool.
Semi-solid Preparations aa following requirements.
ASSAY
Content of zinc, Zn
Gently heat 4 g, taking precautions to avoid loss caused by 7.8 to 9.4% wiw.
spitting, until the basis is completely volatilised or charred,
IDENTIFICATION .
increase the temperature until the carbon is removed and
ignite the residue to constant weight. Each g of residue is The residue obtainedin theAssay i is yelloy when hot and
equivalent to 0.8034 g of Zn. white when cool.
ASSAY
Gently heat 1 g until the basisis completely vola il
charred, increase the heat until all the carbonisremg
Calamine Lotion ignite the residue until, after further ignition, two successive
weighings do not differ by more than 0.2% of the weight of
Calamine Cutaneous Suspension
the residue. Each g of residue is equivalent to 0.8034 g of
DEFINITION Zn.
hae ad
Calamine Lotion is a cutaneous suspension.
Calamine 150 g
Zinc Oxide 50 g
Bentonite 30 ¢g
Sodium Citrate 5g Calamine and Coal Tar Ointment
Liquefied Phenol 5 mL Compound Calamine Ointment
Glycerol 50 mL
DEFINITION
Purified Water, freshly boiled Sufficient to produce
Calamine and Coal Tar Ointment contains 12.5% w/w each
and cooled 1000 mL
of Calamine and Zinc Oxide and 2.5% w/w of Strong Coal
Extemporaneous preparation Tar Solution in a suitable water-emulsifying basis.
2016 Calcipotriol Preparations III-233
Extemporaneous preparation it in a water bath at 60° for 2 hours (generation of pre-

The following formula and directions apply. calcipotriol).
Calamine, finely sifted 125 g CHROMATOGRAPHIC CONDITIONS
Zinc Oxide, finely sifted 125 g
(a) Use as the coating stlca gel F54.
Strong Coal Tar Solution 25g
Hydrous Wool Fat 250 g (b) Use the mobile phase as described below.
White Soft Paraffin 475 g (c) Apply 50 uL of each solution.
Melt together the Hydrous Wool Fat and the White Soft (d) Develop the plate to 15 cm.
Paraffin. Triturate the Calamine and Zinc Oxide in the (e) After removal of the plate, dry in air and then heat at
melted basis and stir gently, when cooled, to about 40°. 140° for 10 minutes. Whilst hot, spray the plate with an
Gradually incorporate the Strong Coal Tar Solution and stir alcoholic solution of sulfuric acid, dry at 140° for not more than
until cold
1 minute and examine in ultraviolet ight (366 nm).
MOBILE PHASE
20 volumes of 2-methylpropanol and 80 volumes of
dichloromethane.
SYSTEM SUITABILITY
The residue obtained solution (3) shows two clearly separated spots.
white when cool.
CONFIRMATION
ASSAY The principal spot in the chromatogram obtained with
Gently heat 1 g until the basis'is cormpl ely volatilised or solution (1) corresponds in position and colour to that in the
charred. Increase the heat until the fh is removed and chromatogram obtained with solution (2). A secondary spot
ignite the residue of ZnO until, after rtherdgnition, two in the chromatogram obtained with solution (1) corresponds
successive weighings do not differ by mof 0.2% of the in position and colour to the pre-calcipotriol spot in
weight of the residue. Each g of residue is: lent to solution (3).
0.8034 g of Zn.
STORAGE solution (1) shows a peak with the same retention time as the
Calamine and Coal Tar Ointment should be kept in a peak due to calcipotriol in the chromatogram obtained with
container that minimises evaporation losses. solution (2).
substances
Calcipotriol Cream III D, protected from light, using the following
Action and use

Vitamin D analogue.
(1) To a quantity of
DEFINITION 0.5 mg of calcipet
Calcipotriol Cream contains either Anhydrous Calcipotriol or
Calcipotriol Monohydrate in a suitable basis. of the filtrate to dryn
The cream complies with the requirements stated under Topical and dissolve the residue
Content of calcipotriol, C,7H4)O3
(4) Dilute 1 volume of solution (23
A reversible isomerisation to pre-calcipotriol takes place in solution,
depending on temperature and time. The activity 1s due to both
compounds. (a) Use a stainless steel column (10 cm
with octadecylsilyl silica gel for chromatography’
IDENTIFICATION C18 is suitable).
Appendix III A, protected from light, using the following
below.
solutions.
Solvent A 1 volume of triethylamine and 9 volumes of
dichloromethane. (d) Use an ambient column temperature.
(1) To a quantity of the cream containing the equivalent of (e) Use a detection wavelength of 264 nm.
0.5 mg of calcipotriol, add 50 mL of absolute ethanol and (f) Inject 50 wL of each solution.
shake vigorously. Cool in ice and filter. Evaporate the filtrate (g) For solution (1), allow the chromatography to proceed
to dryness at a temperature not exceeding 30° and dissolve for 2 times the retention time of calcipotriol.
the residue in 1 mL of solvent A.
MOBILE PHASE
(2) 0.05% w/v of calcipotriol monohydrate EPCRS in
solvent A.
(3) Place 2 mg of calcipotriol monohydrate EPCRS ina vial
conditions the retention times relative to calcipotriol
and dissolve in 200 uL of solvent A. Close the vial and keep
II-234 Calcipotriol Preparations 2016
(retention time, about 13.5 minutes) are: pre-calcipotriol,

about 0.86; impurity C, about 0.92 and impurity D,
Calcipotriol Ointment
wnt about 1.3. Action and use
SYSTEM SUITABILITY Vitamin D analogue.
DEFINITION
with solution (3), the peak-to-valley ratio between calcipotriol
and impurity C is at least 5. Calcipotriol Ointment contains either Anhydrous Calcipotriol
or Calcipotriol Monohydrate in a suitable basis.
LIMITS
In the chromatogram obtained with solution (1): Semi-solid Preparations and with the following requirements.
the area of any peak corresponding to impurity C is not
Content of calcipotriol, C,7H4)03
greater tharithe area of the principal peak in the
: ined with solution (2) (1%);
‘away
A reversible isomensation to pre-calcipotriol takes place in solution,
the area of any . corresponding to impurity D is not
depending on temperature and time. The activity 1s due to both
greater than twi é'area of the principal peak in the
compounds.
chromatogram obta rith solution (2) (2%);
the area of any other, y peak is not greater than twice IDENTIFICATION
the area of the princip kin the chromatogram obtained A. Carry out the method for thin-layer chromatography,
with solution (4) (0.2% Appendix III A, protected from light, using the following
solutions.
the sum of the areas of any 6t SE adary peak 1s not greater
k in the chromatogram Solvent A 1 volume of triethylamine and 9 volumes of
obtained with solution (2) (0.5% dichloromethane.
Disregard any peak with an area less thin the area of the (1) To a quantity of the ointment containing the equivalent
principal peak in the chromatogram obtain _ of 0.5 mg of calcipotriol, add 50 mL of absolute ethanol and
a shake vigorously. Cool in ice and filter. Evaporate the filtrate
to dryness at a temperature not exceeding 30° and dissolve
ASSAY |
the residue in 1 mL of solvent A.
Appendix III D, protected from light, using the follow
solvent A.
solutions. |
@) Place 2 mg of calcipotriol monohydrate EPCRS ina vial
(1) To a quantity of the cream containing the equivalent of’
tssolve in 200 uL of solvent A. Close the vial and keep
0.25 mg of calcipotriol, add 7 mL of methanol and shake
bath at 60° for 2 hours (generation of pre-
vigorously. Dilute to 20 mL with 0.01mM ammonium phosphate.
Cool in ice, centrifuge and filter.
GRAPHIC CONDITIONS
solvent B. € Coating silica gel Fz54.

substances may be used with an injection volume of 200 uL.
SYSTEM SUITABILITY dry in air and then heat at
pray the plate with an
and impurity C is at least 5.
MOBILE PHASE
20 volumes of 2-methylpropanol and 8¢
Calculate the content of C»7H4 903 in the cream using the
dichloromethane.
combined areas of the peaks due to calcipotriol and pre-
calcipotriol in the chromatograms obtained with solutions (1) SYSTEM SUITABILITY
and (2) and the declared content of C7H 4,03 in calcipotriol The test is not valid unless the chromatogram a
monohydrate EPCRS. solution (3) shows two clearly separated spots.
STORAGE CONFIRMATION
Calcipotriol Cream should be protected from light. The principal spot in the chromatogram obtained with
ean
LABELLING
The quantity of active ingredient is stated in terms of the chromatogram obtained with solution (2). A secondary spot
in the chromatogram obtained with solution (1) corresponds
equivalent amount of calcipotriol.
in position and colour to the pre-calcipotriol spot in
solution (3).
peak due to calcipotriol in the chromatogram obtained with
solution (2).
2016 Calcipotriol Preparations III-235
TESTS (1) To a quantity of the ointment containing the equivalent

Related substances of 0.25 mg of calcipotriol, add 7 mL of methanol and shake
Carry out the method for liguid chromatography, vigorously. Dilute to 20 mL with 0.01M ammonium phosphate.
Appendix III D, protected from light, using the following Cool in ice, centrifuge and filter.
solutions prepared in solvent B. (2) 0.0013% w/v of calcipotriol monohydrate EPCRS in
Solvent B 30 volumes of 0.01M ammonium phosphate and solvent B.
70 volumes of methanol. CHROMATOGRAPHIC CONDITIONS
(1) To a quantity of the ointment containing the equivalent The chromatographic conditions described under Related
of 0.5 mg of calcipotriol, add 10 mL of methanol and shake substances may be used with an injection volume of 200 uL.
vigorously. Cool in ice, centrifuge and filter. Evaporate 5 mL
SYSTEM SUITABILITY
ofthe oe to dryness at a temperature not exceeding 30°
Calculate the content of C,7H4,)O03 in the ointment using the
ITIONS
combined areas of the peaks due to calcipotriol and pre-
mmn (10 cm x 4.0 mm) packed calcipotriol in the chromatograms obtained with solutions (1)
with octadecylsilyl silica and (2) and the declared content of C27H4,Q3 in calcipotriol
C18 is suitable). monohydrate EPCRS.
STORAGE
below.
Calctpotriol Ointment should be protected from light.
(c) Use a flow rate of 1.0 mL per minut
LABELLING
(d) Use an ambient column temperature
(e) Use a detection wavelength of 264 n s equivalent amount of calcipotriol.
(g) For solution (1), allow the chromatography te pr
for 2 times the retention time of calcipotriol.
MOBILE PHASE
Calcipotriol Scalp Application
conditions the retention times relative to calcipotriol
(retention time, about 13.5 minutes) are: pre-calcipotriol,
about 0.86; impurity C, about 0.92 and impurity D,
about 1.3.
SYSTEM SUITABILITY
Liquids For
requirements.
90.0 to 110.0%ofth
LIMITS
A reversible isomerisation t
depending on temperature an
the area of any peak corresponding to impurity C is not compounds.
IDENTIFICATION
A. Carry out the method for thin-laye
the area of any peak corresponding to impurity D is not
Appendix III A, protected from light, u
solutions.
Solvent A 1 volume of triethylamine and 9 volur
the area of any other secondary peak is not greater than twice
dichloromethane.
(1) Evaporate a quantity of the scalp application containing
the equivalent of 0.5 mg of calcipotriol to dryness at a
the sum of the areas of any other secondary peak is not greater temperature not exceeding 30° and dissolve the residue in
than half the area of the principal peak in the chromatogram
1 mL of solvent A.
(2) 0.05% w/v of calctpotriol monohydrate EPCRS in
solvent A.
(3) Place 2 mg of calctpotriol monohydrate EPCRS ina vial
and dissolve in 200 wL of solvent A. Close the vial and keep
ASSAY it in a water bath at 60° for 2 hours (generation of pre-
Carry out the method for liquid chromatography, calcipotriol).
Appendix III D, protected from light, using the following CHROMATOGRAPHIC CONDITIONS
saa solutions. on
ss (a) Use as the coating silica gel F254.
: (b) Use the mobile phase as described below.

II-236 Calcitonin (Salmon) Preparations 2016
(c) Apply 50 uL of each solution. LIMITS
(d) Develop the plate to 15 cm. In the chromatogram obtained with solution (1):
(e) After removal of the plate, dry in air and then heat at the area of any peak corresponding to impurity C is not
140° for 10 minutes. Whilst hot, spray the plate with an greater than the area of the principal peak in the
alcoholic solution of sulfuric acid, dry at 140° for not more than chromatogram obtained with solution (2) (1%);
1 minute and examine in ultraviolet light (365 nm). the area of any peak corresponding to impurity D is not
MOBILE PHASE greater than 3.5 times the area of the principal peak in the
20 volumes of 2-methylpropanol and 80 volumes of chromatogram obtained with solution (2) (3.5%);
dichloromethane. the area of any other secondary peak is not greater than twice
SYSTEM SUITABILITY
the sum of the areas of any other secondary peak is not greater
than half the area of the principal peak in the chromatogram
ASSAY
in position and colour to|
solution (3). Carry out the method for liquid chromatography,
solutions prepared in solvent B, as described under Related
substances.
peak due to calcipotriol in the chromati obtained with
solution (2). (1) Dilute a weight of the scalp application containing the
equivalent of 0.35 mg of calcipotriol to 10 mL.
TESTS
(2) 0.0037% w/v of calcipotriol monohydrate EPCRS.
Carry out the method for liguid chromatography, |
Appendix III D, protected from light, using the followy The chromatographic conditions described under Related
solutions prepared in solvent B. substances may be used.
Solvent B 30 volumes of 0.01M ammonium phosphate and SUITABILITY
70 volumes of methanol. not valid unless, in the chromatogram obtained
(1) Evaporate a quantity of the scalp application containing
the equivalent of 0.5 mg of calcipotriol to dryness at a
temperature not exceeding 30° and dissolve the residue in
4 mL.
(2) Dilute 0.1 mL of solution (1) to 10 mL. s of the peaks due to calcipotriol and
(3) 0.004% w/v of calcipotriol monohydrate EPCRS. fromatograms obtained with
(4) Dilute 1 volume of solution (2) to 10 volumes. e declared content of C,7H4,03
(a) Use a stainless steel column (10 cm x 4.0 mm) packed STORAGE
with octadecylsilyl silica gel for chromatography (3 wm) (Luna Calcipotriol Scalp Solution
C18 is suitable). LABELLING o
(b) Use isocratic elution and the mobile phase described The quantity of active ingredient is :
below. equivalent amount of calcipotriol.
(f) Inject 50 pL of each solution. Calcitonin (Salmon) Injection
for 2 times the retention time of calcipotriol. Action and use
Hormone.
ey,
MOBILE PHASE
30 volumes of water and 70 volumes of methanol. DEFINITION

When the chromatograms are recorded under the prescribed Calcitonin (Salmon) Injection is a sterile solution of
conditions the retention times relative to calcipotriol Calcitonin (Salmon) in Water for Injections.
(retention time, about 13.5 minutes) are: pre-calcipotriol, The injection complies with the requirements stated under
about 0.86; impurity C, about 0.92 and impurity D, Parenteral Preparations and with the following requirements.
about 1.3. Content of calcitonin (salmon), C,4;H549N440482
SYSTEM SUITABILITY 90.0 to 115.0% of the stated amount of the peptide.
we
The test is not valid unless, in the chromatogram obtained CHARACTERISTICS
Aw
~~
2016 Calcitonin (Salmon) Preparations III-237
IDENTIFICATION Related peptides

In the Assay, the retention time of the principal peak in the Carry out the method for liguid chromatography,
chromatogram obtained with solution (1) is similar to that of Appendix III D, using the following solutions.
the principal peak in the chromatogram obtained with (1) Dilute the injection, if necessary, with mobile phase A to
solution (2). give a final concentration of 10 ug of calcitonin (salmon) per
TESTS mL.
Acidity (2) Dissolve the contents of a vial of N-acetyl-cys'
pH, 3.9 to 4.5, Appendix V L. calcitonin EPCRS in 0.4 mL of mobile phase A, dilute to
Calcitonin C 40 mL with mobile phase A and add 0.1 mL of solution (1).
Carry out the method for liquid chromatography, CHROMATOGRAPHIC CONDITIONS
Appendix Il D, using the following solutions. (a) Use a stainless steel column (25 cm x 4.6 mm) packed
with octadecylsilyl sihca gel for chromatography (5 um).
(b) Use gradient elution and the mobile phases described
below.
(3) Heat the injection at
dilute as described for solutie MOBILE PHASE
CHROMATOGRAPHIC CONDI] Mobile phase A Dissolve 3.26 g of tetramethylammonium

hydroxide pentahydrate in 900 mL of water, adjust the pH to
(a) Use a stainless steel column (25. )
2.5 with orthophosphoric acid and mix with 100 mL of
with octadecylsilyl silica gel for chromatog} .
acetonitrile for chromatography.
C18, 300 A wide pore column for prote iF tides is
suitable). . Mobile phase B_ Dissolve 1.45 g of tetramethylammonium
hydroxide pentahydrate in 400 mL of water, adjust the pH to
(b) Use gradient elution and the mobile phases d
2.5 with orthophosphoric acid and mix with 600 mL of
below.
acetonitrile for chromatography.
Use the following gradient.
Mobile phase A Mobile phase B Comment
(f) Inject 200 uL of each solution. (% viv) (% viv)
MOBILE PHASE 7248 28-52 linear gradient
Mobile phase A 100 volumes of a 0.363% w/v solution of _ 48-72 5228 linear gradient
tetramethylammonum hydroxide pentahydrate and 150 volumes
28 re-equilibration
of acetonitrile adjusted to pH 2.5 with orthophosphoric acid.
Mobile phase B 50 volumes of acetonitrile and 450 volumes
of a 0.402% w/v solution of tetramethyl-ammonium hydroxide .for solution (2) is recorded in the
pentahydrate adjusted to pH 2.5 with orthophosphoric acid. elative retention time of N-acetyl-
Use the following gradient. cys’ calcitonin is abot lative to the principal peak.
SYSTEM SUITABILITY

en factor between the
peaks corresponding to calcitonin’ and N-acetyl-cys*
: ‘actor for the
0-24 3557 6543 linear gradient
N-acetyl-cys’ calcitonin peak is not g cate
21-22 57-35 43-65 linear gradient A
If necessary, adjust the initial ratio of
22-30 35 65 re-equilibration phase.
LIMITS
In the chromatogram obtained with solution (3) the peak due In the chromatogram obtained with solution (1):
to calcitonin C is the largest peak to elute after the injection the area of any secondary peak is not greater than 3% of the
buffer salts and before the principal peak with a relative total area of all the peaks; :
retention to that of calcitonin (salmon) of between 0.5 and the sum of the areas of any such peaks is not greater than
0.6. 5% of the total area of all the peaks by normalisation;
SYSTEM SUITABILITY disregard any peak with an area less than 0.1 % of that of the
The test is not valid unless the resolution factor between the principal peak.
peaks due to calcitonin C and calcitonin (salmon) in the ASSAY
chromatogram obtained with solution (3) is at least 3.0. Carry out the method described under the test for
LIMITS Calcitonin C.
In the chromatogram obtained with solution (1) the area of Calculate the content of calcitonin (salmon) from the areas
any peak corresponding to calcitonin C is not greater than of the peak due to calcitonin (salmon) and that of any peak
7% by normalisation. due to calcitonin C, using the declared content of
Cy 45H2490N44O0488>2 1n calcitonin (salmon) BPCRS.
I-238 Calcitriol Preparations 2016
STORAGE SYSTEM SUITABILITY

aL eas
ee ete
Calcitonin (Salmon) Injection should be protected from light The Assay is not valid unless, in the chromatogram obtained
aN ey and stored at a temperature of 2° to 8°. with solution (1), the peak due to calcitriol is clearly
LABELLING separated from the peak due to the fixed oil.
The label states the strength as the number of IU (Units) per DETERMINATION OF CONTENT
mL. The label also states the equivalent number of Combine the peak areas of calcitriol and pre-calcitriol in
micrograms of the peptide per mL. solutions (1) and (2) respectively. Calculate the content of
calcitriol, C27H,,03 in the capsules, using the declared
content of C,7H4,03 in calcitriol EPCRS.
Calcitriol.Capsules
Action ait us Calcium and Colecalciferol Tablets
Vitamin D ang
DEFINITION
DEFINITION Calcium and Colecalciferol Tablets contain Calcium
lution of Calcitriol in a Carbonate and Colecalciferol.
suitable fixed oil. The tablets comply with the requirements stated under Tablets and
The capsules comply with the ts stated under Capsules with the following requirements.
and with the following require Content of calcium
Content of calcitriol, C,;H44! 85.0 to 115.0% of the stated amount.
90.0 to 110.0% of the stated am Content of colecalciferol, C,7H,,O
A reversible isomerisation to pre-calcitriol take cean solution, 90.0 to 120.0% of the stated amount.
depending on temperature and time. The activ IDENTIFICATION
compounds.
A. Carry out the method for liguid chromatography,
IDENTIFICATION Appendix III D, using the following solutions.
In the Assay, the chromatogram obtained with solution ¢ (1) Shake a quantity of the powdered tablets containing
shows a peak with the same retention time as the peak“d 20 ug of Colecalciferol with 20 mL of the mobile phase with
calcitriol in the chromatogram obtained with solution (2 the aid of ultrasound for 15 minutes, cool to room
ASSAY imperature, centrifuge and use the supernatant liquid.
Mix the contents of 20 capsules. Carry out the method for % wiy each of colecalciferol BPCRS and
liqud chromatography, Appendix III D, using the following 1 BPCRS in the mobile phase.
solutions.
For capsules containing 0.25 wg of Calcitriol or less, prepare
solution (1) 1n the following manner:
column (25 cm x 4.6 mm) packed
(1)Use an undiluted quantity of the mixed capsule content. el for chromatography (5 um)
For capsules containing more than 0.25 wg of Calcitriol, prepare
solution (1) 1n the following manner:
(1) To a quantity of the mixed capsule content containing
1.5 ug of Calcitriol, add sufficient mobile phase to produce
1 mL.
(2) 0.00015% w/v of calcitriol EPCRS in the mobile phase.
(e) Use a detection wavelength of2
MOBILE PHASE
with silica gel for chromatography (5 um) (Lichrosorb S160 is
10 volumes of water and 90 volumes of meth
suitable).
(b) Use isocratic elution and the mobile phase described SYSTEM SUITABILITY
below. The test is not valid unless, in the chromatogram obtained
(c) Use a flow rate of 1.2 mL per minute. with solution (2), the resolution factor between the two
principal peaks is at least 1.4. If necessary, adjust the
Lwe no
‘een
se composition of the mobile phase to obtain the required
resolution.
a an

CONFIRMATION
(g) If necessary, adjust the composition of the mobile phase
A peak in the chromatogram obtained with solution (1) has
so that the principal peak in the chromatogram obtained with
the same retention time as the peak due to colecalciferol in
solution (1) is clearly separated from the tail of the peak due
to the excipient (fixed oil).
B. Shake a quantity of the powdered tablets containing the
MOBILE PHASE
equivalent of 10 mg of calcium with 50 mL of water and
1 volume of propan-1-ol, 2 volumes of methanol, 40 volumes filter. The solution yields reaction A characteristic of calcrum
Lew aed
of hexane and 60 volumes of ethyl acetate. salts, Appendix VI.
ea a4
Lt HL, ELAS eR Dal tet Mea etaheitone tie a ed oe De ESE OR EI ittae on eeAE el Oe
2016 Calcium Preparations III-239
TESTS LABELLING
Uniformity of content The label states (1) the equivalent number of IU (Units) of
Tablets containing less than 2 mg and/or less than 2% w/w antirachitic activity (vitamin D); (2) the equivalent amount of
of Colecalciferol comply with the requirements stated under calcium.
Tablets, with respect to the content of Colecalciferol, using Each microgram of Colecalciferol is equivalent to 40 IU of
the following method of analysis. Carry out the following antirachitic activity (vitamin D).
procedure protected from light. Carry out the method for
solutions.
(1) Add 15 mL of methanol (90%), mix with the aid of
ultrasound until the tablet is dispersed and then for a further Chewable Calcium and Colecalciferol
dilute to 20 mL with methanol (90%), mix, Tablets
DEFINITION
Chewable Calcium and Colecalciferol Tablets contain
Calcium Carbonate and Colecalciferol.
be used.
Content of calcium
DETERMINATION OF © 85.0 to 115.0% of the stated amount.
Calculate the content of Content of colecalciferol, C,,H,,O
declared content of C57H 4,4 90.0 to 120.0% of the stated amount.
ASSAY IDENTIFICATION
For calctum A. Carry out the method for liguid chromatography,
Weigh and powder 20 tablets. To a quant Appendix III D, using the following solutions.
containing the equivalent of 50 mg of calei
water and 5 mL of hydrochloric acid. Heat the ¢
20 ug of colecalciferol with 20 mL of the mobile phase with
gently to boiling and continue to boil for about
the aid of ultrasound for 15 minutes, cool to room
Allow to cool and add 50 mL of 0.05m disodium edet
temperature, centrifuge and use the supernatant liquid.
Neutralise the solution using 2m sodium hydroxide, add |
of ammoma buffer pH 10.9 and 50 mL of water. Titrate
t (2) 0.0001% w/v each of colecalciferol BPCRS and
excess of disodium edetate with 0.05m zinc chloride VS us alciferol BPCRS in the mobile phase.
mordant black II solution as indicator. Each mL of 1% wiv of colecalciferol BPCRS in the mobile phase.
0.05M disodium edetate VS is equivalent to 2.004 mg of Ca. TOGRAPHIC CONDITIONS
For colecalciferol stainless steel column (25 cm x 4.6 mm) packed
Carry out the following procedure protected from light. uyl silica gel for chromatography (5 sm)
Weigh and powder 20 tablets. Carry out the method for )S 14s suitable).
solutions.
0.1 mg of Colecalciferol with about 1770 mL of methanol
(90%) for 5 minutes and then mix with ultrasound for
Naw ad
5 minutes, dilute to 200 mL with methanol (90%), mix,
centrifuge and filter through a glass-fibre filter (Whatman (f) Inject 50 wL of each so
GF/C is suitable). MOBILE PHASE
(2) 0.00005% w/v of colecalciferol BPCRS in methanol. 10 volumes of water and 90 volumés
CHROMATOGRAPHIC CONDITIONS SYSTEM SUITABILITY
(5 um) (Hypersil ODS is suitable). principal peaks is at least 1.4. If necessary, adjust the
(b) Use isocratic elution and the mobile phase described composition of the mobile phase to obtain the required
below. resolution.
(c) Use a flow rate of 1 mL per minute. CONFIRMATION
(d) Use an ambient column temperature. A peak in the chromatogram obtained with solution (1) has
(e) Use a detection wavelength of 264 nm. the same retention time as the peak due to colecalciferol in
(f) Inject 50 pL of each solution. the chromatogram obtained with solution (3).
MOBILE PHASE
B. Shake a quantity of the powdered tablets containing the
equivalent of 10 mg of calcium with 50 mL of water and
filter. The solution yields reaction A characteristic of calcium
DETERMINATION OF CONTENT salts, Appendix VI.
Calculate the content of C27H4,O in the tablets using the
declared content of C27H4,O in colecalciferol BPCRS.
ce ee a oe
WI-240 Calcium Preparations 2016
TESTS DETERMINATION OF CONTENT

Disintegration Calculate the content of C,7H4,0 in the tablets using the
The requirement for Disintegration does not apply to declared content of C7H,4,0O in colecalciferol BPCRS.
Chewable Calcium and Colecalciferol Tablets.
~ we
Mee ote
ewe
LABELLING
Tablets containing less than 2 mg and/or less than 2% w/w antirachitic activity (vitamin D); (2) the equivalent amount of
of Colecalciferol comply with the requirements stated under calctum.
Tablets, with respect to the content of Colecalciferol, using
Each microgram of Colecalciferol is equivalent to 40 IU of
the following method of analysis. Carry out the following
antirachitic activity (vitamin D).
procedure protected from light. Carry out the method for
solutions.
eee wo of methanol (90%), mix with the aid of
tablet is dispersed and then for a further Calcium and Ergocalciferol Tablets
0 mL with methanol (90%), mix,
DEFINITION
centrifuge and filter ugh a glass-fibre filter (Whatman
Calcium and Ergocalciferol Tablets contain Calcium Lactate
GF/Cis suitable).
Pentahydrate, Calcium Phosphate and Ergocalciferol.
(2) 0.00005% w/v rol BPCRS in methanol (90%).
The chromatographic cond t Content of calcium
be used. 85.0 to 115.0% of the stated amount.
DETERMINATION OF CONTEN Content of ergocalciferol, C;3;H,,O
Calculate the content of C,7H4,O in each tablet using the 90.0 to 120.0% of the stated amount.
declared content of C,7H4,40O in colecalctfeto
IDENTIFICATION
ASSAY A. Carry out the method for liquid chromatography,
For calcium : | Appendix II D, using the following solutions.
Weigh and powder 20 tablets. To a quantity of the, (1) Shake a quantity of the powdered tablets containing
4
containing the equivalent of 50 mg of calcium add 50.aiL 20 ug of Ergocalciferol with 20 mL of the mobile phase with
~4
water and 5 mL of hydrochloric acid. Heat the dispersion the aid of ultrasound for 15 minutes, cool to room
my
sf
]
f
gently to boiling and continue to boil for about 2 minut ture, centrifuge and use the supernatant liquid.
Allow to cool and add 50 mL of 0.05m disodium edetate VS.
y
% wily each of colecalciferol BPCRS and

Neutralise the solution using 2M sodium hydroxide, add 10 mL
ol BPCRS in the mobile phase.
of ammoma buffer pH 10.9 and 50 mL of water. Titrate the
w/v of ergocalciferol BPCRS in the mobile phase.
excess of disodium edetate with 0.05m zinc chloride VS using
mordant black II solution as indicator. Each mL of RAPHIC CONDITIONS
0.05M disodium edetate VS is equivalent to 2.004 mg of Ca.
For colecalciferol
liquid chromatography, Appendix III D, protect from light (b) Use isocratic elus
throughout the procedure and using the following solutions. below.
(1) Shake a quantity of the powdered tablets containing (c) Use a flow rate of
0.1 mg of Colecalciferol with about 170 mL of methanol (d) Use an ambient colum
(90%) for 5 minutes and then mix with ultrasound for
(e) Use a detection wavelength ef 26%
5 minutes, dilute to 200 mL with methanol (90%), mix,
centrifuge and filter through a glass-fibre filter (Whatman (f) Inject 50 uL of each solution.
(2) 0.00005% w/v of colecalciferol BPCRS in methanol. 10 volumes of water and 90 volumes of me
(a) Use a stainless steel column (10 cm x 4.6 mm) packed The test is not valid unless, in the chromatogram
with end-capped octadecylsilyl silica gel for chromatography with solution (2), the resolution factor between the two
(5 um) (Hypersil ODS is suitable). principal peaks is at least 1.4. If necessary, adjust the
below. resolution.
ree A
(d) Use an ambient column temperature. The chromatogram obtained with solution (1) shows a peak
(e) Use a detection wavelength of 264 nm. with the same retention time as the peak due to ergocalciferol
B. Disperse a quantity of the powdered tablets containing the
MOBILE PHASE
equivalent of 10 mg of calcium in 5 mL of water and filter.
3 volumes of water and 97 volumes of methanol. The filtrate yields reaction A characteristic of lactates,
Appendix VI.
2016 Calcium Preparations II-241
C. Warm a quantity of the powdered tablets containing the (e) Use a detection wavelength of 264 nm.
equivalent of 90 mg of calcium with 10 mL of 2m nitric acid, (f) Inject 50 wL of each solution.
aaa
SS cool and filter. Add 10 mL of ammonium molybdate solution to
oo, — MOBILE PHASE
Se the filtrate. A yellow precipitate is produced, characteristic of
a ten. ee
phosphates.
D. Shake a quantity of the powdered tablets containing the DETERMINATION OF CONTENT
equivalent of 10 mg of calctum with 50 mL of water and Calculate the content of C,gH,,0 in the tablets using the
filter. The solution yields reaction A characteristic of calcium declared content of CygH4,O in ergocalciferol BPCRS.
salts, Appendix VI.
LABELLING
TESTS The label states (1) the equivalent number of IU (Units) of
Uniformity of content antirachitic activity (vitamin D); (2) the equivalent amount of
taining less than 2 mg and/or less than 2% w/w calcium.
Bee Each microgram of Ergocalciferol is equivalent to 40 IU of
Chewable Calcium and Ergocalciferol

5 minutes, dilute to 20 mL ‘wi
Tablets
centrifuge and filter through DEFINITION
GF/C is suitable). | Chewable Calcium and Ergocalciferol Tablets contain
(2) 0.00005% w/v of ergocalciferol BPC] thanol (90%). Calcium Lactate Pentahydrate, Calcium Phosphate and
Ergocalciferol.
CHROMATOGRAPHIC CONDITIONS _
The chromatographic conditions described ui for with the following requirements.
ergocalciferol may be used.
Content of calcium
DETERMINATION OF CONTENT 85.0 to 115.0% of the stated amount.
Calculate the content of C23H4,O in each tablet using.¢ . Content of ergocalciferol, C,3;H4,O
declared content of C,3H4,O in ergocalciferol BPCRS. o 120.0% of the stated amount.
ASSAY IFICATION
For calctum out the method for liquid chromatography,
Weigh and powder 20 tablets. To a quantity of the powder III D, using the following solutions.
containing the equivalent of 50 mg of calctum add 50 mL of
water and 5 mL of hydrochloric acid. Heat the dispersion
20 igo
gently to boiling and continue for about 2 minutes. Allow to
the aid
cool and add 50 mL of 0.05m disodium edetate VS. Neutralise
the solution using 2m sodium hydroxide, add 10 mL of
ammonia buffer pH 10.9 and 50 mL of water. Titrate the
excess of disodium edetate with 0.05m zinc chloride VS using
mordant black IT solution as indicator. Each mL of
0.05M disodium edetate VS is equivalent to 2.004 mg of Ca.
For ergocalciferol
Weigh and powder 20 tablets. Carry out the method for (Spherisorb ODS1 is suitable).
(b) Use isocratic elution and the mobil
solutions.
below.
0.1 mg of Ergocalciferol with about 170 mL of methanol
(90%) for 5 minutes. Mix with the aid of ultrasound for a (d) Use an ambient column temperature.
further 5 minutes, dilute to 200 mL with methanol (90%), (e) Use a detection wavelength of 265 nm.
centrifuge and filter througha glass fibre filter (Whatman (f) Inject 50 wL of each solution.
(2) 0.00005% w/v of ergocalciferol BPCRS in methanol. 10 volumes of water and 90 volumes of methanol.
SYSTEM SUITABILITY
(a) Use a stainless steel column (10 cm x 4.6 mm) packed The test is not valid unless, in the chromatogram obtained
with end-capped octadecylsilyl silica gel for chromatography with solution (2), the resolution factor between the two
(5 um) (Hypersil 5 ODS is suitable). principal peaks is at least 1.4. If necessary, adjust the
below. resolution.
II-242 Calcium Preparations 2016
CONFIRMATION centrifuge and filter througha glass fibre filter (Whatman

The chromatogram obtained with solution (1) shows a peak GF/C is suitable).
we
avons
with the same retention time as the peak due to ergocalciferol (2) 0.00005% w/v of ergocalciferol BPCRS in methanol.
B. Disperse a quantity of the powdered tablets containing the
equivalent of 10 mg of calcium in 5 mL of water and filter.
The filtrate yields reaction A characteristic of lactates,
(5 um) (Hypersil 5 ODS is suitable).
Appendix VI.
C. Warm a quantity of the powdered tablets containing the
below.
equivalent of 90 mg of calcium with 10 mL of 2m nitric acid,
cool and filter. Add 10 mL of ammonium molybdate solution to
yellow precipitate is produced, characteristic of (d) Use an ambient column temperature.
MOBILE PHASE

TESTS
Disintegration Calculate the content of C,3H4,0O in the tablets using the
The requirement for Disintég declared content of C23H4,O in ergocalciferol BPCRS.
Chewable Calcium and Ergo LABELLING
en eal
Tablets containing less than 2 mg and antirachitic activity (vitamin D); (2) the equivalent amount of
of Ergocalciferol comply with the require Stated under calcium.
Tablets, with respect to the content of Ergocalciferol, using Each microgram of Ergocalciferol is equivalent to 40 IU of
the following method of analysis. Carry out the antirachitic activity (vitamin D).
procedure protected from light. Carry out the méthod
liquid chromatography, Appendix III D, using the foliowir
solutions.
(1) Add 15 mL of methanol (90%), mix with the aid of
ultrasound until the tablet is dispersed and then for a furth
Chewable Calcium Carbonate Tablets
5 minutes, dilute to 20 mL with methanol (90%), mix, ION
centrifuge and filter through a glass-fibre filter (Whatman Calcium Carbonate Tablets contain Calcium
GF/C is suitable).
(2) 0.00005% w/v of ergocalciferol BPCRS in methanol (90%).
The chromatographic conditions described under Assay for

ergocalciferol may be used.
DETERMINATION OF CONTENT IDENTIFICATION |
Calculate the content of C23H,4,O in each tablet using the A. The powdered tablé action B characteristic of
declared content of C.3H,,0 in ergocalciferol BPCRS. calcium salts, Appendix VI.
B. The powdered tablets yiek e reactions characteristic of
twee
vet tet
ASSAY
carbonates, Appendix VI.
For calcium
rere
i
containing the equivalent of 50 mg of calcium add 50 mL of TESTS
water and 5 mL of hydrochloric acid. Heat the dispersion Disintegration
gently to boiling and continue for about 2 minutes. Allow to |
The requirement for Disintegration does not apph
cool and add 50 mL of 0.05m disodium edetate VS. Neutralise
Chewable Calcium Carbonate Tablets. :
the solution using 2m sodium hydroxide, add 10 mL of
ammonia buffer pH 10.9 and 50 mL of water. Titrate the ASSAY
excess of disodium edetate with 0.05m zinc chloride VS using Weigh and powder 20 tablets. To a quantity of the powder
|
|
mordant black II solution as indicator. Each mL of containing the equivalent of 0.25 g of calcium add 50 mL of
an eed 0.05m disodium edetate VS is equivalent to 2.004 mg of Ca. water and 5 mL of hydrochloric acid. Heat the dispersion
gently to boiling and continue to boil for about 2 minutes.
For ergocalciferol
Allow to cool, add sufficient water to produce 250 mL and
filter, if necessary. To 50 mL of this solution add 50 mL of
0.05m disodium edetate VS. Neutralise the solution using
liquid chromatography, Appendix III D,using the following
2M sodium hydroxide and add 10 mL of ammonia buffer
solutions.
pH 10.9 and 50 mL of water. Titrate the excess of disodium
(1) Shake a quantity of the powdered tablets containing edetate with 0.05m zinc chloride VS using mordant black
0.1 mg of Ergocalciferol with about 170 mL of methanol IT solution as indicator. Each mL of 0.05m disodium edetate VS
astratete (90%) for 5 minutes. Mix with the aid of ultrasound for a is equivalent to 2.004 mg of Ca.
te
aw ay
Ae a
Lea
Aa
further 5 minutes, dilute to 200 mL with methanol (90%),
eae an
ase?
fae ve wo
2016 Calcium Preparations I-243
STORAGE Appendix II D, measuring at 422.7 nm using the standard

Chewable Calcium Carbonate Tablets should be protected solutions and solution (2) as the blank.
from moisture. For magnesium
LABELLING Weigh and powder 20 tablets. For solution (3) disperse a
The quantity of active ingredient is stated in terms of the quantity of the powdered tablets containing the equivalent of
equivalent amount of calcium. 22 mg of magnesium in 10 mL of 6m hydrochloric acid, stir
for 15 minutes and add sufficient water to produce 500 mL,
mix and filter. To 1 volume of the filtrate add 5 volumes of
lanthanum trioxide solution and dilute to 100 volumes with
water.
Chewable Calcium Carbonate and Heavy Prepare the standard solutions using a suitable volume of
Magnesium Carbonate Tablets magnesium standard solution (100 ppm Mg), add 10 mL of
6M hydrochloric acid and sufficient water to produce 500 mL,
mix and filter. To 1 volume of the filtrate add 5 volumes of
lanthanum tnoxide solution and dilute to 100 volumes with
water.
Determine the total content of magnesium in solution (3) by
Chewable Calci ate and Heavy Magnesium
Method I for atomic absorption spectrophotometry,
Carbonate Tablets c tain Calcium Carbonate and Heavy
Appendix II D, measuring at 285.2 nm using the standard
Magnesium Carbona aay be flavoured.
solutions and solution (2) as the blank.
The tablets comply with the uirements stated under Tablets and
STORAGE
with the following requiremen
Chewable Calcium Carbonate and Heavy Magnesium
Content of Calcium, Ca Carbonate Tablets should be protected from moisture.
LABELLING
Content of magnesium, Mg
equivalent amount of calcium and magnesium.
IDENTIFICATION :
A. In the Assay, solution (1) exhibits a similar absorpt
the standard solutions at 422.7 nm (calcium).
B. In the Assay, solution (3) exhibits a similar absorption,
the standard solutions at 285.2 nm (magnesium). Calcium Chloride Injection
C. The powdered tablets yield reaction B characteristic of ITION
calcium salts, Appendix VI. mn Chloride Injection is a sterile solution of Calcium
D. The powdered tablets yield reaction B characteristic of
magnesium and magnesium salts, Appendix VI.
E. The powdered tablets yield the reactions characteristic of
carbonates, Appendix VI.
TESTS
Disintegration
The requirement for Disintegration does not apply to
Chewable Calcium Carbonate and Heavy Magnesium
Carbonate Tablets.
ASSAY The resulting solution yields re
For calcium chlorides, Appendix VI.
Weigh and powder 20 tablets. For solution (1) disperse a TESTS
quantity of the powdered tablets containing the equivalent of Acidity or alkalinity
0.272 g of calcium in 10 mL of 6m hydrochloric acid, stir for pH 5.0 to 8.0, Appendix V L.
15 minutes, and add sufficient water to produce 500 mL, mix
Colour of solution
and filter. To 1 volume of the filtrate add 5 volumes of
lanthanum trioxide solution and dilute to 100 volumes with
solution BY,, Appendix IV B, Method II.
water.
Prepare the standard solutions using a suitable volume of ASSAY
calcium standard solution (1000 ppm Ca) add 10 mL of Carry out the complexometric titration of calcium,
6m hydrochloric acid, and sufficient water to produce 500 mL, Appendix VIII D. Use a volume of the injection containing
mix and filter. To 1 volume of the filtrate add 5 volumes of about 0.3 g of Calcium Chloride Dihydrate.
lanthanum tnoxide solution and dilute to 100 volumes with LABELLING
water. The label states (1) the percentage w/v of Calcium Chloride
For solution (2) to 10 mL of 6m hydrochloric acid add Dihydrate; (2) the concentration of calcium ion as millimoles
sufficient water to produce 500 mL, mix and filter. in a suitable volume; (3) the concentration of chloride ion as
To 1 volume of the filtrate add 5 volumes of lanthanum millimoles in a suitable volume; (4) that solutions containing
trioxide solution and dilute to 100 volumes with water. visible solid particles must not be used.
Determine the total content of calcium in solution (1) by
Method I for atomic absorption spectrophotometry,
IWI-244 Calcium Preparations 2016
When calcium chloride intravenous infusion is prescribed or MOBILE PHASE

demanded, Calcium Chloride Injection shall be dispensed or 220 mL of methanol and 780 mL of a solution containing
supplied. 2.0 mL of tetrabutylammonium hydroxide solution and 2.2 g of
disodium hydrogen orthophosphate, previously adjusted to
pH 7.5 with 10% v/v orthophosphoric acid.
SYSTEM SUITABILITY
Calcium Folinate Injection The test is not valid unless, in the chromatogram obtained
with solution (5), the resolution between the peaks
Action and use corresponding to calcium folinate and formylfolic acid is at
Vitamin B component. least 2.2. If necessary, adjust the methanol content in the
mobile phase.
DEFINITION
LIMITS

the area of any peak corresponding to formylfolic acid is not
the requisite @ greater than the area of the principal peak in the
before use. chromatogram obtained with solution (3) (1%);
Parenteral Preparations at area of the principal peak in the chromatogram obtained with
solution, with the followin solution (2) (1%);
Content of folinic acid, C the sum of the areas of any secondary peaks, excluding the
peak corresponding to formylfolic acid, is not greater than
swe nd
acid add 40 mL of acetone, mix, allow to ‘Stag Disregard any peak with an area less than that of the
centrifuge, discarding the solvent.
t Suspend . principal peak in the chromatogram obtained with
ASSAY
The infrared absorption spectrum of the residue, Append Protect the solutions from light. Carry out the method for
is concordant with the reference spectrum of calctum folina iquid chromatography, Appendix III D, using the following
(RS 368).
B. Yields reaction B characteristic of calcium salts,
Appendix VI.
TESTS
Related substances
Appendix III D, using the following solutions protected from
light.
(1) Dilute with water, if necessary, a volume of the injection substances may be used
to produce a solution containing the equivalent of 0.1% w/v
SYSTEM SUITABILITY
of folinic acid.
water.
corresponding to calcium folinate an yliglic acidis at
(3) 0.001% w/v offormylfolic acid EPCRS in the mobile
least 2.2. If necessary, adjust the metha in the
phase.
mobile phase.
(4) Dilute 1 volume of solution (2) to 10 volumes with water.
(5) Mix 10 volumes of solution (2) with 5 volumes of
Calculate the content of C39H23N7O; in the injection using
solution (3).
the declared content of C,,>H,,;CaN-7O, in calcium
paenie
CHROMATOGRAPHIC CONDITIONS folinate BPCRS. Each mg of C29H,;CaN7O7 is equivalent to
AAA
(a) Use a stainless steel column (25 cm x 4.6 mm) packed 0.9255 mg of C390H23N707.
net oa
STORAGE
sate
(5 um) (Hypersil ODS 1s suitable).

When supplied as a ready-to-use solution, Calcium Folinate
(b) Use isocratic elution and the mobile phase described Injection should be protected from light and stored at a
below. temperature of 2° to 8°.
LABELLING
(d) Use a column temperature of 40°. The quantity of active ingredient is stated in terms of the
(e) Use a detection wavelength of 280 nm. equivalent amount of folinic acid.
ae
ee
:
al
ae Ae
s)
2.5 times the retention time of folinate.
we
aS .
wal gw!
aa}
‘aN
2016 Calcium Preparations TII-245
CALCIUM FOLINATE FOR INJECTION ammonium oxalate to the filtrate, shake, and centrifuge until a
clear supernatant liquid is obtained. To the supernatant add
DEFINITION
1 mL of methanol and 3 drops of hydrochloric acid, and shake.
eMeN to
Calcium Folinate for Injection is a sterile material consisting

If the preparation is cloudy, add methanol until a clear
of Calcium Folinate with or without excipients. It is supplied
solution is obtained and filter, if necessary, to remove any
in a sealed container.
undissolved material. Cool the preparation at 0° until a
The contents of the sealed container comply with the requirements precipitate forms and centrifuge. The cooling and
for Powders for Injections or Infusions stated under Parenteral centrifuging steps may be repeated, if necessary, to increase
Preparations and with the following requirements. the amount of precipitate collected. Decant the supernatant
Content of folinic acid, C,)H,3N,O, liquid and dissolve the precipitate in 2 mL of methanol.
90.0 to 110.0% of the stated amount. Evaporate to dryness under a current of air and dry the
residue at 50° for 30 minutes. The infrared absorption spectrum
of the residue, Appendix IT A, is concordant with the reference
sorption spectrum, Appendix II A, is
spectrum of calcium folinate (RS 368).
concordant« reference spectrum of calcium folinate
B. The powdered tablets yield reaction B characteristic of
(RS 368). Ifthe s; ra are not concordant prepare a
solution contain w/v of Calctum Folmate and carry
out Identificatio em the ready-to-use solution. TESTS
B. Yield reaction B acteristic of calcium salts, Related substances
Appendix VI. Protect the solutions from light. Carry out the method for
TESTS
solutions.
(1) Add 20 mL of water to a quantity of the powdered tablets
pH of a solution containing © of 1.0% w/v of
containing the equivalent of 25 mg of folinic acid, shake for
folinic acid, 6.5 to 8.5, Appendix V*
te Ne]
sas!
15 minutes and dilute to 25 mL with water. Filter through a

Related substances ! glass fibre filter (Whatman GF/C is suitable).
Carry out the test described for the ready
using the following solution as solution (1). Ds
water.
sufficient of the mixed contents of 10 containers 4fi w
produce a solution containing the equivalent of 0.1%" (3) 0.001% w/v offormylfolic acid EPCRS in the mobile
folinic acid. phase.
4) 0.001% w/v of calcium folinate BPCRS in water.
ASSAY
Determine the weight of the contents of 10 containers as 0.001% w/v of calcium folinate BPCRS in water.
described in the test for uniformity of weight, 5 volumes of solution (3) with 10 volumes of
Appendix XII C1, Powders for Parenteral Use.
Carry out the Assay described for the ready-to-use solution
but using the following solution as solution (1). Dissolve
sufficient of the mixed contents of the 10 containers in water
to produce a solution containing the equivalent of 0.01% w/v (5 wm) (Hypersi is suitable).
of folinic acid. nd the mobile phase described
(b) Use isocratic e
Calculate the content of C,9H»3N7O in a container of below.
average content weight using the declared content of ow rate of”
(c) Use a fl
C39H2;CaN7O7 in calcium folinate BPCRS. Each mg of
Co0H2,;CaN7O7 is equivalent to 0.9255 mg of Cx)9H.3N7O7. (d) Use a column tempera:
(e) Use a detection wavelength, of
2
LABELLING
equivalent amount of folinic acid. (g) For solution (1) allow the chromatogr to proceed for
2.5 times the retention time of folina
MOBILE PHASE
220 mL of methanol and 780 mL of a solution c@fitaining

Calcium Folinate Tablets 2.0 mL of tetrabutylammonium hydroxide solution and 2.2 g of
disodium hydrogen orthophosphate, previously adjusted to
Action and use pH 7.5 with 10% v/v orthophosphonic acid.
AVANT Vitamin B component.
SYSTEM SUITABILITY
Aveo
DEFINITION The test is not valid unless, in the chromatogram obtained

Calcium Folinate Tablets contain Calcium Folinate. with solution (6), the resolution factor between the peaks
corresponding to calcium folinate and formylfolic acid is at
least 2.2. If necessary, adjust the methanol content in the
mobile phase.
Content of folinic acid, C,)H,3N,O,
LIMITS
tee ee
IDENTIFICATION
the area of any peak corresponding to formylfolic acid is not
A. To a quantity of the powdered tablets containing the
NAN
° A
Naee]
equivalent of 180 mg of folinic acid add 10 mL of water, mix
with the aid of ultrasound, and filter. Add 125 mg of
~~ Ne oF
cme ane
II-246 Calcium Preparations 2016
the area of any other secondary peak is not greater than the B. Warm a volume containing the equivalent of 0.5 g of
area of the principal peak in the chromatogram obtained with Calcium Gluconate, add 0.65 mL of glacial acetic acid and
tet
an ewat
solution (2) (1%); 1 mL of phenylhydrazine. Heat on a water bath for
30 minutes, allow to cool and induce crystallisation. Filter,
we Ne
the sum of the areas of any secondary peaks, excluding the

peak corresponding to formylfolic acid, is not greater than dissolve the residue in 10 mL of hot water, add a few mg of
2.5 times the area of the principal peak in the chromatogram activated charcoal, shake, filter, allow the filtrate to cool and
obtained with solution (2) (2.5%). induce crystallisation. A white, crystalline precipitate is
produced. The melting point of the crystals, after drying, is
Disregard any peak with an area less than that of the
about 200°, with decomposition, Appendix V A.
solution (5) (0.1%). C. Yields the reactions characteristic of calcium salts,
Appendix VI.
ASSAY
Protect; tions from light. Weigh and powder TEST
20 tablets: t the method for liguid chromatography, Bacterial endotoxins
the following solutions. Carry out the test for bacterial endotoxins, Appendix XIV C.
Dilute the injection in water BET if necessary to give a
(1) Add 200 ni
solution containing 100 mg of Calcium Gluconate per
tablets containing
millilitre (solution A). The endotoxin limit concentration of
e to 250 mL with water. Filter
solution A is 16.7 IU per mL.
atman GF/C is suitable).
ASSAY
To a volume containing the equivalent of 0.5 g of Calcium
Gluconate add 300 mL of water and carry out the
tee
0.001% w/v solution of calcium folina complexometnic titration of calcium, Appendix VIII D, beginning
at the words ‘add 6 mL of ...’.
LABELLING
The label states (1) the percentage w/v of Calcium Gluconate
equivalent to the total amount of calctum present; (2) that
SYSTEM SUITABILITY é solutions containing visible solid particles must not be used;
The Assay is not valid unless, in the chromatogram obfain (3) the name and the percentage of any added stabilising
with solution (3), the resolution factor between the peaks agent.
corresponding to calcium folinate and formylfolic acid is a
least 2.2. If necessary, adjust the methanol content in the
mobile phase.
1 Gluconate Tablets
Calculate the content of C.,>H»23N7O7 in the tablets using the
declared content of Cr9H2;CaN-7O, in calcium
folinate BPCRS. Each mg of C2)>H»;CaN7O7 is equivalent to
eas
7
0.9255 mg of C59H23N707.
STORAGE
‘
Calcium Folinate Tablets should be stored at a temperature

not exceeding 30°.
A
LABELLING IDENTIFICATION :
The quantity of active ingredient is stated in terms of the A. Extract five tablets, finely powde ith two 25-mL
equivalent amount of folinic acid. 0° to 60°), discard
ee
a a
and to 0.5 mL of the filtrate add 0.05 mL of

Calcium Gluconate Injection
we,
solution R1, An intense yellow colour is produced.

Fee
DEFINITION B. To a volume of the filtrate obtained in test A containing

Calcium Gluconate Injection is a sterile solution of Calcium 0.5 g of Calcium Gluconate add 0.65 mL of glacial acetic acid
Gluconate for Injection in Water for Injections. Not more and 1 mL of phenylhydrazine, heat on a water bath for
LOE Gye
O
than 5.0% of the Calctum Gluconate may be replaced with 30 minutes, cool and induce crystallisation. Filter, dissolve
PASa>
calcium m-saccharate, or other suitable calcium salt, as a the residue in 10 mL of hot water, add a few mg of activated
»
stabilising agent. charcoal, shake, filter, allow the filtrate to cool and induce
crystallisation. A white, crystalline precipitate is produced.
The melting point of the crystals, after drying, is about 201°,
with decomposition, Appendix V A.
Content of calcium, Ca
C. The powdered tablets yield the reactions characteristic of
8.5 to 9.4% of the content of Calcium Gluconate stated on
the label.
TESTS
IDENTIFICATION
Dissolution
A. To 1 mL add 0.05 mL of tron(im) chloride solution R1.
An intense yellow colour is produced.
2016 Calcium Preparations III-247
Appendix XII B1, using Apparatus 2. Use as the medium ASSAY

900 mL of water and rotate the paddle at 50 revolutions per Weigh and powder 20 tablets. Ignite a quantity of the
minute. Withdraw a sample of 20 mL of the medium and powder containing 0.5 g of Calcium Gluconate, cool and
filter. Carry out the method for atomic absorption dissolve the residue with gentle heat in 5 mL of
spectrophotometry, Appendix II D, measuring at 422.7 nm 2M hydrochloric acid. Filter, wash the residue on the filter with
using a calcium hollow-cathode lamp as the radiation source, water and dilute the combined filtrate and washings to 50 mL
an air-acetylene flame and the following solutions. with water. Neutralise with 5m ammonia, using methyl orange
Test solution Use the filtered dissolution medium diluted, if solution as indicator, add 5 mL of 8m sodium hydroxide and
necessary, with water to give a concentration suitable for the titrate with 0.05m disodium edetate VS using calconcarboxylic
instrument used. acid triturate as indicator. Each mL of 0.05m disodium
edetate VS is equivalent to 22.42 mg of C,2H»2.CaOj,4,H.O.
Standard solutions Use calcium standard solution
) suitably diluted with water.
Effervescent Calcium Gluconate Tablets

Cy2H,Ca04,H
DEFINITION
ASSAY Effervescent Calcium Gluconate Tablets contain Calcium
Gluconate in a suitable effervescent basis.
powder containing 0.5 ¢ The tablets comply with the requirements stated under Tablets and
dissolve the residue with
Content of calcium gluconate, C,;,H,,Ca0O,4,,H,O
with water. Neutralise with 5m amme} 95.0 to 105.0% of the stated amount.
solution as indicator, add 5 mL of 8M sa ydroxide and IDENTIFICATION |
titrate with 0.05m disodium edetate VS usi “thle rboxylic A. Dissolve a quantity of the powdered tablets containing 1 g
acid triturate as indicator. Each mL of 0.05M., of Calctum Gluconate in 20 mL of hot water, cool and filter.
edetate VS is equivalent to 22.42 mg of C,,H»5;CaQ To 0.5 mL of the filtrate add 0.05 mL of zron(im) chloride
solution R1. An intense yellow colour is produced.
B. To 5 mL of the filtrate obtained in test A add 0.65 mL of
glacial acetic acid and 1 mL of phenylhydrazine, heat on a
Chewable Calcium Gluconate Tablets bath for 30 minutes, allow to cool and induce
ation. Filter, dissolve the residue in 10 mL of hot
DEFINITION d a suitable quantity of activated charcoal, shake,
Chewable Calcium Gluconate Tablets contain Calci1um the filtrate to cool and induce crystallisation.
Gluconate in a Chocolate Basis or other suitable basis with a ryStalline precipitate is produced. The melting point
chocolate flavour.
Content of calcium gluconate, C,;,H,,CaO,,,H,O
IDENTIFICATION
A. Extract five tablets, finely powdered, with two 25-mL Ignite a quantity of the
quantities of petroleum spirit (boiling range, 40° to 60°), discard uconate, cool and
the extracts and repeat the extraction with three 10-mL dissolve the residue with gentle héat i
quantities of water, again discarding the extracts. Dissolve the 2M hydrochloric acid. Filter, wash thie idue.on the filter with
residue as completely as possible in 30 mL of hot water, filter water and dilute the combined filtrate ‘and shings to 50 mL
and to 0.5 mL of the filtrate add 0.05 mL of zron(im) chloride with water. Neutralise with 5M ammonia, hyl orange
solution R1. An intense yellow colour is produced. solution as indicator, add 5 mL of 8M sodium hyxiro and
B. To a volume of the filtrate obtained in test A containing titrate with 0.05m disodium edetate VS using calcontarboxylic
0.5 g of Calctum Gluconate add 0.65 mL of glacial acetic acid acid triturate as indicator. Each mL of 0.05m disodium
and 1 mL of phenylhydrazine, heat on a water bath for edetate VS is equivalent to 22.42 mg of C,2H».,CaO,4,H.20.
30 minutes, cool and induce crystallisation. Filter, dissolve
the residue in 10 mL of hot water, add a few mg of activated
charcoal, shake, filter, allow the filtrate to cool and induce
crystallisation. A white, crystalline precipitate is produced.
The melting point of the crystals, after drying, is about 201°, Calcium Hydroxide Solution
with decomposition, Appendix V A. Lime Water
C. The powdered tablets yield the reactions characteristic of DEFINITION
calcium salts, Appendix VI. Calcium Hydroxide 10g
TESTS Purified Water, freshly Sufficient to produce
boiled and cooled 1000 mL
Disintegration
The requirement for Disintegration does not apply to Extemporaneous preparation
Chewable Calcium Gluconate Tablets. The following directions apply.
WI-248 Calcium Preparations 2016
tee re
Shake together thoroughly and repeatedly; allow to stand

swarvd
Neen ety
ed
until clear. Siphon off the clear solution as required. Concentrated Camphor Water
Powter
Content of calcium hydroxide, Ca(OH), DEFINITION

Not less than 0.15% w/v. Racemic Camphor 40 g
Ethanol (90 per cent) 600 mL
CHARACTERISTICS Water Sufficient to produce
A colourless liquid. It absorbs carbon dioxide from the air, a 1000 mL.
film of calcium carbonate being formed on the surface of the
liquid. It becomes turbid when boiled and clear again on Extemporaneous preparation
cooling.
Dissolve the Racemic Camphor in the Ethanol (90 per cent)
IDENTIFICATION
and add, gradually, with vigorous shaking after each addition,
Yields the tions characteristic of calcium salts, sufficient Water to produce 1000 mL.
‘awe
The water complies with the requirements stated under Aromatic
Waters and with the following requirement.
Ethanol content
0.1m hydrochloric aci¢
Ca(OH))>.
STORAGE
Calcium Hydroxide Solutio
container. Captopril Oral Solution
NOTE: Captopril Oral Solution 1s not currently licensed in the
United Kingdom.
Action and use

Calcium Lactate Tablets Angiotensin-converting enzyme inhibitor.
Calcium Lactate Tablets contain Calcium Lactate — Captopril Oral Solution is a solution containing Captopril in
Pentahydrate or Calcium Lactate Trihydrate. a suitable flavoured vehicle. Itis supplied as a ready-to-use
The tablets comply with the requirements stated under Tablets ar or it 1s prepared by dissolving Captopril Powder for
with the following requirements. ion in the requisite volume of the vehicle provided
Content of calcium lactate, calculated as issue for use.
C.<H,;,)Ca0,,5H,O ion complies with the requirements stated under Oral
95.0 to 105.0% of the stated amount. ith the requirements stated under Unlicensed
IDENTIFICATION
A. Triturate a quantity of the powdered tablets containing
0.3 g of Calcium Lactate Pentahydrate or its equivalent with be stored at the temperature and
5 mL of methanol and filter. To 0.2 mL of the filtrate add ted on the label.
2 mL of sulfuric acid, heat at 85° for 2 minutes, cool and add
4 mg of 4-hydroxybiphenyl. A violet-red colour is produced.
B. The powdered tablets, when moistened with hydrochloric
acid and introduced on a platinum wire into a flame, impart
a brick red colour to the flame.
Disintegration
ASSAY
powder containing 0.3 g of Calctum Lactate Pentahydrate or quantities of dichloromethane, combine the organic ex acts
its equivalent as completely as possible in 50 mL of water and filter through anhydrous sodium sulfate. Mix 1 mL of the
and titrate with 0.05m disodium edetate VS to within a few filtrate with 0.5 g of potassium bromide, dry at room
millilitres of the expected end point. Add 8 mL of 5m sodium temperature at a pressure of 2 kPa, grind to a uniform
hydroxide and 0.1 g of solochrome dark blue mixture and mixture and prepare a disc. The infrared absorption spectrum,
continue the titration until the colour changes from pink to Appendix II A, is concordant with the reference spectrum of
full blue. Each mL of 0.05m disodium edetate VS is equivalent captopril (RS 038).
to 15.41 mg of CgH;9CaO,,5H.O. B. In the Assay, the principal peak in the chromatogram
LABELLING obtained with solution (1) has the same retention time as the
When the active ingredient is Calcium Lactate Trihydrate the peak due to captopril in the chromatogram obtained with
quantity is stated in terms of the equivalent amount of solution (2).
Calcium Lactate Pentahydrate. TESTS
Captopril disulfide
ae NT a
nie A
RA ALL
-rwe
tate as

Vea
2016 Captopril Preparations JIII-249
(1) Dilute a quantity of the oral solution containing 25 mg of CAPTOPRIL POWDER FOR ORAL
Captopril to 50 mL with methanol and mix. SOLUTION
(2) 0.0015% w/v of captopril disulfide BPCRS in methanol.
DEFINITION
Captopril Powder for Oral Solution is a dry powder
solution (2).
consisting of Captopril with or without excipients. It is
CHROMATOGRAPHIC CONDITIONS supplied in a sealed container.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed The dry ingredients comply with the requirements for Powders and
with end-capped octadecylsilyl silica gel for chromatography Granules for Oral Solutions and Oral Suspensions stated under
(5 um) (Nucleosil C18 is suitable). Oral Liquids.
(b) Use isocratic elution and the mobile phase described Content of captopril, CoH,;;NO;3S
IDENTIFICATION
The infrared absorption spectrum, Appendix II A, is concordant
with the reference spectrum of captopril (RS 038).
(f) Inject 20 pL 6 TESTS
MOBILE PHASE Acidity
0.5 volume of orthophe: p eid, 450 volumes of water and pH of a solution containing 2% w/v of Captopril, 2.0 to 2.6,
Appendix V L.
SYSTEM SUITABILITY
Clarity of solution
A solution containing 2% w/v of Captopril in carbon dioxide-
The test is not valid unless, itt ogram obtained
free water is clear, Appendix IV A, and colourless,
with solution (3), the resolution factor etween the peaks due
Appendix IV B, Method II.
to captopril and captopril disulfideis al
Related substances
LIMITS
In the chromatogram obtained with solution’ Appendix III D, using the following solutions.
any peak corresponding to captopril disulfide is n :
(1) Dissolve a quantity of the contents of the sealed container
than the area of the peak in the chromatogram obtainié
containing 50 mg of Captopril in the mobile phase and add
solution (2) (3%).
sufficient mobile phase to produce 100 mL.
ASSAY ilute 2 volumes of solution (1) to 100 volumes with the
(1) Dilute a weighed quantity of the oral solution containing 10 mg of Captoprilin mobile phase, add 0.25 mL
25 mg of Captopril to 50 mL with mobile phase, mix and gdine and sufficient mobile phase to produce
dilute 1 volume of the resulting solution to 5 volumes with
the mobile phase.
(2) 0.01% w/v of captopril BPCRS and 0.0005% w/v of
captopril disulfide BPCRS in the mobile phase.
umn (12.5 cm x 4 mm) packed
CHROMATOGRAPHIC CONDITIONS wromatography (5 um) (Nucleosil
(a) Use a stainless steel column (25 cm x 4.6 mm) packed C8 is suitable).
with end-capped octadecylsilyl silica gel for chromatography (b) Use isocratic elution ar
(10 um) (Nucleosil C18 is suitable). below.
below.
(d) Use an ambient column temp
(c) Use a flow rate of 1 mL per minute. (e) Use a detection wavelength of 220:
(d) Use an ambient column temperature. (f) Inject 20 wL of each solution.
(g) For solution (1), allow the chromatograp toe<proceed
(f) Inject 20 wL of each solution. for 3 times the retention time of Captopril.
MOBILE PHASE MOBILE PHASE
0.5 volume of orthophosphoric acid, 450 volumes of water and 0.5 volume of orthophosphoric acid, 500 volumes of methanol
550 volumes of methanol. and 500 volumes of water.
SYSTEM SUITABILITY SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained The test is not valid unless the chromatogram obtained with
with solution (2), the resolution factor between the peaks due solution (3) shows three principal peaks and the resolution
to captopril and captopril disulfide is at least 2.0. factor between the last two eluting principal peaks is at
DETERMINATION OF CONTENT least 2.0.
Determine the weight per mL of the oral solution, LIMITS
Appendix V G, and calculate the content of Cp)H,;5NO3S, In the chromatogram obtained with solution (1):
weight in volume, using the declared content of C)pH,;;NO3S
in captopril BPCRS.
WI-250 Captopril Preparations 2016
the area of any secondary peak is not greater than 0.5 times (d) Use an ambient column temperature.
the area of the principal peak in the chromatogram obtained (e) Use a detection wavelength of 220 nm.
the sum of the areas of all such peaks is not greater than the
raw e 4
MOBILE PHASE
solution (2) (2%). 0.5 volume of orthophosphoric acid, 450 volumes of water and
550 volumes of methanol.
of the principal peakin the chromatogram obtained with SYSTEM SUITABILITY
solution (2) (0.2%) and any peak with a retention time less The test is not valid unless, in the chromatogram obtained
than 1.4 minutes. with solution (3), the resolution factor between the peaks due
to captopril and captopril disulfide is at least 2.0.
LIMITS
any peak corresponding to captopril disulfide is not greater
than the area of the peak in the chromatogram obtained with
solution (2) (3%).
ASSAY
CoH 5NO3S.
solutions.
(1) Transfer a quantity of the powdered tablets containing
Captopril Tablets 25 mg of Captopril to a centrifuge tube, add 25 mL of the
mobile phase, mix with the aid of ultrasound for 15 minutes
Action and use and centrifuge. Dilute 1 volume of the supernatant liquid to
Angiotensin converting enzyme inhibitor. 10 volumes with the mobile phase.
(2) 0.01% w/v of captopril BPCRS and 0.0005% w/v of
DEFINITION
captopril disulfide BPCRS in the mobile phase.
Captopril Tablets contain Captopril.
The tablets comply with the requirements stated under Tablets
with the following requirements. he chromatographic conditions described under Related
ces may be used.
Content of captopril, Co.H,;NO3S
95.0 to 105.0% of the stated amount. ITABILITY
ot valid unless, in the chromatogram obtained

IDENTIFICATION
A. Dissolve a quantity of the powdered tablets containing
0.1 g of Captopril in 25 mL of methanol with the aid of
ultrasound and filter. Mix 1 mL of the filtrate with 0.5 g of
potassium bromide, dry at room temperature at 2 kPa, grind to ' f CoH,5;NO3S 1n the tablets using the
a uniform mixture and prepare a disc. The infrared absorption J1,5;NO3S in captopril BPCRS.
spectrum, Appendix II A, is concordant with the reference
spectrum of captopril (RS 038).
paws d
Fae ad obtained with solution (1) has the same retention time as the
peak due to captopril in the chromatogram obtained with
solution (2).
TESTS
interchangeable.
Captopril disulfide
Carry out the method for liquid chromatography, Action and use
Appendix III D, using the following solutions. Antiepileptic.
(1) Transfer a quantity of the powdered tablets containing
25 mg of Captopril to a centrifuge tube, add 25 mL of DEFINITION
methanol, centrifuge for 15 minutes and use the supernatant Carbamazepine Tablets contain Carbamazepine.
liquid. PRODUCTION
(2) 0.0030% w/v of captopril disulfide BPCRS in methanol. A suitable dissolution test is carried out to demonstrate the
(3) Dilute 1 volume of solution (1) to 100 volumes with appropriate release of Carbamazepine. The dissolution profile
solution (2). reflects the 1m vivo performance which in turn is compatible
(5 um) (Ace C18 is suitable). Content of carbamazepine, C,;H,,N,O
(b) Use isocratic elution and the mobile phase described 95.0 to 105.0% of the stated amount.
below.
2016 Carbaryl Preparations III-251
IDENTIFICATION Dilute to 200 mL with water, mix, filter and further dilute
Boil a quantity of the powdered tablets containing 0.2 g of 1 volume of the filtrate to 5 volumes with methanol (50%).
Carbamazepine with 15 mL of acetone, filter the hot solution, (2) 0.03% w/v of carbamazepine BPCRS in methanol (50%).
wash the filtrate with two 5-mL quantities of hot acetone, cool (3) Dissolve 7.5 mg each of carbamazepine BPCRS and
in ice and evaporate the combined filtrates to dryness. The carbamazepine impurity A EPCRS in methanol and dilute to
infrared absorption spectrum of the crystals, Appendix II A, is 100 mL with the same solvent. Dilute 1.0 mL of the
concordant with the reference spectrum of carbamazepine resulting solution to 50 mL with methanol (50%).
(RS 406).
TESTS
Related substances
substances may be used, with the exception of the run time.
sing the following solutions. SYSTEM SUITABILITY
ity of the powdered tablets containing 0.3 g The test is not valid unless, in the chromatogram obtained
ith 100 mL of methanol for 15 minutes. with solution (3), the resolution factor between the peaks due
water, mix and filter. to carbamazepine and carbamazepine impurity A is at
least 1.7.
Calculate the content of C,;;H,.N.O in the tablets using the

declared content of C,;5H,,N.20O in carbamazepine BPCRS.
IMPURITIES
CHROMATOGRAPHIC CONDITION monograph include those listed under Carbamazepine.
(a) Usea stainless steel column (25cm
with nitrile silica gel for chromatography (1
CN is suitable). é
(b) Use isocratic elution and the mobile phasé’
below.
deseyt
‘
Carbaryl Lotion
Carbaryl Cutaneous Solution
MOBILE PHASE
30 volumes of tetrahydrofuran, 120 volumes of methanol and
850 volumes of water, adding 0.2 volume of anhydrous formic ith the requirements stated under Liquids for
acid and 0.5 volume of triethylamine to 1000 volumes of the 1 and with the following requirements.
solution.
C,.H,,NO,
SYSTEM SUITABILITY ed amount.
The test is not valid unless, in the chromatogram obtained IDENTIFICATIO!
with solution (3), the resolution factor between the peaks due A. Carry out the me -layer chromatography,
to carbamazepine and carbamazepine impurity A 1s at
least 1.7.
LIMITS
Inject solution (1) and continue the chromatography for phase. Apply separately to the plates}.4
10 times the retention time of carbamazepine, which is about following solutions. For solution (1)
10 minutes.
sodium chloride and 50 mL of ether, shake, allow £
separate, wash the ether layer with two 10-mL quantities of
the peak due to carbamazepine in the chromatogram
water, filter through anhydrous sodium sulfate and evaporate
obtained with solution (2) (0.2%);
the filtrate to dryness using a rotary evaporator. Dissolve the
the sum of the areas of any secondary peaks is not greater than residue in 1 mL of absolute ethanol. Solution (2) contains
2.5 times the area of the peak due to carbamazepine in the 0.4% w/v of carbaryl BPCRS in absolute ethanol. After removal
chromatogram obtained with solution (2) (0.5%). of the plate, allow it to dry in air and examine under
Disregard any peak with an area less than 0.25 times the area ultraviolet light (254 nm). The principal spot in the
of the peak due to carbamazepine in the chromatogram chromatogram obtained with solution (1) corresponds to that
obtained with solution (2) (0.05%). in the chromatogram obtained with solution (2).
ASSAY B. In the Assay, the chromatogram obtained with solution
Carry out the method for liquid chromatography, (1) shows a peak with the same retention time as that of the
Appendix III D, using the following solutions. principal peak in the chromatogram obtained with
solution (2).
of Carbamazepine with 100 mL of methanol for 15 minutes.
WI-252 Carbimazole Preparations
TESTS pressure not exceeding 0.7 kPa for 30 minutes is concordant

1-Naphthol with the reference spectrum of carbimazole (RS 042).
Carry out the method for liquid chromatography, Thiamazole and other related substances
Appendix III D, using the following solutions. For solution Carry out the test protected from light and prepare the solutions
(1) dilute a quantity of the preparation being examined with wmmediately before use. , |
sufficient acetonitrile to produce a solution containing
0.1% w/v of Carbaryl. Solution (2) contains 0.003% w/v of
1-naphthol in the mobile phase. Solution (3) contains
0.005% w/v of carbaryl BPCRS and 0.005% w/v of 1-naphthol (1) Disperse a quantity of the powdered tablets containing
20 mg of Carbimazole in 10 mL of acetonitrile with the aid of
in the mobile phase.
ultrasound for 5 minutes, filter through a nylon syringe, filter
and dilute 1 volume of the filtrate to 20 volumes with water.
be used.
mobile phase A.
(3) 0.0001% w/v of thiamazole in mobile phase A.
(4) 0.002% w/v of carbimazole BPCRS and 0.0001% w/v of
thiamazole in mobile phase A.
solution (2) (3%). (a) Use a stainless steel column (15 cm x 3.9 mm) packed
ASSAY with base-deactivated octadecylsilyl sihca gel for chromatography
(1) dilute a quantity of the preparation®being examined with below.
sufficient methanol to produce a solution 1 (c) Use a flow rate of 1 mL per minute.
0.005% w/v of Carbaryl. Solution (2) contains (d) Use an ambient column temperature.
carbaryl BPCRS in methanol. Solution (3) con
0.005% w/v of carbaryl BPCRS and 0.005% w/v of
in the mobile phase. (f) Inject 100 wL of each solution.
The chromatographic procedure may be carried out usin MOBILE PHASE
(a) a stainless steel column (10 cm x 4.6 mm) packed w obile phase A 5 volumes of acetomitrile and 95 volumes of
4 .
end-capped octadecylsilyl silica gel for chromatography (5 wm)
(Spherisorb ODS 2 is suitable), (b) a mixture of 1 volume of hase B 20 volumes of acetonitrile and 80 volumes of
glacial acetic acid, 25 volumes of acetonitrile and 75 volumes of
water as the mobile phase with a flow rate of 2.5 mL per
minute and (c) a detection wavelength of 280 nm.
Mobile phase B Comment
Inject 20 uL of each solution. The test is not valid unless in a (% viv)
the chromatogram obtained with solution (3) the resolution isocratic

factor between the two principal peaks is at least 2.0. linear gradient
Calculate the content of C;.H,;,;NO>, using the declared linear gradient
content of Ci2H, ,NO, in carbaryl BPCRS. re-equilibration
STORAGE
Carbaryl Lotion should be protected from light.
m obtained
ks due to
carbimazole and thiamazole is at least 5.
Carbimazole Tablets LIMITS
Action and use

Thionamide antithyroid drug.
DEFINITION chromatogram obtained with solution (3) (1%);
Carbimazole Tablets contain Carbimazole. the area of any other secondary peak is not greater than the
The tablets comply with the requirements stated under Tablets and area of the principal peak in the chromatogram obtained with
with the following requirements. solution (2) (0.5%).
Content of carbimazole, C,H,)N,0O2S ASSAY
90.0 to 110.0% of the stated amount. Carry out the test protected from light and prepare the solutions
IDENTIFICATION
Extract a quantity of the powdered tablets containing 50 mg Weigh and powder 20 tablets. Carry out the method for
of Carbimazole with two 5-mL quantities of dichloromethane. liquid chromatography, Appendix III D, using the following
Combine the dichloromethane extracts, filter and evaporate solutions.
the filtrate to dryness. The zmfrared absorption spectrum, (1) Disperse a quantity of the powdered tablets containing
Appendix II A, of the residue after drying at 60° at a 20 mg of Carbimazole in 10 mL of acetonitrile with the aid of
ultrasound for 5 minutes, filter through a nylon syringe filter
2016 Carboplatin Preparations III-253
and dilute 1 volume of this solution to 40 volumes with a

5% v/v solution of acetonitrile.
Carboplatin Injection
(2) 0.005% w/v of carbimazole BPCRS in mobile phase A. Action and use
(3) 0.01% w/v of carbimazole BPCRS and 0.0005% w/v of Platinum-containing cytotoxic.
thiamazole in mobile phase A.
DEFINITION
Carboplatin Injection is a sterile solution of Carboplatin in
The chromatographic procedure described under Related Water for Injections.
SYSTEM SUITABILITY Parenteral Preparations and with the following requirements.
The test is not valid unless, in the chromatogram obtained Content of carboplatin, Cg;H,,N,O0,Pt
(3), the resolution between the peaks due to 90.0 to 105.0% of the stated amount.
ithiamazole is at least 5.0.
Carry out the following procedures protected from light.
IDENTIFICATION
Appendix III A, using the following solutions within 2 hours
of preparation.
The impurities limited:h: (1) Use the injection diluted, if necessary, with water to
monograph include thos produce a solution containing 1.0% w/v of Carboplatin.
(2) 1.0% w/v of carboplatin BPCRS in water.
(a) Use a TLC silica gel plate.

Carbomer Eye Drops (b) Use the mobile phase as described below.
Action and use (c) Apply 10 uL of each solution.

Stabilizer in pharmaceutical products. (d) Develop the plate to 15 cm.
(e) After removal of the plate, dry in air for 2 hours. Spray
DEFINITION the plate with a solution prepared immediately before use by
Carbomer Eye Drops area sterile viscous solution of dissolving 5.6 g of tin(u) chloride in 10 mL of hydrochloric acid
Carbomer 940 or Carbomer 980 in Purified Water. solution may not be complete, filter if necessary), adding
The eye drops comply with the requirements stated under Eye of water and 1 g of potassium todide and stirring. Heat
Preparations and with the following requirements. e at 100° for 10 minutes and examine in daylight.
IDENTIFICATION
A. Add 15 g of the eye drops to 85 mL of water and mix
thoroughly. To 3 mL add 1 mL of calcium chloride solution, a
fine white precipitate is produced.
B. Add 0.5 mL of thymol blue solution to 10 g of the eye
drops. A yellow colour is produced. Add 0.5 mL of cresol red
solution to 10 g of the eye drops. A yellow colour is
B. In the Assay, the ¢hremategram obtained with solution
produced.
(1) shows a peak with
TESTS principal peak in the chrormatégram obtained with
Acidity or alkalinity solution (2).
TESTS
Apparent viscosity Acidity
75 to 125% of the declared value when determined by the pH, 5.0 to 7.0, Appendix V L.
following method. Empty the contents of sufficient containers
Cyclobutane-1,1-dicarboxylic acid "
to obtain 200 g of the eye drops, taking care to avoid
Carry out the method for liquid chromatograph
incorporation of air bubbles, and homogenise. Allow to stand
at 25° for 60 minutes. Immerse the appropriate spindle of a
Appendix III D, using the following solutions. —
rotational viscometer, switch on after 5 minutes and (1) Dilute the injection with water to produce a solution
determine the viscosity at 25°, Appendix V H, Method III, containing 0.1% w/v of Carboplatin; use within 2 hours of
using a shear speed of 5 per second. preparation.
Clarity of solution (2) 0.001% w/v of cyclobutane-1,1-dicarboxylic acid in water.
The eye drops are not more opalescent than reference (3) Mix 1 volume of solution (1) with 1 volume of
suspension III, Appendix IV A. solution (2).
LABELLING CHROMATOGRAPHIC CONDITIONS
The label states the nominal viscosity in millipascal seconds. (a) Use a stainless steel column (30 cm x 3.9 mm) packed
(u-Bondapak C18 is suitable).
below.
IWI-254 Carmellose Sodium Preparations 2016
(d) Use an ambient column temperature. IMPURITIES

(e) Use a detection wavelength of 220 nm. The impurities limited by the requirements of this
(f) Inject 100 wL of each solution. monograph include those listed in the monograph for
Carboplatin.
for 2.5 times the retention time of the principal peak.
MOBILE PHASE
20 volumes of solution A prepared as described below,

100 volumes of acetonitrile and 880 volumes of water. Carmellose Sodium Eye Drops
To prepare solution A dissolve 8.5 g of tetrabutylammonium
Action and use
hydrogen sulfate in 80 mL of water, add 3.4 mL of
Used in the treatment of tear deficiency.
acid and adjust the pH to 7.55 with
DEFINITION
Carmellose Sodium Eye Drops area sterile colloidal solution
The test is not ) ss, in the chromatogram obtained of Carmellose Sodium in Purified Water.
with solution (3), tion factor between the peak due to The eye drops comply with the requirements stated under Eye
carboplatin and that: yelobutane-1,1-dicarboxylic acid is Preparations and with the following requirements.
at least 2.5. Content of carmellose sodium
LIMITS 95.0 to 115.0% of the stated amount.
In the chromatogram obtain with IDENTIFICATION
the area of any peak correspon: A. To 10 mL of the eye drops, add 1 mL of copper sulfate
dicarboxylic acid is not greater solution. A blue, cotton-like precipitate is formed.
the chromatogram obtained with solution B. In the Assay, the spectrum obtained with solution (1)
Bacterial endotoxins shows maxima at about 295, 366, 519 and 635 nm.
Carry outthe test jor bacterial endotoxins, Ap The spectrum obtained with solution (1) corresponds to the
spectrum obtained with solution (2).
10 mg of Carboplatin per mL (solution A). The endoto;
TESTS
limit concentration of solution A is 5.4 IU of endotoxisi'’p
Clarity and colour of solution
mL.
he eye drops are clear, Appendix IV A, and are not more
ASSAY uy sty coloured than reference solution Ys, Appendix IV B,
Appendix III D, using the following solutions within 2 hours
of preparation. .0O, Appendix V L.
(1) Dilute the injection with water to produce a solution
containing 0.1% w/v of Carboplatin.
drops is 270 to 350 mosmol/kg,
(2) 0.1% w/v of carboplatin BPCRS. Appendix V 'N
CHROMATOGRAPHIC CONDITIONS ASSAY
with aminopropylsilyl silica gel for chromatography (10 um) acid, add 90 mL of hyd
(u-~Bondapak-NH), 1s suitable). (solution A).
(b) Use isocratic elution and the mobile phase described For solution (1), use the ey
below. water to contain 0.01% w/v of Carme
(c) Use a flow rate of 2 mL per minute. 2 mL of this solution into a glass st
(d) Use an ambient column temperature. 5 mL of solution A, mix and imme
MOBILE PHASE
130 volumes of water and 870 volumes of acetonitrile. temperature for not more than 1 hour. For solution (2),
prepare a solution containing 0.01% w/v of carmellose
SYSTEM SUITABILITY
sodium BPCRS in water and treat at the same time and in the
The test is not valid unless, in the chromatogram obtained same manner as solution (1), starting at the words “‘pipette
with solution (1), the capacity factor is not less than 4.0, the 2 mL of this solution ....”. For solution (3), use water and
number of theoretical plates is not less than 5000 and the treat at the same time and in the same manner as solution
symmetry factor is not more than 2.0. (1), starting at the words “‘pipette 2 mL of this
solution....”’.
33
Calculate the content of Cs;H,,N.O,Pt in the injection using Measure the absorbance of solution (1) and solution (2) at the
the declared content of CgH,2,N2O,Pt in carboplatin BPCRS. maximum at about 635 nm, Appendix II B, using solution
(3) in the reference cell. Calculate the content of Carmellose
STORAGE
Sodium in the eye drops from the values of the absorbances
Carboplatin Injection should be protected from light and free
obtained and using the declared content of Carmellose
from contact with metals.
Sodium in carmellose sodium BPCRS.
2016 Carvedilol Preparations III-255
Carteolol Eye Drops (f) Inject 20 uwL of each solution.

MOBILE PHASE
Action and use 1 volume of methanol, 20 volumes of acetonitrile and
Beta-adrenoceptor antagonist. 79 volumes of a 0.282% w/v solution of sodium
hexanesulfonate.
DEFINITION
SYSTEM SUITABILITY
Carteolol Eye Drops are a sterile solution of Carteolol
Hydrochloride in Purified Water. The test is not valid unless in the chromatogram obtained
The eye drops comply with the requirements stated under Eye with solution (2) the column efficiency, determined on the
Preparations and with the following requirements. principal peak, is at least 6000 theoretical plates per metre.
LIMITS
Content, of carteolol hydrochloride, C,;;H,,N,03,HCl
the area of any secondary peak is not greater than twice the
the area of not more than one such peak is greater than the
the sum of the areas of all such peaks is not greater than
CHROMATOGRAPHIC CO? 0.6 times the area of the principal peak in the chromatogram
(a) Use as the coating silica @ obtained with solution (2) (0.6%).
(b) Use the mobile phase as ASSAY
(c) Apply 2 wL of each solution. Carry out the method for liquid chromatography,
(d) Develop the plate to 15 cm. Appendix III D, using the following solutions.
(e) After removal of the plate, dry in air under (1) Dilute the eye drops to contain 0.002% w/v of Carteolol
ultraviolet light (254 nm). Hydrochloride.
MOBILE PHASE (2) 0.002% w/v of carteolol hydrochloride BPCRS.
1 volume of 13.5mM ammonia, 20 volumes of methanol CHROMATOGRAPHIC CONDITIONS
50 volumes of chloroform. Use a stainless steel column (12.5 cm x 4 mm) packed
CONFIRMATION

solution (1) corresponds in position to that in the
solution (2).
TESTS MOBILE PHASE
Acidity
1.0 g of potassium d
80 mL of acetonitrile an
Related substances
SYSTEM SUITABILITY a
Appendix III D, using the following solutions. The test is not valid unless in th
with solution (2) the column effic
(1) Dilute the eye drops with the mobile phase to contain
principal peak, is at least 6000 theoretie
0.20% w/v of Carteolol Hydrochloride.
mobile phase. Calculate the content of C,;g6H24N,03,HC (
(3) Dilute 1 volume of solution (2) to 10 volumes with the fusing the declared content of C)gH24N203,HCI in carteolol
mobile phase. hydrochloride BPCRS.

(5 um) (YMC-Pack ODS-A is suitable). Carvedilol Tablets
Action and use
below.
Beta-adrenoceptor antagonist; arteriolar vasodilator.
(c) Use a flow rate such that the retention time of carteolol
hydrochloride is about 14 minutes (1 mL per minute may be DEFINITION
suitable). Carvedilol Tablets contain Carvedilol.
II-256 Carvedilol Preparations 2016
The tablets comply with the requirements stated under Tablets and 30 minutes. Dilute to 100 mL with diluent, mix and
one nl
with the following requirements. centrifuge. Dilute 1 volume of the supernatant liquid to
aN wa!
Content of Carvedilol, C,,H>,N,O, 2 volumes with water and filter (a 0.45-m filter is suitable).
95.0 to 105.0% of the stated amount. (2) Dilute 1 volume of solution (1) to 100 volumes with
diluent. Dilute 1 volume of this solution to 10 volumes with
IDENTIFICATION
diluent.
A. Shake a quantity of powdered tablets containing 50 mg of
Carvedilol with 20 mL of dichloromethane for 15 minutes. (3) Dissolve 3.125 mg of carvedilol impurity C EPCRS in a
Filter (a GF/C filter is suitable), evaporate the filtrate to solution consisting of 1 volume of water and 9 volumes of
dryness under a stream of nitrogen and dry at 60° for 1 hour. diluent. Dilute to 250 mL with methanol (50%). Dilute
The infrared absorption spectrum of the residue, Appendix JIA, 10 mL of this solution to 100 mL with a solution consisting
is concordant,.with the :frared absorption spectrum of of 1 volume of diluent and 1 volume of water. Dilute
1 volume of this solution to 50 volumes with a solution
consisting of 1 volume of diluent and 1 volume of water.
(4) 0.1% w/v of carvedilol for system suitability EPCRS in
methanol (50%).
solution (2). (a) Use a stainless steel column (5 cm x 4.6 mm) packed
TESTS with octylsilyl silica gel for chromatography (3 um) (Hypersil
Dissolution MOS-1 is suitable).
Comply with the requirements ‘iz (b) Use gradient elution and the mobile phase described
and capsules, Appendix XII Bl below.
TEST CONDITIONS : (c) Use a flow rate of 1.0 mL per minute.
(a) Use Apparatus 2, rotating the paddle a (d) Use a column temperature of 40°.
per minute. (e) Use a detection wavelength of 240 nm.
(b) Use 900 mL of a 0.7% v/v solution of hydrochléric (f) Inject 25 wL of each solution.
adjusted to pH 1.5 using sodium hydroxide (50%), at MOBILE PHASE
temperature of 37°, as the medium.
Buffer solution
PROCEDURE
volumes of triethylamine and 500 volumes of a 0.14% w/v
(1) After 45 minutes withdraw a 10-mL sample of the , of potassium dihydrogen phosphate, adjusted to pH 3.0
suitably diluted with the dissolution medium if necessary, to
A 75 volumes of a 0.69% w/v solution of
produce a solution expected to contain 0.00035% w/v of
yl sulfate in buffer solution and 360 volumes of
Carvedilol, at 285 nm and 380 nm, Appendix II B using
luted to 1000 volumes with water.
volumes of a 0.69% w/v solution of
in’ buffer solution and 450 volumes of
carvedilol BPCRS at 285 nm and 380 nm_ in dissolution
acetonitrile dilute: 0 volumes with water.
medium, using dissolution medium in the reference cell.
Calculate the corrected absorbance from the following
Time Mobile phase B Comment
expression:
(Minutes) (% viv) Ce ly)
0-20 100 isocratic

hea
Acorr = 4285 - A380
25-45 0 isocratic
Where:
45-46 0-100 inear gradient
Acorr = the corrected absorbance
46-60 100 0
Aogs = the absorbance at 285 nm
A3g9 = the absorbance at 380 nm
DETERMINATION OF CONTENT When the chromatograms are recorded under the
Calculate the total content of carvedilol, C.4,H».N2Ou., in the conditions, the relative retentions with reference to carvedilol
medium from the corrected absorbances obtained and using (retention time about 12 minutes) are: impurity A, about 2.6;
eee
the declared content of C3,H2.N2O,, in carvedilol BPCRS. impurity C, about 2.5; impurity D, about 2.7.
vrate
SYSTEM SUITABILITY
q>.
LIMITS
a
Pee,
The amount of carvedilol released is not less than 75% (Q)

’
Lo
of the stated amount. in the chromatogram obtained with solution (4), the peak-to-
oe
way
Tt
valley ratio is at least 3.5, where H, is the height above the

Related substances
ve
on
Loe
baseline of the peak due to impurity A and H, is the height

Yo .

oe
‘
,
ca
above the baseline of the lowest point of the curve separating

.

.
ty
vf
this peak from the peak due to impurity D;

Cf
mixture of 1 volume of 1m hydrochloric acid and 9 volumes of

ey
sot
in the chromatogram obtained with solution (3), the szgnal-to-

at
an
methanol (diluent).
Cec
vo
noise ratio of the peak due to impurity C is at least 10.

oy
eee? oo

es ey
eprpior yg
eo
25 mg of Carvedilol in 10 mL of water for 20 minutes.

Cys
Cer
.
y
>
Add 70 mL of diluent and mix with the aid of ultrasound for

2016 Cefaclor Preparations III-257
LIMITS
Identify any peak in the chromatogram obtained with
Cefaclor Capsules
solution (1) corresponding to impurity A using the Action and use
chromatogram obtained with solution (4). Multiply the area Cephalosporin antibacterial.
of this peak by a correction factor of 2.0
In the chromatogram obtained with solution (1): DEFINITION
the area of any peak corresponding to impurityC is not Cefaclor Capsules contain Cefaclor.
greater than the area of the principal peak in the The capsules comply with the requirements stated under Capsules
chromatogram obtained with solution (3) (0.02%); and with the following requirements.
the area of any other secondary peak is not greater than twice Content of anhydrous cefaclor, C,;;H,,CIN3;0,S
IDENTIFICATION
reas of any secondary peaks, excluding the A. Shake a quantity of the contents of the capsules
arity C, is not greater than 5 times the area containing the equivalent of 0.3 g of anhydrous cefaclor with
in the chromatogram obtained with 100 mL of water, filter and dilute 1 mL of the filtrate to
100 mL with water. The light absorption, Appendix II B, in
the range 190 nm to 310 nm, of the final solution exhibits a
solution (2) (0.1%). B. In the Assay, the chromatogram obtained with
ASSAY solution (1) shows a peak with the same retention time as the
Weigh and powder 20 tablets; principal peak in the chromatogram obtained with
liquid chromatography, Appendix solution (2).
solutions in the mobile phase. TESTS
(1) Shake a quantity of the powdered Dissolution
and filter (a 0.7-um glass microfilter is suitable) Appendix XII Bl.
(2) 0.0125% w/v of carvedilol BPCRS. TEST CONDITIONS
CHROMATOGRAPHIC CONDITIONS (a) Use Apparatus 2, rotating the paddle at 50 revolutions

(a) Use a stainless steel column (12.5 cm x 4.6 mm) packe minute.
with octadecylsilyl sihca gel for chromatography (10 um) se 900 mL of water, at a temperature of 37°, as the
(Nucleosil 100-C18 is suitable).
below.
(c) Use a flow rate of 1.5 mL per minute. er and dilute the filtered solution, if necessary,
(d) Use an ambient column temperature. i produce a solution expected to
(e) Use a detection wavelength of 285 nm. of about 0.025% w/v of anhydrous
maximum at 264
MOBILE PHASE reference cell.
50 volumes of methanol and 50 volumes of (2) Measure the absorba
0.1m orthophosphoric acid adjusted to pH 2.0 with cefaclor BPCRS in water us Wale,
0.1M potassium dihydrogen orthophosphate.
DETERMINATION OF CONTENT?
SYSTEM SUITABILITY
Calculate the total content of anhydr
The Assay is not valid unless, in the chromatogram obtained C,5H,4CIN30,S, in the medium fro i
with solution (2), the symmetry factor of the peak due to obtained and using the declared content ef
carvedilol is between 0.8 and 1.8. in cefaclor BPCRS.
DETERMINATION OF CONTENT Related substances
Calculate the content of C2,H..6N2O, in the tablets using the Carry out the method for liquid chromatography,
declared content of C,,H25N2O, in carvedilol BPCRS. Appendix III D, using the following solutions in a 0.27% w/v
solution of sodium dihydrogen orthophosphate which has been
IMPURITIES
adjusted to pH 2.5, if necessary, with orthophosphoric acid
(solution A). The solutions should be freshly prepared.
monograph include impurities A, C and D listed under
Carvedilol. (1) Shake a quantity of the contents of the capsules
containing the equivalent of 0.5 g of anhydrous cefaclor with
200 mL of solution A, add sufficient of solution A to
produce 250 mL and filter.
(2) 0.002% w/v of cefaclor BPCRS.
(3) 0.0025% w/v of cefaclor BPCRS and 0.005% w/v of
delta-3-cefaclor BPCRS.
II-258 Cefaclor Preparations 2016
CHROMATOGRAPHIC CONDITIONS (b) Use isocratic elution and the mobile phase described
(a) Use a stainless steel column (25 cm x 4.6 mm) packed below.
with end-capped octadecylsilyl silica gel for chromatography (c) Use a flow rate of 1.5 mL per minute.
ole
(5 um) (Spherisorb ODS-2 is suitable). (d) Use an ambient column temperature.

(b) Use gradient elution and the mobile phase described (e) Use a detection wavelength of 265 nm.
below.
MOBILE PHASE
Dissolve 1 g of sodium pentanesulfonate in a mixture of
780 mL of water and 10 mL of triethylamine, adjust the pH
(f) Inject 20 wL of each solution. to 2.5 using orthophosphoric acid, add 220 mL of methanol and
mix.
SYSTEM SUITABILITY
to cefaclor and delta-3-cefaclor is at least 2.5 and the
symmetry factor of the peak due to cefaclor is at most 1.5.
Calculate the content of C;5H,4CIN30O,S in the capsules

following gradient elution. from the chromatograms obtained and using the declared
content of C,5H,4CIN30,S in cefaclor BPCRS.
Time Mobile phase A. Mobile phe STORAGE
(min) (% viv) (% viv) Cefaclor Capsules should be stored at a temperature not
0 > 30 95 ~» 75 i» 25 exceeding 30°.
30-45 75 >0 25 —> 100 LABELLING
45» 55 0 100 The quantity of active ingredient is stated in terms of the
355-470 O-%95 190
>5 equivalent amount of anhydrous cefaclor.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained Oral Suspension
to cefaclor and delta-3-cefaclor is at least 2.0. If necessary,
adjust the proportion of acetonitrile in the mobile phase.
LIMITS

the area of any secondary peak 1s not greater than half the area suitable flavoured vehi
of the principal peak in the chromatogram obtained with ingredients in the spec
solution (2) (0.5%); for use.
the sum of the areas of any such peaks is not greater than The dry ingredients comply wit.
twice the area of the principal peak in the chromatogram Granules for Oral Solutions and
obtained with solution (2) (2%). Oral Liguids.
Disregard any peak with an area less than 0.1 times the area STORAGE
of the principal peak in the chromatogram obtained with The dry ingredients should be protected
solution (2) (0.1%). stored at a temperature not exceeding 30°.
ASSAY
Carry out the method for liquid chromatography, the label. The suspension, examined immediately after pr
Appendix III D, using the following solutions. unless otherurse indicated, complies with the requirements stated
(1) Shake a quantity of the powdered, mixed contents of under Oral Liquids and with the following requirements.
20 capsules containing the equivalent of 75 mg of anhydrous Content of anhydrous cefaclor, C,;;H,,CIN3;0,S
cefaclor with the mobile phase, add sufficient mobile phase When freshly constituted, not more than 120.0% of the
to produce 250 mL and filter. stated amount. When stored at the temperature and for the
(2) 0.03% w/v of cefaclor BPCRS in the mobile phase. period stated on the label during which the Oral Suspension
(3) 0.03% w/v of each of cefaclor BPCRS and may be expected to be satisfactory for use, not less than
delta-3-cefaclor BPCRS in the mobile phase. 80.0% of the stated amount.

A. Shake a quantity of the oral suspension containing the
equivalent of 0.3 g of anhydrous cefaclor with 500 mL of
(5 um) (Beckman Ultrasphere ODS and Supelcosil LC-18- water, filter and use the filtrate. The light absorption,
Appendix II B, in the range 190 nm to 310 nm, of the final
DB are suitable).
solution exhibits a maximum only at 264 nm.
2016 Cefaclor Preparations III-259
B. In the Assay, the chromatogram obtained with solution Disregard any peak with an area less than 0.1 times that of
(1) shows a peak with the same retention time as the the area of the principal peak in the chromatogram obtained
principal peak in the chromatogram obtained with with solution (2) (0.1%).
solution (2).
ASSAY
TESTS Carry out the method for liquid chromatography,
Related substances Appendix III D, using the following solutions.
Carry out the method for liguid chromatography, (1) Shake a quantity of the oral suspension containing the
Appendix III D, using the following solutions in a 0.27% w/v equivalent of 75 mg of anhydrous cefaclor with 200 mL of
solution of sodium dihydrogen orthophosphate which has been the mobile phase, add sufficient of the mobile phase to
adjusted to pH 2.5, if necessary, with orthophosphoric acid produce 250 mL and filter.
(2) 0.03% w/v of cefaclor BPC'RS in the mobile phase.
(1) Shaké® uantity of the oral suspension containing the
(3) 0.03% w/v of each of cefaclor BPCRS and
oD
delta-3-cefaclor BPCRS in the mobile phase.

gs.
vio
=
sates
ri
and filter. < CHROMATOGRAPHIC CONDITIONS

2
‘
:
.,
(2) 0.001% f (a) Use a stainless steel column (25 cm x 4.6 mm) packed
.

mae
(3) 0.0025% w/v'ef.ce

(5 um) (Beckman Ultrasphere ODS and Supelcosil LC-18-
.
delta-3-cefaclor BPCRS
:
:
sof
DB are suitable).
.
£
CHROMATOGRAPHIC
ee oye

ony
pollen
below.
Te,
4
with end-capped octadecylsilyl

ny
sor

eh,
(5 um) (Spherisorb ODS-2

o> ea pe
aye
ey

te

wey
below.
:

oe

ee
-
(d) Use an ambient column temperature. MOBILE PHASE
(e) Use a detection wavelength of 220 nm. Dissolve 1 g of sodium pentanesulfonate in a mixture of
780 mL of water and 10 mL of triethylamine, adjust the pH
to 2.5 using orthophosphoric acid, add 220 mL of methanol and
MOBILE PHASE
Mobile phase A A 0.78% w/v solution of sodium dihydrogen PSTER SUITAB
ILITY
orthophosphate adjusted to pH 4.0 with orthophosphoric acid.
y is not valid unless, in the chromatogram obtained
Mobile phase B_ Mix 450 volumes of acetomitrile with ition (3), the resolution factor between the peaks due
550 volumes of mobile phase A.
Equilibrate the column with a mixture of 5 volumes of
mobile phase B and 95 volumes of mobile phase A for at
least 15 minutes. Inject the solutions and carry out the
following gradient elution.
Time Mobile phase A | Mobile phase B Comment content of C,5H,4CIN3O

(min) Ce viv) (% viv)
Repeat the procedure usi ortion of the oral suspension
0-30 95-75 5 > 25 linear gradient that has been stored at the mperature and for the period
30->45 75-0 25 -» 100 linear gradient stated on the label during which i be expected to be
satisfactory for use. |
45» 45 90 100 isocratic
55-370 0-95 100 -» 5 re-equilibration
The Oral Suspension should be storedat thé temperature
and used within the period stated on the la
SYSTEM SUITABILITY LABELLING
The test is not valid unless, in the chromatogram obtained The quantity of active ingredient is stated in terms of the
with solution (3), the resolution factor between the peaks due equivalent amount of anhydrous cefaclor.
LIMITS

solution (2) (1%);
the sum of the areas of any such peaks is not greater than
three times the area of the principal peak in the
IlI-260 Cefaclor Preparations 2016
Equilibrate the column with a mixture of 5 volumes of

Prolonged-release Cefaclor Tablets mobile phase B and 95 volumes of mobile phase A for at
Prolonged-release Cefaclor Tablets from different manufacturers, least 15 minutes. Inject the solutions and carry out the
"Nw ae
y Nat
whilst complying with the requirements of the monograph, are not following gradient elution.
Action and use ‘Time Mobile phase A Mobile phase B Comment

Cephalosporin antibacterial. (min) (Ms viv} (4 VAD
DEFINITION 0 —» 30 95 —» 75 omy 25 linear gradient

Prolonged-release Cefaclor Tablets contain Cefaclor. They 30> 45 75 -> 0 25 ~» 100 linear gradient
are formulated so that the medicamentis released over a 45 +55 0 100 isocratic
§5->70 0-95 100 5 re-equilibration
faclor. The dissolution profile SYSTEM SUITABILITY

ance which in turn is compatible The test is not valid unless, in the chromatogram obtained
2commended by the manufacturer. with solution (3), the resolution factor between the peaks due
LIMITS
90.0 to 105.0% of the stated a In the chromatogram obtained with solution (1):
IDENTIFICATION the area of any secondary peak is not greater than 0.6 times
A. Shake a quantity of the powdered tabl the area of the principal peak in the chromatogram obtained
equivalent of 0.3 g of anhydrous cefaclor* with solution (2) (0.6%);
water, filter and dilute 1 mL of the filtrate t the sum of the areas of any such peaks is not greater than
water. The light absorption, Appendix IT B, in the, 3 twice the area of the principal peak in the chromatogram
190 nm to 310 nm, of the final solution exhibits a n obtained with solution (2) (2%).
only at 264 nm. . Disregard any peak with an area less than 0.1 times that of
B. In the Assay, the chromatogram obtained with solution the area of the principal peak in the chromatogram obtained
(1) shows a peak with the same retention time as the tion (2) (0.1%).
solution (2).
TESTS
Related substances
Appendix III D, using the following solutions in a 0.27% wiv
solution of sodium dihydrogen orthophosphate which has been
adjusted to pH 2.5, if necessary, with orthophosphoric acid
equivalent of 0.75 g of anhydrous cefaclor with 200 mL of
solution A, add sufficient of solution A to produce 250 mL
and filter.
(2) 0.003% w/v of cefaclor BPCRS.
(3) 0.0025% w/v of cefaclor BPCRS and 0.005% w/v of
delta-3-cefaclor EPCRS.
(5 um) (Spherisorb ODS-2 is suitable).
oe ane
below.
(c) Use a flow rate of 1 mL per minute. (f) Inject 20 uL of each solution.
(d) Use an ambient column temperature. MOBILE PHASE
(e) Use a detection wavelength of 220 nm. Dissolve 1 g of sodium pentanesulfonate in a mixture of
(f) Inject 20 wL of each solution. 780 mL of water and 10 mL of triethylamine, adjust the pH
to 2.5 using orthophosphoric acid, add 220 mL of methanol and
MOBILE PHASE mix.
Mobile phase A A 0.78% w/v solution of sodium dihydrogen
SYSTEM SUITABILITY
orthophosphate adjusted to pH 4.0 with orthophosphonic acid.
Mobile phase B- Mix 450 volumes of acetonitrile with
a
te
le
550 volumes of mobile phase A.

2016 Cefadroxil Preparations III-261
to cefaclor and delta-3-cefaclor is at least 2.5 and the the absorbance obtained from a 0.003% w/v solution of
symmetry factor of the peak due to cefaclor is at most 1.5. cefadroxil BPCRS in water and using the declared content of
C,6H,7N30;5S in cefadroxil BPCRS.
Calculate the content of C;5H,,CIN30,S in the tablets from Related substances

the chromatograms obtained and using the declared content Carry out the method for liguid chromatography,
of C,5H,4CIN30.,S in cefaclor BPCRS. Appendix III D, using the following freshly prepared
solutions. For solution (1) add 50 mL of the mobile phase to
STORAGE a quantity of the contents of the capsules containing the
Prolonged-release Cefaclor Tablets should be stored at a equivalent of 0.5 g of anhydrous cefadroxil, mix, stir
temperature not exceeding 30°. magnetically for 10 minutes, filter and use the filtrate.
LABELLING Solution (2) contains 0.01% w/v of cefadroxil BPCRS in the
The quatt ity of active ingredient is stated in terms of the mobile phase. Solution (3) contains 0.01% w/v of
t of anhydrous cefaclor. p-a-(4-hydroxyphenyl) glycme BPCRS (cefadroxil impurity A)
in the mobile phase. Solution (4) contains 0.01% w/v of
7-aminodesacetoxycephalosporanic acid BPCRS (cefadroxil
impurity B) in the mobile phase.
Cefadroxil (a) a stainless steel column (30 cm x 3.9 mm) packed with
Action and use
(uBondapak C18 is suitable), (b) as the mobile phase with a
Cephalosporin antibactert
flow rate of 1 mL per minutea solution prepared as
described below and (c) a detection wavelength of 254 nm.
DEFINITION :
For the mobile phase add 200 mL of 1m potassium hydroxide,
Cefadroxil Capsules contain Cefadr
40 mL of 0.4m tetrabutylammonium hydroxide and 80 mL of
The capsules comply with the requiremen methanol to 1600 mL of water, mix, add sufficient water to
and with the following requirements. produce 2000 mL and adjust the pH to 7.0, if necessary,
Content of anhydrous cefadroxil, CicH; with orthophosphoric acid. For solution (1) allow the
92.5 to 107.5% of the stated amount. chromatography to proceed for 6 times the retention time of
IDENTIFICATION the principal peak.
A. Carry out the method for thin-layer chromatography, When the chromatograms are recorded under the conditions
Appendix III A, using a TLC silica gel plate (Merck silica described above the retention time of cefadroxil is 8 to
60 plates are suitable) and a mixture of 3 volumes of a nutes. If necessary, adjust the composition of the
6.7% w/v solution of ninhydrin in acetone, 80 volumes of a ‘phase (increasing the methanol content decreases the
0.1m solution of disodium hydrogen orthophosphate and time, decreasing the methanol content increases the
120 volumes of a 0.1m solution of citric acid as the mobile
phase. Impregnate the plate by development with a 5% v/v
solution of n-tetradecane in hexane. Allow the solvent to to cefadroxil in the chromatogram obtained
evaporate and carry out the chromatography in the same ig at least 1500 theoretical plates per metre
direction as the impregnation. Apply separately to the plate fer of the principal peak is at most 1.6.
20 uL of each of the following solutions. For solution (1) stir Inject solution(2
a quantity of the contents of the capsules containing the relative standard
equivalent of 0.2 g of anhydrous cefadroxil with 100 mL of at most 2.0%.
water, filter and use the filtrate. Solution (2) contains
with solution (1) the area of
0.2% w/v of cefadroxil BPCRS in water. After removal of the fadroxil.impurity A is not
any peak corresponding to
plate allow it to dry in air, spray with a 0.2% w/v solution of
greater than the area of the princ:
ninhydrin in absolute ethanol, heat the plate at 110° for
10 minutes and allow to cool. The principal spot in the
chromatogram obtained with solution (1) is similar in
position and size to that in the chromatogram obtained with
solution (2).
B. In the Assay, the chromatogram obtained with solution principal peak in the chromatogram obtained with solution
(1) shows a peak with the same retention time as the (2) (1%). Disregard any peak with an area less than
principal peak in the chromatogram obtained with 0.1 times the area of the principal peak in the chromatogram
solution (2). obtained with solution (2) (0.1%).
TESTS Water
Dissolution The contents of the capsules contain not more than 7.0%
Comply with the requirements for Monographs of the British w/w of water, Appendix IX C. Use 0.5 g.
ASSAY
Appendix XII B1, using as the medium 900 mL of water and
rotating the basket at 100 revolutions per minute. Withdraw
a sample of 10 mL of the medium and filter. Measure the
(1) shake a quantity of the mixed contents of 20 capsules
absorbance of the filtered medium, diluted if necessary with
containing the equivalent of 0.2 g of anhydrous cefadroxil
water, at the maximum at 263 nm using water in the
with 150 mL of a phosphate buffer prepared by dissolving
reference cell, Appendix II B. Calculate the total content of
13.6 g of potassium dihydrogen orthophosphate in sufficient
anhydrous cefadroxil, C;6H,7N305S, in the medium from
IWI-262 Cefadroxil Preparations 2016
water to produce 2000 mL and adjusting the pH, if direction as the impregnation. Apply separately to the plate
necessary, to 5.0 with 10m potassium hydroxide for 5 minutes. 20 uL of each of the following solutions. For solution (1)
Add sufficient of the buffer solution to produce 200 mL and dilute a volume of the oral suspension containing the
filter. Solution (2) contains 0.1% w/v of cefadroxil BPCRS in equivalent of 0.2 g of anhydrous cefadroxil to 100 mL with
the buffer solution. Solution (3) contains 0.005% w/v of water, filter and use the filtrate. Solution (2) contains
cefadroxil BPCRS and 0.05% w/v of amoxicillin 0.2% w/v of cefadroxil BPCRS in water. After removal of the
trihydrate BPCRS in the buffer solution. plate, allow it to dry in air, spray with a 0.2% w/v solution of
The chromatographic procedure may be carried out using ninhydrin in absolute ethanol, heat the plate at 110° for
(a) a stainless steel column (25 cm x 4.6 mm) packed with 10 minutes and allow to cool. The principal spot in the
end-capped octadecylsilyl silica gel for chromatography (5 um or chromatogram obtained with solution (1) is similar in
10 um) (Hypersil ODS is suitable), (b) as the mobile phase position and size to that in the chromatogram obtained with
of 1.0 mL per minute a mixture of 4 volumes solution (2).
The assay is not solution (2).
with solution (3), t jon factor between the peaks TESTS
corresponding to cefé amoxicillin is at least 5.0. Acidity
If necessary, adjust the a rile content in the mobile pH, 4.5 to 6.0, Appendix V L.
phase.
Related substances
the declared content of C,¢.H;7 Appendix III D, using the following solutions. For solution
LABELLING | (1) dilute a volume of the oral suspension with sufficient of
mobile phase A to produce a solution containing the
equivalent amount of anhydrous cefadroxil. . equivalent of 0.1% w/v of anhydrous cefadroxil, mix, stir
magnetically for 10 minutes, filter through a 0.45-um filter
and use the filtrate. Solution (2) contains 0.001% w/v of
cefadroxil BPCRS in mobile phase A. Solution (3) contains
0.001% w/v of p-a-(4-hydroxyphenyl)glycme BPCRS
Cefadroxil Oral Suspension (cefadroxil impurity A) in mobile phase A. Solution (4)
contains 0.001% w/v of 7-aminodesacetoxycephalosporanic
Action and use
S (cefadroxil impurity B) in mobile phase A.
Cephalosporin antibacterial.
atographic procedure may be carried out using
DEFINITION s steel column (25 cm x 4 mm) packed with
Cefadroxil Oral Suspension is a suspension of Cefadroxil tlica gel for chromatography (10 um) (Lichrosorb
Monohydrate in a suitable flavoured vehicle. It is prepared by
dispersing the dry ingredients in the specified volume of
Water just before issue for use.
The dry ingredients comply with the requirements for Powders and
Granules for Oral Solutions and Oral Suspensions stated under
Oral Liquids.
hydroxide.
STORAGE
The dry ingredients should be stored at a temperature not Mobile phase B Add 400
exceeding 30°.
For the following tests prepare the Oral Suspension as directed on
the label. The suspension, examined immediately after preparation
Content of anhydrous cefadroxil, C,;,H,7,N3;0;S 35 minutes. Elute isocratically for 25 minutes with,@’ mixture
When freshly constituted not more than 110.0% of the stated of 32% of mobile phase B and 68% of mobile phase A.
amount. When stored at the temperature and for the period Carry out a linear gradient elution for 1 minute to 100% of
stated on the label, during which the Oral Suspension may mobile phase A and elute for a further 9 minutes with mobile
be expected to be satisfactory for use, not less than 90.0% of phase A.
the stated amount.
When the chromatograms are recorded under the conditions
IDENTIFICATION described above the retention time of cefadroxil is 14 to
A. Carry out the method for thin-layer chromatography, 20 minutes. If necessary, adjust the proportion of mobile
Appendix III A, using a TLC silica gel plate (Merck silica gel phase A to mobile phase B to achieve the stated retention
60 plates are suitable) and a mixture of 3 volumes of a time.
6.7% w/v solution of ninhydrin in acetone, 80 volumes of a The test is not valid unless the column efficiency, determined
0.1m solution of disodium hydrogen orthophosphate and on the peak due to cefadroxil in the chromatogram obtained
120 volumes of a 0.1M solution of citric acid as the mobile with solution (2), is at least 2000 theoretical plates per metre
phase. Impregnate the plate by development with a 5% v/v and the symmetry factor of the principal peak is at most 1.5.
solution of n-tetradecane in hexane. Allow the solvent to
rlate! tye]
ew a
evaporate and carry out the chromatography in the same
2016 Cefalexin Preparations II-263
Inject solution (2) five times. The test is not valid unless the
Cefalexin Capsules
at most 2.0%. Action and use
In the chromatogram obtained with solution (1) the area of Cephalosporin antibacterial.
any peak corresponding to cefadroxil impurity A is not
greater than the area of the principal peak in the DEFINITION
chromatogram obtained with solution (3) (1%), the area of Cefalexin Capsules contain Cefalexin Monohydrate.
any peak corresponding to cefadroxil impurity B is not The capsules comply with the requirements stated under Capsules
greater than the area of the principal peak in the and with the following requirements.
chromatogram obtained with solution (4) (1%) and the area
Content of anhydrous cefalexin, C,¢;H,;N3;0,S
of any other secondary peak is not greater than the area of the
(2) (Le isregard any peak with an area less than IDENTIFICATION
f eaof the principal peak in the chromatogram A. Shake a quantity of the contents of the capsules
ion (2) (0.1%). containing the equivalent of 0.5 g of anhydrous cefalexin
with 1 mL of water and 1.4 mL of 1m hydrochloric acid, filter
and wash the filter with 1 mL of water. Add slowly to the
filtrate a saturated solution of sodium acetate until
precipitation occurs. Add 5 mL of methanol, filter, wash the
precipitate with two 1-mL quantities of methanol and dry the
containing the equivalent of anhydrous cefadroxil
residue at a pressure not exceeding 0.7 kPa. The infrared
with 250 mL of a phosphate. repared by dissolving
absorption spectrum of the dried residue, Appendix II A, is
13.6 g of potassium dihydrogen
concordant with the reference spectrum of cefalexin (RS 049).
water to produce 2000 mL ai
Retain the dried residue for use in test C.
cefadroxil BPCRS in the buffer solution. S Appendix III A, using the following solutions in a mixture of
0.005% w/v of cefadroxil BPCRS and 0.05%‘: equal volumes of methanol and 0.067M mixed phosphate buffer
trihydrate BPCRS in the buffer solution. pH 7.0.
The chromatographic procedure may be carried out (1) Shake a quantity of the contents of the capsules
(a) a stainless steel column (25 cm x 4.6 mm) packe containing the equivalent of 0.2 g of anhydrous cefalexin
end-capped octadecylsilyl silica gel for chromatography (5 with 25 mL, dilute to 50 mL, filter and use the filtrate.
10 um) (Hypersil ODS is suitable), (b) as the mobile phasé* 4% w/v of cefalexin BPCRS.
at a flow rate of 1.0 mL per minute a mixture of 4 volumes o w/v of each of cefalexin BPCRS and
of acetonitrile and 96 volumes of a 0.272% w/v solution of
potassium dihydrogen orthophosphate and (c) a detection
wavelength of 254 nm.
corresponding to cefadroxil and amoxicillin is at least 5.0. (c) Apply 1; g solution.
If necessary, adjust the acetonitrile content in the mobile (d) Develop the pl 5 cm.
phase. (e) After removal of: ate, allow it to dry and examine
Determine the weight per mL of the oral suspension, under ultraviolet light ton
Appendix V G, and calculate the content of C,;,.H,7N30;S,
MOBILE PHASE
weight in volume, using the declared content of
15 volumes of acetone and 85 yolur fa 15.4% wiv
C16H17N305S in cefadroxil BPCRS.
solution of ammonium acetate, previoust djusted to pH 6.2
with 5Maceticacid, = “se
stated on the label during which it may be expected to be SYSTEM SUITABILITY
satisfactory for use. The test is not valid unless the chromatogf
solution (3) shows two clearly separated spots
STORAGE
Cefadroxil Oral Suspension should be kept at the CONFIRMATION
temperature and used within the period stated on the label. The principal spot in the chromatogram obtained with
solution (1) is similar in position and size to that in the
LABELLING
equivalent amount of anhydrous cefadroxil. C. Mix 20 mg of the dried residue obtained in test A with
0.25 mL of a 1% v/v solution of glacial acetic acid and add
0.1 mL of a 1% w/Yv solution of copper(m) sulfate and 0.1 mL
of 2M sodium hydroxide. An olive-green colour is produced.
TESTS
Disintegration
Maximum time, 15 minutes, using a 0.6% v/v solution of
hydrochloric acid in place of water, Appendix XII Al.
II-264 Cefalexin Preparations 2016
Related substances (b) Use isocratic elution and the mobile phase described
Carry out the method for thin-layer chromatography, below.
Appendix III A, using the following solutions in (c) Use a flow rate of 1.5 mL per minute.
2M hydrochloric acid. (d) Use an ambient column temperature.
(1) Shake a quantity of the contents of the capsules (e) Use a detection wavelength of 254 nm.
containing the equivalent of 0.25 g of anhydrous cefalexin
with 10 mL, filter and use the filtrate.
MOBILE PHASE
(3) 0.025% wiv of 7-aminodesacetoxycephalosporanic 2 volumes of methanol, 5 volumes of acetonitrile, 10 volumes
acid BPCRS. of a 1.36% w/v solution of potassium dihydrogen orthophosphate
and 83 volumes of water.
(4) 0.025% w/v of pL-phenylglycine.
SYSTEM SUITABILITY
j cefalexin BPCRS and 0.025% w/v of each of
corresponding to cefalexin and cefradine is at least 4.0;
if necessary, adjust the acetonitrile content of the mobile
IF précoated plate (Analtech plates are phase.
she plate by development with a 5% v/v
Inject solution (2) six times. ‘The Assay is not valid unless the
at most 1.0%.
(c) Apply 5 pL of each solutio Calculate the content of C;gH,7N30,S in the capsules using
the declared content of C;gH ,7N304S in cefalexin BPCRS.
(e) After removal of the plate, dry it at 9 ) STORAGE
spray the hot plate with a 0.1% w/v solution 6 dein in Cefalexin Capsules should be stored at a temperature not
the mobile phase, heat the plate at 90° for 15 mixu exceeding 30°.
allow to cool. LABELLING
MOBILE PHASE The quantity of active ingredient is stated in terms of the
3 volumes of acetone, 80 volumes of a 7.2% w/v solution quivalent amount of anhydrous cefalexin.
disodium hydrogen orthophosphate and 120 volumes of a
2.1% w/v solution of citric acid.
SYSTEM SUITABILITY
The test is not valid unless the chromatogram obtained with n Oral Suspension
solution (5) shows three clearly separated spots.
LIMITS
any spot corresponding to 7-aminodesacetoxycephalosporanic
acid is not more intense than the spot in the chromatogram
obtained with solution (3) (1%); gured vehicle. It is prepared by
any spot corresponding to pL-phenylglycine is not more dispersing the dry ingredien in the specified volume of
intense than the spot in the chromatogram obtained with Water just before issue for u
solution (4) (1%); The dry ingredients comply with thesrequi
any other secondary spot is not more intense than the spot in Granules for Oral Solutions and Oral «
the chromatogram obtained with solution (2) (1%). Oral Liquids.
ASSAY STORAGE
Carry out the method for liquid chromatography, The dry ingredients should be protected fro
Appendix III D, using the following solutions in water. stored at a temperature not exceeding 30°.
(1) Shake a quantity of the powdered, mixed contents of For the following tests prepare the Oral Suspension as directed on
20 capsules containing the equivalent of 0.25 g of anhydrous the label. The suspension, examined immediately after preparation
cefalexin with 100 mL of water for 30 minutes.
Add sufficient water to produce 250 mL, filter and dilute under Oral Liquids and with the following requirements.
25 mL of the filtrate to 50 mL. Content of anhydrous cefalexin, C,;H,;,N3;0,S
(2) 0.05% w/v of cefalexin BPCRS. When freshly constituted, not more than 120.0% of the
stated amount. When stored at the temperature and for the
(3) 0.01% w/v of each of cefalexin BPCRS and
period stated on the label during which the Oral Suspension
cefradine BPCRS.
may be expected to be satisfactory for use, not less than
CHROMATOGRAPHIC CONDITIONS 80.0% of the stated amount.
IDENTIFICATION
2016 Cefalexin Preparations ITI-265
(1) Shake a quantity of the oral suspension containing the MOBILE PHASE
equivalent of 0.2 g of anhydrous cefalexin with 70 mL of 2 volumes of methanol, 5 volumes of acetonitrile, 10 volumes
methanol, filter, evaporate to dryness using a rotary of a 1.36% w/v solution of potasstum dihydrogen orthophosphate
evaporator and dissolve the residue in sufficient and 83 volumes of water.
0.5m hydrochloric acid to produce 50 mL.
SYSTEM SUITABILITY
(2) 0.4% w/v of cefalexin BPCRS in a mixture of equal
volumes of methanol and 0.067M mixed phosphate buffer
DA 7.0.
corresponding to cefalexin and cefradine 1s at least 4.0;
(3) 0.4% w/v of each of cefalexin BPCRS and if necessary, adjust the acetonitrile content of the mobile
cefradine BPCRS in a mixture of equal volumes of methanol phase.
and 0.067M mixed phosphate buffer pH 7.0.
Inject solution (2) six times. The Assay is not valid unless the
CHROMATOGRAPHIC CONDITIONS relative standard deviation of the area of the principal peak is
at most 1.0%.
Appendix V G, and calculate the content of C,gH,7N30,S,
Ci6H,7N30,S8 in cefalexin BPCRS.

stated on the label during which it may be expected to be
with 5M acetic acid.
STORAGE |
SYSTEM SUITABILITY
The Oral Suspension should be stored at the temperature
and used within the period stated on the label.
solution (3) shows two clearly separated
LABELLING
CONFIRMATION
equivalent amount of anhydrous cefalexin.

B. Shake a quantity of the oral suspension containing the :
equivalent of 0.1 g of anhydrous cefalexin with 70 mL of
methanol, filter and evaporate the filtrate to dryness using a exin Tablets
rotary evaporator. Dissolve the residue in the minimum
volume of a 1% v/v solution of glacial acetic acid, decolourise
if necessary by the addition of sufficient activated charcoal,
shake and filter. To 0.25 mL of the resulting solution add
0.1 mL of a 1% w/v solution of copper(m) sulfate and 0.05 mL
of 2M sodium hydroxide. An olive-green colour is produced.
ASSAY
Carry out the method for liquid chromatography, cefal :
Content of anhydrous
Appendix III D, using the following solutions in water.
92.5 to 110.0% of the stated”s
(1) Shake a weighed quantity of the oral suspension
containing the equivalent of 0.25 g of anhydrous cefalexin IDENTIFICATION
with 100 mL of water for 30 minutes. Add sufficient water to
produce 250 mL, filter and dilute 25 mL of the filtrate to cores containing the equivalent of 0.5. g
50 mL. cefalexin with 1 mL of water and 1.4.
acid, add 0.1 g of activated charcoal, shake, if
(2) 0.05% w/v of cefalexin BPCRS.
filter with 1 mL of water. Add slowly to the ‘filtrate
(3) 0.01% w/v of each of cefalexin BPCRS and saturated solution of sodium acetate until precipitation occurs.
cefradine BPCRS. Add 5 mL of methanol, filter and wash the precipitate with
CHROMATOGRAPHIC CONDITIONS two 1-mL quantities of methanol. The residue, after drying at
(a) Use a stainless steel column (25 cm x 4.6 mm) packed a pressure not exceeding 0.7 kPa, complies with the following
Aw
with end-capped octadecylsilyl silica gel for chromatography tests.
(5 um) (Nucleosil C18 is suitable). A. The infrared absorption spectrum, Appendix II A, is

(b) Use isocratic elution and the mobile phase described concordant with the reference spectrum of cefalexin (RS 049).
below. : B. Carry out the method for thin-layer chromatography,
(c) Use a flow rate of 1.5 mL per minute. Appendix III A, using the following solutions in a mixture of
equal volumes of methanol and 0.067M mixed phosphate buffer
pH 7.0.
(1) Shake 0.2 g with 25 mL, dilute to 50 mL, filter and use
the filtrate.
untae
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IWI-266 Cefalexin Preparations 2016
(3) 0.4% w/v of each of cefalexim BPCRS and SYSTEM SUITABILITY

cefradine BPCRS. The test is not valid unless the chromatogram obtained with
CHROMATOGRAPHIC CONDITIONS solution (5) shows three clearly separated spots.
(a) Use as the coating silamised silica gel HF 54. LIMITS |
(b) Use the mobile phase as described below. In the chromatogram obtained with solution (1):
(c) Apply 1 wL of each solution. any spot corresponding to 7-aminodesacetoxycephalosporanic
(d) Develop the plate to 15 cm. acid is not more intense than the spot in the chromatogram
(e) After removal of the plate, allow it to dry and examine
under ultraviolet ight (254 nm). any spot corresponding to pi-phenylglycine is not more
intense than the spot in the chromatogram obtained with
MOBILE PHASE
solution (4) (1%);
any other secondary spot is not more intense than the spot in
the chromatogram obtained with solution (2) (1%).
ASSAY
The test is not valida liquid chromatography, Appendix III D, using the following
solution (3) shows solutions in water.
CONFIRMATION (1) Shake a quantity of the powdered tablets containing the
equivalent of 0.25 g of anhydrous cefalexin with 100 mL of
solution (1) is similar in positio% water for 30 minutes. Add sufficient water to produce
chromatogram obtained with so 250 mL, filter and dilute 25 mL of the filtrate to 50 mL.
C. Mix 20 mg with 0.25 mL ofa (2) 0.05% w/v of cefalexin BPCRS.
(3) 0.01% w/v of each of cefalexin BPCRS and
sulfate and 0.1 mL of 2m sodium hydroxide cefradine BPCRS.
colour is produced.
TESTS (a) Use a stainless steel column (25 cm x 4.6 mm) packed
Disintegration with end-capped octadecylsilyl silica gel for chromatography
Maximum time, 30 minutes, Appendix XII Al. um) (Nucleosil C18 is suitable).
Related substances ) Use isocratic elution and the mobile phase described
Appendix III A, using the following solutions in
w rate of 1.5 mL per minute.
umbient column temperature.
equivalent of 0.25 g of anhydrous cefalexin with 10 mL, filter
and use the filtrate.
(3) 0.025% wiv of 7-aminodesacetoxycephalosporanic
acid BPCRS.
(4) 0.025% w/v of DL-phenylglycine. and 83 volumes of wat
(5) 2.5% wiv of cefalexin BPCRS and 0.025% w/v of each of SYSTEM SUITABILITY
7-aminodesacetoxycephalosporanic acid BPCRS and The Assay is not valid unless, in.the chromatogram obtained
DL-phenylglycine. with solution (3), the resolution facg ween the peaks
CHROMATOGRAPHIC CONDITIONS corresponding to cefalexin and cefradineisat least 4.0;
(a) Use a silica gel HF precoated plate (Analtech plates are
phase.
suitable). Impregnate the plate by development with a 5% v/v
solution of n-tetradecane in hexane. Allow the solvent to Inject solution (2) six times. The Assay is not jai
evaporate and carry out the chromatography in the same relative standard deviation of the area of the pring
direction as the impregnation. at most 1.0%.
(b) Use the mobile phase as described below. DETERMINATION OF CONTENT
(c) Apply 5 wL of each solution. Calculate the content of C,¢H,7N304S in the tablets using
(d) Develop the plate to 15 cm. the declared content of C,;6H,;7N3O0,S in cefalexin BPCRS.
(e) After removal of the plate, dry it at 90° for 3 minutes; STORAGE
spray the hot plate with a 0.1% w/v solution of ninhydrin in Cefalexin Tablets should be stored at a temperature not
the mobile phase, heat the plate at 90° for 15 minutes and exceeding 30°.
allow to cool. LABELLING
MOBILE PHASE The quantity of active ingredient is stated in terms of the
3 volumes of acetone, 80 volumes of a 7.2% w/v solution of equivalent amount of anhydrous cefalexin.
disodium hydrogen orthophosphate and 120 volumes of a
2.1% w/v solution of citric acid.
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2016 Cefazolin Preparations III-267

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TESTS
Cefazolin Injection Acidity
Action and use pH of a solution containing the equivalent of 10.0% w/v of
Cephalosporin antibacterial. cefazolin, 4.0 to 6.0, Appendix V L.
Clarity of solution
DEFINITION A solution containing the equivalent of 10.0% w/v of
Cefazolin Injection is a sterile solution of Cefazolin Sodium cefazolin in carbon dioxide-free water is clear, Appendix IV A.
in Water for Injections. It is prepared by dissolving Cefazolin The absorbance of the solution measured at 430 nm is not
Sodium for Injection in the requisite amount of Water for greater than 0.15, Appendix II B.
Injections.
Related substances
The injection complies with the requirements stated under Carry out the method for liquid chromatography,
(1) Dissolve the contents of a sealed container in sufficient
should be used immediately after mobile phase A to produce a solution containing the
any case, within the period recommended equivalent of 0.25% w/v of cefazolin.
when prepared and stored strictly in (2) Dilute 1 volume of solution (1) to 100 volumes with
mobile phase A.
(3) Dissolve 20 mg of cefazolin EPCRS in 10 mL of a
0.2% w/v solution of sodium hydroxide, allow to stand for
15 to 30 minutes and dilute 1 volume to 20 volumes with
DEFINITION
mobile phase A.
Cefazolin Sodium for Injec a Sterile. material consisting
of Cefazolin Sodium with it excipients. It is supplied CHROMATOGRAPHIC CONDITIONS
in a sealed container. (a) Use a stainless steel column (12.5 cm x 4 mm) packed
(3 um) (Nucleosil 120-3 C18 is suitable).
Preparations and with the following requiremer (b) Use gradient elution and the mobile phase described
below.
Content of cefazolin, C,;,H,4,N;,0,8;3
90.0 to 105.0% of the stated amount. (c) Use a flow rate of 1.2 mL per minute.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Use a detection wavelength of 254 nm.
Appendix III A, using the following solutions. 1 ject 5 wL of each solution.
in sufficient of a mixture of equal volumes of methanol and
0.067M mixed phosphate buffer pH 7.0 to produce a solution
containing the equivalent of 0.4% w/v of cefazolin.
(2) 0.4% w/v of cefazolin EPCRS in a mixture of equal
volumes of methanol and 0.067M mixed phosphate buffer
pH 7.0.
Time Mobilé phase” Mobile phase B Comment
(3) 0.4% w/v each of cefazolin EPCRS and cefoxitin (Minutes) (% ¥ (% viv)
sodium BPCRS in a mixture of equal volumes of methanol and
0-2 98 2 isocratic
0.067M mixed phosphate buffer pH 7.0.
2-4 98 — 85 linear gradient
4-10 85 > 60 linear gradient
(a) Use as the coating silanised silica gel HF 254.
10-11.5 60 — 35 linear gradient
11.5-12 35 isocratic
(c) Apply 1 wL of each solution
12-15 35 > 98 ear gradient
15-21 98 3
(e) After removal of the plate, allow it to dry in a current of
warm air and examine under ultraviolet light (254 nm).
SYSTEM SUITABILITY
MOBILE PHASE |
15 volumes of acetonitrile and 85 volumes of a 15% w/v
solution of ammonium acetate, previously adjusted to pH 6.2
to cefazolin and the peak with a retention time relative to
cefazolin of about 1.1 (cefazolin impurity L) is at least 2.0.
CONFIRMATION
LIMITS
solution (1) corresponds to that in the chromatogram In the chromatogram obtained with solution (1):
obtained with solution (2). The test is not valid unless the the area of any secondary peak is not greater than the area of
chromatogram obtained with solution (3) shows two clearly the principal peak in the chromatogram obtained with
separated principal spots. solution (2) (1%);
B. Yield reaction A characteristic of sodium salts, the sum of the areas of any such peaks is not greater than
Appendix VI. 3.5 times the area of the principal peak in the chromatogram
IlI-268 Cefotaxime Preparations 2016
Cefotaxime Injection
solution (2) (0.05%). Action and use
Water Cephalosporin antibacterial.
Not more than 6.0% w/w, Appendix IX C, Method I.
Use 0.3 g. DEFINITION
Bacterial endotoxins Cefotaxime Injection is a sterile solution of Cefotaxime
Carry out the test for bacterial endotoxins, Appendix XIV C. Sodium in Water for Injections. It is prepared by dissolving
Dissolve the contents of the sealed container in water BET to Cefotaxime Sodium for Injection in the requisite amount of
give a solution containing the equivalent of 10 mg of Water for Injections before use.
cefazolin per mL (solution A). The endotoxin limit The injection complies with the requirements stated under
ion of solution A is 1.5 IU per mL. Parenteral Preparations.
STORAGE
Cefotaxime Injection should be used immediately after
Appendix III D, using
phase. CEFOTAXIME SODIUM FOR INJECTION
(1) Dissolve a quantity of th ontents of the 10 DEFINITION
containers to producea solutioft itaitiing the equivalent of
Cefotaxime Sodium for Injection is a sterile material
0.1% w/v of cefazolin.
consisting of Cefotaxime Sodium with or without excipients.
(2) 0.1% wiv of cefazolin EPCRS. It is supplied in a sealed container.
(3) 0.005% w/v of cefuroxime sodium BPCR 1.01% wiv The contents of the sealed container comply with the requirements
of cefazolin EPCRS. for Powders for Injections or Infusions stated under Parenteral
CHROMATOGRAPHIC CONDITIONS Preparations and with the following requirements.
(a) Use a stainless steel column (25 cm x 4.6 mm). Content of cefotaxime, C,,;H,,N;O-S,
with octadecylsilyl silica gel for chromatography (5 wm) 90.0 to 110.0% of the stated amount.
DENTIFICATION
(b) Use isocratic elution and the mobile phase described infrared absorption spectrum, Appendix II A, is
below.
(d) Use an ambient column temperature. * the method for thin-layer chromatography,
(e) Use a detection wavelength of 270 nm. using the following solutions.
: of equal volumes of methanol and
MOBILE PHASE
suffer pH 7.0 (solution A) to produce
A mixture of 10 volumes of acetonitrile and 90 volumes of a
solution containing 0.277% w/v of disodium hydrogen
orthophosphate and 0.186% w/v of citric acid.
SYSTEM SUITABILITY
oe|
The test is not valid unless, in the chromatogram obtained cefoxitin sodium BPCRS in solu
CHROMATOGRAPHIC CONDITIONS :
corresponding to cefazolin and cefuroxime is at least 2.0.
If necessary, adjust the concentration of acetonitrile in the (a) Use as the coating silanised silica géi
mobile phase. (b) Use the mobile phase as described belg
DETERMINATION OF CONTENT (c) Apply 1 wL of each solution.
Calculate the content of C;,H,4N,0,S3 in a container of (d) Develop the plate to 15 cm.
average content weight from the declared content of (e) After removal of the plate, allow it to dry in air and
C, 4H 4Ns0,83 in cefazolin EPCRS. examine under ultraviolet light (254 nm).
STORAGE MOBILE PHASE
The sealed container should be protected from light and 15 volumes of acetone and 85 volumes of a 15.4% w/v
stored at a temperature not exceeding 30°. solution of ammonium acetate, previously adjusted to pH 6.2
LABELLING with glacial acetic acid.
The label on the sealed container states the quantity of
a
SYSTEM SUITABILITY
Cefazolin Sodium contained in it in terms of the equivalent The test is not valid unless the chromatogram obtained with
amount of cefazolin. solution (3) shows two clearly separated principal spots.
CONFIRMATION
2016 Cefoxitin Preparations III-269
C. Yields reaction A characteristic of sodium salts, Water

Appendix VI. Not more than 3.0% w/v, Appendix IX C. Use 0.300 g.
TESTS Bacterial endotoxins
Acidity Carry out the test for bacterial endotoxins, Appendix XIV C.
pH of a solution containing the equivalent of 10.0% w/v of Dissolve the contents of the sealed container in water BET to
cefotaxime, 4.5 to 6.5, Appendix V L. give a solution containing the equivalent of 10 mg of
cefotaxime per mL (solution A). The endotoxin limit
concentration of solution A is 0.5 IU per mL.
A solution containing the equivalent of 10.0% w/v of
cefotaxime in carbon dioxide-free water is clear, Appendix IV A. ASSAY
The absorbance of the solution at 430 nm is not greater than Determine the weight of the contents of 10 containers as
0.60, Appendix II B. described in the test for uniformity of weight,
Rel stances Appendix XII C1, Powders for Parenteral Use.
Appendix III D, using the following freshly prepared
solutions.
(1) Dissolve'a at (1) Dissolve a quantity of the mixed contents of the 10
in sufficient of the containers in sufficient of the mobile phase to produce a
solution containing the equivalent of 0.01% w/v of
cefotaxime.
(2) 0.01% w/v of cefotaxime acid EPCRS in the mobile phase.

(5 um) (Hypersil 5 um ODS is suitable).
Le
no
below.
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oe

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.
(5 um) (Hypersil 5 um ODS is suitable). :

eee

(b) Use isocratic elution and the mobile phase describe
Inject 10 wL of each solution.
below.
(c) Use a flow rate of 1 mL per minute. (BE PHASE
(d) Use an ambient column temperature. 3.5 g of potassium dihydrogen orthophosphate and
disodium hydrogen orthophosphate in 1000 mL of
pHi 7.0 and add 375 mL of methanol.
(f) Inject 10 wL of each solution. Y
HOt yat a nless the symmetry factor of the
for at least 8 times the retention time of cefotaxime.
principal peak'in thé hromatogram obtained with solution
MOBILE PHASE (2) is less than 2st
Dissolve 3.5 g of potassium dihydrogen orthophosphate and
11.6 g of disodium hydrogen orthophosphate in 1000 mL of
water at pH 7.0 and add 375 mL of methanol.
When the chromatograms are recorded under the prescribed C16Hy7N507S> in cefotaxime *tict
conditions the retention time of cefotaxime is about
6 minutes. If necessary, use another stationary phase or
adjust the concentration of methanol in the mobile phase.
SYSTEM SUITABILITY
with solution (3), cefotaxime is eluted as the second of the Cefotaxime Sodium contained in it in terms ofthe equivalent
principal peaks and the resolution factor between the two amount of cefotaxime.
LIMITS

the area of any secondary peak is not greater than the area of Cefoxitin Injection
Action and use
solution (2) (1%);
the sum of the areas of all the secondary peaks is not greater
than 4 times the area of the principal peak in the DEFINITION
chromatogram obtained with solution (2) (4%). Cefoxitin Injection is a sterile solution of Cefoxitin Sodium
Ethanol in Water for Injections. It is prepared by dissolving Cefoxitin
Not more than 1.0% w/v, Appendix VIII L, System A. Sodium for Injection in the requisite amount of Water for
Injections.
II-270 Cefoxitin Preparations 2016
The injection complies with the requirements stated under of reference solutions of the most appropriate colour,
Parenteral Preparations. Appendix IV B, Method II.
STORAGE Related substances
Cefoxitin Injection should be used immediately after Carry out the method for liguid chromatography,
preparation but, in any case, within the period recommended Appendix III D, using the following solutions prepared
by the manufacturer when prepared and stored strictly in immediately before use. Dilute 20 mL of a 3.48% w/v
accordance with the manufacturer’s instructions. solution of dipotassium hydrogen orthophosphate, adjusted to
pH 6.8 with orthophosphoric acid, to 1000 mL with water
(solution B).
CEFOXITIN SODIUM FOR INJECTION
DEFINITION in sufficient of solution B to producea solution containing
Cefoxitin Sodium for Injection is a sterile material consisting the equivalent of 0.5% w/v of cefoxitin.
solution B.
(3) Add 7 mL of water and 2 mL of methanol to 1 mL of a
0.5% w/v solution of cefoxitin sodium BPCRS in solution B.
Preparations and with the feallowing requirements. Add 25 mg of sodium carbonate, stir for 10 minutes at room
Content of cefoxitin i}5N;,0-,S, temperature, heat in a water-bath at 70° for 30 minutes and
95.0 to 110.0% of the stated unt. allow to cool. Add 3 drops of glacial acetic acid and 0.4 mL
of a 0.5% w/v solution of cefoxitin sodium BPCRS in
IDENTIFICATION
solution B and mix (generation of cefoxitin lactone).
A. The infrared absorption spectriim, Appéadix II A, is
concordant with the reference spe of titin sodium CHROMATOGRAPHIC CONDITIONS
(RS 045). | (a) Use a stainless steel column (25 cm x 4.6 mm) packed
B. Carry out the method for thin-layer chr with phenylsilyl silica gel for chromatography (5 um) with a
Appendix III A, using the following soluti specific surface area of 300 m7/g and a pore size of 7 nm
(Zorbax SB Phenyl is suitable).
(1) Dissolve a quantity of the contents of a seal¢
in sufficient of a mixture of equal volumes of meth (b) Use gradient elution and the mobile phase described
0.067m mixed phosphate buffer pH 7.0 (solution A) to below.
a solution containing the equivalent of 0.4% w/v of cefoxitin (c) Use a flow rate of 1 mL per minute.
(2) 0.4% w/v of cefoxitin sodium BPCRS in solution A. ) Use an ambient column temperature.
(3) 0.4% w/v of each of cefoxitin sodium BPCRS and cefazolin a..detection wavelength of 235 nm.
sodium BPCRS in solution A. 12 uL of each solution.

(e) After removal of the plate, allow it to dry in a current of Time Mobile phase B
warm air and examine under ultraviolet hght (254 nm). (min) {per cent V/V)
MOBILE PHASE 0-12 10
10 volumes of tetrahydrofuran and 90 volumes of a 15.4% w/v 12 «37 10 - 20
solution of ammonium acetate previously adjusted to pH 6.2
37 - 50
50 - 55
SYSTEM SUITABILITY
55 - 60
solution (3) shows two clearly separated principal spots. 60 - 62
CONFIRMATION 62 - 70

obtained with solution (2). When the chromatograms are recorded under the prescribed
conditions the retention time of cefoxitin is about
34 minutes.
Appendix VI.
SYSTEM SUITABILITY
TESTS
roe aay
with solution (3), the resolution factor between the peak due to
cefoxitin and the peak with a retention time relative to
cefoxitin, 4.2 to 7.0, Appendix V L.
cefoxitin of about 1.31 (cefoxitin lactone) is at least 5.0.
LIMITS
cefoxitin in carbon dioxide-free water is clear, Appendix IV A, In the chromatogram obtained with solution (1):
and not more intensely coloured than intensity 5 of the range
2016 Cefradine Preparations III-271
the area of any secondary peak is not greater than the area of LABELLING
the principal peak in the chromatogram obtained with The label of the sealed container states the quantity of
solution (2) (1%); Cefoxitin Sodium contained in it in terms of the equivalent
the area of not more than three such peaks is greater than amount of cefoxitin.
half the area of the principal peak in the chromatogram
than 4 times the area of the principal peak in the
Cefradine Capsules
Disregard any peak with an area less than 0.05 times the area Action and use
of the principal peak in the chromatogram obtained with Cephalosporin antibacterial.
solution <2) (0.05%).
DEFINITION
Cefradine Capsules contain Cefradine.
Content of cephalosporins, calculated as the sum of
cefradine (Cig6Hi9N30,S), cefalexin (C,6H,7N30,S) and
valent of 10 mg of 4',5’'-dihydrocefradine (C,;H,,N30,S)

e. endotoxin limit 90.0 to 105.0% of the stated amount of Cefradine.
concentration of solution A : IDENTIFICATION
ASSAY A. The infrared absorption spectrum of the contents of the
Determine the weight of the contents’of capsules, Appendix II A, is concordant with the reference
described in the test for uniformity of wei, spectrum of cefradine (RS 050). If the spectra are not
concordant, dissolve a quantity of the capsule contents
containing 30 mg of Cefradine in 10 mL of methanol,
Appendix ITI D, using the following solutions
1in evaporate to dryness at 40° at a pressure of 2 kPa and
prepare a new spectrum.
(1) Dissolve a quantity of the mixed contents of
containers to produce a solution containing the equival B. Carry out the method for thin-layer chromatography,
0.1% w/v of cefoxitin. Appendix III A, using the following solutions.
(2) 0.1% w/v of cefoxitin sodium BPCRS. hake a quantity of the contents of the capsules
4ing 0.1 g of Cefradine with 25 mL of 0.01M ammonia
(3) 0.08% wiv of 2-(2-thienyl) acetic acid.
inutes and dilute 1 mL of the resulting solution to
(4) Mix 1 volume of solution (2) and 5 volumes of ‘ith 0.01M ammonia.
solution (3).

with octadecylsilyl silica gel for chromatography (5 um to 10 um)
Impregnate the
(Hypersil ODS is suitable).
shallow layer of ad
(b) Use isocratic elution and the mobile phase described hexane, allowing the }
below. top, removing the pla fe tank and allowing the
(c) Use a flow rate of 1 mL per minute. solvent to evaporate; use A eflow of the mobilephase in
(d) Use an ambient column temperature. the same direction that the
(e) Use a detection wavelength of 254 nm. (b) Use the mobile phase as desc
(f) Inject 20 uwL of each solution. (c) Apply 5 uL of each solution.
MOBILE PHASE (d) Develop the plate to 15 cm.
1 volume of 5m acetic acid, 19 volumes of acetonitrile and
81 volumes of water.
in the mobile phase. Heat at 90° for 15 minutesin a
SYSTEM SUITABILITY
circulating air oven with the plates parallel to the airflow,
The test is not valid unless, in the chromatogram obtained cool for 15 minutes protected from light and examine in
with solution (4), the resolution factor between the two daylight.
MOBILE PHASE
3 volume of acetone, 80 volumes of 0.2M anhydrous disodium
Calculate the content of C;,.H,7N3O7S, in a container of hydrogen orthophosphate and 120 volumes of 0.1M citric acid.
average content weight from the declared content of —
CONFIRMATION
C16HigN3NaO7Sz in cefoxitin sodium BPCRS. Each mg of
Ci6Hi6N3Na0O-7S, is equivalent to 0.9510 mg of The principal spot in the chromatogram obtained with
C16Hi7N307S2.
STORAGE
The sealed container should be protected from light and
stored at a temperature not exceeding 30°.
a IlI-272 Cefradine Preparations 2016
TESTS Time Mobile phase A _—- Mobile phase B Comment

Dissolution (Minutes) (% viv) (% viv)
20 Comply with the requirements for Monographs of the British 0-25 99 5-597 05-33 linear gradient
Beta Pharmacopoeia in the dissolution test for tablets and capsules,
one A dix XII B1 2.5-11 97-75 3-25 linear gradient
oo ppendix ,
P 11-13 75—60 25-40 linear gradient
TEST CONDITIONS
. 13-16 60 40 isocratic
(a) Use Apparatus 1, rotating the basket at 100 revolutions
per minute 16-19 60-20 40-80 linear gradient
(b) Use 900 mL of 0.12m hydrochloric acid, at a temperature 19-19.1 2099.5 800.5 linear gradient
of 37°, as the medium. 19.1-25 99.5 0.5 re-equilibration
PROCEDURE
conditions the retention times relative to Cefradine (retention
time = about 15 minutes) are: impurity A = about 0.27;
impurity B = about 0.32; impurity C = about 0.53;
impurity D = about 0.63; impurity E = about 0.80;
impurity F = about 0.92; cefalexin = about 0.95;
0.12m hydrochloric acid i 4',5'-dihydrocefradine = about 1.06; impurity G = about 1.32.
(2) Measure the absorbar SYSTEM SUITABILITY
cefradine BPCRS in 0.12 hy The test is not valid unless, in the chromatogram obtained
we 0.12m hydrochloric acid in the r with solution (3), the resolution factor between the peaks due
ise DETERMINATION OF CONTEN to cefalexin and cefradine is at least 4.0.
a LIMITS
Identify any peaks in the chromatogram obtained with
solution (1) due to impurities C, D and E using the
and using the declared content of total cephailo
cefradine BPCRS. chromatogram supplied with cefradine for peak
Related substances identification EPCRS. Identify any peaks in the chromatogram
Carry out the method for liquid chromatography, btained with solution (1) due to impurities A and G using
Appendix III D, using the following solutions. h omatogram obtained with solution (6) and the
(1) Shake a quantity of the contents of the capsules gram supplied with cefradine
containing 0.3 g of Cefradine in mobile phase A, add mixture EPCRS. Identify any peak in the
sufficient mobile phase A to produce 50 mL and filter matogram obtained with solution (1) due to ane B
through a 0.45-um filter.
mobile phase A.
(3) 0.012% w/v of each of cefradine BPCRS and
cefalexin BPCRS in mobile phase A.
(4) 0.003% w/v of cyclohexa-1,4-dienylglycine EPCRS G is not greater than
(impurity B) in mobile phase A. peak in the
0.25% f chromato
bh:
(5) Dissolve 6 mg of cefradine for peak identification EPCRS (0.25%for each);
8 (containing impurities C, D and E) in 1 mL of mobile phase the area of any peak corresponding to impurity C is not
Sas A. greater than 0.5 times the area of, 1 cipal peakin the
chromatogram obtained with solutid (2).(0.5%)5
(6) Dissolve the contents of a vial of cefradine
impurity mixture EPCRS (containing impurities A and G) in the area of any peak corresponding ¥ E is not
1 mL of mobile phase A. greater than the area of the principal pe
chromatogram obtained with solution (2)
the area of any other secondary peak is not greatef th
(a) Use a stainless steel column (15 cm x 4.6 mm) packed 0.25 times the area of the principal peak in the
with octadecylsilyl silica gel for chromatography (5 um) (Varian chromatogram obtained with solution (2) (0.25%);
Chrompack Inertsil ODS-3 is suitable).
a ; ; the sum of the areas of all the secondary peaks is not greater
8 (b) Use gradient elution and the mobile phase described than twice the area of the principal peak in the
SS below. chromatogram obtained with solution (2) (2%).
. (c) Use a flow rate of 1.0 mL. per minute. Disregard the peaks due to cefalexin, and
(d) Use a column temperature of 30°. 4',5'-dihydrocefradine and any peak with an area less than
(e) Use a detection wavelength of 220 nm. 0.05 times the area of the principal peak in the
(f) Inject 25 pL of each solution. chromatogram obtained with solution (2) (0.05%).
MOBILE PHASE Cefalexin
Not more than 10.0%, calculated as the percentage of
Mobile phase A 0.272% wiv of potassium dihydrogen
Ci6H,7N30.48S in the sum of C,6H,9N30.,S, C16H17N304S
orthophosphate adjusted to pH 3.0 with dilute orthophosphoric
and C;¢H2;N30.,S determined in the Assay.
acid,
= Mobile phase B- methanol R2.
2016 Cefradine Preparations JIII-273
4',5'-Dihydrocefradine
Cefradine Injection
Ci6H21N3048 in the sum of Ci6HioN30,S, Ci6H17N30.4S
Action and use
and C,¢.H»,;N30,S determined in the Assay. Cephalosporin antibacterial.
Loss on drying
The contents of the capsules, when dried at 60° at a pressure DEFINITION
not exceeding 0.7 kPa for 3 hours, lose not more than 7.0% Cefradine Injection is a sterile solution of Cefradine in Water
of their weight. Use 1 g. for Injections. It is prepared by dissolving Cefradine for
Injection in the requisite amount of Water for Injections. .
ASSAY
Carry out the method for liquid chromatography, The injection complies with the requirements stated under
Appendix III D, using the following solutions in a mixture of Parenteral Preparations.
0.7M glacial acetic acid, 15 volumes of STORAGE
‘e, 200 volumes of methanol and Cefradine Injection should be used immediately after
(1) Dissol by the manufacturer when prepared and stored strictly in
20 capsules to pre accordance with the manufacturer’s instructions.
Cefradine.
CEFRADINE FOR INJECTION
DEFINITION
Cefradine for Injection is a sterile material consisting of
solution A. Mix equal volumeés.¢ solution and Cefradine with or without excipients. It is supplied in a
solution (3). sealed container.
CHROMATOGRAPHIC CONDITIONS * The contents of the sealed container comply with the requirements
(a) Use a stainless steel column (10 cm m) packed for Powders for Injections or Infusions stated under Parenteral
with octadecylsilyl silica gel for chromatographis Preparations and with the following requirements.
ODS is suitable). Content of cephalosporins, calculated as the sum of
(b) Use isocratic elution and the mobile phase dei cefradine (Ci6H15N30,8), cefalexin (C,¢6H,7N30,S) and
below. 4',5'-dihydrocefradine (C,6H21N30,S)
(c) Use a flow rate of 1.5 mL per minute. 95.0 to 110.0% of the stated amount of Cefradine.
(d) Use an ambient column temperature. NTIFICATION
(e) Use a detection wavelength of 254 nm. ry out the method for thin-layer chromatography,
(f) Inject 5 uL of each solution. III A, using the following solutions.
ea quantity of the contents of a sealed container
MOBILE PHASE
25 volumes of methanol and 75 volumes of phosphate buffer

solution pH 5.0.
et ‘

a
conditions, the retention time of the peak due to

4’,5’-dihydrocefradine relative to that of cefradine is about 1.6. gel (Analtech plates are suitable).
oe .
tt it in a tank containing a
SYSTEM SUITABILITY
.

gi lay
tet
'

ee
Fg
corresponding to cefradine and cefalexin is at least 4.0.

the same direction that the
1impre as carried out.
et
Ee
Calculate the content of cephalosporins in the capsules by (b) Use the mobile phase as describe
wee
determining the sum of the contents of C,g¢H ,9N30,S, (c) Apply 10 uL of each solution.
7
C16H17N30,S and C16H21N304S. Calculate the content of

es

C16HjoN30,S (cefradine) using the declared content of
ep
(e) After removal of the plate, allow it to dry at 105° and

Or ec,
Ci 6Hy9N30,4S in cefradine BPCRS. Calculate the content of

C16H17N30,S (cefalexin) using the declared content of examine in daylight.
COG
Cy6H17N304S in cefalexin BPCRS. Calculate the content of MOBILE PHASE

Cy6H2)N30,S (4’,5’/-dihydrocefradine) using the declared 3 volumes of a 6.7% w/v solution of ninhydrin in acetone,
eM T
content of C,;gH,7N30,S in cefalexin BPCRS and multiplying 80 volumes of 0.1M anhydrous disodium hydrogen
the area of the peak due to 4’,5’-dihydrocefradine by a orthophosphate and 120 volumes of 0.1M citric acid.
correction factor of 1.6.
CONFIRMATION
IMPURITIES The principal spot in the chromatogram obtained with
The impurities limited by the requirements of this solution (1) corresponds to that in the chromatogram
monograph include those listed under Cefradine. obtained with solution (2).
the chromatogram obtained with solution (1) is the same as
4
Wate
4
oie
solution (2).
IWI-274 Cefradine Preparations 2016
TESTS SYSTEM SUITABILITY

Alkalinity The test is not valid unless, in the chromatogram obtained
PH of a solution containing 1% w/v of Cefradine, 8.0 to 9.6, with solution (3), the resolution factor between the peaks due
Appendix V L. to cefalexin and cefradine is at least 4.0.
Clarity and colour of solution LIMITS
A solution containing 13.6% w/v of Cefradine in water is Identify any peaks in the chromatogram obtained with
clear, Appendix IV A. The absorbance of the solution at solution (1) due to impurities C, D and E using the
450 nm is not greater than 0.6, Appendix II B. chromatogram obtained with solution (5) and the
Related substances chromatogram supplied with cefradine for peak
Carry out the method for liquid chromatography, identification EPCRS. Identify any peaks in the chromatogram
Appendix HI D, using the following solutions. obtained with solution (1) due to impurities A and G using
(1) Dissol quantity of the contents of a sealed container the chromatogram obtained with solution (6) and the
chromatogram supplied with cefradine
impurity mixture EPCRS. Identify any peak in the
chromatogram obtained with solution (1) due to impurity B
using the chromatogram obtained with solution (4). Multiply
the area of any peak corresponding to impurity B by the
following correction factor: 3.4.
the area of any peak corresponding to impurity A, B, C, D,
E, F or G is not greater than 0.25 times the area of the
(5) Dissolve 6 mg of cefradine
(containing impurities C, D an
(2) (0.25% for each);
A.
(6) Dissolve the contents of a vial of cefra
0.25 times the area of the principal peak in the
impurity mixture EPCRS (containing impurit
1 mL of mobile phase A.
(7) 0.1% w/v of arginine in mobile phase A.
than twice the area of the principal peak in the
CHROMATOGRAPHIC CONDITIONS chromatogram obtained with solution (2) (2%).
(a) Use a stainless steel column (15 cm x 4.6 mm) packé isregard the peaks due to cefalexin, 4’,5’-dihydrocefradine
with octadecylsilyl sihca gel for chromatography (5 wm) (Vari peak corresponding to the principal peak in the
Chrompack Inertsil ODS-3 is suitable). gram obtained with solution (7) (arginine) and any
(b) Use gradient elution and the mobile phase described an area less than 0.05 times the area of the
below. al’ peak in the chromatogram obtained with solution
MOBILE PHASE 4’,5'-Dihydrocefradi
Mobile phase A 0.272% w/v of potasstum dihydrogen Not more than 2.0%, caler the percentage of
orthophosphate adjusted to pH 3.0 with dilute orthophosphonic C16H21N30,48 in the sum Ci6 19N30,S, C16H17N304S
acid. 1éd"in the Assay.
Mobile phase B- methanol R2.

0-2.5 99.5-+97 0.53 linear gradient described in the test for uniformity of weight,
2.5-11 97-75 325 linear gradient Appendix XII C1, Powders for Parental Administration.
11-13 75-60 25-40 linear gradient Carry out the method for liquid chromatography,
Appendix ITI D, using the following solutions in a mixture of
3 volumes of 0.7M glacial acetic acid, 15 volumes of
0.5m sodium acetate, 200 volumes of methanol and
19-19.1 2099.5 800.5 linear gradient 782 volumes of water (solution A).
19.1-25 99.5 0.5 re-equilibration (1) Dissolve a quantity of the mixed contents of the 10
containers in sufficient of solution A to produce a solution
containing 0.05% w/v of Cefradine.
conditions the retention times relative to Cefradine (retention (2) 0.05% w/v of cefradine BPCRS.
time = about 15 minutes) are: impurity A = about 0.27; (3) 0.005% w/v of cefalexin BPCRS.
impurity B = about 0.32; impurity C = about 0.53; (4) Dilute 1 volume of solution (2) to 10 volumes with
impurity D = about 0.63; impurity E = about 0.80; solution A. Mix equal volumes of this solution and
impurity F = about 0.92; cefalexin = about 0.95; solution (3).
4',5'-dihydrocefradine = about 1.06; impurity G = about 1.32.
2016 Cefradine Preparations TII-275
CHROMATOGRAPHIC CONDITIONS Suspension may be expected to be satisfactory for use, not

(a) Use a stainless steel column (10 cm x 4.6 mm) packed less than 90.0% of the stated amount of Cefradine.
with octadecylsilyl silica gel for chromatography (5 Hm) (Hypersil IDENTIFICATION
ODS is suitable). A. Shake a quantity of the oral suspension containing 25 mg
(b) Use isocratic elution and the mobile phase described of Cefradine with 100 mL of water. The light absorption of the
below. resulting solution, Appendix II B, in the range 230 to
(c) Use a flow rate of 1.5 mL per minute. 350 nm exhibits a maximum at 261 nm.
(d) Use an ambient column temperature. B. Carry out the method for thin-layer chromatography,
(e) Use a detection wavelength of 254 nm. Appendix III A, using the following solutions.
(f) Inject 5 wL of each solution. (1) Shake a quantity of the oral suspension with sufficient
water to produce a solution containing 0.3% w/v of
MOBILE P## OE
Cefradine, filter and use the filtrate.
(2) 0.3% w/v of cefradine BPCRS in water.
time of the peak due to (a) Use as the coating szlica gel (Analtech plates are suitable).
to that of cefradineis about 1.6. Impregnate the plate by placing it in a tank containing a
shallow layer of a 5% v/v solution of n-tetradecane in
n-hexane, allowing the impregnating solvent to ascend to the
e chromatogram obtained top, removing the plate from the tank and allowing the
between the peaks solvent to evaporate; use with the flow of the mobile phase in
corresponding to cefradine and’ the same direction that the impregnation was carried out.
DETERMINATION OF CONTE (b) Use the mobile phase as described below.
(e) After removal of the plate allow it to dry at 105° and
examine in daylight.
(cefradine) using the declared content of C 6HioNS ),S.
cefradine BPCRS. Calculate the content of C,;,.H,7N MOBILE PHASE
(cefalexin) using the declared content of C;.H)7N30.,S - 3 volumes of a 6.7% w/v solution of ninhydrin in acetone,
_ cefalexin BPCRS. Calculate the content of C;g¢.H2;N30,S 80 volumes of 0.1M anhydrous disodium hydrogen
(4’,5'-dihydrocefradine) using the declared content of osphate and 120 volumes of 0.1M citric acid.
Ci6H,7N30,4S in cefalexin BPCRS and multiplying the area MATION
of the peak due to 4’,5’-dihydrocefradine by a correction
pal spot in the chromatogram obtained with
factor of 1.6.
IMPURITIES
monograph include those listed under Cefradine.
Carry out the method tfor'/¢

Cefradine Oral Suspension Appendix III D, using thet
Action and use

DEFINITION (2) Dilute 1 volume of solution (1) t to with

Cefradine Oral Suspension is a suspension of Cefradine in a mobile phase A.
suitable flavoured vehicle. It is prepared by dispersing the dry (3) 0.012% w/v of each of cefradine BPCRS an
2
ingredients in the specified volume of Water just before issue cefalexin BPCRSin mobile phase A.
for use. (4) 0.003% w/v of cyclohexa-1,4-dienylglycine EPCRS
The dry ingredients comply with the requirements for Powders and (impurity B)in mobile phase A.
Granules for the Preparation of Oral Liquids stated under Oral (5) Dissolve 6 mg of cefradine for peak identification EPCRS
Liquids. (containing impurities C, D and E) in 1 mL of mobile phase
For the following tests prepare the Oral Suspension as directed on A.
the label. The suspension, examined immediately after preparation (6) Dissolve the contents of a vial of cefradine
unless otherwise indicated, complies with the requirements stated impunity mixture EPCRS (containing impurities A and G) in
under Oral Liquids and with the following requirements. 1 mL of mobile phase A.
Content of cephalosporins, calculated as the sum of CHROMATOGRAPHIC CONDITIONS
cefradine (C,6H19N30,S), cefalexin (C,6H,7N30,8) and
4’ > ‘=dihydrocefradine (C,¢H21N30,S)
with octadecylsilyl silica gel for chromatography (5 um) (Varian
When freshly constituted, not more than 110.0% of the
Chrompack Inertsil ODS-3 is suitable).
stated amount of Cefradine. When stored at the temperature
and for the period stated on the label during which the Oral
Ae Ne!
i
IWI-276 Cefradine Preparations
(b) Use gradient elution and the mobile phase described the sum of the areas of all the secondary peaks is not greater
te wae
below. than twice the area of the principal peak in the
ea
(c) Use a flow rate of 1.0 mL per minute. chromatogram obtained with solution (2) (2%).
Disregard the peaks due to cefalexin, and 4’,5’-
ate Ne

dihydrocefradine and any peak with an area less than
MOBILE PHASE
Cefalexin
Mobile phase A 0.272% wv of potassium dihydrogen Not more than 10.0%, calculated as the percentage of
orthophosphate adjusted to pH 3.0 with dilute orthophosphoric C16H17N3048 in the sum of Cy 6H 9N30,S, C16H 7N3048
acid. and C,¢6H2,;N30,S determined in the Assay.
Nw AAS
Mobile phase methanol R2. 4',5’-Dihydrocefradine
wAY~ es
Time : i hase A Mobile phase B Comment Ci6H21N30,S in the sum of Ci6HioN30.8S, Ci 6H17N30,48
(Minutes) (% viv) and C,¢H2;N30,S determined in the Assay.

0-2.5 0.53 linear gradient ASSAY
2.5-11 97> 3-525 linear gradient Carry out the method for liguid chromatography,
3 volumes of 0.7M glacial acetic acid, 15 volumes of
13-16 60 isocratic 0.5M sodium acetate, 200 volumes of methanol and
16-19 60-20 linear gradient 782 volumes of water (solution A).
aya
19-19.1 2099.5 linear gradient (1) Shake a weighed quantity of the oral suspension with
19.1-25 99.5 0.5 sufficient of the mobile phase to produce a solution
containing 0.05% w/v of Cefradine and filter through a
0.5-um filter, discarding the first few mL of filtrate.
(2) 0.05% w/v of cefradine BPCRS.
impurity B = about 0.32; impurity C = about 0.53;
olution A. Mix equal volumes of this solution and
impurity D = about 0.63; impurity E = about 0.80;
impurity F = about 0.92; cefalexin = about 0.95; ion (3).
4',5’'-dihydrocefradine = about 1.06; impurity G = about 1.32. 'TOGRAPHIC CONDITIONS
SYSTEM SUITABILITY ainless steel column (10 cm x 4.6 mm) packed
silyl sihca gel for chromatography (5 um) (Hypersil
to cefalexin and cefradine is at least 4.0.
LIMITS
solution (1) due to impurities C, D and E using the
chromatogram supplied with cefradine for peak
identification EPCRS. Identify any peaks in the chromatogram
obtained with solution (1) due to impurities A and G using
the chromatogram obtained with solution (6) and the
solution pH 5.0. |
chromatogram supplied with cefradine
sos impurity mixture EPCRS. Identify any peak in the When the chromatograms are recorded under: e. prescribed
a chromatogram obtained with solution (1) due to impurity B conditions, the retention time of the peak due,
. |
using the chromatogram obtained with solution (4). Multiply
the area of any peak corresponding to impurity B by the
4’,5’-dihydrocefradine relative to that of cefradin
SYSTEM SUITABILITY
following correction factor: 3.4. The Assay is not valid unless, in the chromatogram obtained
In the chromatogram obtained with solution (1): with solution (4), the resolution factor between the peaks
the area of any peak corresponding to impurity A, B, C, D, corresponding to cefradine and cefalexin is at least 4.0.
F or Gis not greater than 0.25 times the area of the DETERMINATION OF CONTENT
(2) (0.25% for each);
Appendix V G, and calculate the content of cephalosporins,
the area of any peak corresponding to impurity E is not weight in volume, by determining the sum of the contents of
greater than the area of the principal peak in the C1 6Hj9oN3048S, Ci6Hi7N3048 and C16H2)N30,S. Calculate
chromatogram obtained with solution (2) (1%); the content of C,;,H;9N30,S (cefradine) using the declared
the area of any other secondary peak is not greater than content of C,;6H,9N30,S in cefradine BPCRS. Calculate the
0.25 times the area of the principal peak in the. content of C,;gH,7N30,S (cefalexin) using the declared
chromatogram obtained with solution (2) (0.25%); content of C,;gH,7N30,S in cefalexin BPCRS. Calculate the
content of C;¢6H2,;N30,S (4’,5’-dihydrocefradine) using the
declared content of C;gH,7N30,S in cefalexin BPCRS and
2016 Ceftazidime Preparations III-277
multiplying the area of the peak due to (d) Use a column temperature of 40°.
4',5'-dihydrocefradine by a correction factor of 1.6. (e) Use a detection wavelength of 254 nm.
Repeat the procedure using a portion of the oral suspension (f) Inject 20 wL of each solution.
MOBILE PHASE
satisfactory for use. Mobile phase A
Dissolve 3.6 g of disodium hydrogen orthophosphate and 1.4 g
STORAGE
of potasstum dihydrogen orthophosphate in 1000 mL of water
The Oral Suspension should be stored at the temperature
and adjust the pH to 3.4 with a 10% v/v solution of
and used within the period stated on the label.
orthophosphoric acid.
IMPURITIES Mobile phase B
The impurities limited by the requirements of this acetonitrile.
yawn
: nclude those listed under Cefradine.
ve NA

Ceftazidime 0-4 96-89 4-11 linear gradient
4-7 89 11 isocratic
NOTE: Ceftazidime Ey
United Kingdom. 7-10 89-84 1116 linear gradient

Action and use
Cephalosporin antibacterial. .
DEFINITION 20-24 20 80 isocratic
Ceftazidime Eye Drops areasterile solutiét,, 24-25 20-96 804 linear gradient
Pentahydrate and Anhydrous Sodium Cara:
Water. .
The eye drops comply with the requirements stated uxier
Preparations, the requirements stated under Unlicensed Xi When the chromatograms are recorded under the prescribed
and with the following requirements. conditions the retention time of ceftazidime is about
Content of ceftazidime, C,,H,,N,O0,S, minutes and the retention of pyridine relative to
90.0 to 110.0% of the stated amount. ime is about 0.4.
Content of anhydrous sodium carbonate, Na,CO;
8.0 to 10.0% w/w. iromatogram obtained with solution (1):
CHARACTERISTICS f'any peak due to pyridine is not greater than
A colourless or pale yellow solution.
IDENTIFICATION
A. In the Assay, the retention time of the principal peak in Related subst ne
the chromatogram obtained with solution (1) is similar to Carry out the met
solution (2). 1 volume of acetonitrile’a
protected from light.
B. Yields reaction A characteristic of carbonates and reaction
A characteristic of sodium salts, Appendix VI. if necessary, to produce
a solution containing the equival. 0.1% w/v of
TESTS ceftazidime.
(2) Dilute 3 volumes of solution (1)
Pyridine
at 80° for 15 minutes.
light.
(1) Dilute a volume of the eye drops, if necessary, to produce CHROMATOGRAPHIC CONDITIONS
eNewsnd
a solution containing the equivalent of 0.5% w/v of The chromatographic conditions described under Pyridine
ceftazidime in a mixture of 1 volume of acetonitrile and may be used, but using an injection volume of 5 uL.
40 volumes of mobile phase A. When the chromatograms are recorded under the prescribed
(2) 0.00025% w/v of pyridine in mobile phase A. conditions the retention time of ceftazidime is about
8 minutes. The retentions relative to ceftazidime are:
impurity A, about 0.9; impurity B, about 1.4; impurity F
(pyridine), about 0.4; impurity G, about 0.8.
with octadecylsilyl silica gel for chromatography (5 wm) (Inertsil
ODS2 is suitable). SYSTEM SUITABILITY
(b) Use gradient elution and the mobile phase described The test is not valid unless:
below.
IWI-278 Ceftazidime Preparations 2016
in the chromatogram obtained with solution (3), the resolution Ceftazidime Eye Drops should be stored at a temperature of
between the peaks due to impurity A and ceftazidime is at 2° to 8°.
least 2.0.
LABELLING
LIMITS The quantity of active ingredient is stated in terms of the
Multiply the area of any peak due to impurity G by the equivalent amount of Ceftazidime.
corresponding correction factor: 3.0. IMPURITIES
In the chromatogram obtained with solution (1): The impurities limited by the requirements of this
the area of any peaks corresponding to impurities A, B and monograph include those listed under Ceftazidime
G is not greater than the area of the principal peak in the Pentahydrate and under Ceftazidime Pentahydrate with
chromatogram obtained with solution (2) (0.3% of each); Sodium Carbonate for Injection.
ther secondary peak is not greater than half
incipal peak in the chromatogram obtained
than 5 times the f

ll the secondary peaks is not greater
principal peak in the
Ceftazidime Injection
chromatogram obtained lution (2) (1.5%). Action and use
Disregard any peak w ess than 0.5 times the area Cephalosporin antibacterial.
of the principal peak in the étogram obtained with
solution (4) (0.05%) and any to pyridine DEFINITION
(impurity F). Ceftazidime Injection is a sterile solution of Ceftazidime
Pentahydrate in Water for Injections. It is prepared by
ASSAY
dissolving Ceftazidime for Injection in the requisite amount
For ceftazidime
of Water for Injections before use.
Carry out the method for liquid chromatogray
Appendix III D, using the following solutions 4%.
1 volume of acetonitrile and 20 volumes of mobile: Parenteral Preparations.
protected from light. Storage
(1) Dilute a volume of the eye drops, if necessary, to Ceftazidime Injection should be used immediately after
a solution containing the equivalent of 0.1% w/v of preparation but, in any case, within the period recommended
ceftazidime. the manufacturer when prepared and stored strictly in
cordance with the manufacturer’s instructions.
(2) 0.1% w/v of ceftazidime EPCRS.
DIME FOR INJECTION
The chromatographic conditions described under Pyridine
may be used, but using an injection volume of 5 pL.
Calculate the content of Cz.H»»N,¢O7S> in the eye drops
using the declared content of C.,H»2N,O7S> in
tainer comply with the requirements
ceftazidime EPCRS.
for Powders for Injections sions stated under Parenteral
For anhydrous sodium carbonate Preparations and with the j lo requirements.
Carry out the method for atomic absorption spectrophotometry,
Appendix II D, using the following solutions. Content of ceftazidime 792
90.0 to 110.0% of the stated an
Test solution Dilute the eye drops, if necessary, with
sufficient water to produce a solution containing the Content of anhydrous sodium carberiate, Na,CO;
equivalent of 0.65% w/v of ceftazidime. To 10 mL of this 8.0 to 10.0% w/w.
solution add 5 mL of a caesium chloride buffer solution, CHARACTERISTICS
prepared by adding 500 mL of water and 86 mL of White or slightly yellow powder.
hydrochloric acid to 12.7 g of caesium chloride and diluting to
IDENTIFICATION
1000 mL with water; dilute this solution to 50 mL with
water. A. In the Assay, the retention time of the principal es in
Reference solution ‘Transfer 20 mL of the caesium chloride
buffer solution into each of 4 identical flasks. Add 0 mL,
solution (2).
5 mL, 10 mL and 15 mL, respectively, of a sodium standard
solution (containing 1000 mg per litre) into the flasks and B. Yields reaction A characteristic of carbonates and reaction
add sufficient water to produce 200 mL. To prepare the A characteristic of sodium salts, Appendix VI.
sodium standard solution dissolve 3.70 g of sodium nitrate in TESTS
water and add sufficient water to produce 500 mL; Acidity or alkalinity
add 48.5 g of mitric acid and dilute to 1000 mL with water. pH of a solution containing the equivalent of 10% w/v of
Measure the absorbance at 330 nm using a sodium hollow- ceftazidime, 5.0 to 7.5, Appendix V L.
cathode lamp and an air-acetylene flame. Each mg of sodium Clarity of solution
is equivalent to 4.6087 mg of Na,CO3. A solution containing the equivalent of 10% w/v of
STORAGE ceftazidime in carbon dioxide-free water is clear,
Ceftazidime Eye Drops should be protected from light and Appendix IV A.
stored at a temperature not exceeding -20°. When thawed,
2016 Ceftazidime Preparations II-279
Pyridine (b) Use gradient elution and the mobile phase described
le
Carry out the method for liguid chromatography, below.

.
Appendix II D, using the following solutions prepared (c) Use a flow rate of 1.3 mL per minute.
. Tas eee

he

ey
(1) Disperse a quantity of the contents of a sealed container

ee

‘
containing the equivalent of 0.5 g of ceftazidime in 10 mL of

a 10% v/v solution of phosphate buffer solution pH 7.0 R4 and
add sufficient of the same buffer solution to produce MOBILE PHASE
100 mL. Mobile phase A Dissolve 3.6 g of disodium hydrogen
(2) To 1 volume of a solution containing 0.025% w/v of orthophosphate and 1.4 g of potassium dihydrogen orthophosphate
yam in water, add 10 volumes of phosphate Pulte solution in 1000 mL of water and adjust the pH to 3.4 with a
10% v/v solution of orthophosphoric acid.
Mobile phase B acetomitrile for chromatography.
10% c phosphate buffer solution pH 7.0 R4.
ais solution add 20 volumes of solution (2)
0-4 96 > 89 4>11 linear gradient
CHROMATOGRAPHIC, SITIONS
(a) Use a stainless ste 5 cm x 4.6 mm) packed 4-5 89 11 isocratic
with octadecylsilyl sihca gel: atography (5 um) 5-8 89 > 84 11 + 16 linear gradient
(Spherisorb S5 ODS 1 1s suitable}: 8-11 84 — 80 16 — 20 linear gradient
(b) Use isocratic elution and4] meabile: thase described
11-15 80 > 50 20 + 50 linear gradient
below.
15-18 50 > 20 50 > 80 linear gradient
(c) Use a flow rate of 1.0 mL per minut
18 - 22 20 80 isocratic
(f) Inject 20 uwL of each solution. When the chromatograms are recorded under the prescribed
MOBILE PHASE conditions the retention times relative to ceftazidime
(retention time = about 8 minutes) are:
impurity F = about 0.4; impurity G = about 0.8;
orthophosphate, previously adjusted to pH 7.0 with ammo
nity A = about 0.9; impurity B = about 1.4.
24 volumes of acetonitrile and 68 volumes of water.
SUITABILITY
SYSTEM SUITABILITY
4s not valid unless, in the chromatogram obtained
|(4), the resolution factor between the peaks due
7 Asand ceftazidime iis at least 4.0.
to ceftazidime and pyridine is at least 7.0.
LIMITS

the area of any peak due to pyridine is not greater than ined with solutions (3) and (4) and
10 times the area of the peak due to pyridine in the vith ceftazidime for peak
Related substances corresponding to impurity "G«
Carry out the method for liquid chromatography, factor: 3.0. &
Appendix III D, using the following solutions. In the chromatogram obtained w
(1) Disperse a quantity of the contents of a sealed container
containing the equivalent of 0.15 g of ceftazidime in 5 mL of
acetonitrile, dissolve by adding water and add sufficient water
to produce 100 mL.
(2) To 1 volume of solution (1) add 5 volumes of acetonitrile 0.5 times the area of the principal peak in the chromatogram
and add sufficient water to produce 100 volumes. Dilute obtained with solution (2) (0.1%);
1 volume of this solution to 5 volumes with water. the sum of the areas of any such peaks is not greater than
(3) Expose 5 mL of solution (1) to ultraviolet ight (254 nm) 5 times the area of the principal peak in the chromatogram
for 24 hours (generation of impurity B). obtained with solution (2) (1%).
(4) Disperse 3 mg of ceftazidime for peak identification EPCRS Disregard any peak with an area less than 0.25 times the area
(containing impurities A and G) in 0.5 mL of acetonitrile, of the principal peak in the chromatogram obtained with
dissolve by adding water and add sufficient water to produce solution (2) (0.05%) and any peak due to impurity F
2 mL. (pyridine).
CHROMATOGRAPHIC CONDITIONS Loss on drying
(a) Use a stainless steel column (25 cm x 4.6 mm) packed When dried in vacuo at 25° at a pressure not exceeding
with octadecylsilyl silica gel for chromatography (5 wm) 0.67 kPa for 4 hours, lose not more than 13.5% of their
(Bakerbond BDC and Inertsil ODS 3 are suitable). weight. Use 0.3 g.
wa
we
IWI-280 Ceftriaxone Preparations 2016
Bacterial endotoxins 5 mL, 10 mL and 15 mL, respectively, of a sodium standard

Carry out the test for bacterial endotoxins, Appendix XIV C. solution (containing 1000 mg per litre) into the flasks and
Dissolve the contents of the sealed container in water BET to add sufficient water to produce 200 mL. To prepare the
give a solution containing the equivalent of 10 mg per mL of sodium standard solution dissolve 3.7 g of sodium nitrate in
ceftazidime (solution A). The endotoxin limit concentration water and add sufficient water to produce 500 mL;
of solution A is 1.0 IU per mL. add 48.5 g of mitnc acid and dilute to 1000 mL with water.
ASSAY Measure the absorbance at 330 nm using a sodium hollow-
Determine the weight of the contents of 10 containers as cathode lamp and an air-acetylene flame. Each mg of sodium
described in the test for uniformity of weight, is equivalent to 4.6087 mg of Na2CO3.
Appendix XII C1, Powders for Parenteral Administration. STORAGE
For ceftazidime The sealed container should be protected from light.
Carry out the.method for liquid chromatography, LABELLING |
(1) Dispe equivalent amount of ceftazidime.
containers c
IMPURITIES
in 10 mL of the mg!
phase to produce The impurities limited by the requirements of this
monograph include those listed under Ceftazidime
(2) 0.1% w/v of coftazidi €
Pentahydrate and under Ceftazidime Pentahydrate with
(3) 0.1% w/v of ceftazidi Sodium Carbonate for Injection.
the mobile phase.
(a) Use a stainless steel column'(1 ; “6 mm) packed

with hexylsilyl silica gel for chromatography im), (Spherisorb
hexyl is suitable).
Ceftriaxone Injection
(b) Use isocratic elution and the mobile phase.descrit Action and use
below. Cephalosporin antibacterial.
DEFINITION
eftriaxone Injection is a sterile solution of Ceftriaxone
(e) Use a detection wavelength of 245 nm. dium in Water for Injections. It is prepared by dissolving
(f) Inject 20 uL of each solution. vane Sodium for Injection in the requisite amount of
MOBILE PHASE or Injections.
2 volumes of acetomtrile and 98 volumes of a solution omplies with the requirements stated under
containing equal volumes of 0.43% w/v of disodium hydrogen
orthophosphate and 0.27% wiv of potassium dihydrogen
orthophosphate.
When the chromatograms are recorded under the prescribed preparation but, ing se, within the period recommended
conditions the retention time of ceftazidime is about by the manufacttire epared and stored strictly in
4.5 minutes and the retention time of impurity A relative to
that of ceftazidime is about 0.7.
SYSTEM SUITABILITY
DEFINITION &
Ceftriaxone Sodium for Injection is:
to impurity A and ceftazidime is at least 1.5.
Calculate the content of C2.H..N,.O7S> in a container of The contents of the sealed container comply with ahe re
average content weight from the chromatograms obtained for Powders for Injections or Infusions stated unde
and from the declared content of C2,H».»N,O7S> in Preparations and with the following requirements.
ceftazidime EPCRS.
Content of ceftriaxone, C,;3H;3NsO-S;
For sodium carbonate 92.0 to 108.0% of the stated amount.
[aw
4
Carry out the method for atomic absorption spectrophotometry,
Appendix II D, using the following solutions. IDENTIFICATION
A. The infrared absorption spectrum, Appendix II A, 1s
Test solution Dissolve a quantity of the mixed contents of
concordant with the reference spectrum of ceftriaxone sodium
the 10 containers in sufficient water to produce a solution
(RS 046).
containing the equivalent of 0.65% w/v of ceftazidime.
To 10 mL of this solution add 5 mL of a caesium chloride B. In the Assay, the principal peak in the chromatogram
buffer solution, prepared by adding 500 mL of water and obtained with solution (1) has the same retention time as
86 mL of hydrochloric acid to 12.7 g of caesium chloride and that of the principal peak in the chromatogram obtained with
diluting to 1000 mL with water; dilute this solution to 50 mL solution (2).
with water. C. Yield reaction A characteristic of sodium salts,
Reference solution ‘Transfer 20 mL of the caesium chloride Appendix VI.
buffer solution into each of 4 identical flasks. Add 0 mL,
2016 Cefuroxime Preparations III-281
TESTS (e) Use a detection wavelength of 254 nm.

Acidity or alkalinity (f) Inject 20 wL of each solution.
MOBILE PHASE
ceftriaxone, 6.0 to 8.0, Appendix V L.
Dissolve 2 g of tetradecylammomium bromide and 2 g of
tetraheptylammonium bromide in a mixture of 440 mL of water,
55 mL of 0.067M mixed phosphate buffer pH 7.0, 5 mL of a
ceftriaxone in carbon dioxide-free water is clear,
citrate buffer solution pH 5.0 prepared by dissolving 20.17 ¢
Appendix IV A, and not more intensely coloured than
of citric acid in 800 mL of water, adjusting to pH 5.0 with
reference solution Y; or BY5, Appendix IV B.
10m sodium hydroxide and diluting to 1000 mL with water,
Related substances and 500 mL of acetomitrile.
Carry out the method forliquid chromatography,
SYSTEM SUITABILITY

>HIC CONDITIONS
to ceftriaxone sodium and ceftriaxone sodium E-isomer is at
phic conditions described under Assay may least 3.0.
Calculate the content of C,;g3H;gN,O7S3 in a container of
least twice the ret
average content weight from the declared content of
LIMITS Ci8Hi6NgNa20783,3'2H.0 in ceftriaxone sodium BPCRS.
In the chromatogram obt Each mg of C,;gH;6NgNa20783,3/2H.0O is equivalent to
0.8383 mg of CisHigNsO07S3.
the area of any secondary pe fer than the area of
the principal peak in the chrém ained with STORAGE
solution (4) (1%); The sealed container should be stored at a temperature not
the sum of the areas of all the seconda exceeding 30°.
LABELLING
The label of the sealed container states the quantity of
Ceftriaxone Sodium contained in it in terms of the equivalent
amount of ceftriaxone.
Water
Not more than 11.0% w/w, Appendix IX C,Method I.
Use 0.1 g.
Jroxime Eye Drops
Carry out the test for bacterial endotoxins, Appendix XIV C. roxime Etye Drops are not currently licensed in the
give a solution containing the equivalent of 10 mg of
ceftriaxone per mL (solution A). The endotoxin limit
concentration of solution A is 0.8 IU per mL.
ASSAY DEFINITION
Determine the weight of the contents of 10 containers as Cefuroxime Eye Dr rile solution of Cefuroxime
described in the test for uniformity of weight, Sodium in Purified Wat
Appendix XII C1, Powders for Parenteral Administration. The eye drops comply with thé require ts stated under Eye
Carry out the method for liquid chromatography, Preparations, the requirements stated: xy Unlicensed Medicines
Appendix III D, using the following solutions in the mobile and with the following requirements
phase. Content of cefuroxime, C,¢H,6N,
(1) Dissolve a quantity of the mixed contents of the 10 95.0 to 105.0% of the stated amount.
containers to produce a solution containing the equivalent of IDENTIFICATION
0.030% w/v of ceftriaxone.
A. In the Assay, the retention time of theprincy peakin
(2) 0.030% w/v of ceftriaxone sodium BPCRS. the chromatogram obtained with solution (1) is the same as
(3) 0.0050% w/v each of ceftriaxone sodium BPCRS and that of the principal peakin the chromatogram obtained with
ceftriaxone sodium E-isomer BPCRS. solution (2).
(4) Dilute 1 volume of solution (1) to 100 volumes. B. Yield reaction A characteristic of sodium salts,
CHROMATOGRAPHIC CONDITIONS Appendix VI.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed TESTS
with end-capped octadecylsilyl silica gel for chromatography Acidity or alkalinity
(5 um) (Lichrospher RP-18 is suitable). pH, 5.5 to 8.5, Appendix V L.
(b) Use isocratic elution and the mobile phase described ASSAY
below. Carry out the method for liguid chromatography,
(c) Use a flow rate of 1.5 mL per minute. Appendix II D, using the following solutions.
:
IWi-282 Cefuroxime Preparations

tt
2016
(1) Dilute a volume of the eye drops containing the The contents of the sealed container comply with the requirements
equivalent of 55 mg of cefuroxime with sufficient water to for Powders for Injections or Infusions stated under Parenteral
produce 100 mL. Preparations and with the following requirements.
cA A
(2) 0.058% w/v of cefuroxime sodium BPCRS in water. Content of cefuroxime, C,;H,<.N,O<S
CHROMATOGRAPHIC CONDITIONS 90.0 to 105.0% of the stated amount.
(a) Use a stainless steel column (30 cm x 3.9 mm) packed IDENTIFICATION
with end-capped octadecylsilyl silica gel for chromatography A. The imfrared absorption spectrum, Appendix II A, is
(10 um) (uBondapak is suitable). concordant with the reference spectrum of cefuroxime sodium
(b) Use isocratic elution and the mobile phase described (RS 048).
below. B. Carry out the method for thin-layer chromatography,
(c) Use a flow rate of 2 mL per minute. Appendix III A, using the following solutions.
(d) Use ient column temperature. (1) Dissolve a quantity of the contents of a sealed container
(e) Use | in sufficient of a mixture of equal volumes of methanol and
0.067m mixed phosphate buffer pH 7.0 (solution A) to produce
a solution containing the equivalent of 0.4% w/v of
cefuroxime.
(2) 0.4% w/v of cefuroxime sodium BCPRS in solution A.
(3) 0.4% w/v of each of cefuroxime sodium BCPRS and
cefoxitin sodium BPCRS in solution A.
Calculate the content of C,gHj6N, (a) Use as the coating silanised silica gel HFy5,.
using the declared content of Cy
to 0.9508 mg of Ci6HigN4Oss. (c) Apply 1 uL of each solution.
STORAGE
MOBILE PHASE
2° to 8°. 0 volumes of tetrahydrofuran and 90 volumes of a 15.0% w/v
LABELLING lution of ammonium acetate, previously adjusted to pH 6.2
equivalent amount of cefuroxime.
Cefuroxime Injection
Action and use
C. Yield reaction ng
A
Appendix VI.
DEFINITION
TESTS
ste ny
rere
Cefuroxime Injection is a sterile solution or suspension of
Cefuroxime Sodium in Water for Injections. It is prepared by Acidity orAlkalinity —
dissolving or suspending Cefuroxime Sodium for Injection in
the requisite amount of Water for Injections before use. cefuroxime, 5.5 to 8.5, Appendix Vv
The injection complies with the requirements stated under Clarity of solution
Parenteral Preparations. A solution containing the equivalent of 10.0%
STORAGE cefuroxime in carbon dioxide-free water is not m Opaescent
than reference suspension I, Appendix IV A.
Cefuroxime Injection should be used immediately after
preparation but, in any case, within the period recommended Related substances
by the manufacturer when prepared and stored strictly in Carry out the method for liguid chromatography,
accordance with the manufacturer’s instructions. Appendix III D, using the following solutions in water.
CEFUROXIME SODIUM FOR INJECTION
of cefuroxime.
DEFINITION
Cefuroxime Sodium for Injection is a sterile material
(3) Heat 20 mL of a 0.1% w/v solution of cefuroxime
consisting of Cefuroxime Sodium with or without excipients.
sodium BPCRS in a water bath at 60° for 10 minutes, cool
It is supplied in a sealed container.
and inject immediately (generation of
descarbamoylcefuroxime).
PS
CHROMATOGRAPHIC CONDITIONS CHROMATOGRAPHIC CONDITIONS

(a) Use a stainless steel column (12.5 cm x 4.6 mm) packed (a) Use a stainless steel column (12.5 cm x 4.6 mm) packed
with particles of silica the surface of which has been modified with particles of silica the surface of which has been modified
-A7AN ee
with chemically-bonded hexylsilyl groups (5 um) (Spherisorb with chemically-bonded hexylsilyl groups (5 um) (Spherisorb
howe ad
S5 C6 is suitable). S5 C6 is suitable).
(b) Use isocratic elution and the mobile phase described (b) Use isocratic elution and the mobile phase described
below. below.
(c) Use a flow rate of 1.5 mL per minute. (c) Use a flow rate of 1.5 mL per minute.
(d) Use an ambient column temperature. (d) Use an ambient column temperature.
(e) Use a detection wavelength of 273 nm. (e) Use a detection wavelength of 273 nm.
MOBILE PHASE
rena”
1 volume of acetonitrile and 99 volumes of acetate buffer

pH 3.4.
SYSTEM SUITABILITY
chromatogram obtained corresponding to cefuroxime and descarbamoylcefuroxime is
no
os
at least 2.0. If necessary, adjust the concentration of

a
with solution (3), the resolute tor between the peaks

wt
oe
corresponding to cefuroxim acetonitrile in the mobile phase.

Oye.
pet es
acetonitrile in the mobile phase.
ya
Calculate the content of C;g6H;.N4OgS in a container of

ran
LIMITS average content weight from the declared content of

In the chromatogram obtained with soluti Ci6Hi5N4aNaOseS in cefuroxime sodium BCPRS. Each mg of
.
Ci6H,5N4NaQOgS is equivalent to 0.9508 mg of

the area of any peak corresponding to
Lo
pee
Ci6HieNaOss.
descarbamoylcefuroxime (located by comparison wi
aan
chromatogram obtained with solution (3)) is not great STORAGE

the area of the principal peak in the chromatogram ob The sealed container should be protected from light.
na
with solution (2) (1%); . SLLING

the area of any other secondary peak is not greater than the label on the sealed container states the quantity of
area of the principal peak in the chromatogram obtained wi ime Sodium contained in it in terms of the
solution (2) (1%); amount of cefuroxime.
in the United Kingdor
Water
Not more than 3.5% w/w, Appendix IX C. Use 0.4 g. Action and use
Dissolve the contents of the sealed container in water BET to DEFINITION :
give a solution containing the equivalent of 10 mg of Cefuroxime Intracameral Injection is ‘4 st olution
cefuroxime per mL (solution A). The endotoxin limit
concentration of solution A is 1.0 IU per mL. supplied as a ready-to-use solution.
ASSAY The injection complies with the requirements stated lu
Determine the weight of the contents of 10 containers as Parenteral Preparations, the requirements stated under Unlicensed
described in the test for uniformity of weight, Medicines and with the following requirements.
Appendix XII C1, Powders for Parenteral Use. Content of cefuroxime, C,¢.H;<.N,OsS
Carry out the method for guid chromatography, 95.0 to 105.0% of the stated amount.
Appendix III D, using the following solutions in water. IDENTIFICATION
(1) Dissolve a quantity of the mixed contents of the 10 A. Complies with the test for Osmolality.
containers to produce a solution containing the equivalent of B. Carry out the method for thin-layer chromatography,
0.1% w/v of cefuroxime. Appendix III A, using the following solutions in a mixture of
(2) 0.1% w/v of cefuroxime sodium BCPRS. equal volumes of methanol and 0.067M mixed phosphate buffer
(3) Heat 20 mL of a 0.1% w/v solution of cefuroxime pH 7.0 (solution A).
sodium BPCRS in a water bath at 60° for 10 minutes, cool (1) Dilute a quantity of the injection in sufficient of solution
and inject immediately (generation of A to produce a solution containing the equivalent of
descarbamoylcefuroxime). 0.4% w/v of cefuroxime.
(2) 0.4% w/v of cefuroxime sodium BCPRS in solution A.
Me te te et ted
eaves
vee ue
II-284 Cefuroxime Preparations 2016
(3) 0.4% w/v of each of cefuroxime sodium BCPRS and MOBILE PHASE
ely ee
cefoxitin sodium BPCRS in solution A. 17 volumes of methanol and 83 volumes of a buffer solution
ote otetl
Nee CHROMATOGRAPHIC CONDITIONS prepared by dissolving 0.7708 g of ammonium acetate in
996 mL of water, adding 4 mL of tnethylamine and adjusting
the pH to 3.6 with acetic acid.
(c) Apply 1 uL of each solution. conditions the retention time of cefuroxime is about
(d) Develop the plate to 15 cm. 8.4 minutes.
(e) After removal of the plate, allow it to dry in a current of SYSTEM SUITABILITY
MOBILE PHASE with solution (3), the resolution factor between the peaks
corresponding to cefuroxime and descarbamoylcefuroxime is
at least 2.0.
LIMITS
SYSTEM SUITASBILI In the chromatogram obtained with solution (1):
The test is not vali
. chromatogram obtain
ed with the area of any peak corresponding to
the
solution (3) shows tw rly.separated principal spots. descarbamoylcefuroxime (located by comparison with the
CONFIRMATION chromatogram obtained with solution (3)) is not greater than
The principal spot in the chix
solution (1) corresponds to that*1 with solution (2) (1%);
obtained with solution (2). the area of any other secondary peak is not greater than the
Verne
C. In the Assay, the retention time of icipal peak in area of the principal peak in the chromatogram obtained with
the chromatogram obtained with solution he same as solution (2) (1%);
that of the principal peak in the chromatogr ‘ebtained with the sum of the areas of all the secondary peaks is not greater
solution (2). than 3 times the area of the principal peak in the
TESTS
pH of a solution containing the equivalent of 10.0% wiv ¢
‘solution (2) (0.1%).
cefuroxime, 5.5 to 8.5, Appendix V L. .
endotoxins
Clarity of solution
the test for bacterial endotoxins, Appendix XIV C.
njection, if necessary, in water BET to give a
cefuroxime in carbon dioxide-free water is not more opalescent
. ntaining the equivalent of 10 mg of cefuroxime
than reference suspension II, Appendix IV A.
per iniL (solution A). The endotoxin limit concentration of
Osmolality solution A’1 HU per mL.
The osmolality of the injection is 240 to 380 mosmol/kg,
Appendix V N. ASSAY
Carry out the met liquid chromatography,
Related substances
Appendix III D, usin allowing solutions in water.
Prepare the solutions immediately before use or store at 2° to
8°.
Awe Prepare the solutions immediately before use or store at 2° to
8°. (1) Dilute a quantity of the n to produce a solution
f cefuroxime.
(1) Dilute a quantity of the injection to produce a solution
vary
containing the equivalent of 0.05% w/v of cefuroxime.

15 minutes, cool and inject immediately
(3) Heat 20 mL of a 0.05% w/V solution of cefuroxime
descarbamoylcefuroxime).
sodium BPCRS in a water bath at 80° for 15 minutes, cool
and inject immediately (generation of CHROMATOGRAPHIC CONDITIONS
descarbamoylcefuroxime). (a) Use a stainless steel column (15 cm x 4.6m packed

with octadecylsilyl silica gel for chromatography (5 um) (Hypersil
ODS is suitable).
we aw (a) Use a stainless steel column (15 cm x 4.6 mm) packed
at etete ed
aN AN

wet we"
Lwin
ODS is suitable). below.

(b) Use isocratic elution and the mobile phase described (c) Use a flow rate of 1.0 mL per minute.
below. (d) Use an ambient column temperature.
(c) Use a flow rate of 1.0 mL per minute. (e) Use a detection wavelength of 274 nm.
(d) Use an ambient column temperature. (f) Inject 15 pL of each solution.
(e) Use a detection wavelength of 274 nm. MOBILE PHASE
(f) Inject 15 wL of each solution. 17 volumes of methanol and 83 volumes of a buffer solution
prepared by dissolving 0.7708 g of ammonium acetate in
996 mL of water, adding 4 mL of triethylamine and adjusting
the pH to 3.6 with acetic acid.
ee Re
SYSTEM SUITABILITY orthophosphoric acid or 1M sodium hydroxide, as necessary

The test is not valid unless, in the chromatogram obtained (solution A).
with solution (3), the resolution factor between the peaks TEST CONDITIONS
corresponding to cefuroxime and descarbamoylcefuroxime is
at least 2.0.
per minute.
DETERMINATION OF CONTENT (b) Use 900 mL of solution A, at a temperature of 37°, as
Calculate the content of C,;gH,¢N4OsS in the injection from the medium.
the declared content of C;gH,5N4NaOgS in cefuroxime sodium
PROCEDURE
BCPRS. Each mg of C,6H )5N4NaOsg°S is equivalent to
0.9508 mg of Cy6HigN4OsS.
(1) Shake the container containing the oral suspension being
examined for 30 seconds and accurately remove a volume
containing one dose at a depth of 1 cm below the meniscus.
Introduce the dose to the medium in the dissolution vessel.
After 30 minutes withdraw a 10 mL sample of the medium
and measure the absorbance of the filtered sample, suitably
ingredient is stated in terms of the diluted with the dissolution medium if necessary, at the
equivalent amoun ‘oxime. maximum at 282 nm, Appendix II B, using solution A in the
reference cell.
(2) Measure the absorbance of a suitable solution of cefuroxime
axetil BPCRS, prepared by dissolving cefuroxime axetil BPCRS
in 5 volumes of methanol and then diluting to 100 volumes
Cefuroxime Axetil with solution A, using solution A in the reference cell.
The equivalent concentration of cefuroxime in the final
Action and use solution should be the same as that expected for solution (1).
DEFINITION : Calculate the total content of cefuroxime, C;¢6H1¢6N40¢S, in
Cefuroxime Axetil Oral Suspension is a suspefisio the medium from the absorbances obtained and using the
Cefuroxime Axetil in a suitable flavoured vehicle? It 1 declared content of C9H22N4Oj0S in cefuroxime
prepared by dispersing the dry ingredients in the spécified axetil BPCRS. Each mg of Cy9H22N4Oj0S is equivalent to
volume of Water just before issue for use. : 0.8313 mg of CisHi6NaOsS.
The dry ingredients comply with the requirements for Powders

ar
Granules for Oral Solutions and Oral Suspensions stated under — unt of cefuroxime released is not less than 60% (Q)
Oral Liquids.
For the following tests prepare the Oral Suspension as directed on
the label. The suspension, examined immediately after preparation
Content of cefuroxime, C,¢H,<.N,0;.S ntity of the oral suspension with
When freshly constituted not more than 110.0% of the stated duce a solution containing the
amount. When stored at the temperature and for the period cefuroxime and mix with the aid
stated on the label during which the Oral Suspension may be of ultrasound for 5 minu b occasional swirling. Allow to
expected to be satisfactory for use, not less than 90.0% of the cool to room temperatur
stated amount. es of the resulting
IDENTIFICATION
A. Shake a quantity of the oral suspension with sufficient through a 0.45-um PTFE filter, disgard
methanol to produce a solution containing the equivalent of filtrate. The solution should be used itnm
0.00131% w/v of cefuroxime. The light absorption of the
solution, Appendix II B, in the range 230 to 320 nm exhibits
a maximum at 276 nm. sufficient impurities (A°-isomers) have been g eraited.
B. In the Assay, the retention times of the principal peaks in (3) Expose a quantity of solution (1) to ultraviolet light
the chromatogram obtained with solution (1) correspond to (254 nm) for 24 hours or until sufficient impurities
Ae as
those of the peaks due to diastereoisomers A and B of (E-isomers) have been generated.
cefuroxime axetil in the chromatogram obtained with
yw ead
oe:
solution (2).
TESTS with particles of silica (5 um) the surface of which has been
Acidity or alkalinity modified by chemically-bonded trimethylsilyl groups
pH, 3.5 to 7.0, Appendix V L. (Hypersil SAS is suitable).
Dissolution (b) Use isocratic elution and the mobile phase described
Carry out the test for dissolution described under dissolution below.
test for tablets and capsules, Appendix XII B1. (c) Use a flow rate of 1.2 mL per minute.
Prepare a solution containing 1.43% w/v of disodium hydrogen (d) Use an ambient column temperature.
orthophosphate and 0.42% wiv of sodium dihydrogen
yaw

orthophosphate and adjust the pH to 7.0 with 20% v/v
IWI-286 Cefuroxime Preparations 2016
(f) Inject 20 wL of each solution. corresponding to diastereoisomers A and B of cefuroxime

tA Ne AN MOBILE PHASE axetil using the declared content of C.9H22N4010S in
cefuroxime axetil BPCRS. Each mg of C.9H22N4010S is
38 volumes of methanol and 62 volumes of 0.2M ammonium
er wn
equivalent to 0.8313 mg of Cyg6H;6N4OsS.

dihydrogen orthophosphate.
conditions the retention time of cefuroxime axetil
diastereoisomer A is 7 to 11 minutes. The retention times
relative to cefuroxime axetil diastereoisomer A are:
cefuroxime, about 0.35; cefuroxime axetil diastereoisomer B, STORAGE
about 0.9; cefuroxime axetil A°-isomers (impurity A), about The Oral Suspension should be kept at the temperature and
1.2; B-isomers (impurity B), about 1.7 and 2.1. used within the period stated on the label.
~ AN aa
LABELLING |
eye ad
equivalent amount of cefuroxime.
ereoisomer A and cefuroxime axetil IMPURITIES
if necessary, adjust the composition The impurities limited by the requirements of this
of the mobile phase).
monograph include those listed under Cefuroxime Axetil.
LIMITS
In the chromatogram obtairie

the area of any peak correspo
greater that 1.0%;
Cefuroxime Axetil Tablets
a a re
wey
the sum of the areas of the pair of pedis coffesponding to the
E-isomers in the chromatogram obtained Action and use
not greater than 1.5%; Cephalosporin antibacterial.
DEFINITION
not greater than 2.0%; Cefuroxime Axetil Tablets contain Cefuroxime Axetil. They
may be coated.
the area of any other secondary peak is not greater than 0.
he tablets comply with the requirements stated under Tablets and
the,following requirements.
than 4.5%.
Disregard any peak with an area less than 0.05%.
ASSAY
Appendix III D, using the following solutions. The solutions
should be used immediately or stored in the dark at a
temperature of 2° to 8° before analysis.
dichloromethanies filte
The infrared absotptioi
(1) Shake a weighed quantity of the oral suspension with is concordant with th
sufficient methanol to produce a solution containing the (RS 047).
equivalent of 0.25% w/v of cefuroxime and mix with the aid
of ultrasound for 5 minutes with occasional swirling. Allow to
cool to room temperature, shake vigorously and allow to
stand for 10 minutes. Dilute 10 volumes of the resulting
cefuroxime axetil in the chromato
solution to 50 volumes with methanol (23%) and filter
solution (4).
through a 0.45-um PTFE filter, discarding the first 5 mL of
filtrate. TESTS
(2) Dilute 10 volumes of a 0.3% w/V solution of cefuroxime Related substances (
axetil BPCRS in methanol to 50 volumes with methanol Carry out the method for liquid chromatographys
(23%). Appendix III D, using solutions (1) to (3) describ d under
Assay.
+ fete we
substances may be used. The chromatographic conditions described under Assay may
be used.
SYSTEM SUITABILITY
SYSTEM SUITABILITY
with solution (2), the resolution factor between the peaks The requirements stated under Assay apply.
corresponding to cefuroxime axetil diastereoisomers A and B LIMITS
is at least 1.5 Gif necessary, adjust the composition of the In the chromatogram obtained with solution (1):
mobile phase).
the sum of the areas of the pair of peaks corresponding to the
DETERMINATION OF CONTENT E-isomers in the chromatogram obtained with solution (3) is
Determine the weight per mL of the oral suspension, not greater than 1.5% by normalisation;
Appendix V G, and calculate the content of C,g¢H,6N,0sS,
weight in volume, as the sum of the areas of the two peaks
2016 Celiprolol Preparations II-287
the sum of the areas of any peaks corresponding to the (c) Use a flow rate of 1.2 mL per minute.
A?-isomers in the chromatogram obtained with solution (2) is (d) Use an ambient column temperature.
not greater than 2.0% by normalsation;
the area of any other secondary peak is not greater than 1.0% (f) Inject 20 wL of each solution.
by normalisation.
MOBILE PHASE
Dissolution
Comply with the requirements for Monographs of the British 38 volumes of methanol and 62 volumes of 0.2M ammonium
Pharmacopoeia in the dissolution test for tablets and capsules, dihydrogen orthophosphate.
Appendix XII B1. When the chromatograms are recorded under the prescribed
conditions the retention times relative to cefuroxime axetil
TEST CONDITIONS
diastereoisomer A are approximately 0.9 for cefuroxime axetil
diastereoisomer B, 1.2 for the cefuroxime axetil A?-isomers
and 1.7 and 2.1 for the E-isomers.
SYSTEM SUITABILITY
The Assay is not valid unless:

factor between the peaks due to cefuroxime axetil
diastereoisomer A and the cefuroxime axetil A°-isomer is at
least 1.5 Gif necessary, adjust the composition of the mobile
expected to contain the phase);
cefuroxime per mL, at the rf
factor between the peaks corresponding to cefuroxime axetil
diastereoisomers A andB is at least 1.5 (if necessary, adjust
Bg the composition of the mobile phase).
axetil BPCRS in 0.1m hydrochloric acidcoxs
0.1m hydrochloric acid in the reference cell. Calculate the content of C,;gH,¢N4O¢S as the sum of the
areas of the two peaks corresponding to diastereoisomers A
and B of cefuroxime axetil and using the declared content of
Calculate the total content of cefuroxime axetil, C49H22N40 10S 1n cefuroxime axetil BPCRS. Each mg of
C146H16N4088S, in the medium from the absorbances Cx9H22N40O10S 1s equivalent to 0.8313 mg of Cyg6Hi6N4OsS.
obtained and using the declared content of Coj9H22N4049
cefuroxime axetil BPCRS. Each mg of Cy9H22N4Oj0S is
equivalent to 0.8313 mg of CygH,6N4OsgS. latity of active ingredient is stated in terms of the
amount of cefuroxime.
ASSAY
should be used immediately or stored in the dark at a
temperature of 2° to 8° before analysis.
(1) Disperse 5 tablets in 0.2m ammonium dihydrogen
orthophosphate, previously adjusted to pH 2.4 with
orthophosphoric acid, using 10 mL per g of the stated content
of cefuroxime. Immediately add 375 mL of methanol and
shake vigorously for 10 minutes. Mix with the aid of
ultrasound for a further 10 minutes and add sufficient
methanol to produce 500 mL. Centrifuge a portion of the
solution for at least 5 minutes at 2500 rpm and then dilute a with the following requirements.
quantity of the supernatant liquid with sufficient of the Content of celiprolol hydrochloride
mobile phase to produce a solution containing the equivalent 95.0 to 105.0% of the stated amount.
of 0.025% w/v of cefuroxime.
IDENTIFICATION :
(2) Heat a quantity of solution (1) at 60° for 1 hour or until Mix with the aid of ultrasound a quantity of the powdered
sufficient impurities (A°-isomers) have been generated. tablets containing 200 mg of Celiprolol Hydrochloride with
(3) Expose a quantity of solution (1) to ultraviolet light 100 mL of dichloromethane for 30 minutes, filter (Whatman
(254 nm) for 24 hours or until sufficient impurities filter paper No. 42 is suitable), remove the dichloromethane
(£-isomers) have been generated. using a rotary evaporator and dry the residue over phosphorus
(4) 0.03% w/v of cefuroxime axetil BPCRS in the mobile pentoxide at 110° at a pressure not exceeding 2 kPa for
phase. 1 hour. The infrared absorption spectrum of the dried residue,
celiprolol hydrochloride (RS 420).
with particles of silica (5 um) the surface of which has been TESTS
modified by chemically-bonded trimethylsilyl groups Dissolution
(Hypersil SAS is suitable). Comply with the dissolution test for tablets and capsules,
(b) Use isocratic elution and the mobile phase described Appendix XII B1.
below.
II-288 Celiprolol Preparations 2016
TEST CONDITIONS the area of any peak due to celiprolol impurity A is not
(a) Use Apparatus 2 rotating the paddle at 50 revolutions per greater than twice the area of the principal peak in the
minute. chromatogram obtained with solution (2) (0.2%);
(b) Use 900 mL of water at a temperature of 37° as the the area of any other secondary peak is not greater than the
medium. area of the principal peak in the chromatogram obtained with
aye ay

PROCEDURE
not more than one such peak has an area not greater than
(1) Withdraw a sample of 10 mL of the medium and filter;
to 1 volume of the filtrate add sufficient water to produce
20 volumes and filter using a 0.45 um membrane filter.
Measure the absorbance of the filtrate, suitably diluted with the sum of the areas of any secondary peaks is not greater than
water if necessary, at the maximum at 231 nm, 5 times the area of the principal peak in the chromatogram
Appendix JJ..B, using water in the reference cell. obtained with solution (2) (0.5%).
Disregard any peak with an area of less than a fifth of the
whe Nee
) BPCRS in the dissolution medium at area of the peak in the chromatogram obtained with solution
‘nm, Appendix II B, using water in the (2) (0.02%).
ASSAY
Carry out method for liquid chromatography, Appendix III D,
using the following solutions.
C590H33N30.4,;HCI, inth sing the declared content (1) Disperse with the aid of ultrasound a quantity of the
of C29H33N30,4,HCI in celig rochloride BPCRS. powdered tablets containing 0.1 g of Celiprolol
Hydrochloride in 100 mL of the mobile phase for
Related substances &
15 minutes, cool and filter. Dilute 1 volume of the filtrate to
Carry out method for liquid chre ‘ Appendix III D,
50 volumes with the mobile phase and filter using a 0.45 um
maw ead
aN a using the following solutions.

membrane filter.
(1) Disperse with the aid of ultrasound
(2) 0.002% w/v solution of celiprolol hydrochloride BPCRS in
powdered tablets containing 0.1 g of Celiprol
the mobile phase.
Hydrochloride in 100 mL of the mobile pha
with occasional shaking, cool and filter using a 074 CHROMATOGRAPHIC CONDITIONS
membrane filter. The chromatographic conditions described under Related
(2) Dilute 1 volume of solution (1) to 50 volumes with t ubstances may be used.
mobile phase and further dilute 1 volume of this solution ETERMINATION OF CONTENT
20 volumes with the mobile phase.
Be
(3) Prepare a solution containing 0.1% w/v of celiprolol

hydrochloride BPCRS in water, add 5 drops of 5m sodium
hydroxide and heat at 70° for 20 minutes (generation of
impurity A).

with octadecylsilyl silica gel for chromatography (10 wm) (Waters
uBondapak is suitable).
below.
twice the retention time of the principal peak.
MOBILE PHASE
A mixture of 25 volumes of acetonitrile and 75 volumes of

0.025M sodium dihydrogen phosphate monohydrate adjusted to 1. 3-acetyl-4- {3-(1, 1-dimethyl-ethylamino)-2-
Viet ale
pH 3.0 with 3m orthophosphonic acid. If necessary adjust the hydroxy} propoxybutyranilide
aN ae
composition of the mobile phase so that, in the

tween
we Ne
LT ead
chromatogram obtained with solution (3), the peak due to

celiprolol impurity A is resolved from the solvent front.
SYSTEM SUITABILITY
with solution (3), the peak due to celiprolol impurity A is
resolved from the solvent front.
LIMITS

s Aye
yawns
yaNw AN
2016 Cetirizine Preparations TTT-289
Cetirizine Capsules dissolution medium in the reference cell and calculate the
difference between the two readings (AA) for each
Action and use measurement.
Histamine H, receptor antagonist; antihistamine. (2) Measure the absorbance of a 0.00050% w/v solution of
cetirizine hydrochloride BPCRS in water at the maximum
DEFINITION wavelengths at 230 nm and 260 nm using the dissolution
Cetirizine Capsules contain Cetirizine Hydrochloride in a medium in the reference cell and calculate the difference
suitable aqueous vehicle. between the two readings (AA) for each measurement.
The capsules comply with the requirements stated under Capsules DETERMINATION OF CONTENT
and with the following requirements. Calculate the total content of Cetirizine hydrochloride,
Content of cetirizine hydrochloride, C,,H25CIN2,0O3,2HCI, in the medium using the values of AA
C21H25CIN,O3,2HCl and from the declared content of C.,;H25CIN.O3,2HCI in
cetirizine hydrochloride BPCRS.
LIMITS
sethod for thin-layer chromatography, The amount of cetirizine hydrochloride released is not less
: he following solutions. than 80% (Q) of the stated amount.
Related substances
contain 0.1% wiv O Carry out the method for liquid chromatography,
a 0.45-um nylon filte Appendix III D, using the following solutions in mobile
phase A.
(1) Dilute a quantity of the capsule contents, if necessary, to
of chlorphenamine maleate BPG produce a solution containing 0.02% w/v of Cetirizine
CHROMATOGRAPHIC CONDITIONS «
Hydrochloride and filter through a 0.45-um nylon filter.
(a) Use as the coating silica gel F254 (Mer (2) Dilute 1 volume of solution (1) to 100 volumes and
plates are suitable). further dilute 1 volume to 10 volumes.
(b) Use the mobile phase as described below. (3) 0.02% w/v of cetirizine impurity standard BPCRS.
(c) Apply 5 uL of each solution. | (4) 0.00006% w/v of cetirizine N-oxide BPCRS.
' (d) Develop the plate to 15 cm. CHROMATOGRAPHIC CONDITIONS
(e) After removal of the plate, dry in air and examine wi (a) Use a stainless steel column (25 cm x 4.6 mm) packed
ultraviolet light (254 nm). octadecylsilyl silica gel for chromatography (5 um)
menex Luna C18(2)is suitable).
MOBILE PHASE
1 volume of 18M ammonia, 10 volumes of methanol and
90 volumes of dichloromethane.
SYSTEM SUITABILITY
(f) Inject 20
CONFIRMATION
MOBILE PHASE
Mobile phase A 17 i l
acid.
Mobile phase B35 volumes of,
water previously adjusted to pH 1
solution (2).
Time Mobile phase A
TESTS
(Minutes) % viv % VIV
Dissolution
0-50 100-0 0100 ,
Appendix XII Bl. 50-53 0 100 isocratic
53-54 0->100 1000 linear gradient

TEST CONDITIONS
(a) Use Apparatus 2, and rotate the paddle at 50 revolutions
per minute.
medium. SYSTEM SUITABILITY
PROCEDURE The test is not valid unless, in the chromatogram obtained

(1) After 45 minutes withdraw a sample of 10 mL of the
cetirizine and cetirizine impurityB is at least 1.5.
medium, filter and dilute the filtrate with sufficient of the
dissolution medium to give a solution expected to contain LIMITS
about 0.00050% w/v of Cetirizine Hydrochloride. Measure In the chromatogram obtained with solution (1):
the absorbance of this solution, Appendix IT B, at the identify any peak corresponding to impurity A using solution
maximum wavelengths at 230 nm and at 260 nm using the (3) and the chromatogram supplied with cetirizine
IWI-290 Cetirizine Preparations 2016
impurity standard BPCRS and multiply the area of this peak

by a correction factor of 0.7.
Cetirizine Oral Solution
the area of any peak due to cetirizine N-oxide is not greater Action and use
than the area of the principal peak in the chromatogram Histamine H, receptor antagonist; antihistamine.
the area of any other secondary peak is not greater than twice DEFINITION
the area of the principal peak in the chromatogram obtained Cetirizine Oral Solution is a solution of Cetirizine
with solution (2) (0.2%); Hydrochloride in a suitable flavoured vehicle.
the total content of impurities is not greater than 10 times The oral solution complies with the requirements stated under Oral
the area of the principal peak in the chromatogram obtained Liquids and with the following requirements.
with solution (2) (1.0%). Content of cetirizine hydrochloride,
Disregard an ak with an area less than the area of the C,,H,;CIN,O3,2HCl
principal eghromatogram obtained with solution 95.0 to 105.0% of the stated amount.
(2) (0.1%) IDENTIFICATION
ASSAY A. Carry out the method for thin-layer chromatography,
Mix the content of 2 es. Carry out the method for Appendix III A, using the following solutions.
liquid chromatography kx III D, using the following (1) Dilute a quantity of the oral solution, if necessary, to
solutions in mobile phase contain 0.1% w/v of Cetirizine Hydrochloride, filter through
(1) Dilute a weighed quantit: ixed contents of a 0.45-m nylon filter and use the filtrate.
20 capsules to produce a soluti (2) 0.1% w/v of cetirizine hydrochloride BPCRS.
Cetirizine Hydrochloride and fi (3) 0.1% w/v of cetirizine hydrochloride BPCRS and 0.1% w/v
filter. , of chlorphenamine maleate BPCRS.
(2) 0.002% w/v of cetirizine hydrochloride g8PC
(3) 0.02% w/v of cetirizine impurity standard:
(a) Use as the coating silica gel F254 (Merck silica gel 60 Fos,
CHROMATOGRAPHIC CONDITIONS plates are suitable).
(a) Use a stainless steel column (25 cm x 4.6 mm (b) Use the mobile phase as described below.
with octadecylsilyl silica gel for chromatography (5 um) « (c) Apply 5 uwL of each solution.
(Phenomenex Luna C18(2) is suitable).
) Develop the plate to 15 cm.
) After removal of the plate, dry in air and examine under
below.
ght (254 nm).
M ammonia, 10 volumes of methanol and
dichloromethane.
MOBILE PHASE
30 volumes of acetonitrile and 70 volumes of
solution (3) shows 1
0.0025m potassium dihydrogen orthophosphate, previously
CONFIRMATION
adjusted to pH 1.5 with orthophosphoric acid.
The principal spot in the
SYSTEM SUITABILITY
solution (1) corresponds
The test is not valid unless, in the chromatogram obtained obtained with solution (2).
cetirizine and cetirizine impurity B is at least 1.5.
B. In the Assay, the principal peak in
obtained with solution (1) has the sam
Calculate the content of C,;H25;CIN,03,2HCI in the principal peak in the chromatogram obtained
capsules using the declared content of C2;H.5CIN2O3,2HCl solution (2).
in cetirizine hydrochloride BPCRS.
TESTS
IMPURITIES Acidity
The impurities limited by the requirements of this pH, 4.5 to 5.5, Appendix V L.
monograph include impurities A, B and G listed under
Related substances
Cetirizine Hydrochloride and the following.
Appendix III D, using the following solutions in mobile
QS
Cl “~_ OH phase A.
N
(1) Dilute a weighed quantity of the oral solution, if
necessary, to contain 0.02% w/v of Cetirizine Hydrochloride
and filter through a 0.45-um nylon filter.
further dilute 2 volumes of the resulting solution to
10 volumes.
Cetirizine N-oxide.
(4) 0.02% w/v of cetirizine impurity standard BPCRS.
2016 Cetirizine Preparations TI-291
with octadecylsilyl silica gel for chromatography (5 um) (c) Use a flow rate of 1.0 mL per minute.
(Phenomenex Luna C18(2) is suitable). (d) Use a column temperature of 30°.
(b) Use gradient elution and the mobile phases described (e) Use a detection wavelength of 230 nm.
below. (f) Inject 20 pL of each solution.
(c) Use a flow rate of 1.0 mL per minute. MOBILE PHASE
(d) Use a column temperature of 30°. 30 volumes of acetonitrile and 70 volumes of
(e) Use a detection wavelength of 230 nm. 0.0025mM potassium dihydrogen orthophosphate, previously
(f) Inject 20 pL of each solution. adjusted to pH 1.5 with orthophosphoric acid.
MOBILE PHASE SYSTEM SUITABILITY
cetirizine and cetirizine impurityB is at least 1.5.
Determine the weight per mL of the oral solution,
Time Mobile phase & Comment C,,H25CIN203,2HCI, weight in volume, using the declared
(Minutes) % viv content of C,,;H»5CIN2,03,2HC] in cetirizine
0-50 100-0 linear gradient hydrochlonde BPCRS.
50-53 0 400 <<” isocratic IMPURITIES
53-54 0100 : linear gradient The impurities limited by the requirements of this
54-60 100 0 uilibration monograph include impurities A, B and G listed under
Cetirizine Hydrochloride.
SYSTEM SUITABILITY ;
The test is not valid unless, in the chromatogram obtairie

with solution (4), the resolution between the peaks due t Cetirizine Tablets
cetirizine and cetirizine impurity B is at least 1.5.
LIMITS

identify any peak corresponding to impurity A using solution
(4) and the chromatogram supplied with cetirizine
impurity standard BPCRS and multiply the area of this peak
by a correction factor of 0.7.
the areas of any peaks corresponding to impurities A, B or G
are not greater than 1.5 times the area of the principal peak
in the chromatogram obtained with solution (2) (0.3%);
the total content of impurities is not greater than 5 times the
area of the principal peak in the chromatogram obtained with filter (Whatman GF/C is suitable), évay .
solution (2) (1.0%). dry the residue at 60° for 1 hour. The z#fra
Disregard any peak with an area less than the principal peak
in the chromatogram obtained with solution (3) (0.05%). the reference spectrum of cetirizine hydrochloride (&
ASSAY TESTS
Carry out the method for liguid chromatography, Dissolution
Appendix III D, using the following solutions in mobile Comply with the dissolution test for tablets and capsules,
phase A. Appendix XII B1.
(1) Dilute a weighed quantity of the oral solution to contain TEST CONDITIONS
0.002% w/v of Cetirizine Hydrochloride and filter through a (a) Use Apparatus 2, rotating the paddle at 50 revolutions
0.45-~m nylon filter. per minute.
(2) 0.002% w/v of cetirizine hydrochloride BPCRS. (b) Use 900 mL of water, at a temperature of 37°, as the
(3) 0.02% w/v of cetirizine impurity standard BPCRS. medium.
CHROMATOGRAPHIC CONDITIONS PROCEDURE
(a) Use a stainless steel column (25 cm x 4.6 mm) packed (1) After 45 minutes withdraw a sample of 10 mL of the
with octadecylsilyl silica gel for chromatography (5 um) medium, filter and dilute the filtrate with sufficient of the
(Phenomenex Luna C18(2) is suitable). dissolution medium to give a solution expected to contain
about 0.00050% w/v of Cetirizine Hydrochloride. Measure
IWI-292 Cetirizine Preparations
te Ne
2016
the absorbance of this solution, Appendix II B, at the supplied with cetirizine impurity standard BPCRS. Multiply the
maximum wavelengths at 230 nm and at 260 nm using the area of any peak corresponding to impurity A by a correction
Aven,
dissolution medium in the reference cell. factor of 0.7.
(2) Measure the absorbance of a suitable solution of cetirizine the areas of any peaks corresponding to impurities A, B or G
BPCRS in water at the maximum wavelengths at 230 nm and are not greater than 1.5 times the area of the principal peak
see A
260 nm using the dissolution medium in the reference cell in the chromatogram obtained with solution (2) (0.3%);
and calculate the difference between the two readings (AA) the area of any other secondary peak is not greater than the
for each measurement. area of the principal peak in the chromatogram obtained with
DETERMINATION OF CONTENT solution (2) (0.2%);
Calculate the total content of Cetirizine Hydrochloride, the total content of impurities is not greater than 5 times the
C,,H25CIN203,2HCI, in the medium using the values of AA area of the principal peak in the chromatogram obtained with
and from the declared content of C,;H.;CIN.0O3,2HCI in solution (2) (1.0%).
cetirizin ‘echloride BPCRS. Disregard any peak with an area less than the area of the
ewe ad
(3) (0.05%)
The amount ‘zine hydrochloride released is not less
than 80% (Q): : ASSAY
Carry out the metho« liquid chromatography, Appendix III D, using the following
Appendix III D, using th: solutions in the mobile phase.
phase A. (1) Shake a quantity of the powdered tablets containing
20 mg of Cetirizine Hydrochloride in 100 mL and filter
20 mg of Cetirizine Hydrochloy L of the mobile through a 0.45-um nylon filter. Dilute 10 mL of the filtrate
to 100 mL with the mobile phase.
YN aN
Nw ante
phase A, filter through a 0.45-u -and use the
filtrate. (2) 0.002% w/v of cetirizine hydrochloride BPCRS.
(3) 0.02% w/v of cetirizine impurity standard BPCRS.
dilute 2 volumes of the resulting solution to TQ CHROMATOGRAPHIC CONDITIONS
(3) Dilute 1 volume of solution (2) to 4 volumes. (a) Use a stainless steel column (25 cm x 4.6 mm) packed
(4) 0.02% w/v of cetirizine impurity standard BPCRS. with octadecylsilyl silica gel for chromatography (5 um)
CHROMATOGRAPHIC CONDITIONS (Phenomenex Luna C18(2) is suitable).
(a) Use a stainless steel column (25 cm x 4.6 mm) packe b) Use isocratic elution and the mobile phase described
with octadecylsilyl sitca gel for chromatography (5 um)
(Phenomenex Luna C18(2) is suitable). ow rate of 1.0 mL per minute.
(b) Use gradient elution and the mobile phase described column temperature of 30°.
below.
MOBILE PHASE adjusted to pH 1.5 with
Mobile phase A 17 volumes of acetonitrile and 83 volumes of SYSTEM SUITABILITY
eR A
we nee water previously adjusted to pH 1.5 with orthophosphoric acid. The test is not valid unless, ‘iz chromatogram obtained
Mobile phase B35 volumes of acetonitrile and 65 volumes of the peaks due to
water previously adjusted to pH 1.5 with orthophosphoric acid.
Time Mobile phase A Mobile phase B Comment Calculate the content of C.;H25CIN2O
(Minutes) % Viv % viv using the declared content of C2;H2sCIN2O4 2H
0-50 100-0 0-100 linear gradient cetirizine hydrochloride BPCRS.
50-53 0 100 isocratic IMPURITIES.
53-54 0-100 1000 linear gradient The impurities limited by the requirements of this
sowte ns of
AN aS
54-60 100 0 re-equilibration monograph include impurities A, B and G listed under
Cetirizine Hydrochloride.
iw awe
Rete
aawad
fete ates
we AN
wa 4
SYSTEM SUITABILITY

cetirizine and impurityB is at least 1.5.
LIMITS

identify any peaks corresponding to impurity A, impurity B
and impurity G using solution (4) and the chromatogram
re we nw
2016 Cetrimide Preparations ITI-293
Saponification value
Cetomacrogol Emulsifying Ointment Not more than 2.0, Appendix X G. Use 20 g.
reve 4
Action and use Sulfated ash
Emulsifying agent. Not more than 0.1%, Appendix IX A.
see ad
DEFINITION
White Soft Paraffin 500 g
Cetomacrogol Emulsifying Wax 300 g
Liquid Paraffin 200 g Cetrimide Cream
Extemporaneous preparation Action and use
The following directions apply. Antiseptic.
Melt together and stir until cold.
DEFINITION
Cetrimide Cream contains the stated percentage w/w of
Cetrimide in a suitable basis.
The following formula and directions apply.
Cetrimide 5 g, or a sufficient quantity
Cetomacrogol Emulsifying Wax Cetostearyl Alcohol 50 g
Non-ionic Emulsifying™ Liquid Paraffin 500 g
Purified Water, freshly boiled Sufficient to produce 1000 g
Action and use and cooled
Emulsifying agent.
Melt the Cetostearyl Alcohol and heat with the Liquid
DEFINITION Paraffin to about 60°. Dissolve the Cetrimide in sufficient
Cetostearyl Alcohol 800 g Purified Water to produce about 450 g. Add the aqueous
Macrogol Cetostearyl Ether (22) 200 g solution to the oily phase when both are at about 60° and
mix. Stir gently until cool, add sufficient of the Purified
Extemporaneous preparation Water to produce 1000 g and mix.
Melt together and stir until cold. Semi-solid Preparations and with the following requirements.
CHARACTERISTICS ent of cetrimide, C,,H3,BrN
A white or almost white, waxy solid or flakes melting when: 106.0% of the stated amount.
heated to a clear almost colourless liquid.
Practically insoluble in water, producing an emulsion;
moderately soluble in ethanol (96%); partly soluble in ether.
IDENTIFICATION
A. Incinerate at a temperature not exceeding 450° until free
from carbon and cool. The residue is negligible (distinction
from Emulsifying Wax).
F wairer with 1 mL of 1m sulfuric acid, 2 mL
5 f methyl orange solution. Add 2 mL
B. Complies with the test for Sulfated ash.
TESTS colour develops in these
Acid value ASSAY
Not more than 0.5, Appendix X B.
Refractive index
At 60°, 1.435 to 1.439, Appendix V E.
Solidifying point
45° to 53°, Appendix V B, using the following modifications.
Place in the inner test tube sufficient of the melted substance
to fill the tube to a depth of about 50 mm. Stir the substance LABELLING |
gently and steadily, without scraping the wall of the tube, The strength is stated as the percentage w/w of Cetrimide.
while the tube and its contents are allowed to cool. When Cetrimide Cream is prescribed or demanded, no
The temperature at which the level of the mercury in the strength being stated, a cream containing 5% w/v shall be
thermometer remains stationary for a short time is regarded dispensed or supplied.
as the solidifying point.
Alkalinity
Dissolve 10 g in 10 mL of water and 10 mL of ethanol
(96%). Not more than 0.5 mL of 0.1m hydrochlonc acid VS is
required for neutralisation using phenolphthalein solution R1 as
indicator.
Hydroxyl value
175 to 192, Appendix X D. Use 3.5 g.
IlI-294 Cetrimide Preparations 2016
Cetrimide Emulsifying Ointment shaking, until the chloroform layer no longer changes colour.
Carry out a blank titration on a mixture of 10 mL of the
Action and use
freshly prepared 8.0% w/v potassium iodide solution, 20 mL
Antiseptic. of water and 40 mL of hydrochloric acid. The difference
between the titrations represents the amount of potasstum
DEFINITION iodate required. Each mL of 0.05M potassium todate VS is
White Soft Paraffin 500 g equivalent to 0.03364 g of C,;7H3gBrN.
Cetostearyl Alcohol 270g
Liquid Paraffin 200 g STERILE CETRIMIDE SOLUTION
Cetrimide 30 g Sterile Cetrimide Cutaneous Solution
Extemporaneous preparation DEFINITION
The following directions apply. Sterile Cetrimide Solution is Cetrimide Solution that has
been sterilised by heating in an autoclave.
the Cetrimide and stir until cold.
Content of cetrimide; Identification
with the requirements stated under Topical Complies with the requirements stated under Cetrimide
Solution.
ASSAY
2.5 to 3.3% w/w.
Carry out the Assay described under Cetrimide Solution.
ASSAY Sterility
Complies with the test for sterility, Appendix XVI A.
Chloral Hydrate Oral Solution

NOTE: Chloral Hydrate Oral Solution 1s not currently licensed 1n
the United Kingdom.
Cetrimide Solution
Cetrimide Cutaneous Solution
Action and use

Antiseptic.
lution complies with the requirements stated under Oral
DEFINITION
: sments stated under Unlicensed Medicines and
Cetrimide Solution is a cutaneous solution of cetrimide
prepared by appropriately diluting Strong Cetrimide Solution
with Purified Water. Content of chi
95.0 to 105.0% o
The solution comphes with the requirements stated under Liquids
for Cutaneous Applicaton and with the following requirements.
Content of cetrimide, C,,H3,BrN
95.0 to 105.0% of the stated amount. solution; a yellow colour is prod
reddish-brown. On standing for
IDENTIFICATION is formed.
A. To a quantity containing 100 mg of Cetrimide, add 2 mL
B. Dilute a quantity of the oral solutio
of a 5% w/v solution of potassium hexacyanoferrate(i).
to produce a solution containing 0.01%"
A yellow precipitate is produced. ton To 10 mL of this solution add 1
B. Shake together 5 mL of water, 1 mL of 1M sulfuric acid,
2 mL of chloroform and 0.05 mL of methyl orange solution;
the chloroform layer is colourless. Add a quantity of the
solution being examined containing 20 mg of Cetrimide and Mix and heat j in a water bath at 60° for 15 minutes; a blue
shake. A yellow colour is produced slowly in the chloroform colouris produced.
layer.
ASSAY
C. Yields reaction A characteristic of bromides, Appendix VI.
To a weighed quantity of the oral solution containing 0.125 g
ASSAY of Chloral Hydrate add 2.5 g of zinc powder, 15 mL of glacial
To a quantity of the solution containing 1 g of Cetrimide acetic acid and 30 mL of water. Boil under a reflux condenser
add 25 mL of chloroform, 10 mL of 0.1M sodium hydroxide for 30 minutes, cool, filter through absorbent cotton and
and 10 mL ofa freshly prepared 8.0% w/v solution of wash the residue with water. Combine the filtrate and
potassium iodide. Shake well, allow to separate and discard the washings, add 20 mL of 2m nitric acid and 30 mL of
chloroform layer. Wash the aqueous layer with three 10-mL 0.1m silver nitrate VS, shake vigorously and filter. Wash the
quantities of chloroform and discard the washings. Add 40 mL residue with water and titrate the excess of silver nitrate in
of hydrochloric acid, cool and titrate with 0.05M potassium the combined filtrate and washings with 0.1M ammonium
todate VS until the deep brown colour is almost discharged. thiocyanate VS using ammonium iron(m) sulfate solution R2 as
Add 2 mL of chloroform and continue the titration, with indicator. Each mL of 0.1m silver nitrate VS is equivalent to
2016 Chloramphenicol Preparations IT-295
5.513 mg of C,H3Cl1,0,. Determine the weight per mL of the ASSAY

oral solution, Appendix V G, and calculate the content of Weigh and powder 20 tablets. Carry out the method for
C,H3Cl1302, weight in volume. liquid chromatography, Appendix III D, using the following
solutions.
(1) Dissolve as completely as possible a quantity of the
powdered tablets containing 10 mg of Chlorambucil in a
mixture of 25 mL of 0.1m hydrochloric acid and 100 mL of
Chiorambucil Tablets acetonitrile by mixing for 10 minutes with the aid of
Action and use ultrasound. Dilute to 250 mL with acetonitnile, filter through
Cytotoxic alkylating agent. a glass microfibre filter (Whatman GF/Cis suitable),
discarding the first 20 mL of filtrate, and dilute 50 mL to
DEFINITION 100 mL with a mixture of 1 volume of 0.1m hydrochloric acid
and 9 volumes of acetonitrile.
(2) 0.0020% w/v of chlorambucil BPCRS in a mixture of
1 volume of 0.1m hydrochloric acid and 9 volumes of
acetonitrile.
90.0 to 110.0% The chromatographic conditions described under Uniformity

IDENTIFICATIO of content may be used.
“Rydrochloric acid, allow to Calculate the content of C,,H,9CI,NO>, in the tablets using
stand for 30 minutes, shakin; nally, and filter. the declared content of C,4H,;)9CI,NO, in
To 5 mL of the filtrate add 0.5 mL ef potassium chlorambucil BPCRS.
tetraiodomercurate solution; a precipitate is produced. To the
remainder of the filtrate add 0.15 mL ‘of.@ilyze potassium
permanganate solution; the colour of the pex fAate is
discharged. :
TESTS
Chloramphenicol Capsules
Uniformity of content Action and use
Tablets containing less than 2 mg and/or less than 2% Antibacterial.
of Chlorambucil comply with the requirements stated un
Tablets using the following method of analysis. 2FINITION
Carry out the method for liquid chromatography, amphenicol Capsules contain Chloramphenicol.
Appendix III D, using the following solutions. ules comply with the requirements stated under Capsules
(1) Dissolve one tablet as completely as possible in 10 mL of following requirements.
0.1m hydrochloric acid, add 40 mL of acetonitrile and mix for
5 minutes with the aid of ultrasound. Add sufficient
acetonitrile to produce a solution containing 0.002% w/v of
chlorambucil, filter through a glass microfibre filter
(Whatman GF/C is suitable), discarding the first 20 mL of
filtrate, and use the filtrate.
two 20-mL quantities"S
(2) 0.0020% w/v of chlorambucil BPCRS in a mixture of
160°). Wash the combine
1 volume of 0.1M hydrochloric acid and 9 volumes of
quantities of water, add th
acetonitrile.
(a) Use a stainless steel column (30 cm x 3.9 mm) packed following tests.
with end-capped octadecylsilyl silica gel for chromatography A. Carry out the method for thin-layer chroy
(10 um) (uBondapak C18 is suitable). Appendix III A, using the following solution
(b) Use isocratic elution and the mobile phase described (96%).
below. (1) 1% w/v of the residue.
(c) Use a flow rate of 2 mL per minute. (2) 1% wWv of chloramphenicol BPCRS.
(d) Use an ambient column temperature. CHROMATOGRAPHIC CONDITIONS
(e) Use a detection wavelength of 254 nm. (a) Use as the coating silica gel GF 254.
(f) Inject 20 wL of each solution. (b) Use the mobile phase as described below.
MOBILE PHASE (c) Apply 1 wL of each solution.
40 volumes of 0.02m potasstum dihydrogen orthophosphate and (d) Develop the plate to 15 cm.
60 volumes of acetonitrile. (e) After removal of the plate, allow it to dry in air and
DETERMINATION OF CONTENT examine under ultraviolet light (254 nm).
Calculate the content of C,,H,),Cl,NO, in the tablet using MOBILE PHASE
the declared content of C,H) 9Cl,NO> in 1 volume of water, 10 volumes of methanol and 90 volumes of
chlorambucil BPCRS. chloroform.
II-296 Chloramphenicol Preparations 2016
CONFIRMATION (1) Dissolve a quantity of the mixed contents of 20 capsules

The principal spot in the chromatogram obtained with containing 0.2 g of Chloramphenicol in 800 mL of water,
solution (1) corresponds to that in the chromatogram warming if necessary to effect solution, and add sufficient
obtained with solution (2). water to produce 1000 mL. Dilute 25 mL of this solution to
B. Dissolve 10 mg of the residue in 2 mL of ethanol (50%), 50 mL with the mobile phase.
add 4.5 mL of 1m sulfuric acid and 50 mg of zinc powder and (2) Dilute 1 volume of a 0.1% w/v solution of
allow to stand for 10 minutes. Decant the supernatant liquid chloramphenicol BPCRS in water to 10 volumes with the
or filter if necessary. Cool the resulting solution in ice and mobile phase.
add 0.5 mL of sodium nitrite solution and, after 2 minutes, 1 g (3) 0.005% w/v of each of chloramphenicol BPCRS and
of urea followed by 1 mL of 2-naphthol solution and 2 mL of 2-amino-1-(4-nitrophenyl)propane-1,3-diol BPCRS in the
10m sodium hydroxide; a red colour is produced. Repeat the mobile phase.
test omitting the zinc powder; no red colour is produced. CHROMATOGRAPHIC CONDITIONS

Aas
re Nt with end-capped octadecylsilyl silica gel for chromatography
irements for Monographs of the British (5 um) (Nucleosil C18 is suitable).
| ssolution test for tablets and capsules, (b) Use isocratic elution and the mobile phase described
Appendix XII B1. below.
TEST CONDITIONS (c) Use a flow rate of 2 mL per minute.
(a) Use Apparatus 1, rota sket at 100 revolutions (d) Use an ambient column temperature.
per minute.
(b) Use 900 mL of 0.1m hydrock cid, at a temperature of
(f) Inject 10 L of each solution.
MOBILE PHASE
PROCEDURE
1 volume of glacial acetic acid, 15 volumes of acetonitrile and
After 45 minutes withdraw a 10 mL samp, medium
and measure the absorbance of the filtered sample
pentanesulfonate.
diluted with 0.1M hydrochloric acid if necessary, &
maximum at 278 nm, Appendix II B, using 0.1M‘hy SYSTEM SUITABILITY
acid in the reference cell. The Assay is not valid unless, in the chromatogram obtained
orresponding to chloramphenicol and 2-amino-1-
Calculate the total content of chloramphenicol,
itraphenyl)propane-1,3-diol is at least 8.0.
C,,Hj2Cl,N20s, in the medium taking 297 as the value of
A(1%, 1 cm) at the maximum at 278 nm. ATION OF CONTENT
2-Amino-1-(4-nitrophenyl) propane-1,3-diol e content of C,;;H,.Cl,N.Os in the capsules

(1) Shake a quantity of the contents of the capsules
containing 40 mg of Chloramphenicol with 100 mL of the
mobile phase for 10 minutes, add sufficient mobile phase to
produce 200 mL, mix and filter.
(2) 0.0002% w/v of 2-amino-1-(4-nitrophenyl)propane-1,3-
diol BPCRS in the mobile phase. Action and use
Antibacterial.
(3) 0.005% w/v of each of chloramphenicol BPCRS and
2-amino-1-(4-nitrophenyl)propane-1,3-diol BPCRS in the
DEFINITION
mobile phase.
Chloramphenicol Ear Drops are a solution:
CHROMATOGRAPHIC CONDITIONS Chloramphenicol in a suitable vehicle.
The chromatographic conditions described under Assay may The ear drops comply with the requirements
be used. Preparations and with the following requirements.’
SYSTEM SUITABILITY Content of chloramphenicol, C,,H,,CLN,0;
The test is not valid unless, in the chromatogram obtained 90.0 to 110.0% of the stated amount.
with solution (3), the resolution factor between the peaks IDENTIFICATION
ete twty |
corresponding to chloramphenicol and 2-amino-1- A. Carry out the method for thin-layer chromatography,
wee
(4-nitrophenyl!) propane-1,3-diol is at least 8.0. Appendix III A, using the following solutions in ethanol
vn nd
‘At ates
LIMIT (96%).
In the chromatogram obtained with solution (1): (1) Dilute a volume of the ear drops containing 0.1 g of
the area of any peak corresponding to 2-amino-1- Chloramphenicol to 10 mL.
(4-nitrophenyl)-propane-1,3-diol is not greater than the area (2) 1% wv of chloramphenicol BPCRS.
of the peak in the chromatogram obtained with solution (2)
(1%).
ASSAY (b) Use the mobile phase as described below.
wm ed
2016 Chloramphenicol Preparations II-297
(d) Develop the plate to 15 cm. CHROMATOGRAPHIC CONDITIONS

(e) After removal of the plate, allow it to dry in air and (a) Use a stainless steel column (10 cm x 4.6 mm) packed
examine under ultraviolet light (254 nm). with end-capped octadecylsilyl silica gel for chromatography
MOBILE PHASE
1 volume of water, 10 volumes of methanol and 90 volumes of (b) Use isocratic elution and the mobile phase described
below.
chloroform.
CONFIRMATION
solution (1) corresponds to that in the chromatogram (e) Use a detection wavelength of 278 nm.
obtained with solution (2). (f) Inject 10 pL of each solution.
B. Dilute a volume of the ear drops containing 50 mg of MOBILE PHASE
enicol to 10 mL with ethanol (50%). To 2 mL 1 volume of glacial acetic acid, 15 volumes of acetonitrile and
Lee
ee ee
x sulfuric acid and 50 mg of zinc powder and 85 volumes of a 0.21% w/v solution of sodium
10 minutes. Decant the supernatant liquid pentanesulfonate.
Cool the resulting solution in ice and
SYSTEM SUITABILITY
add 0.5 mL of iumenitrite solution and, after 2 minutes, 1 g
of urea followed mL, of 2-naphthol solution and 2 mL of The Assay is not valid unless, in the chromatogram obtained
10m sodium hydroxi re colour 1is produced. Repeat the with solution (3), the resolution factor between the peaks
test omitting the zin no red colouris produced. corresponding to chloramphenicol and 2-amino-1-
(4-nitrophenyl) propane-1,3-diol is at least 8.0.
TESTS
2-Amino-1-(4-nitrophe
Calculate the content of C,,;H)2Cl,N,.Os5 in the ear drops
Appendix III D, using the following: using the declared content of C,,;Hj.Cl,N.2Os in
chloramphenicol BPCRS.
(1) Dilute a volume of the ear drops w (
mobile phase to produce a solution containing: 0% w/v of STORAGE
Chloramphenicol. Chloramphenicol Ear Drops should be protected from light.
(2) 0.0025% w/v of 2-amino-1-(t-nisrophensl) rop :
diol BPCRSin the mobile phase. é
(3) 0.005% w/v of each of chloramphenicol BPCRS an
2-amino-1-(4-mitrophenyl)propane-1,3-diol BPCRS in th
mobile phase.

be used.
SYSTEM SUITABILITY
with solution (3), the resolution factor between the peaks ith the requirements stated under Eye
corresponding to chloramphenicol and 2-amino-1- llowing requirements.
Content of chlora
LIMIT 90.0 to 110.0% of
t
IDENTIFICATION
the area of any peak corresponding to 2-amino-1-
(4-nitrophenyl)-propane-1,3-diol is not greater than the area
of the peak in the chromatogram obtained with solution (2) 25-mL quantities of ether. Comb
(5%). evaporate to dryness. The dried residti
ASSAY following tests.
Appendix III D, using the following solutions. Appendix III A, using the following solutions 11
(1) Dilute a volume of the ear drops containing 25 mg of (96%).
Chloramphenicol to 50 mL with water, mix and dilute (1) 1% w/v of the residue.
1 volume of the resulting solution to 5 volumes with the
Ones
(2) 1% wiv of chloramphenicol BPCRS.

mobile phase.
(2) Dilute 1 volume of a 0.1% w/v solution of
chloramphenicol BPCRS in water to 10 volumes with the
mobile phase. (b) Use the mobile phase as described below.
(3) 0.005% w/v of each of chloramphenicol BPCRS and (c) Apply 1 wL of each solution.
2-amino-1-(4-nitrophenyl)propane-1,3-diol BPCRS in the (d) Develop the plate to 15 cm.
mobile phase. (e) After removal of the plate, allow it to dry in air and
II-298 Chloramphenicol Preparations 2016
MOBILE PHASE (c) Use a flow rate of 2 mL per minute.

1 volume of water, 10 volumes of methanol and 90 volumes of (d) Use an ambient column temperature.
chloroform. (e) Use a detection wavelength of 278 nm.
CONFIRMATION (f) Inject 10 wL of each solution.
The principal spot in the chromatogram obtained with MOBILE PHASE
B. Dissolve 10 mg of the residue in 2 mL of ethanol (50%), pentanesulfonate.
add 4.5 mL of 1m sulfuric acid and 50 mg of zinc powder and
SYSTEM SUITABILITY
allow to stand for 10 minutes. Decant the supernatant liquid
or filter if necessary. Cool the resulting solution in ice and The Assay is not valid unless, in the chromatogram obtained
sodium nitrite solution and, after 2 minutes, 1 g with solution (3), the resolution factor between the peaks
y..4 mL of 2-naphthol solution and 2 mL of corresponding to chloramphenicol and 2-amino-1-
a red colour is produced. Repeat the (4-nitrophenyl) propane-1,3-diol is at least 8.0.
test omitting owder; no red colour is produced. DETERMINATION OF CONTENT
TESTS Calculate the content of C,,;H,2Cl,N,Os5 in the eye drops

Acidity or alkalinit using the declared content of C,,;H 2Cl,N2O; in
pH, 7.0 to 7.5, Appen chloramphenicol BPCRS.
2-Amino-1-(4-nitrop ane-1,3-diol STORAGE
Chloramphenicol Eye Drops should be protected from light.
Appendix III D, using thefoll
(1) Dilute a volume of the eye : cient of the
mobile phase to produce a solution con 0.05% w/v of
Chloramphenicol. Chloramphenicol Eye Ointment
(2) 0.004% w/v of 2-amino-1-(4-nitrophenyl)j
diol BPCRSin the mobile phase. Action and use
(3) 0.005% w/v of each of chloramphenicol BPCRS and: Antibacterial.
2-amino-1-(4-nitrophenyl)propane-1,3-diol BPCRSin th
mobile phase.
The chromatographic conditions described under Assay may ment complies with the requirements stated under Eye
be used. and with the following requirements.
SYSTEM SUITABILITY hloramphenicol, C,,H,,Cl1,N,0,;
The test is not valid unless, in the chromatogram obtained f the stated amount.
corresponding to chloramphenicol and 2-amino-1-
e ointment containing 30 mg of
Chloramphenicol mL of petroleum spirit (boiling range,
LIMIT 40° to 60°), centrifuge card the supernatant liquid.
In the chromatogram obtained with solution (1): Repeat this procedure u | 10-mL quantities of the
the area of any peak corresponding to 2-amino-1- same solvent. The dried r plies with the following
(4-nitrophenyl)-propane-1,3-diol is not greater than the area tests.
of the peak in the chromatogram obtained with solution (2) A. Carry out the method for thi lay
(8%). Appendix III A, using the following
ASSAY (96%).
Carry out the method for liguid chromatography, (1) 1% w/v of the residue.
Appendix III D, using the following solutions. (2) 1% wv of chloramphenicol BPCRS.
(1) Dilute a volume of the eye drops containing 5 mg of CHROMATOGRAPHIC CONDITIONS
Chloramphenicol to 50 mL with the mobile phase. (a) Use as the coating silica gel GF 254.
(2) Dilute 1 volume of a 0.1% w/v solution of (b) Use the mobile phase as described below.
chloramphenicol BPCRS in water to 10 volumes with the
ated te
mobile phase.
‘yay

wean
ray 4 (3) 0.005% w/v of each of chloramphenicol BPCRS and

2-amino-1-(4-nitrophenyl)propane-1,3-diol BPCRS in the (e) After removal of the plate, allow it to dry in air and
mobile phase. examine under ultraviolet light (254 nm).
MOBILE PHASE
(a) Use a stainless steel column (10 cm x 4.6 mm) packed 1 volume of water, 10 volumes of methanol and 90 volumes of
with end-capped octadecylsilyl silica gel for chromatography chloroform.
(5 um) (Nucleosil C18 is suitable). CONFIRMATION
(b) Use isocratic elution and the mobile phase described The principal spot in the chromatogram obtained with
swan
below. solution (1) corresponds to that in the chromatogram
rawd
2016 Chloramphenicol Preparations III-299
B. Dissolve 10 mg of the residue in 2 mL of ethanol (50%), CHROMATOGRAPHIC CONDITIONS

add 4.5 mL of 1m sulfuric acid and 50 mg of zinc powder and (a) Use a stainless steel column (10 cm x 4.6 mm) packed
allow to stand for 10 minutes. Decant the supernatant liquid with end-capped octadecylsilyl silica gel for chromatography
or filter if necessary. Cool the resulting solution in ice and (5 um) (Nucleosil C18 is suitable).
add 0.5 mL of sodium nitnite solution and, after 2 minutes, 1 g (b) Use isocratic elution and the mobile phase described
of urea followed by 1 mL of 2-naphthol solution and 2 mL of below.
10m sodium hydroxide; a red colour is produced. Repeat the
test omitting the zinc powder; no red colour is produced.
TESTS
2-Amino-1-(4-nitrophenyl) propane-1,3-diol
Carry out the method for liguid chromatography, (f) Inject 10 pL of each solution.
Appendix III D, using the following solutions. MOBILE PHASE

ol in 50 mL of petroleum spint (boiling 85 volumes of a 0.21% w/v solution of sodium
and extract with successive quantities of 25, pentanesulfonate.
LC of a warm 0.21% w/v solution of sodium SYSTEM SUITABILITY
pentanesulfonate. sombine the extracts, add 15 mL of
acetonitrile and
Filter the resulting cools
filter and then through
(4-nitrophenyl)propane-1,3-diel By Calculate the content of C,;,H),,Cl,N.Os in the eye ointment

100 volumes with the mobile phas using the declared content of C,,Hj2Cl,N2Os in
chloramphenicol BPCRS.
2-amino-1-(4-nitrophenyl)propane-1,3-diol '
mobile phase.
CHROMATOGRAPHIC CONDITIONS ,
The chromatographic conditions described under Ass Chloramphenicol Sodium Succinate

be used.
Injection
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained |

LIMIT

the area of any peak corresponding to 2-amino-1-
(4-nitrophenyl)-propane-1,3-diol is not greater than the area
of the peak in the chromatogram obtained with solution (2)
(1%). Parenteral Preparatio
ASSAY STORAGE
(1) Suspend a quantity of the eye ointment containing 10 mg period recommended by the manufacri hen prepared
of Chloramphenicol in 50 mL of petroleum spirit (boiling and stored strictly in accordance with the nufacturer’s
range, 40° to 60°) and extract with successive quantities of 25, instructions.
25, 15 and 15 mL of a warm 0.21% w/v solution of sodium
pentanesulfonate. Combine the extracts, add 15 mL of CHLORAMPHENICOL SODIUM
acetonitrile and 1 mL of glacial acetic acid, mix and dilute to
SUCCINATE FOR INJECTION
100 mL with a 0.21% w/v solution of sodium pentanesulfonate.
Filter the resulting cooled solution through a 0.7-um glass DEFINITION |
filter and then through a 0.45-um nylon filter. Chloramphenicol Sodium Succinate for Injection is a sterile
(2) Dilute 1 volume of a 0.1% w/v solution of material consisting of Chloramphenicol Sodium Succinate
chloramphenicol BPCRS in water to 10 volumes with the with or without excipients. It is supplied in a sealed
mobile phase. container.
(3) 0.005% w/v of each of chloramphenicol BPCRS and The contents of the sealed container comply with the requirements
2-amtino-1-(4-nitrophenyl)propane-1,3-diol BPCRS in the for Powders for Injections or Infusions stated under Parenteral
mobile phase. Preparations and with the following requirements.
Content of chloramphenicol sodium succinate,
calculated as C,,H;,CLN,O;
atari
I-300 Chlordiazepoxide Preparations 2016
IDENTIFICATION (d) Use an ambient column temperature.

A. Carry out the method for thin-layer chromatography, (e) Use a detection wavelength of 275 nm.
Appendix III A, using the following solutions in acetone. (f) Inject 20 wL of each solution.
(1) Dissolve a sufficient quantity of the contents of the sealed
MOBILE PHASE
container to produce a solution containing the equivalent of
1% w/v of chloramphenicol. 5 volumes of a 2% w/v solution of orthophosphoric acid,
40 volumes of methanol and 55 volumes of water.
(2) 1% wWv of chloramphenicol sodium succinate BPCRS.
SYSTEM SUITABILITY
(3) 1% w/v of chloramphenicol BPCRS.
The test is not valid unless the two peaks in the
chromatogram obtained with solution (4) corresponding to
(a) Use as the coating silica gel GF 254. those in the chromatograms obtained with solutions (2) and
(b) Use the mobile phase as described below. (3) are clearly separated from the peaks corresponding to the
f each solution. two principal peaks in the chromatogram obtained with
(d) Deve Q ‘to 15 cm. solution (1). If necessary, adjust the methanol content of the
mobile phase.
(e) After remeyv plate, allow it to dry in air and
examine under g#itraw light (254 nm). LIMITS
MOBILE PHASE In the chromatogram obtained with solution (1):

1 volume of 2M acetic a olumes of methanol and the areas of any peaks corresponding to chloramphenicol and
85 volumes of chloroform chloramphenicol disodium disuccinate are not greater than
CONFIRMATION
those of the principal peaks in the chromatograms obtained
with solutions (2) and (3) respectively (2% of each).
The two principal spots in the am, obtained with
solution (1) are similar in positig#i & Water
chromatogram obtained with solution and their positions Not more than 5.0% w/w, Appendix IX C. Use 0.5 g.
are different from that of the principal spo Bacterial endotoxins
chromatogram obtained with solution (3). Carry out the test for bacterial endotoxins, Appendix XIV C.
B. Dissolve 10 mg in 1 mL of ethanol (50%), ad Dissolve the contents of the sealed container in water BET to
1% w/v solution of calcium chloride and 50 mg of ‘Zinc po give a solution containing 10 mg per mL (solution A).
and heat on a water bath for 10 minutes. Filter the hot The endotoxin limit of solution A is 2.0 IU per mL.
solution, allow to cool, add 0.1 mL of benzoyl chloride atid
shake for 1 minute. Add 0.5 mL of zronam chloride solutio Determine the weight of the contents of 10 containers as
and 2 mL of chloroform and shake. The aqueous layer is lig
violet-red to purple. II C1, Powders for Parenteral Administration.
C. Yields reaction A characteristic of sodium salts, uantity of the mixed contents of the 10
Appendix VI.
TESTS
PH of a solution containing the equivalent of 20.0% w/v of
chloramphenicol, 6.0 to 7.0, Appendix V L. pendix II B. Calculate the content
Chloramphenicol and chloramphenicol disodium CIL,N2Os, in a container of
disuccinate
Appendix III D, using the following solutions in the mobile STORAGE
phase. The sealed container should be
(1) Dissolve a sufficient quantity of the contents of the sealed LABELLING
container to give a solution containing the equivalent of
The label of the sealed container sta
0.018% w/v of chloramphenicol.
(2) 0.00050% w/v of chloramphenicol BPCRS. of the equivalent amount of chloramphenico
(3) 0.00050% w/v of chloramphenicol disodium
disuccinate EPCRS.
(4) 0.00050% w/v of each of chloramphenicol disodium —
disuccinate EPCRS and chloramphenicol BPCRS and a Chlordiazepoxide Capsules
sufficient quantity of the contents of the sealed container to
give a solution containing the equivalent of 0.025% w/v of Action and use
chloramphenicol. Benzodiazepine.
DEFINITION
(a) Use a stainless steel column (25 cm x 4.6 mm) packed Chlordiazepoxide Capsules contain Chlordiazepoxide
Hydrochloride.
(LiChrosorb RP-18, Hypersil ODS and Polygosil C18 5 um
are suitable).
below. Content of chlordiazepoxide hydrochloride,
i wae C,6H,,CIN;0,HCl
ae
Pea
2016 Chlordiazepoxide Preparations III-301
IDENTIFICATION DETERMINATION OF CONTENT

A. Dilute 1 volume of the final solution obtained in the Calculate the total content of chlordiazepoxide hydrochloride,
Assay to 2 volumes with 0.1m hydrochloric acid. Vhe light C16Hy4CIN30,HCI, in the medium taking 292 as the value
absorption, Appendix II B, in the range 230 to 350 nm of A(1%, 1 cm) at the maximum at 308 nm.
exhibits two maxima, at 246 nm and 308 nm.
ASSAY
B. Shake a quantity of the contents of the capsules Carry out the following procedure protected from light.
containing 25 mg of Chlordiazepoxide Hydrochloride with Shake a quantity of the mixed contents of 20 capsules
2.5 mL of water, add 0.5 mL of 6m ammonia, mix, allow to containing 20 mg of Chlordiazepoxide Hydrochloride with
stand for 5 minutes and filter. The filtrate, after making 150 mL of 0.1m hydrochloric acid for 20 minutes.
acidic with 2m nitric acid, yields reaction A characteristic of Add sufficient 0.1m hydrochloric acid to produce 200 mL and
chlorides, Appendix VI. filter. Dilute 10 mL of the filtrate to 50 mL with
0.1m hydrochloric acid and measure the absorbance of the
ices resulting solution at the maximum at 308 nm,
Appendix II B. Calculate the content of C;,H,,CIN30,HCl
taking 292 as the value of A(1%, 1 cm) at the maximum at
308 nm.
STORAGE
Chlordiazepoxide Capsules should be protected from light.
containing 0.10 g of Ch xide Hydrochloride with
10 mL of the solvent mix to settle and use the
clear supernatant liquid. &
(2) Dilute 3 volumes of solu Chlordiazepoxide Hydrochloride Tablets
(3) 0.01% w/v of 2-amino-5-chlorobénz
Action and use
Benzodiazepine.
(a) Use as the coating silica gel GF 54. é
(b) Use the mobile phase as described below: DEFINITION
2 pL‘
(c) Apply 2 uL and 20 pL of solution (1), Chlordiazepoxide Hydrochloride Tablets contain
(2) and 20 uL of solution (3). Chlordiazepoxide Hydrochloride.
(d) Develop the plate to 15 cm. The tablets comply with the requirements stated under Tablets and
the following requirements.
(e) After removal of the plate, dry in air and examine undé
ultraviolet light (254 nm). nt of chlordiazepoxide, C,,H,,CIN3;O
MOBILE PHASE
1 volume of 13.5m ammonia, 14 volumes of methanol and
LIMITS
<1 By in the range 230 to 350 nm
Any secondary spot in the chromatogram obtained with 2 uL at 246 nm and 308 nm.
of solution (1) is not more intense than the spot in the
y»wdered tablets containing the
chromatogram obtained with solution (2) (33%). Spray the
equivalent of 0.2 g wdiazepoxide add 4 mL of hot
plate with a freshly prepared 1% w/v solution of sodium nitrite
2M hydrochloric acid, ° for 10minutes, cool and
in 1m hydrochloric acid, dry it in a current of cold air and
filter. 2 mL of the filtrat
spray with a 0.4% w/v solution of
primary aromatic amines,App C
N-(1-naphthyl) ethylenediamine dihydrochloride in ethanol
precipitate. .
(96%). Any violet spot corresponding to 2-amino-5-
chlorobenzophenone in the chromatogram obtained with
20 wL of solution (1) is not more intense than the spot in the
Dissolution
2M nitric acid, yields reaction A saracteristie f¢ orides,
Comply with the requirements for Monographs of the British Appendix VI.
Appendix XII Bl. TESTS
Related substances
TEST CONDITIONS
Carry out in subdued light the method for thin-layer
(a) Use Apparatus 1, rotating the basket at 100 revolutions chromatography, Appendix III A, using silica gel GF54 as the
per minute. coating substance and a mixture of 85 volumes of chloroform,
(b) Use 900 mL of 0.1m hydrochloric acid, at a temperature of 14 volumes of methanol and 1 volume of 13.5M ammonia as
37°, as the medium. the mobile phase. Prepare the following solutions
PROCEDURE immediately before use in acetone containing 2% v/v of
13.5M ammonia and 8% v/v of water. For solution (1) shake a
After 45 minutes withdraw a sample of the medium and
quantity of the powdered tablets containing the equivalent of
measure the absorbance of a layer of suitable thickness of the
0.10 g of chlordiazepoxide with 10 mL of the solvent
filtered sample, suitably diluted with the dissolution medium
mixture, allow to settle and use the supernatant liquid.
end
if necessary, at the maximum at 308 nm, Appendix II B
For solution (2) dilute 5 volumes of solution (1) to
using 0.1m hydrochloric acid in the reference cell.
100 volumes with the same solvent mixture. For solution (3)
wee oe ed II-302 Chlorhexidine Preparations 2016
dilute 1 volume of solution (1) to 100 volumes with the same Appendix II A, is concordant with the reference spectrum of
ran as
solvent. Solution (4) contains 0.01% w/v of 2-amino-5- chlorhexidine (RS 449).
TAP
wana
tes chlorobenzophenone. Apply separately to the plate 2-uL and B. In the Assay, the retention time of the principal peak in
20-uL quantities of solution (1), 2 uL of each of solutions the chromatogram obtained with solution (1) is the same as
(2) and (3) and 20 uL of solution (4). After removal of the that of the peak due to chlorhexidine in the chromatogram
plate, allow it to dry in air and examine under ultraviolet light obtained with solution (2).
(254 nm). Any secondary spot in the chromatogram obtained
TESTS
with 2 uL of solution (1) is not more intense than the spot in
the chromatogram obtained with solution (2) (5%) and not Acidity
more than one such spot is more intense than the spot in the pH, 5.0 to 7.5, Appendix V L.
chromatogram obtained with solution (3) (1%). Spray the Related substances
plate with a freshly prepared 1% w/v solution of sodium nitrite Carry out the method for liquid chromatography,
ramen 4
c acid, dry it in a current of cold air and Appendix III D, using the following solutions in the mobile
w/v solution of phase.
(1) Dilute a volume of the eye drops, if necessary, to produce
chromatogram obtained with chlorhexidine gluconate.
«more intense than the spot in the
(2) 0.015% ww of chlorhexidine for performance test EPCRS.
(3) Dilute 3 volumes of solution (1) to 100 volumes.
awe
sh ead sufficient 0.1M hydrochloric acid to prodt with octadecylsilyl sihca gel for chromatography (5 wm)
containing the equivalent of 0.0020% w/v: (Spherisorb ODS is suitable).
below.
of C,gH,4CIN3O taking 327 as the value of A(1%, L.¢ (c) Use a flow rate of 1 mL per minute.
the maximum at 308 nm. ‘
LABELLING e) Use a detection wavelength of 254 nm.
! 100 pL of each solution.
equivalent amount of chlordiazepoxide.
tion (1) allow the chromatography to proceed for
retention time of chlorhexidine.
e column with mobile phase for at least 1 hour.
Chlorhexidine Gluconate Eye Drops tal aeetic acid, 270 volumes of water and
Chlorhexidine Digluconate Eye Drops 730 volumes 6f yal containing 0.2% w/v of sodium
NOTE: Chlorhexidine Gluconate Eye Drops are not currently octanesulfonate.
licensed in the United Kingdom.
SYSTEM SUITABILITY
Action and use The test is not valid unleés womatogram obtained with
Antiseptic. solution (2) closely resembles th reference chromatogram
supplied with chlorhexidine for’ wmance test EPCRS in that
DEFINITION
|
the peaks due to impurities A and:B p de that due to

3 4
Chlorhexidine Gluconate Eye Drops area sterile solution of chlorhexidine. If necessary, adjust the cont ation of acetic
Chlorhexidine Gluconate Solution in Purified Water. acid in the mobile phase; increasing
The eye drops comply with the requirements stated under Eye decreases the retention times.
Preparations, the requirements stated under Unlicensed Medicines LIMITS :
and with the following requirements. In the chromatogram obtained with solution (1)*
Content of chlorhexidine gluconate, the sum of the areas of all the secondary peaks is not greater
C22H39C1,Nj9,2C6H1207 than the area of the principal peak in the chromatogram
95.0 to 115.0% of the stated amount. obtained with solution (3) (3%).
Fae e
IDENTIFICATION Disregard any peak with an area less than the area of the
A. Add 10 mL of concentrated ammonia, drop wise, to a principal peak in the chromatogram obtained with solution
volume of the eye drops containing the equivalent of 20 mg (4) (0.06%) and any peak with a retention time relative to
of chlorhexidine gluconate which has previously been cooled that of chlorhexidine of 0.25 or less.
in ice. Centrifuge at 3000 rpm for 10 minutes, discard the
ASSAY
supernatant liquid and transfer the residue to a filter which
has previously been treated with water (Whatman GF/F
paper is suitable); allow to stand until the ammonia has
evaporated. Wash the residue with 10 mL of water and (1) Dilute a volume of the eye drops, if necessary, with
dissolve in ethanol (70%). Evaporate the solvent under a sufficient water to produce a solution containing the
rN >
ve
oe
ule
Ns
ma
ee
en
° stream of nitrogen and dry the residue at 105° for one hour. equivalent of 0.02% w/v of chlorhexidine gluconate.
enderMe
nese
ea4
The infrared absorption spectrum of the dried residue, (2) 0.014% w/v of chlorhexidine acetate BPCRS in water.
2016 Chlorhexidine Preparations III-303
CHROMATOGRAPHIC CONDITIONS SOLVENT A

(a) Use a stainless steel column (25 cm x 4.6 mm) packed Dissolve 80 mg of 2,6-dimethylaniline (internal standard) in
with octadecylsilyl silica gel for chromatography (10 um) (Partisil 1 mL of 1m hydrochloric acid with the aid of ultrasound, add
ODS is suitable). sufficient water to produce 100 mL and dilute 1 volume of
(b) Use isocratic elution and the mobile phase described this solution to 100 volumes with 0.01m hydrochloric acid.
below. (1) Shake a quantity of the gel containing 0.5 g of
(c) Use a flow rate of 2 mL per minute. Chlorhexidine Gluconate with 20 mL of a mixture of
(d) Use an ambient column temperature. 20 volumes of ether and 80 volumes of hexane and 5 mL of
0.6M sodium hydrogen carbonate solution, allow to separate and
discard the aqueous layer. Shake the organic layer with
(f) Inject 20 wL of each solution. anhydrous sodium sulfate and filter through silica treated filter
paper (Whatman IPS is suitable), add 100 uL of
heptafluorobutyric anhydride and shake for 30 seconds. Allow
the solution to stand for 2 minutes, add 5 mL of 0.6m sodium
hydrogen carbonate solution, shake, allow to separate and use
the upper layer.
Calculate the 92H 39ClN10;2C6H 1207 in the eye
(2) Add 2 mL of solvent A to 50 mL of the gel, shake with
drops using the dec: ontent of C52H39CLNio in
20 mL of a mixture of 20 volumes of ether and 80 volumes of
chlorhexidine acetate . Bach mg of Cy2H39CloNjo is hexane and 5 mL of 0.6m sodium hydrogen carbonate solution,
equivalent to 1.775 mg ( loNi0:2C6H1207. allow to separate and discard the aqueous layer. Shake the
STORAGE organic layer with anhydrous sodium sulfate and filter through
Chlorhexidine Gluconate Eys sh ld be protected silica treated filter paper (Whatman IPS is suitable), add
from light. 100 pL of heptafluorobutyric anhydride and shake for
30 seconds. Allow the solution to stand for 2 minutes, add
LABELLING
5 mL of 0.6m sodium hydrogen carbonate solution, shake, allow
The quantity of active ingredientis stated 1 to separate and use the upper layer.
equivalent amount of chlorhexidine gluco
REFERENCE SOLUTIONS
Prepare a series of reference solutions in the following
manner. Dissolve 25 mg of 4-chloroaniline in 1 mL of
1m hydrochloric acid with the aid of ultrasound, add sufficient
Chlorhexidine Gluconate Gel ter to produce 200 mL and dilute 1 volume to 10 volumes
ith ‘the same solvent. To separate 0, 2, 4, 6 and 8 mL
Action and use s of this solution (containing 0, 25, 50, 75 and 100 pg
Antiseptic.
DEFINITION
Chlorhexidine Gluconate Gel is a solution of Chlorhexidine
Gluconate in a suitable water-miscible basis.
x ayer. Shake the organic layer with
The gel complies with the requirements stated under Topical Semi- anhydrous sodi m u te and filter through silica treated filter
solid Preparations and with the following requirements. paper (Whatma
Content of chlorhexidine gluconate, heptafluorobutyric
C22H39C1LN10,2C6H 1207 the solution to stanc
95.0 to 105.0% of the stated amount. hydrogen carbonate soluti
the upper layer.
IDENTIFICATION
ee ay
A. Disperse a quantity of the gel containing 5 mg of

Chlorhexidine Gluconate in 10 mL of water, mix and dilute
sy en
to 500 mL with water. The light absorption of the resulting silanised diatomaceous support (100 to me sh.) coated with
solution, Appendix IT B, in the range 200 to 320 nm exhibits 15% wiw of cyanopropylmethylphenyl met icone fluid
two maxima, at 231 nm and 255 nm; and two minima, at (OV-225 is suitable).
222 nm and 242 nm. (b) Use a flow rate of 50 mL per minute.
B. Place a quantity of the gel on a white tile and add a drop (c) A column temperature of 190°.
of bromine water. A reddish-yellow colour is produced.
(d) Use an inlet port temperature of 200°.
C. In the Assay, the chromatogram obtained with solution
wea ea
(e) Use a detector temperature of 270°.

awe
(f) Use nitrogen as the carrier gas.

due to chlorhexidine in the chromatogram obtained with
solution (1). (g) Use an electron capture detector.
TESTS (h) Inject 1 uL of each solution.

Acidity Inject the reference solutions and construct a calibration
pH, 5.0 to 7.0, Appendix V L. curve of the concentration of 4-chloroaniline against the ratio
of the area of the peak corresponding to 4-chloroaniline to
4-Chloroaniline
the area of the peak due to the internal standard.
Appendix III B, using the following solutions. LIMITS
In the chromatogram obtained with solution (2) determine
the ratio of the area of any peak due to 4-chloroaniline to the
wea
we tet
~- wel
IlI-304 Chlorhexidine Preparations 2016
area of the peak due to the internal standard and hence IDENTIFICATION
calculate the content of 4-chloroaniline in the gel. Not more Chlorhexidine Irrigation Solution prepared using Chlorhexidine
aa vad
we nee than 20 ppm is detected. Acetate complies with tests A, B and C. Chlorhexidine Irrigation
Solution prepared using Chlorhexidine Gluconate Solution
aA 2a
ven vd
ASSAY
complies with tests A and B only.
Appendix III D, using the following solutions. A. In the Assay, the retention time of the principal peak in
(1) Add 5 mL of a 0.080% w/v solution of diphenylamine the chromatogram obtained with solution (2) is the same as
(internal standard) in the mobile phase to 5 mL of a that of the peak due to chlorhexidine in the chromatogram
0.070% w/v solution of chlorhexidine acetate BPCRS in the
mobile phase and dilute to 100 mLwith the mobile phase. B. To 10 mL of the irrigation solution add 5 mL of a warm
1% w/v solution of cetrmide, 1 mL of 5m sodium hydroxide
Ghiconaypay ufficient of the mobile phase to produce and 1 mL of bromine water. A deep red colour is produced.
C. Evaporate or dilute a volume of the irrigation solution
PAN a
ten ee]
~~ AVA
(3) Prepare nt me manner as solution (2) but add containing the equivalent of about 5 mg of chlorhexidine to
5 mL of the inter alstandard solution before diluting to about 5 mL. The resulting solution yields reaction B
100 mL. characteristic of acetates, Appendix VI.
CHROMATOGRAPHIC'CO ONS
TESTS
Acidity
(a) Useastainless steel c 25 cm x 4.6 mm) packed
with octadecylsilyl silica gel for : matography (10 um)
(Nucleosil C18 is suitable). 4-Chloroaniline
(b) Use isocratic elution and th ile: ph; é described
Not more than 1.5 ppm when determined in the following
below. manner. Dissolve 80 mg of 2,6-dimethylaniine (internal
standard) in 1 mL of 1m hydrochloric acid with the aid of
(c) Use a flow rate of 1.5 mL per minute
ultrasound, add sufficient water to produce 100 mL and
(d) Use an ambient column temperature. dilute 1 volume of this solution to 100 volumes with
(e) Use a detection wavelength of 254 nm. 0.01m hydrochloric acid (solution A). Carry out the method
(f) Inject 100 pL of each solution. for gas chromatography, Appendix III B, using the following
solutions. For solution (1) shake 50 mL of the irrigation
MOBILE PHASE
lution with 20 mL of a mixture of 20 volumes of ether and
0.01M sodium octanesulfonate in methanol (73%) adjusted to 0 volumes of hexane and 5 mL of 0.6m sodium hydrogen
pH 3.0 with glacial acetic acid. rbonate,solution, allow to separate and discard the aqueous
DETERMINATION OF CONTENT ke the organic layer with anhydrous sodium sulfate
Calculate the content of C,.H39Cl,N19,2C6H,207 from the rough silica treated filter paper (Whatman IPS is
declared content of C.2H39CLNjo9 in chlorhexidine 100 uL of heptafluorobutyric anhydride and
acetate BPCRS. Each mg of C22H39Cl,Nj9 is equivalent to econds. Allow the solution to stand for
1.775 mg of C32H39ClLN19,2C.6H1207.
IMPURITIES
irrigation solution;
20 volumes of ether
NH 2
A. 4-chloroaniline.
sufficient water to produce 200 mL a dik
10 volumes with the same solvent. To se
Chlorhexidine Irrigation Solution

Action and use
5 mL of 0.6m sodium hydrogen carbonate solution and continue
Antiseptic.
in the same manner as for solution (1) beginning at the
DEFINITION words ‘allow to separate ...’.?
Chlorhexidine Irrigation Solution is either a sterile solution of The chromatographic procedure may be carried out using
Chlorhexidine Acetate in Water for Irrigation ora sterile (a) a glass column (1.5m x 4 mm) packed with acid-
dilution of Chlorhexidine Gluconate Solution in Water for washed, silamsed diatomaceous support (100 to 120 mesh)
Irrigation. coated with 15% w/w of cyanopropylmethylphenyl methyl
The solution complies with the requirements stated under silicone fluid (OV-225 is suitable) at a temperature of 190°
Preparations for Irrigation and with the following requirements. with the inlet port at 200° and the detector at 270°, (b)
nitrogen as the carrier gas at a flow rate of 50 mL per minute
Content of chlorhexidine acetate, and (c) an electron capture detector.
C,2H39C1,N19,2C2H,O, or chlorhexidine gluconate,
Inject the reference solutions and construct a calibration
C12H39CINj0,2C6H1207
curve of the concentration of 4-chloroaniline against the ratio
of the area of the peak corresponding to 4-chloroaniline to
2016 Chlorhexidine Preparations II-305
the area of the peak due to the internal standard. In the

chromatogram obtained with solution (2) determine the ratio
Chlorhexidine Mouthwash
of the area of any peak due to 4-chloroaniline to the area of Action and use
the peak due to the internal standard and hence calculate the Antiseptic.
content of 4-chloroaniline in the irrigation solution.
Related substances DEFINITION
Carry out the method for liquid chromatography, Chlorhexidine Mouthwash contains Chlorhexidine Gluconate
Appendix III D, using the following solutions. For solution Solution in a suitable flavoured and coloured vehicle.
(1) use the irrigation solution. For solution (2) dilute The mouthwash complies with the requirements stated under
3 volumes of the irrigation solution to 100 volumes with the Oromucosal Preparations and with the following requirements.
mobile phase. For solution (3) dilute 1 volume of solution
Content of chlorhexidine gluconate,
(2) ;Oevolumes with the mobile phase. Solution (4)
C22H39ChLNj0,2C5H, 207
w/v of chlorhexidine for performance
IDENTIFICATION
In the Assay, the retention time of the principal peak in the
octadecylsilyl sihéa chromatogram obtained with solution (1) is the same as that
C18 is suitable), : of the peak due to chlorhexidine in the chromatogram
1.0 mL per minute : ntsining 0.20% wiv of obtained with solution (2).
e of 120 volumes of glacial TESTS
acetic acid, 270 volumes o arid 730 volumes of 4-Chloroaniline
methanol and (c) a detections Not more than 0.3% of the content of chlorhexidine
gluconate when determined in the following manner.
Adjust the sensitivity of the system $ Dissolve 80 mg of 2,6-dimethylaniline (anternal standard) in
principal peak in the chromatogram 1 mL of 1m hydrochloric acid with the aid of ultrasound, add
sufficient water to produce 100 mL and dilute 1 volume of
this solution to 100 volumes with 0.01m hydrochloric acid
resulting chromatogram is similar to the specimen (solution A). Carry out the method for gas chromatography,
chromatogram provided with chlorhexidine for perfortian Appendix III B, using the following solutions. For solution
test EPCRS in that the peaks due to impurity A and (1) dilute a volume of the mouthwash containing the
impurity B precede that due to chlorhexidine. If necess uivalent of 25 mg of chlorhexidine gluconate to 50 mL
adjust the concentration of acetic acid in the mobile phas ‘egvater, Shake with 20 mL of a mixture of 20 volumes of
(increasing the concentration decreases the retention times) and 80 volumes of hexane and 5 mL of 0.6m sodium
*ydrogen carbonate solution, allow to separate and discard the
Inject separately 10 wL of solutions (1), (2) and (3). Record
Ss ayer. Shake the organic layer with anhydrous sodium
the chromatograms of solutions (2) and (3) until the peak
x ilter through silica treated filter paper (Whatman
due to chlorhexidine has been eluted and record the
chromatogram of solution (1) for six times the retention time
of the peak due to chlorhexidine. In the chromatogram
obtained with solution (1), the sum of the areas of any
secondary peaks is not greater than the area of the principal
peak in the chromatogram obtained with solution (2) (3%).
Disregard any peak with a relative retention time of 0.25 or
less with respect to the principal peak and any peak the area
we ate
wa tgs
aw ned
of which is less than that of the principal peak in the

rr ASSAY solution (1) beginning at the words
Carry out the method for liquid chromatography, Prepare a series of reference solutio
Appendix III D, using the following solutions. Solution (1) manner.Dissolve 25 mg of 4-chloroant
contains 0.008% w/v of chlorhexidine acetate BPCRS in the
mobile phase. For solution (2) dilute a quantity of the water to produce 200 mL and dilute 1 volumeg
solution being examined containing 4 mg of Chlorhexidine with the same solvent. To separate 0, 2, 4, 6 and 8 mL
Acetate or the equivalent of 5 mg of chlorhexidine gluconate volumes of this solution (containing 0, 25, 50, 75 and 100 pg
with sufficient of the mobile phase to produce 50 mL. of 4-chloroaniline) add 2 mL of solution A and sufficient
The chromatographic procedure described under Related water to produce 50 mL, shake with 20 mL of a mixture of
substances may be used. 20 volumes of ether and 80 volumes of hexane and 5 mL of
Calculate the content of C.2.H3 9Cl.N19,2C.H,O> or 0.6m sodium hydrogen carbonate solution and continue in the
C42H39Cl.N19,2C6H 207 from the declared content of same manner as for solution (1) beginning at the words
C42H39Cl.N jo in chlorhexidine acetate BPCRS. Each mg of ‘allow to separate ...’. ?
chlorhexidine, C2.H39Cl,Nj9, is equivalent to 1.238 mg of The chromatographic procedure may be carried out using
C42H39Cl12Nj9,2C2H,0> or 1.775 mg of (a) a glass column (1.5 m x 4 mm) packed with acid-
C22H30Cl2N10;2C
6H)207. washed, silanised diatomaceous support (100 to 120 mesh)
coated with 15% w/w of cyanopropylmethylphenyl methyl
STORAGE
silicone fluid (OV-225 is suitable) at a temperature of 190°
Chlorhexidine Irrigation Solution should be protected from
with the inlet port at 200° and the detector at 270°, (b)
light.
yw
IWI-306 Chlormethine Preparations 2016
nitrogen as the carrier gas at a flow rate of 50 mL per minute The contents of the sealed container comply with the requirements
and (c) an electron capture detector. jor Powders for Injections or Infusions stated under Parenteral
Inject the reference solutions and construct a calibration Preparations and with the following requirements.
curve of the concentration of 4-chloroaniline against the ratio Content of chlormethine hydrochloride,
of the area of the peak corresponding to 4-chloroaniline to C.;H,,CLN,HCl
the area of the peak due to the internal standard. In the 90.0 to 110.0% of the stated amount.
chromatogram obtained with solution (2) determine the ratio IDENTIFICATION
of the area of any peak due to 4-chloroaniline to the area of
Dissolve the contents of a sealed container in 1 mL of water
the peak due to the internal standard and hence calculate the
and add 0.02 mL of potassium tetra-todomercurate solution.
content of 4-chloroaniline in the mouthwash with respect to
A cream precipitate is produced.
the labelled content of chlorhexidine gluconate.
TESTS
ren ed
The content of chlormethine hydrochloride,
C5H,,;Cl],N,HCI, in each of 10 individual containers as
determined in the Assay is not less than 80.0% and not more
than 120.0% of the average amount.
chlorhexidine acetate ASSAY

The chromatographic p Dissolve the contents of a sealed container in 2 mL of ethanol
(a) a stainless steel column (96%) previously neutralised to phenolphthalein solution R1,
end-capped octadecylsilyl silica g add 0.1 mL of phenolphthalein solution R1 and titrate with
(Nucleosil C18is suitable), OFg 0.01mM sodium hydroxide VS (carbonate-free). Each mL of
0.01M sodium hydroxide VS is equivalent to 1.925 mg of
sodium octanesulfonatein a mixture of 120 mi Cs5H,,Cl,N,HCI. Calculate the content of C5H,,Cl,N,HCl
acid, 270 mL of water and 730 mL of me in the sealed container. Repeat the procedure with a further
detection wavelength of 254 nm. nine sealed containers. Calculate the average content of
C5H,,;Cl,.N,HCI per container from the 10 individual results
Equilibrate the column with the mobile phase for‘at lea:
thus obtained.
1 hour.
Calculate the content of C5.H39Cl,Nj9,2C.6H207 fro LABELLING
declared content of C.,H39Cl,Nj9 in chlorhexidine he label of the sealed container states (1) the amount of the
acetate BPCRS. Each mg of chlorhexidine, C,,H3 9CI,Njo, 1 tive ingredient containedin it; (2) that the contents are
equivalent to 1.775 mg of C32H39ClN19,2C6H 1207.
STORAGE
Chlorhexidine Mouthwash should be protected from light.
Antiprotozoal
Chlormethine Injection
DEFINITION
Action and use Chloroquine Phosphate
Cytotoxic alkylating agent. Phosphate.
DEFINITION The tablets comply with the reqinvesients stated under Tablets and
Chlormethine Injection is a sterile solution of Chlormethine
Hydrochloride in Water for Injections or Sodium Chloride Content of chloroquine phospha
Intravenous Infusion. It is prepared by dissolving 92.5 to 107.5% of the stated amount.
Chlormethine Hydrochloride for Injection in the requisite IDENTIFICATION
amount of Water for Injections or Sodium Chloride
Intravenous Infusion immediately before use.
Parenteral Preparations. 20-mL quantities of chloroform. Wash the chloroform extracts
rw Nee
STORAGE with water, dry with anhydrous sodium sulfate, evaporate to

dryness and dissolve the residue in 2 mL of chloroform IR.
LA a
es tes,
Chlormethine Injection deteriorates rapidly on storage and
The infrared absorption spectrum of the resulting solution,
eeauad
ee wed
should be used immediately after preparation.

CHLORMETHINE HYDROCHLORIDE FOR chloroquine (RS 054).
INJECTION
DEFINITION 25 mg of Chloroquine Phosphate with 20 mL of water, filter
Chlormethine Hydrochloride for Injection is a sterile material and add 8 mL of picric acid solution R1 to the filtrate. The
consisting of Chlormethine Hydrochloride with or without melting point of the precipitate, after washing successively with
excipients. It is supplied in a sealed container. water, ethanol (96%) and ether, is about 207°, Appendix V A.
C. Extract a quantity of the powdered tablets containing
0.5 g of Chloroquine Phosphate with 25 mL of water and
a
Les ee
filter. To the filtrate add 2.5 mL of 5M sodium hydroxide and

ei ne ORT,
2016 Chloroquine Preparations III-307
extract with three 10 mL quantities of ether. The aqueous with two 20-mL quantities of chloroform. Wash the
layer, after neutralisation with 2m mitric acid, yields the chloroform extracts with water, dry with anhydrous sodium
reactions characteristic ofphosphates, Appendix VI. sulfate, evaporate to dryness and dissolve the residue in 2 mL
TESTS of chloroform. The infrared absorption spectrum of the resulting
Dissolution solution, Appendix IT A, is concordant with the reference
Comply with the requirements for Monographs of the British spectrum of chloroquine (RS 054).
Pharmacopoeia in the dissolution test for tablets and capsules, B. Dilute a volume containing the equivalent of 15 mg of
Appendix XII B1, using as the medium 900 mL of chloroquine to 20 mL with water and add 8 mL of picric acid
0.1m hydrochloric acid and rotating the basket at solution R1. The melting point of the precipitate, after washing
100 revolutions per minute. Withdraw a sample of 10 mL of successively with water, ethanol (96%) and ether, is about
the medium. Measure the absorbance of a layer of suitable 207°, Appendix V A.
C. Yields the reactions characteristic of sulfates, Appendix VI.
TESTS
Acidity
Related substances
layer chromatography, Carry out the method for thin-layer chromatography,
Appendix III A, using silica gel GFy54 as the coating
Appendix III A, using silic‘ GEo54 as the coating
substance and a mixture of 10 volumes of diethylamine,
substance and a mixture o of chloroform,
40 volumes of cyclohexane and 50 volumes of chloroform as
s of diethylamine as
12 cm above the line of application. Apply separately to the
plate 2 wL of each of the following three solutions.
For solution (1) use the injection being examined.
Phosphate with 20 mL of water for 30 minytés,
and use the supernatant liquid; if necessary fi:
oe See ee
100 volumes with water. For solution (3) dilute 1 volume of

tee
glass fibre paper. For solution (2) dilute 1 mL‘

solution (2) to 2 volumes with water. After removal of the
to 100 mL with water. For solution (3) dilute 25 m.
plate, allow it to dry in air and examine under ultraviolet light
solution (2) to 50 mL with water. After removal of th p
be

allow it to dryin air and examine under ultraviolet hght
ee
ith solution (1) is not more intense than the spot in the
et EE
with solution (1) is not more intense than the spot in the atogram obtained with solution (2) (1%) and not more
chromatogram obtained with solution (2) and not more than
wt
one such spot is more intense than the spot in the

.
'

ae
woe
ASSAY
oy
-
a

fy
powder containing 0.5 g of Chloroquine Phosphate in 20 mL

of 1m sodium hydroxide and extract with four 25-mL
wk
.
quantities of chloroform. Combine the chloroform extracts and

aan
wea
evaporate to a volume of about 10 mL. Add 40 mL of

determining the endpoi
St
anhydrous acetic acid and carry out Method I for non-aqueous

0.1m perchloric acid VS is e
fay
ren
titration, Appendix VIII A, determining the end point

ua
potentiometrically. Each mL of 0.1m perchloric acid VS is CigH26CIN3.

equivalent to 25.79 mg of Cy;gH»6CIN3,2H3POx,. LABELLING é
250 mg of Chloroquine Phosphate is approximately The strength is stated as the equivalent-as
equivalent to 155 mg of chloroquine. chloroquine in a suitable dose-volume.
40 mg of chloroquine is approximately equiva}
of Chloroquine Sulfate. :
Chloroquine Sulfate Injection
Chloroquine Sulphate Injection
Action and use Chloroquine Sulfate Tablets

Antiprotozoal (malaria). Chloroquine Sulphate Tablets
DEFINITION
Action and use
Chloroquine Sulfate Injection is a sterile solution of Antiprotozoal (malaria).
Chloroquine Sulfate in Water for Injections.
The injection complies with the requirements stated under DEFINITION
Parenteral Preparations and with the following requirements. Chloroquine Sulfate Tablets contain Chloroquine Sulfate.
Content of chloroquine, C,3;H,<CIN; They are coated.
95.0 to 105.0% of the stated amount. The tablets comply with the requirements stated under Tablets and
IDENTIFICATION with the following requirements.
A. To a volume containing the equivalent of 60 mg of Content of chloroquine sulfate, C,;H,<CIN3,H,SO,,H,O
chloroquine add 2 mL of 2m sodium hydroxide and extract 92.5 to 107.5% of the stated amount.
IiI-308 Chloroxylenol Preparations 2016
IDENTIFICATION ASSAY
A. Dissolve a quantity of the powdered tablets containing Weigh and powder 20 tablets. Dissolve a quantity of the
~we ante
ANA!
0.1 g of Chloroquine Sulfate in a mixture of 10 mL of water powder containing 0.5 g of Chloroquine Sulfate in 20 mL of
Nw AN A
AAS ALA
twee
and 2 mL of 2m sodium hydroxide and extract with two Im sodium hydroxide and extract with four 25-mL quantities
20-mL quantities of chloroform. Wash the chloroform extracts of chloroform. Combine the chloroform extracts and evaporate
Rest
with water, dry with anhydrous sodium sulfate, evaporate to to a volume of about 10 mL. Add 40 mL of anhydrous acetic
dryness and dissolve the residue in 2 mL of chloroform IR. acid and carry out Method I for non-aqueous titration,
The infrared absorption spectrum of the resulting solution, Appendix VII A, determining the end point
Appendix II A, is concordant with the reference spectrum of potentiometrically. Each mL of 0.1m perchloric acid VS is
chloroquine (RS 054). equivalent to 20.90 mg of C,;3H2.CIN3,H.SOx.
B. Shake a quantity of the powdered tablets containing 0.1 g 200 mg of Chloroquine Sulfate is approximately equivalent
of Chloroquine Sulfate with 10 mL of water and 1 mL of to 146 mg of chloroquine.
rae AN
Chloroxylenol Solution
Chloroxylenol Cutaneous Solution
Pharmacopoeia in th
Appendix XII B1. Action and use
TEST CONDITIONS “ Antiseptic.
(a) Use Apparatus 1, rotating't
DEFINITION
per minute.
Chloroxylenol Solution is a cutaneous solution.
ate Net.
(b) Use 900 mL of 0.1m hydroc Oric 4 temperature of

stete oye Chloroxylenol 50.0 g
37°, as the medium. .
Potassium Hydroxide 13.6 g
PROCEDURE Oleic Acid 7.5 mL
(1) After 45 minutes withdraw a 10 mL sampk Virgin Castor Oil 63.0 g
medium and measure the absorbance of a layer of sul Terpineol 100 mL
thickness of the filtered sample, suitably diluted with the Ethanol (96 per cent) 200 mL
dissolution medium if necessary, at the maximum at 344 Purified Water, freshly boiled Sufficient to produce
Appendix II B using 0.01m hydrochloric acid in the refereri¢ and cooled 1000 mL
cell. Chloroxylenol Solution, the Ethanol (96 per cent)
DETERMINATION OF CONTENT placed by Industrial Methylated Spirit’.
Calculate the total content of chloroquine sulfate, neous preparation
CigH»6CIN3,H2SO,4,H.2O, in the medium taking 450 as the g directions apply.
Related substances
(1) Shake a quantity of the powdered tablets containing 2.0 g -urified Water and then add the
of Chloroquine Sulfate with 50 mL of water for 30 minutes, Oleic Acid. Mix the Té \| with a solution of the
centrifuge and use the supernatant liquid; if necessary filter
pour into the soap solution
Sareea
througha glass fibre paper.

aL end to produce 1000 mL.
(2) Dilute 1 mL of solution (1) to 100 mL with water.
ree
(3) Dilute 25 mL of solution (2) to 50 mL with water.
Content of chloroxylenol, CgsH CIO
(a) Use as the coating silica gel GF 254. 4.75 to 5.25% wiv.
TEST
(c) Apply 2 wL of each solution. Ethanol content
(d) Develop the plate to 15 cm. 16 to 21% viv, Appendix VIII F.
arn
ware d
(e) After removal of the plate, dry in air and examine under ASSAY
ene ae
we AR wa
aN
wen
Dissolve 0.4 g of 4-chloro-o-cresol (internal standard) in
MOBILE PHASE sufficient chloroform to produce 50 mL (solution A). Carry
10 volumes of diethylamine, 40 volumes of cyclohexane and out the method for gas chromatography, Appendix III B, using
50 volumes of chloroform. solutions prepared in the following manner. For solution (1)
dissolve 0.10 g of chloroxylenol BPCRS in 10 mL of solution
LIMITS
A and dilute to 20 mL with chloroform. For solution (2) place
Any secondary spot in the chromatogram obtained with 4 mL of the solution being examined in a separating funnel,
solution (1) is not more intense than the spot in the add 20 mL of chloroform, mix, add 4 mL of 2m hydrochloric
chromatogram obtained with solution (2) and not more than acid and shake. Extract with two further 10-mL quantities of
one such spot is more intense than the spot in the chloroform. Combine the chloroform extracts, dry by shaking
wae
Cres
awa
NN
chromatogram obtained with solution (3). with anhydrous sodium sulfate and filter. Prepare solution (3)
CPARAR
maw
en
ae ANS
can aay
2016 Chlorphenamine Preparations II-309
in the same manner as solution (2) but adding 20 mL of a current of nitrogen using the minimum amount of heat,
solution A in place of the 20 mL of chloroform. dissolve the residue as completely as possible in sufficient
The chromatographic procedure may be carried out using a chloroform to produce a solution containing 5% w/v of
glass column (1.5 m x 4 mm) packed with acid-washed, Chlorphenamine Maleate and centrifuge. For solution (2)
silanised diatomaceous support (80 to 100 mesh) coated with dilute 1 volume of solution (1) to 500 volumes with
3% wiw of polyethylene glycol (Carbowax 20M is suitable) chloroform. After removal of the plate, allow it to dry in air
and maintained at 160°. and examine under ultraviolet light (254 nm). Any secondary
spot in the chromatogram obtained with solution (1) is not
Calculate the content of CgH,ClO using the declared
more intense than the spot in the chromatogram obtained
content of CgHoClO in chloroxylenol BPCRS.
with solution (2) (0.2%). Disregard any spot remaining on
1The law and statutory regulations governing the use of Industrial the line of application.
Methylated Spirit must be observed. ASSAY
Dilute a volume containing 10 mg of Chlorphenamine
Maleate to 500 mL with 0.25m sulfuric acid and measure the
absorbance of the resulting solution at the maximum at
265 nm, Appendix IT B. Calculate the content of
Chiorphenamine Injection C16Hy9CIN2,C,H,O, taking 212 as the value of
Action and use
Histamine H, recepto goriist; antihistamine. STORAGE
Chlorphenamine Injection should be protected from light.
DEFINITION
Chlorphenamine Injection is.
he es
Chlorphenamine Maleate in Water |
dissolved air. :
The injection complies with the requirement Chiorphenamine Oral Solution
Parenteral Preparations and with the followin
Action and use
Content of chlorphenamine maleate, Histamine H, receptor antagonist; antihistamine.
C,6Hi9CIN2,C,H,O,
90.0 to 110.0% of the stated amount. DEFINITION
CHARACTERISTICS Chlorphenamine Oral Solution is a solution of
A colourless solution. phenamine Maleate in a suitable flavoured vehicle.
al solution complies with the requirements stated under Oral
IDENTIFICATION
d with the following requirements.
Appendix III A, using silica gel GF 54 as the coating
substance and a mixture of 20 volumes of 1M acetic acid,
30 volumes of methanol and 50 volumes of ethyl acetate as the
mobile phase. Heat the plate at 105° for 30 minutes before
use. Apply separately to the plate 2 wL of each of the
following solutions. For solution (1) evaporate an appropriate chromatogram o
volume to dryness in a current of nitrogen using the spot in the chromato.
minimum amount of heat, dissolve the residue as completely
Related substances
as possible in sufficient chloroform to produce a solution
Carry out the method for thti-layer chromatography,
containing 0.5% w/v of Chlorphenamine Maleate and
Appendix III A, using the folléwing
centrifuge. Solution (2) contains 0.5% w/v of chlorphenamine
maleate BPCRS in chloroform. After removal of the plate, (1) Dilute a volume of the oral s¢
allow it to dry in air and examine under ultraviolet hght Chlorphenamine Maleate with an eq
(254 nm). The two principal spots in the chromatogram 20 mL of a 10% w/v solution of sodiunt#?
obtained with solution (1) correspond to those in the with four 15 mL quantities of chloroform. A
chromatogram obtained with solution (2). Spray the plate
with dilute potassium todobismuthate solution. The principal spot evaporate at a temperature not exceeding 40° ata pressure of
in the chromatogram obtained with solution (1) corresponds 2 kPa and dissolve the residue in 1 mL of chloroform.
to that in the chromatogram obtained with solution (2). (2) Dilute 1 volume of solution (1) to 500 volumes with
chloroform.
TESTS
Acidity (3) Dilute 1 volume of solution (1) to 10 volumes with
pH, 4.0 to 5.2, Appendix V L. chloroform.
(4) 0.1% w/v of chlorphenamine maleate BPCRS in chloroform.
Related substances
Carry out the method for thin-layer chromatography, CHROMATOGRAPHIC CONDITIONS
Appendix II A, using silica gel GF p54 as the coating (a) Use as the coating silica gel G.
see od
substance and a mixture of 10 volumes of diethylamine, (b) Use the mobile phase as described below.
40 volumes of chloroform and 50 volumes of cyclohexane as
12 cm above the line of application. Apply separately to the (d) Develop the plate to 15 cm.
plate 10 uL of each of the following solutions. For solution (e) After removal of the plate, dry in air, spray with dilute
(1) evaporate a suitable volume of the injection to dryness in potassium todobismuthate solution.
II-310 Chlorphenamine Preparations 2016
MOBILE PHASE containing 5 mg of Chlorphenamine Maleate with chloroform,

20 volumes of 1M acetic acid, 30 volumes of methanol and filter, evaporate to dryness and dissolve the residue in 1 mL
50 volumes of ethyl acetate. of chloroform.
LIMITS Related substances
Any secondary spot in the chromatogram obtained with Carry out the method for thin-layer chromatography,
solution (1) is not more intense than the spot in the Appendix III A, using silica gel GF54 as the coating
chromatogram obtained with solution (2). substance and a mixture of 10 volumes of diethylamine,
40 volumes of chloroform and 50 volumes of cyclohexane as
ASSAY the mobile phase but allowing the solvent front to ascend
Carry out the method for gas chromatography, 12 cm above the line of application. Apply separately to the
Appendix III B. plate 10 uL of each of the following solutions. For solution
(1) Add 10 fa 10% w/v solution of sodium hydroxide in (1) extract a quantity of the powdered tablets containing
methanol ax of.a 0.060% w/v solution of 50 mg of Chlorphenamine Maleate with chloroform, filter,
N-phenylcaré: evaporate the filtrate to dryness and dissolve the residue in
ion containing 3 mg of 1 mL of chloroform. For solution (2) dilute 1 volume of
Chlorphenamine J p xtract with four 25 mL quantities solution (1) to 500 volumes with chloroform. After removal of
of chloroform and wask ea act with the same 10 mL of the plate, allow it to dry in air and examine under ultraviolet
tracts, shake with light (254 nm). Any secondary spot in the chromatogram
anhydrous sodium sulfate, filt obtained with solution (1) is not more intense than the spot
exceeding 40° at a pressure 6 in the chromatogram obtained with solution (2) (0.2%).
in 2 mL of chloroform. Disregard any spot remaining on the line of application.
(2) Prepared in the same manner ASSAY
omitting the internal standard. Weigh and powder 20 tablets. Shake a quantity of the
(3) 0.15% w/v of chlorphenamine maleate BPC. powder containing 3 mg of Chlorphenamine Maleate with
0.15% w/v of N-phenylcarbazole (internal stai 20 mL of 0.05 sulfuric acid for 5 minutes, add 20 mL of
chloroform. ether, shake carefully and filter the acid layer into a second
CHROMATOGRAPHIC CONDITIONS separating funnel. Extract the ether layer with two 10-mL
quantities of 0.05m sulfuric acid, filter each acid layer into the
(a) Use a glass column (1.5m x 4 mm) packed with*”
second separating funnel and wash the filter with
acid-washed, silanised diatomaceous support (100 to 120 mesh) 5m sulfuric acid. Make the combined acid extracts and
(Gas Chrom Q or Diatomite CQ is suitable) coated with
shings just alkaline to litmus paper with 1m sodium
3% wiw of dimethyl silicone fluid (OV-101 is suitable).
d 2 mL in excess and extract with two 50 mL
(b) Use mitrogen as the carrier gas at 50 mL per minute.
(e) Use a flame ionisation detector at a temperature of 300°.
DETERMINATION OF CONTENT Appendix II B. Caicut e content of
Calculate the content of C)g6H;9CIN2,C4,H4O, using the C1 6H i9CIN2,C4H4O,tak ing.212 as the value of
declared content of C,g6H,9CIN2,C4H40O, in chlorphenamine A(1%, 1 cm) at the ma
maleate BPCRS.
STORAGE
Chlorphenamine Oral Solution should be protected from
light. Chlorpromazine Injection
Action and use
Chlorphenamine Tablets DEFINITION

Chlorpromazine Injection is a sterile solution of
Action and use Chlorpromazine Hydrochloride in Water for Injections free
Histamine H, receptor antagonist; antihistamine. from dissolved air.
DEFINITION The injection complies with the requirements stated under
Chlorphenamine Tablets contain Chlorphenamine Maleate. Parenteral Preparations and with the following requirements.
The tablets comply with the requirements stated under Tablets and Content of chlorpromazine hydrochloride,
with the following requirements. C,7H,9CIN,S,HC1
Content of chlorphenamine maleate,
Ci6H CIN2,C,H,O, CHARACTERISTICS
92.5 to 107.5% of the stated amount. A colourless or almost colourless solution.
IDENTIFICATION IDENTIFICATION
Comply with the test described under Chlorphenamine A. To a volume containing 0.1 g of Chlorpromazine
Injection using as solution (1) a solution prepared in the Hydrochloride add 20 mL of water and 2 mL of 10M sodium
following manner. Extract a quantity of the powdered tablets hydroxide. Shake and extract with 25 mL of ether. Wash the
2016 Chlorpromazine Preparations III-311
ether layer with two 5 mL quantities of water, dry with TESTS

anhydrous sodium sulfate, evaporate the ether and dissolve the Related substances
residue in 1 mL of chloroform. The infrared absorption spectrum Carry out the procedure protected from light under an
of the resulting solution, Appendix II A, 1s concordant with atmosphere of nitrogen. Carry out the method for thin-layer
the reference spectrum of chlorpromazine (RS 056). chromatography, Appendix III A, using the following
B. Complies with the test for zdentification ofphenothiazines, solutions.
Appendix III A. For solution (1) dilute the injection with (1) Add 40 mL of water and 5 mL of a 20% w/v solution of
water to give a solution containing 0.2% w/v of sodium hydroxide to a quantity of the oral solution containing
Chlorpromazine Hydrochloride. 20 mg of Chlorpromazine Hydrochloride in a separating
funnel and swirl to mix. Extract with two 25-mL quantities
of chloroform, combine the chloroform extracts and filter
through anhydrous sodium sulfate. Wash the sodium sulfate
with a further 25 mL of chloroform and evaporate the
combined filtrate and washings to dryness at about 30° in a
for related substances in phenothiazines, gentle current of nitrogen. Dissolve the residue in 2 mL of a
mobile phase A and applying separately mixture of 5 volumes of diethylamine and 95 volumes of
methanol.
mixture of 5 volumes of diethylamine and 95 volumes of
methanol and 5 volumes"6!
methanol.
containing 0.5% w/v of Cl
For solution (2) dilute 1 vol (3) 0.030% w/v solution of chlorpromazine sulfoxide BPCRS in
a mixture of 5 volumes of diethylamine and 95 volumes of
1 volume of solution (1) to 200 volufiies y methanol.
solvent. Any secondary spot in the chrom: CHROMATOGRAPHIC CONDITIONS

(b) Use the mobile phase as described below. Use an
one such spot is more intense than the spot in“th
atmosphere of nitrogen.
ASSAY
After removal of the plate, dry in air, spray with 20% w/w
Dilute a suitable volume with sufficient 0.1M hydrochloric a
‘ation of perchloric acid and heat at 100° for 5 minutes.
to produce a solution containing 0.0005% w/v of
Chlorpromazine Hydrochloride and measure the absorbance
at the maximum at 254 nm, Appendix II B. Calculate the
content of C,;7H;9CIN»S,HCI taking 915 as the value of
STORAGE btained with solution (1):
Chlorpromazine Injection should be protected from light.
chlorpromazine sulfoxide is not
Chlorpromazine Oral Solution

Chlorpromazine Elixir
Action and use

Dilute a quantity containing 0.1 g of C
DEFINITION Hydrochloride to 500 mL with 2m hydroc
Chlorpromazine Oral Solution is a solution of
Chlorpromazine Hydrochloride in a suitable flavoured
vehicle. extract with six 25 mL quantities of ether. Extract the
combined ether solutions with four 25 mL quantities of a
mixture containing 1 volume of hydrochlonc acid and
99 volumes of water, discard the ether, remove any dissolved
Content of chlorpromazine hydrochloride, ether from the combined extracts with a current of air and
C,,H, ,CIN,S,HCI1 dilute to 250 mL with a mixture containing 1 volume of
90.0 to 110.0% of the stated amount. hydrochloric acid and 99 volumes of water. Measure the
IDENTIFICATION absorbance of the resulting solution at the maximum at
Carry out the method for identification of phenothiazines, 254 nm, Appendix II B. Calculate the content of
Appendix III A. For solution (1) dilute a suitable volume of Cy7H,9CIN2S,HCI taking 914 as the value of A(1%, 1 cm)
the oral solution with water to give a solution containing at the maximum at 254 nm. .
0.2% w/v of Chlorpromazine Hydrochloride. STORAGE
Chlorpromazine Oral Solution should be protected from
light.
ree ed
W-312 Chlorpromazine Preparations 2016
el
Chlorpromazine Suppositories Chlorpromazine Tablets
NaN ete
ee A
Dopamine receptor antagonist; neuroleptic. Dopamine receptor antagonist; neuroleptic.
Chlorpromazine Suppositories contain Chlorpromazine in a Chlorpromazine Tablets contain Chlorpromazine
suitable suppository basis. Hydrochloride. They are coated.
The suppositories comply with the requirements stated under Rectal The tablets comply with the requirements stated under Tablets and
Preparations and with the following requirements. with the following requirements.
Content of. chlorpromazine, C,7H,9CIN,S Content of chlorpromazine hydrochloride,
C,,H,9CIN,S,HCl
Ste 92.5 to 107.5% of the stated amount.

IDENTIFICATION
Appendix IIT A: ion (1) dissolve a quantity of the A. To a quantity of the powdered tablets containing 40 mg
suppositories cont g of Chlorpromazine in 50 mL of Chlorpromazine Hydrochloride add 10 mL of water and
of chloroform. Use ch 2 mL of 10m sodium hydroxide. Shake and extract with 15 mL
prepare solution (2). of ether. Wash the ether layer with two 5-mL quantities of
water, dry with anhydrous sodium sulfate and evaporate the
TESTS
ether. Dissolve the residue in 0.4 mL of chloroform. The
Related substances
infrared absorption spectrum of the resulting solution,
Carry out the method for thin- sf
Appendix III A, protected from light
chlorpromazine (RS 056).
solutions. "
B. Comply with the test for identification of phenothiazines,
Appendix III A. For solution (1) shake a quantity of the
of Chlorpromazine in sufficient chloroform to pi
powdered tablets with sufficient chloroform to produce a
(2) Dilute 1 volume of solution (1) to 200 volumes yw solution containing 0.20% w/v of Chlorpromazine
chloroform. “ Hydrochloride, centrifuge and use the supernatant liquid.
TESTS
(a) Use as the coating silica gel GF 254. substances
(b) Use the mobile phase as described below. ith the test for related substances in phenothiazines,
(c) Apply 10 pL of each solution. III A, using mobile phase A and the following
‘pared solutions. For solution (1) extract a quantity
wdered tablets containing 0.1 g of Chlorpromazine
MOBILE PHASE
10 volumes of acetone, 10 volumes of diethylamine and 200 volumes wi me solvent mixture.

80 volumes of cyclohexane. Dissolution
LIMITS Carry out the procedu
Any secondary spot in the chromatogram obtained with the requirements for M of the British
Pharmacopoeia in the dissolity test for tablets and capsules,
Nie aed

chromatogram obtained with solution (2) (0.5%). Appendix XII Bl.
Disregard any spot remaining on the line of application. TEST CONDITIONS
(a) Use Apparatus 2, rotating the pa revolutions

ASSAY
per minute.
Weigh five suppositories. Dissolve a quantity containing 0.5 g
of Chlorpromazine in sufficient chloroform to produce (b) Use 900 mL of 0.1m hydrochloric acid, ata tepapéxature of
100 mL and dilute 20 mL to 100 mL with ethanol (96%). 37°, as the medium. <
Dilute 10 mL of this solution to 100 mL with ethanol (96%) PROCEDURE
and further dilute 5 mL of this solution to 100 mL with the (1) After 45 minutes withdraw a 10 mL sample of the
vw Ae
same solvent. Measure the absorbance of the resulting solution medium and measure the absorbance of the filtered sample,
twat at the maximum at 258 nm, Appendix II B, using ethanol suitably diluted with the dissolution medium to produce a
yAM ANY (96%) in the reference cell. Calculate the content of solution containing 0.0005% % w/v of Chlorpromazine
C,7Hj9CIN2S taking 1150 as the value of A(1%, 1 cm) at Hydrochloride, at the maximum at 254 nm, Appendix II B
the maximum at 258 nm. using 0.1m hydrochloric acid in the reference cell.
STORAGE DETERMINATION OF CONTENT
Chlorpromazine Suppositories should be protected from Calculate the total content of C;7H,)>CIN2S,HCI, in the
light. medium taking 914 as the value of A(1%, 1 cm) at the
maximum at 254 nm.
ASSAY
Powder 10 tablets without loss, triturate the powder with
2016 Chlorpropamide Preparations TI-313
10 mL of absolute ethanol, add about 300 mL of (3) 0.015% w/v of 1,3-dipropylurea in acetone.
0.1m hydrochloric acid and shake for 15 minutes. (4) Dilute 0.3 volume of solution (1) to 100 volumes with
Add sufficient 0.1m hydrochloric acid to produce 500 mL, acetone.
filter, dilute a volume of the filtrate containing 5 mg of
Chlorpromazine Hydrochloride to 100 mL with
acetone.
0.1M hydrochloric acid and further dilute 10 mL to 100 mL
with the same solvent. Measure the absorbance of the (6) Dissolve 5 mg of 4-chlorobenzenesulfonamide and 5 mg of
resulting solution at the maximum at 254 nm, 1,3-dipropylurea in 2 mL of solution (1) and add sufficient
acetone to produce 10 mL.
Appendix II B. Calculate the content of C,7H,)CIN2S,HCl
taking 915 as the value of A(1%, 1 cm) at the maximum at CHROMATOGRAPHIC CONDITIONS
254 nm. (a) Use as the coating silica gel 60.
|
(e) After removal of the plate, dry it in a current of cold air
and heat at 110° for 10 minutes. Place the hot plate in a tank
of chlorine gas prepared by the addition of hydrochloric acid to
a 5% w/v solution of potassium permanganate contained in a
beaker placed in the tank and allow to stand for 2 minutes.
Dry it in a current of cold air until the excess of chlorine is
DEFINITION
removed and an area of the plate below the line of
Chlorpropamide Tablets co
application gives at most a very faint blue colour with a
AN ALY
The tablets comply with the requir ed under Tablets and 0.5% w/v solution of potassium todide in starch mucilage; avoid
with the following requirements. prolonged exposure to cold air. Spray the plate with a
Content of chlorpropamide, C; 9H,3 0.5% w/v solution of potassium iodide in starch mucilage.
IDENTIFICATION 11.5 volumes of 13.5mM ammonia, 30 volumes of cyclohexane,
Extract a quantity of the powdered tablets cont 50 volumes of methanol and 100 volumes of dichloromethane.
Chlorpropamide with five 4-mL quantities of acetone,
SYSTEM SUITABILITY
and evaporate the filtrate carefully to dryness on a wa
test is not valid unless the chromatogram obtained with
bath. The infrared absorption spectrum of the residue,
values of approximately 0.4, 0.6 and 0.9
chlorpropamide (RS 057).
onding to chlorpropamide,
TESTS
Dissolution
Appendix XII Bl.
TEST CONDITIONS
(a) Use Apparatus 1, rotating the basket at 100 revolutions
per minute.
dipropylurea is not more
(b) Use 900 mL of a 0.68% w/v solution of potassium intense than the spot in : ram obtained with
dihydrogen orthophosphate adjusted to pH 6.8 by the addition solution (3) (0.3%); o
of 1m sodium hydroxide, at a temperature of 37°C, as the
any other secondary spot is not mi
medium.
PROCEDURE
ASSAY
suitably diluted with the dissolution medium if necessary, at
the maximum at 230 nm, Appendix II B using the medium Weigh and powder 20 tablets. Shake a quantity of the
in the reference cell. powder containing 0.25 g of Chlorpropamide with 40 mL of
methanol for 20 minutes, add sufficient methanol to produce
Nate FUN,
AWA
Fe, eS
eyawvad
en wee
Lawlad
DETERMINATION OF CONTENT 50 mL, mix, filter and dilute 5 mL of the filtrate to 100 mL
ce Ne A
Calculate the total content of chlorpropamide, with 0.1m hydrochloric acid. Dilute 10 mL of this solution to
C10H13CIN203S, in the medium taking 469 as the value of 250 mL with 0.1m hydrochloric acid and measure the
A(1%, 1 cm) at the maximum at 230 nm. absorbance of the resulting solution at the maximum at
Related substances 232 nm, Appendix II B. Calculate the content of
Carry out the method for thin-layer chromatography, C190H,3CIN2O3S taking 598 as the value of A(1 cm, 1%) at
Appendix III A, using the following solutions. the maximum at 232 nm.
of Chlorpropamide with 10 mL of acetone for 10 minutes and
filter (Whatman GF/C filter paper is suitable).
wr wen wl
ar
(2) 0.015% wv of 4-chlorobenzenesulfonamide in acetone.
II-314 Chlortalidone Preparations 2016
Chlortalidone Tablets Chiortetracycline Eye Ointment

Thiazide-like diuretic. Tetracycline antibacterial.
Chlortalidone Tablets contain Chlortalidone. Chlortetracycline Eye Ointment is a sterile preparation
The tablets comply with the requirements stated under Tablets and containing Chlortetracycline Hydrochloride in a suitable
with the following requirements. basis.
Content of chlortalidone, C,,H,,CIN,O,S The eye ointment complies with the requirements stated under Eye
92.5 to 107.5% of the stated amount. Preparations and with the following requirements.
Content of chlortetracycline hydrochloride,
C,,H,3;CIN,O;s,HCl
‘the powdered tablets containing 0.2 g of
O mL of acetone on a water bath for
IDENTIFICATION
bath for 20 minutes using a A. Disperse a quantity of the eye ointment containing 10 mg
wave the acetone. Cool the solution of Chlortetracycline Hydrochloride in 10 mL of
dichloromethane, extract with two 10-mL quantities of
0.01m hydrochloric acid, filter and dilute the filtrate to 100 mL
with 0.01m hydrochloric acid. Dilute 20 mL of the resulting
solution to 100 mL with 0.01m hydrochloric acid. The light
range 220 to 420 nm exhibits two maxima, at 266 nm and
368 nm.
18m ammonia, 30 volumes of 1,4-dioxan and 30 (1) Disperse a quantity of the eye ointment containing 25 mg
propan-2-ol as the mobile phase. Apply separately tosthe of Chlortetracycline Hydrochloride in 25 mL of
5 uL of each of the following solutions. For solution (4) dichloromethane, extract with two quantities of
a quantity of the powdered tablets containing 0.1 g of 0.01m hydrochloric acid, filter the aqueous layer and dilute to
Chlortalidone to 5 mL of ethanol (96%), mix with the aid of
ultrasound for 15 minutes, centrifuge and use the
supernatant liquid. For solution (2) dilute 1 volume of
solution (1) to 200 volumes with ethanol (96%). Solution (3)
/v of each of chlortetracycline
contains 0.020% w/w of 2-(4-chloro-3-sulfamoylbenzoyl) benzoic
PCRS, tetracycline hydrochloride BPCRS and
acid BPCRS in ethanol (96%). After removal of the plate,
allow it to dry in air and examine under ultraviolet light
(254 nm). Any spot corresponding to 2-(4-chloro-3-
sulfamoylbenzoyl)benzoic acid in the chromatogram obtained
with solution (1) is not more intense than the spot in the
chromatogram obtained with solution (3) (1%) and any other
secondary spot is not more intense than the spot in the
ea
we we
maw
ASSAY At the time of use, dry the pla

1 hour.
Weigh and powder 20 tablets. Boil a quantity of the powder
containing 0.1 g of Chlortalidone under a reflux condenser
with 30 mL of methanol for 5 minutes, shake vigorously for (c) Apply 1 wL of each solution.
15 minutes, cool and filter. Wash the residue and filter with (d) Develop the plate to 15 cm.
methanol and dilute the combined filtrate and washings to t of
100 mL with methanol. To 5 mL add 2 mL of 1m hydrochloric
air and examine under ultraviolet ight (365 nm).
acid and sufficient methanol to produce 50 mL and measure
the absorbance of the resulting solution at the maximum at MOBILE PHASE
275 nm, Appendix II B. Calculate the content of 6 volumes of water, 35 volumes of methanol and 59 volumes
gs,
|
C,4H,,CIN2O,S taking 57.4 as the value of A170, 1 cm) at of dichloromethane.
eae
we ae
SYSTEM SUITABILITY

CONFIRMATION

C. To a quantity of the eye ointment containing 0.5 mg of
Chlortetracycline Hydrochloride add 2 mL of sulfuric acid;
sty
mn
1
rey
rans
oye
‘
.
\
'
te
tae
toa
hoe a
oye
ate
2016 Chlortetracycline Preparations III-315

L
a deep blue colour is produced, which becomes bluish green.

Add 1 mL of water; a brown colour is produced.
Chliortetracycline Ointment
TESTS Action and use
Tetracycline hydrochloride and 4-epichlortetracycline Tetracycline antibacterial.
hydrochloride
Not more than 8.0% and 6.0% respectively, determined as DEFINITION
described under Assay. Inject separately solutions (1) and Chlortetracycline Ointment contains Chlortetracycline
(4). Hydrochloride in a suitable basis.
ASSAY
Sem1-solid Preparations and with the following requirements.
Appendix III D, using the following solutions. Content of chlortetracycline hydrochloride,
C,,H,3;CIN,Os,HCl
hydrochloric acid and shake for IDENTIFICATION
4 100 mL with 0.01m hydrochloric acid, A. Disperse a quantity of the ointment containing 10 mg of
mix thoroughly, Chlortetracycline Hydrochloride in 10 mL of dichloromethane,
layer. extract with two 10-mL quantities of 0.01m hydrochloric acid,
(2) Dissolve 25 mg tracycline hydrochloride BPCRS in combine the aqueous extracts, filter and extract the filtrate
20 mL of chloroform and 0.01m hydrochloric acid with two 10-mL quantities of ether. Discard the ether extracts
and shake for 15 minute 100 mL with and dilute the aqueous layer to 100 mL with
0.01mM hydrochloric acid, mix 0.01m hydrochloric acid. Dilute 20 mL of the resulting
Neate
filter the aqueous layer. solution to 100 mL with 0.01m hydrochloric acid. The light
(3) 0.025% w/v of each of chlortetraéych absorption of the resulting solution, Appendix II B, in the
hydrochlonde BPCRS and 4-epichlortetra range 220 to 420 nm exhibits two maxima, at 266 nm and
368 nm.
0.01mM hydrochlonc acid. (1) Disperse a quantity of the ointment containing 25 mg of
Chlortetracycline Hydrochloride in 25 mL of dichloromethane,
extract with two quantities of 0.01m hydrochloric acid, filter
(a) Use a stainless steel column (25 cm x 4.6 mm) pa eous layer and dilute to 50 mL with water.
% wiv of chlortetracycline hydrochlonde BPCRS in
03% w/v of each of chlortetracycline
below.
PCRS, tetracycline hydrochloride BPCRS and
(c) Use a flow rate of 2 mL per minute. ide EPCRS in water.
CONDITIONS
MOBILE PHASE hydroxide and spray 1
20 volumes of dimethylformamide and 80 volumes of 10 mL for a plate 10
es
ve NS
0.1m oxalic acid the pH of which has been adjusted to 2.2

with triethylamine.
(b) Use the mobile phase as des
SYSTEM SUITABILITY
with solution (3), the resolution factor between the two (d) Develop the plate to 15 cm.
principal peaks is at least 1.5. (e) After removal of the plate, allow it to dry
i
air and examine under uwitraviolet light (365 nn
Calculate the content of C,H »3CIN2Og,HCI in the eye MOBILE PHASE
ointment using the declared content of C2.H»3CIN2.Og,HCl 6 volumes of water, 35 volumes of methanol and 59 volumes
awe se
in chlortetracycline hydrochloride BPCRS. of dichloromethane.
wae ate A
Chlortetracycline Eye Ointment should be protected from The test is not valid unless the chromatogram obtained with
light. solution (3) shows three clearly separated spots.
Le le
CONFIRMATION

ve owed
C. To a quantity of the ointment containing 0.5 mg of
Chlortetracycline Hydrochloride add 2 mL of sulfuric acid;
ee
III-316 Choline Preparations 2016
a deep blue colour is produced, which becomes bluish green.

Add 1 mL of water; a brown colour is produced.
Choline Salicylate Ear Drops
Action and use
eaves
TESTS
vera
Salicylate; non-selective cyclo-oxygenase inhibitor; analgesic;

yeaa
Tetracycline hydrochloride and 4-epichlortetracycline

hydrochloride anti-inflammatory.
Not more than 8.0% and 6.0% respectively, determined as
described under Assay. Inject separately solutions (1) and DEFINITION
Choline Salicylate Ear Drops are a solution of choline
(4).
salicylate in Propylene Glycol. They are prepared by diluting
ASSAY Choline Salicylate Solution.
The ear drops comply with the requirements stated under Ear
quantity of the ointment containing 25 mg of
Sew
Content of choline salicylate, C;,H,;>NO,
Ydrochloride in 20 mL of chloroform and
ene ad

sdvochloric acid and shake for 15 minutes.
Ne
50 mL of 0.0. iM
Dilute to 100 ith..0.01mM hydrochloric acid, mix IDENTIFICATION
rate and filter the aqueous layer. A. Heat 2 mL with sodium hydroxide until fumes are evolved.
(2) Dissolve 25 mg ertéteacycline hydrochloride BPCRS in Triethylamine vapour is evolved, which turns moist red litmus
20 mL of chloroform and 50 mL.of 0.01m hydrochloric acid paper blue.
and shake for 15 minutes .100 mL with B. Dilute a quantity containing 2 g of choline salicylate to
0.01mM hydrochloric acid, mix allow to separate and 20 mL with water. The resulting solution yields the reactions
filter the aqueous layer. : characteristic of salicylates, Appendix VI.
,e nea
(3) 0.025% w/v of each of chi ASSAY
hydrochloride BPCRS and 4-epichlortetracychye To a quantity containing 0.4 g of choline salicylate add
hydrochloride EPCRS in 0.01m hydrochlorié acid. 50 mL of 1,4-dioxan and 5 mL of acetic anhydride and carry
(4) 0.002% w/v of tetracycline hydrochloride B out Method I for non-aqueous titration, Appendix VIII A,
0.0015% wiv of 4-epichlortetracychne hydrochlorideE using 0.25 mL of methyl orange-xylene cyanol FF solution as
0.01m hydrochloric acid. | indicator. Each mL of 0.1m perchloric acid VS is equivalent to
CHROMATOGRAPHIC CONDITIONS 24.13 mg of Cy2Hi9NOsz.
(a) Use a stainless steel column (25 cm x 4.6 mm) packt ABELLING
with end-capped octadecylsilyl silica gel for chromatography rength is stated as the percentage w/v of choline
below.
MOBILE PHASE
20 volumes of dimethylformamide and 80 volumes of anti-inflammatory.

0.1m oxalic acid the pH of which has been adjusted to 2.2
with triethylamine. DEFINITION
SYSTEM SUITABILITY Choline Salicylate Oromucosal elution of choline
salicylate in a suitable water-miscible b It is prepared
principal peaks 1s at least 1.5.
Content of choline salicylate, C,,H,.NO,
Calculate the content of C,.H,3CIN2Og,HCI in the ointment
using the declared content of C22H,3CIN»,Og,HC! in
chlortetracycline hydrochloride BPCRS. IDENTIFICATION
A. Mix a quantity containing 0.1 g of choline salicylate with
STORAGE
9 mL of water (solution A). To 1 mL of solution A add
Chlortetracycline Ointment should be protected from light.
1 mL of ammonium reineckate solution, filter and wash the
precipitate produced. The precipitate is pink.
B. 1 mL of solution A yields reaction A characteristic of
salicylates, Appendix VI.
C. Mix a quantity containing 0.2 g of choline salicylate with
15 mL of water, heat on a water bath for 15 minutes and
filter. The filtrate yields reaction B characteristic of salicylates,
Appendix VI.
2016 Chorionic Gonadotrophin Preparations II-317
ASSAY | ASSAY
mee”
To a quantity containing 0.5 g of choline salicylate in a Weigh and powder 20 tablets. To a quantity of the powder
tw Nw
conical flask add 25 mL of 1,4-dioxan and 5 mL of acetic containing 0.1 g of Choline Theophyllinate add 500 mL of
anhydride. Shake well until the gel has completely dispersed water shake vigorously for 2 minutes, dilute to 1000 mL with
and wash the inside wall of the flask with 25 mL of water, mix and filter. To 10 mL of the filtrate add 10 mL of
1,4-dioxan. Carry out Method I for non-aqueous titration, 0.1M sodium hydroxide and dilute to 100 mL with water.
Appendix VIII A, using 0.25 mL of methyl orange-xylene Measure the absorbance of the resulting solution at the
cyanol FF solution as indicator. Each mL of 0.1m perchloric maximum at 275 nm, Appendix II B. Calculate the content
acid VS is equivalent to 24.13 mg of C,2H;9NOx,. of C,,H2,N503 taking 415 as the value of A(1%, 1 cm) at
LABELLING
The quantity of active ingredient is stated as the amount of STORAGE
rey 4
Choline Theophyllinate Tablets should be protected from
light.
LM ALN
- aN Ss
Chorionic Gonadotrophin Injection

Action and use
Non-selective phospho Action and use
treatment of reversible ai Gonadotrophic hormone.
aes
wawos
Choline Theophyllinate Tablets contain Gholine Chorionic Gonadotrophin Injection is a sterile solution of
Theophyllinate. They are coated. Chorionic Gonadotrophin in Water for Injections. It is
The tablets comply with the requirements st prepared by dissolving Chorionic Gonadotrophin for
with the following requirements. Injection in the requisite amount of Water for Injections
Content of choline theophyllinate, C,,H>;
95.0 to 105.0% of the stated amount. The injection complies with the requirements stated under
IDENTIFICATION é
A. Shake a quantity of the powdered tablets containing 0 STORAGE
of Choline Theophyllinate with 20 mL of absolute ethanol f tonic Gonadotrophin Injection should be used
10 minutes, filter and evaporate the filtrate to dryness. The ately after preparation.
infrared absorption spectrum of the residue, Appendix II A, is
concordant with the reference spectrum of choline
theophyllinate (RS 060).
B. The light absorption of the final solution obtained in the
Assay, Appendix II B, exhibits a maximum at 275 nm.
TESTS consisting of Choy =Gonadotrophin with or without
Related substances excipients. It is supplied in
Carry out the method for thin-layer chromatography, The contents of the sealed comply with the requirements
ee tee Appendix III A, using the following solutions. for Powders for Injections or. ns stated under Parenteral
Pye AS]
(1) Shake a quantity of the powdered tablets containing 0.1 g Preparations and with the fo
of Choline Theophyllinate with 10 mL of ethanol (96%) for
mae ne
Potency
10 minutes and filter.
rons
The estimated potency is not les and not more

(2) Dilute 1 volume of solution (1) to 100 volumes with than 125% of the stated potency.
ethanol (96%).
CHARACTERISTICS
A white or almost white, amorphous powde
(a) Use as the coating silica gel HF p54.
IDENTIFICATION
Causes an increase in the weight of the seminal vesicles or
(c) Apply 5 uL of each solution. the prostate glands of immature male rats when administered
(d) Develop the plate to 15 cm. as directed under the Assay.
a aes
Nee
wm A
se aw
vee tet a
TESTS
tee
ultraviolet light (254 nm). Acidity or alkalinity
MOBILE PHASE pH of a 1% w/v solution, 6.0 to 8.0, Appendix V L.
5 volumes of ethanol (96%) and 95 volumes of chloroform. Clarity and colour of solution
LIMITS A 1.0% w/v solution is clear, Appendix IV A, and colourless,
Appendix IV B, Method I.
solution (1) is not more intense than the spot in the Bacterial endotoxins
chromatogram obtained with solution (2). Carry out the test for bacterial endotoxins, Appendix XIV C.
give a solution containing 500 IU of Chorionic
IWI-318 Ciclosporin Preparations 2016
Gonadotrophin per mL (solution A). The endotoxin limit

concentration of solution A is 15 IU of endotoxin per mL.
Sterile Ciclosporin Concentrate
i ry
ae ea ASSAY Action and use

The potency of chorionic gonadotrophin is estimated by Calcineurin inhibitor; immunosuppressant.
comparing under given conditions its effect of increasing the
mass of the seminal vesicles (or the prostate gland) of DEFINITION
immature rats with the same effect of the International Sterile Ciclosporin Concentrate is a sterile solution of
Standard of chorionic gonadotrophin or of a reference Ciclosporin in a suitable solvent.
preparation calibrated in International Units. The concentrate complies with the requirements for Concentrates
The International Unit is the activity contained in a stated for Injections or Infusions stated under Parenteral Preparations
amount ofthe International Standard, which consists of a and with the following requirements.
Content of ciclosporin, Ce62Hi11Niy0p
aN an
gnant women with lactose. 95.0 to 105.0% of the stated amount.

eam te
TaN es
»International Units of the International

IDENTIFICATION
(1) Dilute the concentrate, if necessary, with sufficient
and the lightest rat is not
Ciclosporin.
random to 6 equal groups of
(2) 0.05% w/v of ciclosporin EPCRS in methanol.
wena ee 4
suitable).
initial approximation total doses of 4 IU, 8 IU and*i6- (d) Develop the plate to 15 cm with mobile phase A, dry in
may be tried although the dose will depend on the se air and then develop the plate to 15 cm in the same direction
of the animals used, which may vary widely. . with mobile phase B.
Dissolve separately the total quantities of the preparation to’: er removal of the plate, dry in air, spray the plate with
be examined and of the reference preparation corresponding ~
to the daily doses to be used in sufficient phosphate-albumin bismuth subnitrate, 5 volumes of a 40% w/v
buffered saline pH 7.2 such that the daily dose is administered potassium todide, 20 volumes ofglacial acetic acid
in a volume of about 0.5 mL. Add a suitable antimicrobial
preservative such as 0.4% w/v of phenol or 0.002% w/v of
thiomersal. Store the solutions at 5 + 3°.
Inject subcutaneously into each rat the daily dose allocated to Mobile phase
its group, on 4 consecutive days at the same time each day. Mobile phase B
On the fifth day, about 24 hours after the last injection,
euthanise the rats and remove the seminal vesicles. Remove
any extraneous fluid and tissue and weigh the vesicles
immediately. Calculate the results by the usual statistical gram obtained with
methods, using the weight of the vesicles as the response. size to that in the
(The precision of the assay may be improved by a suitable
correction of the organ weight with reference to the body
mass of the animal from which it was taken; an analysis of
covariance may be used). that of the principal peak in the chromato
The fiducial limits of error are not less than 64% and not solution (2)
more than 156% of the stated potency. TESTS
STORAGE Acidity or alkalinity
The sealed container should be protected from light and pH, 6.0 to 7.0, Appendix V L.
wncen
stored at a temperature not exceeding 20°. Related substances
ie i
ae
LABELLING
The label of the sealed container states the number of IU
(Units) contained in it. (1) Dilute a quantity of the concentrate containing 30 mg of
Ciclosporin to 25 mL with a mixture of equal volumes of
acetonitrile R1 and water.
mixture of equal volumes of acetonitrile R1 and water.
(3) Dissolve the contents of a vial of ciclosporin for system
rah wd suitability EPCRS in 5 mL of the mobile phase.
Aa ad
Lew aa
2016 Ciclosporin Preparations IIT-319
(4) Dilute 1 volume of solution (2) to 20 volumes with a U and H, = height above the baseline of the lowest point of
mixture of equal volumes of acetonitrile R1 and water. the curve separating this peak from the peak due to
CHROMATOGRAPHIC CONDITIONS ciclosporin. If necessary, adjust the ratio of 1,1-dimethyethyl
methyl ether to acetonitrile R1 in the mobile phase.
with octadecylsilyl silica gel for chromatography (3-5 wm) Inject solution (2) six times. The Assay is not valid unless the
(Supelco Superspher is suitable). relative standard deviation of the area of the principal peak is
not more than 1.0%.
below. DETERMINATION OF CONTENT
(c) Use a flow rate of 1.5 mL per minute. Calculate the content of Cg7H,,,N,,Oj2 in the concentrate
using the declared content of Cg5H,,;N ,Oj> in
ciclosporin EPCRS.
(e) Use detection wavelength of 210 nm.
IMPURITIES
f each solution.
), allow the chromatography to proceed
monograph include those listed under Ciclosporin.
the retention time of the principal peak.
‘ ic acid, 5 volumes of
1,1-dimethylethylmeth 6 volumes of acetonitrile R1 Ciclosporin Eye Drops
and 49 volumes of w NOTE: Ciclosporin Eye Drops are not currently licensed in the
When the chromatogram United Kingdom.
conditions the peak due to cI
Action and use
25 to 30 minutes. :
Calcineurin inhibitor; immunosuppressant; treatment of
SYSTEM SUITABILITY allergic and autoimmune eye disease.
The test is not valid unless, in the chrom
with solution (3), the peak-to-valley ratio DEFINITION
H, = height above the baseline of the peak d Ciclosporin Eye Drops are a sterile solution of Ciclosporin in
U andH, = height above the baseline of the low. a suitable oily vehicle.
the curve separating this peak from the peak due tog The eye drops comply with the requirements stated under Eye
ciclosporin. If necessary, adjust the ratio of 1,1-dimethy Preparations, the requirements stated under Unlicensed Medicines
methyl ether to acetonitrile R1 in the mobile phase. with the following requirements.
LIMITS of ciclosporin, C¢.H11,N;1012
In the chromatogram obtained with solution (1): 05.0% of the stated amount.
the area of any secondary peak is not greater than 1.3 times FICATION
the area of the principal peak in the chromatogram obtained : of absolute ethanol to a quantity of the eye
with solution (2) (1.3%); 0.1.g of Ciclosporin and mix. Allow to
the area of not more than one such peak is greater than per ethanolic layer and evaporate to
0.7 times the area of the principal peak in the chromatogram im of nitrogen. Add 10 mL of hexane to
obtained with solution (2) (0.7%); pitate is formed) and filter the
the sum of the areas of any secondary peaks is not greater than resulting mixture.
1.5 times the area of the principal peak in the chromatogram and allow to dry in ine:
obtained with solution (2) (1.5%). dried residue, Appendix
Disregard any peak with an area less than the area of the spectrum of ciclosporin CRS '#:
principal peak in the chromatogram obtained with solution occurring at about 1700 cm”
(4) (0.05%). B. In the Assay, the retention tim
ASSAY
that of the principal peak in the chrom
solution (2).
equal volumes of acetomtrile and water. ASSAY
(1) Dilute a quantity of the concentrate containing 30 mg of Carry out the method for liguid chromatography,
Ciclosporin to 25 mL with a mixture of equal volumes of Appendix III D, using the following solutions in a mixture of
AS AL acetonitrile R1 and water. 20 volumes of chloroform and 80 volumes of methanol.
~yen
tow
rn we 4
Ne
(2) 0.12% w/v of ciclosporin EPCRS in a mixture of equal (1) Dilute a volume of the eye drops containing 20 mg of
volumes of acetonitrile RI and water. Ciclosporin to produce 100 mL.
(3) Dissolve the contents of a vial of ciclosporin for system (2) 0.02% w/v of ciclosporin EPCRS.
suitability EPCRS in 5 mL of the mobile phase. CHROMATOGRAPHIC CONDITIONS
CHROMATOGRAPHIC CONDITIONS (a) Use a stainless steel column (25 cm x 4.6 mm) packed
The chromatographic conditions described under Related with ethylsilyl silica gel for chromatography (5 wm)
substances may be used. (Phenomenex Maxsil RP2 is suitable).
ee
Lo
oe
SYSTEM SUITABILITY (b) Use isocratic elution and the mobile phase described
below.
Ft

Pg key
&

Rb
with solution (3), the peak-to-valley ratio is at least 1.4, where

H, = height above the baseline of the peak due to ciclosporin (d) Use a column temperature of 50°.
II-320 Ciclosporin Preparations 2016
(e) Use a detection wavelength of 210 nm. CONFIRMATION
Meta eteee (f) Inject 10 uL of each solution. The principal spot in the chromatogram obtained with
ANY MOBILE PHASE
solution (1) corresponds in position and size to that in the
te
0.5 volumes of orthophosphoric acid, 50 volumes of methanol,

Lt

aes

SYSTEM SUITABILITY that of the principal peak in the chromatogram obtained with
The Assay is not valid unless the column efficiency, solution (2)
determined on the peak due to ciclosporin in the
ASSAY
chromatogram obtained with solution (2), is at least 700
theoretical plates per metre and the symmetry factor of the
principal pé#k.is 1.5 or less.
(1) Dilute a weighed quantity of the oral solution containing
CONTENT
30 mg of Ciclosporin to 25 mL with a mixture of equal
at. of Ce62H11,;N ,1Oj2 in the eye drops volumes of acetonitrile RI and water.
(2) 0.12% w/v of ciclosporin EPCRS in a mixture of equal
volumes of acetonitrile R1 and water.
STORAGE (3) Dissolve the contents of a vial of ciclosporin for system
Ciclosporin Eye Drops suitability EPCRS in 5 mL of the mobile phase.

with octadecylsilyl silica gel for chromatography (3-5 wm)
Ciclosporin Oral Solution. (Supelco Superspher is suitable).
Action and use below.
Calcineurin inhibitor; immunosuppressant.
DEFINITION . (d) Use a column temperature of 80°.
Ciclosporin Oral Solution is a solution containing Ciclg (e) Use a detection wavelength of 210 nm.
in a suitable flavoured vehicle. (f) Inject 20 uL of each solution.
The oral solution complies with the requirements stated under Oré
of orthophosphonic acid, 5 volumes of
PRODUCTION ethyl methyl ether, 46 volumes of acetonitrile R1
A suitable Related substances test is carried out to mes of water.
demonstrate the appropriate control of impurities.
Content of ciclosporin, C,H; 114N;;012 id wnless, in the chromatogram obtained
peak-to-valley ratio is at least 1.4, where
IDENTIFICATION
(1) Dilute a quantity of the oral solution with sufficient e ratio of 1,1-dimethyethyl
methanol to produce a solution containing 0.05% w/v of methyl ether to acetonitrile R1 in the mobile phase.
Ciclosporin. Inject solution (2) six times. The,As not valid unless the
AA aS
(2) 0.05% w/v of ciclosporin EPCRS in methanol. relative standard deviation of the area of he principal peak is
not more than 1.0%. |
suitable). Determine the weight per mL of the oral soluts
Appendix V G, and calculate the content of Cex
(c) Apply 10 uL of each solution. Co2Hi11Ni 1012 in ciclosporin EPCRS.
(d) Develop the plate to 15 cm with mobile phase A, dry in
air and then develop the plate to 15 cm in the same direction
with mobile phase B.
(e) After removal of the plate, dry in air, spray the plate with
a freshly prepared mixture containing 5 volumes of 1.7% w/v Cimetidine Injection
solution of bismuth subnitrate, 5 volumes of a 40% w/v
re wee
Action and use
solution of potassium 1odide, 20 volumes of glacial acetic acid
Histamine H, receptor antagonist; treatment of peptic
and 70 volumes of water. Immediately spray again with dilute
ulceration.
hydrogen peroxide solution and examine in daylight.
MOBILE PHASE DEFINITION
Mobile phase A_ ether. Cimetidine Injection is a sterile solution in Water for
Injections of cimetidine hydrochloride, prepared by the
Mobile phase B- 1 volume of formic acid, 2 volumes of water,
interaction of Cimetidine and Hydrochloric Acid.
40 volumes of butan-2-one and 60 volumes of ethyl acetate.
ett
2016
aN ee
Cimetidine Preparations III-321
The injection complies with the requirements stated under with solution (4) (0.1% each). The tests are not valid unless
Parenteral Preparations and with the following requirements. the chromatograms obtained with solution (5) show clearly
Content of cimetidine, C,)>H,<.N,S visible spots.
95.0 to 105.0% of the stated amount. ASSAY
IDENTIFICATION Dilute a volume containing the equivalent of 0.5 g of
A. The light absorption, Appendix II B, in the range 210 to Cimetidine with sufficient 0.05m sulfuric acid to produce a
310 nm of solution A used in the Assay exhibits a maximum solution containing 0.001% w/v (solution A). Prepare a
at about 218 nm. 0.001% w/v solution of cimetidine BPCRS in 0.05M sulfuric
acid (solution B). Measure the absorbance of solutions A
B. In the test for Related substances, the principal spot in the
and B at the maximum at 218 nm and at 260 nm,
Appendix II B. Calculate the content of Cy;9Hi¢6N¢S using
the difference between the absorbances of solutions A and B
at the two wavelengths and the declared content of
CyoHi6NeS in cimetidine BPCRS.
LABELLING
The strength is stated in terms of the equivalent amount of
Cimetidine in a suitable dose-volume.
Appendix III A, using l GF 54 as the coating
substance and using t ving solutions. For solution (1)
dilute a quantity of the in vith sufficient methanol to
give a solution containing
Cimetidine Oral Solution
Action and use
ulceration.
DEFINITION
For solution (6) dissolve 2.24 mg of 2-carbamoyl-1 1 Cimetidine Oral Solution is a solution containing Cimetidine
[2-(5-methylimidazol-4-ylmethylthio) ethyl]guanidine in a suitable flavoured vehicle.
dthydrochlonde BPCRS (‘amide’ impurity) in 5 mL ofa The oral solution complies with the requirements stated under Oral
1.65% w/v solution of sodium chloride in methanol (50%). bs and with the following requirements.
For solution (7) dissolve 6.6 mg of 1-methyl-3-[2- nt of cimetidine, CyyH,.N¢S
(5-methylimidazol-4-yl-methylthio) ethyl]guanidine 5.0% of the stated amount.
dihydrochloride BPCRS (‘guanidine’ impurity) in 5 mL ofa
1.65% w/v solution of sodium chloride in methanol (50%).
For solution (8) dissolve 5.0 mg of cimetidine BPCRS in
1 mL of methanol. Carry out the following tests.
A. Apply separately to the plate 4 uL of each solution. Allow
of Cimetidine.
the plate to stand for 15 minutes in the tank saturated with
vapour from the mobile phase which consists of a mixture of (2) 0.04% w/v of
15 volumes of 13.5m ammonia, 20 volumes of methanol and
65 volumes of ethyl acetate. After development and removal
of the plate, dry it in a current of cold air, expose to iodine
+4
vapour until maximum contrast of the spots has been

obtained and examine under wiltraviolet ight (254 nm). (c) Apply 5 uL of each solution. |
B. Apply separately to the plate 4 wL of each solution. (d) Develop the plate to 15 cm.
Develop using a mixture of 8 volumes of 13.5M ammonia, (e) After removal of the plate, allow it te
8 volumes of methanol and 84 volumes of ethyl acetate. After iodine vapour until maximum contrast betw
removal of the plate, dry it in a current of cold air, expose to obtained.
iodine vapour until maximum contrast of the spots has been MOBILE PHASE
obtained and examine under witraviolet ight (254 nm).
15 volumes of 13.5mM ammonia, 20 volumes of methanol and
The following limits apply to both methods. Any spot in the 65 volumes of ethyl acetate.
CONFIRMATION
the ‘amide’ impurity is not more intense than the principal
Lg at not
spot in the chromatogram obtained with solution (6) (0.7%, The principal spot in the chromatogram obtained with
.
calculated as the ‘amide’ base and with reference to solution (1) corresponds to that in the chromatogram
tage,
cimetidine) and any spot corresponding to the ‘guanidine’ obtained with solution (2).
impurity is not more intense than the principal spot in the B. In the Assay, the principal peak in the chromatogram
ray
chromatogram obtained with solution (7) (2%, calculated as obtained with solution (1) has the same retention time as the
the ‘guanidine’ base and with reference to cimetidine). principal peak in the chromatogram obtained with
Any other secondary spot is not more intense than the solution (2).
principal spot in the chromatogram obtained with solution
Pe Oa Cb re
eyelet
TESTS
Pega
(3) (0.2%) and not more than two such spots are more
Acidity
intense than the principal spot in the chromatogram obtained
Stone

rN eA
IWI-322 Cimetidine Preparations 2016
Related substances (1) Dilute a weighed quantity of the preparation containing

Carry out the method for liquid chromatography, 0.2 g of Cimetidine to produce 200 mL. Dilute 5 mL of this
Appendix III D, using the following solutions in the mobile solution to 100 mL.
caN A
Puma ny
phase.
swat
(2) 0.005% w/v of cimetidine BPCRS.

(1) Dilute a volume of the preparation to contain (3) 0.004% w/v of saccharin and 0.005% w/v of
0.050% w/v of Cimetidine. cimetidine BPCRS.
(2) 0.0020% w/v of 1-methyl-3-(2-(5-methylimidazol-4-yl- CHROMATOGRAPHIC CONDITIONS
methylthio) ethyl) guanidine dihydrochloride BPCRS (‘guanidine’
impurity).
(3) 0.0019% w/v of 2-carbamoyl-1-methyl-3-
SYSTEM SUITABILITY
(2- (5-methylimdazol-4-ylmethylthio) ethyl)guanidine
dihydroch ».BPCRS (‘amide’ impurity). The test is not valid unless the chromatogram obtained with
01.5% wh of 2-cyano-1-methyl-3-(2-(5-methylimidazol- solution (3) shows two clearly separated principal peaks.
4-yl-methylsul} hyl)guanidine BPCRS (‘sulfoxide’ DETERMINATION OF CONTENT
impurity). Determine the weight per mL of the preparation,
(5) 0.00025% w/ h of the ‘guanidine’, ‘amide’ and Appendix V G, and calculate the content of C)j>Hi¢N¢S
‘sulfoxide’ impurities 002% w/v of saccharin. using the declared content of CjpH,¢N,S in
(6) Dilute 1 volume of | cimetidine BPCRS.
STORAGE
Cimetidine Oral Solution should be protected from light.
chromatography (Bondapak pheny :

(b) Use isocratic elution and themobile p
below. Cimetidine Oral Suspension
Action and use
(e) Use a detection wavelength of 228 nm. ulceration.
DEFINITION
(g) For solution (1) allow the chromatography to proceed
3 times the retention time of the peak due to cimetidine. dine Oral Suspension is a suspension containing
if e in a suitable flavoured vehicle.
MOBILE PHASE
spension complies with the requirements stated under
4 volumes of acetomitrile and 96 volumes of a 0.25% viv
solution of orthophosphoric acid, the pH of the mixture being
adjusted to 3.0 using 10M potassium hydroxide.
SYSTEM SUITABILITY
solution (5) shows four clearly separated peaks.
LIMITS
(1) Shake a volume of '
ayes In the chromatogram obtained with solution (1): of Cimetidine with 50 mL
the area of any peak corresponding to ‘guanidine’ is not
ela ee

chromatogram obtained with solution (2) (3% calculated as
the base and with reference to cimetidine);
(a) Use as the coating silica gel GF254.
the area of any peak corresponding to ‘amide’ is not greater
than the area of the principal peak in the chromatogram (b) Use the mobile phase as described belo
obtained with solution (3) (3% calculated as the base and (c) Apply 5 uL of each solution.
with reference to cimetidine); (d) Develop the plate to 15 cm.
the area of any other secondary peak, except that of any peak (e) After removal of the plate, allow it to dry and expose it to
corresponding to saccharin, is not greater than the area of the iodine vapour until maximum contrast between the spots is
principal peak in the chromatogram obtained with solution obtained.
(6) (0.5%); MOBILE PHASE
calculate the content of the individual named impurities
15 volumes of 13.5m ammonia, 20 volumes of methanol and
using the respective reference solutions and the content of
65 volumes of ethyl acetate.
unnamed impurities using solution (6);
CONFIRMATION
the total content of impurities is not greater than 4.0%.
ASSAY
fa
aa en ¥
phase. TESTS
Nae
wen
Alkalinity
neery 4
ee ST
2016 Cimetidine Preparations III-323
Related substances (3) 0.004% w/v of saccharin in solution (2).

Carry out the method for liquid chromatography, CHROMATOGRAPHIC CONDITIONS
rate

phase.
(1) To a quantity of the oral suspension containing 0.1 g of
SYSTEM SUITABILITY
Cimetidine add 100 mL of the mobile phase and shake for
10 minutes. Dilute to 200 mL with the mobile phase, mix The test is not valid unless, in the chromatogram obtained
and filter through a Whatman GF’/F filter paper. Dilute with solution (3), the resolution factor between cimetidine and
5 mL of the filtrate to 50 mL with the mobile phase. saccharin is at least 1.5.
(2) 0.0020% w/v of 1-methyl-3-(2-(5-methylimidazol-4-yl- DETERMINATION OF CONTENT
methylthio) ethyl)guanidine dihydrochloride BPCRS (‘guanidine’ Determine the weight per mL of the preparation,
Appendix V G, and calculate the content of C;gH,6N.6S
hpof 2-carbamoyl-1-methyl-3- using the declared content of Ci9H;¢N¢,S in
z0l-4-ylmethylthio) ethyl) guanidine cimetidine BPCRS.
STORAGE
(4) 0.0015%" Cimetidine Oral Suspension should be protected from light.
4-yl-methylsulfin
impurity).
(5) 0.00025% w/v each:
‘sulfoxide’ reference subst
saccharin. Cimetidine Tablets
Action and use
ulceration.
with particles of silica (10 um) phenyl silica,
chromatography (uBondapak phenyl is suitabi DEFINITION
Cimetidine Tablets contain Cimetidine.
(b) Use isocratic elution and the mobile phase de
below. The tablets comply with the requirements stated under Tablets and
tent of cimetidine, CioHicNe6S
MOBILE PHASE
4 volumes of acetonitrile and 96 volumes of a 0.25% viv
solution of orthophosphoric acid, the pH of the mixture being jorafor using gentle heat. Dissolve the residue
adjusted to 3.0 using 10m potassium hydroxide. 9 and evaporate to dryness with the aid
SYSTEM SUITABILITY ir. Lgry the residue at 60° at a pressure not
The test is not valid unless the chromatogram obtained with exceeding 0.7 kPa." ifrared absorption spectrum of the
solution (5) shows four clearly separated peaks. residue, Appendix Ii concordant with the reference
ter ne
LIMITS
aa

wea
the areas of any peaks corresponding to ‘guanidine’ and

‘amide’ are not greater than the areas of the principal peaks
TESTS
in the chromatograms obtained with solutions (2) and (3)
Related substances
respectively (3% each, calculated as the bases and with
Carry out the method for thin-layer chrome
reference to cimetidine);
Appendix III A, using the following solutions
the areas of any other secondary peaks, except that of any
peak corresponding to saccharin, are not greater than the
(1) Add 20 mL of methanol to a quantity of the*powdered
tablets containing 1 g of Cimetidine, mix with the aid of
ultrasound for 2 minutes, shake for 3 minutes and filter using
a suitable 0.2-umi filter. ,
The total content of impurities is not greater than 4.0%.
ASSAY methanol.
Carry out the method for liguid chromatography, (3) Dilute 1 volume of solution (2) to 20 volumes with
Appendix III D, using the following solutions in mobile methanol.
phase.
(1) To a weighed quantity of the oral suspension containing methanol and dilute 20 volumes of this solution to
0.1 g of Cimetidine add 100 mL of the mobile phase and 100 volumes with methanol.
shake for 10 minutes. Dilute to 200 mL with the mobile
(5) Dilute 5 volumes of solution (4) to 10 volumes with
phase, mix and filter through a Whatman GF’F filter paper.
methanol.
Dilute 5 mL of the filtrate to 50 mL with the mobile phase.
(6) 0.50% w/v of cimetidine BPCRS in methanol.
(2) 0.005% w/v of cimetidine BPCRS.
es ee Ne
IWI-324 Ciprofloxacin Preparations 2016
Carry out the following tests.

Ciprofloxacin Eye Drops
A. CHROMATOGRAPHIC CONDITIONS
we el
ve AS NOTE: Ciprofloxacin Eye Drops are not currently licensed in the
als wet
Nwany
watete ft
(a) Use a TLC silica gel GF254 plate. United Kingdom.
(c) Apply 4 pL of each solution. Action and use
Fluoroquinolone antibacterial.
(d) Develop the plate for 15 minutes in the tank saturated
with vapour from the mobile phase. DEFINITION
(e) After removal of the plate, dry in a current of cold air, Ciprofloxacin Eye Drops are a sterile solution of
expose to iodine vapour until maximum contrast of the spots ciprofloxacin lactate, prepared by the interaction of
has been obtained and examine under ultraviolet light Ciprofloxacin and Lactic Acid, in a suitable vehicle.
(254 nm). The eye drops comply with the requirements stated under Eye
Preparations, the requirements stated under Unlicensed Medicines
|

ere
M ammonia, 20 volumes of methanol and

Content of ciprofloxacin, C,,H,3;FN3;0;
IDENTIFICATION
(b) Use themobile pha A. Carry out the method for thin-layer chromatography,
(c) Apply 4 pL of each
(1) Dilute a volume of the eye drops with sufficient water to
produce a solution containing the equivalent of 0.05% w/v of
tee Ne
ciprofloxacin.
utrast of the spots
has been obtained and examine undeful wrolet light (2) 0.058% w/v of c1profloxacin hydrochloride BPCRS in water.
(254 nm). (3) Mrx 1 volume of solution (1) and 1 volume of
MOBILE PHASE solution (2).
8 volumes of 13.5mM ammonia, 8 volumes of methanol avid: CHROMATOGRAPHIC CONDITIONS
84 volumes of ethyl acetate. (a) Use as the coating sica gel F254 (Merck silica gel 60 Fy54
SYSTEM SUITABILITY HPTLC plates are suitable).
The tests are not valid unless the chromatograms obtain (b) Use the mobile phase as described below.
with solution (5) show clearly visible spots.
LIMITS
solution (1) in tests A and B:
is NOt more intense than the principal spot in the
not more than two such spots are more intense than the , 20 volumes of 13.5mM ammonia,
principal spot in the chromatogram obtained with solution thane and 40 volumes of methanol.
(4) (0.2% of each).
ASSAY The principal band in’ atogram obtained with
~wve rd
Weigh and finely powder 20 tablets. Shake a quantity of the solution (1) corresponds to i the chromatogram
avcaand powdered tablets containing 0.1 g of Cimetidine with obtained with solution (2). bandin the
300 mL of 0.05m sulfuric acid for 20 minutes, add sufficient appears as a single,
aN a
0.05M sulfunc acid to produce 500 mL and filter (Whatman
GF/C is suitable). Dilute 5 mL of the filtrate to 100 mL with
0.05m sulfuric acid (solution A). Prepare a 0.001% w/v Appendix II D, using the following solutié
solution of cimetidine BPCRS in 0.05m sulfunc acid (solution (1) Dilute a quantity of the eye drops, if necessary,
B). Measure the absorbance of solutions A and B at the
water to produce a solution containing the equival a
maximum at 218 nm and at 260 nm, Appendix II B. 0.2% wy of Ciprofloxacin, = ©
Calculate the content of Cj 9H 6N.S using the difference
(2) 0.07% wiv of lithium lactate BPCRS in water.
between the absorbances of solutions A and B at the two
6 ae aw
wavelengths and the declared content of Cy9Hi¢6N¢S in CHROMATOGRAPHIC CONDITIONS
cimetidine BPCRS. (a) Use a stainless steel column (30 cm x 7.8 mm) packed
Pedodion
ww nw
with a strong cation-exchange resin of sulfonated, cross-

linked styrene-divinylbenzene copolymer in the hydrogen form
(7 to 11 pm) (Aminex HPX-87H is suitable).
below.
we awry
ae
aw aan
we oy ee
Nm al
2016 Ciprofloxacin Preparations TI-325
MOBILE PHASE LIMITS

tee A
15 volumes of acetonitrile and 85 volumes of 0.0025m sulfuric Identify any peaks in the chromatogram obtained with
Neng
acid, solution (1) corresponding to ciprofloxacin impurities B, C,
After each analysis the column should be rinsed with a D and E using solution (2) and multiply the area of these
mixture of 0.005m sulfuric acid and acetomtrile and then peaks by the following correction factors: 0.7, 0.6, 1.4 and
regenerated with 0.025m sulfuric acid. 6.7 respectively.
CONFIRMATION In the chromatogram obtained with solution (1):
The chromatogram obtained with solution (1) shows a peak the area of any peak corresponding to
due to lactate with the same retention time as the principal 7-[(2-aminoethyl) amino]-1-cyclopropyl-6-fluoro-1,4-dihydro-
peak in the chromatogram obtained with solution (2). 4-oxoquinoline-3-carboxylic acid (ciprofloxacin impurity C)
is not greater than the area of the principal peak in the
Assay, the retention time of the principal peak in
obtained with solution (1) is the same as
1 peak in the chromatogram obtained with the area of any other secondary peak is not greater than the
solution (2y. ' area of the principal peak in the chromatogram obtained with
TESTS
Acidity
peak corresponding to ciprofloxacin impurity C, is not
PH, 3.9 to 4.5, Appet
Related substances chromatogram obtained with solution (3) (0.5%).
Carry out the method for Disregard any peak with an area less than 0.25 times the area
Appendix III D, using the f of the principal peak in the chromatogram obtained with
(1) Dilute a volume of the eye solution (4) (0.05%).
wee ed
mobile phase to produce a solution,
ASSAY
of 0.05% w/v of ciprofloxacin. |
(2) 0.05% wiv of ciprofloxacin impurity stan BPCRS in the
mobile phase.
(1) Dilute a volume of the eye drops with sufficient of the
mobile phase to produce a solution containing the equivalent
mobile phase and further dilute 1 volume to 2 v umé:
of 0.05% w/v of ciprofloxacin.
the mobile phase.
(2) 0.058% w/v of ciprofloxacin hydrochloride BPCRS in the
(4) Dilute 1 volume of solution (1) to 100 volumes wi
ile phase.
mobile phase and further dilute 1 volume to 5 volumes wi
the mobile phase. OMATOGRAPHIC CONDITIONS
matographic conditions described under Related
tanges may be used.
with base-deactivated octadecylsilyl silica gel for chromatography SATION OF CONTENT
(5 um) (Nucleosil 120-C18 and LiChrospher 100 RP 18 are .cagntent of C;7H;gsFN303 in the eye drops
suitable). Le L tent of C,7H;sFN303,HCI in
(b) Use isocratic elution and the mobile phase described ciprofloxacin hy¢ rochleride BPCRS. Each mg of
below. C 1 7H, 3FN;03,H a qe ialent to 0.9010 mg of

(d) Use a column temperature of 40°. STORAGE
Ciprofloxacin Eye Drops skexi d be protected from light.
(f) Inject 5 wL of each solution. LABELLING © g
ye one wy
(g) For solution (1), allow the chromatography to proceed The quantity of active ingredient terms of the
for twice the retention time of ciprofloxacin. equivalent amount of ciprofloxacin.
MOBILE PHASE IMPURITIES

The impurities limited by the requirements o
13 volumes of acetonitrile and 87 volumes of a 0.245% w/v
monograph include impurities B, C, D, E and
solution of orthophosphoric acid the pH of which has been
adjusted to 3.0 with triethylamine.
Ciprofloxacin. .
conditions the retention time of ciprofloxacin is about
nN weed
enw el
9 minutes. Retention times relative to ciprofloxacin are:
impurity E, about 0.4; impurity F, about 0.5; impurity B, Ciprofloxacin Infusion
about 0.6; impurity C, about 0.7; impurity D, about 1.2. Ciprofloxacin Intravenous Infusion
SYSTEM SUITABILITY
Action and use
The test is not valid unless, in the chromatogram obtained Fluoroquinolone antibacterial.
to ciprofloxacin impurity B and ciprofloxacin impurity C is at DEFINITION
least 1.3. Ciprofloxacin Infusion is a sterile solution, in Glucose
ee
Infusion or in Sodium Chloride Infusion, of ciprofloxacin
lactate prepared by the interaction of Ciprofloxacin and
eres
Lactic Acid. It is supplied as a ready-to-use solution.
award
IWI-326 Ciprofloxacin Preparations 2016
The infusion complies with the requirements stated under C. In the Assay, the retention time of the principal peak in
Parenteral Preparations and with the following requirements. the chromatogram obtained with solution (1) is the same as
TAS
wee,
Content of ciprofloxacin, C,,H,sFN303 that of the principal peak in the chromatogram obtained with
95.0 to 105.0% of the stated amount. solution (2).
IDENTIFICATION TESTS
A. Carry out the method for thin-layer chromatography, Acidity
Appendix III A, using the following solutions. For infusions prepared in Glucose Infusion
(1) Dilute a quantity of the infusion with sufficient water to pH, 3.5 to 4.6, Appendix V L.
produce a solution containing the equivalent of 0.05% w/v of For infusions prepared in Sodium Chloride Infusion
ciprofloxacin. pH, 3.9 to 4.5, Appendix V L.
(2) 0.058%.w/v of ciprofloxacin hydrochloride BPCRS in water. Colour of solution
Swen d
|
The infusion is not more intensely coloured than reference
solution GY, Appendix IV B, Method II.
5-Hydroxymethylfurfural
Infusions prepared in Glucose Infusion comply with the following
test. Carry out the method for liguid chromatography,
(1) Dilute 1 volume of the infusion to 4 volumes with the
mobile phase (contains 1.25% w/v of glucose).
(2) 0.000625% w/v of 5-hydroxymethylfurfural in the mobile
phase.
365 nm).
MOBILE PHASE
be used.
10 volumes of acetonitrile, 20 volumes of 13.
40 volumes of dichloromethane and 40 volumes o LIMITS
CONFIRMATION
any peak corresponding to 5-hydroxymethylfurfural is not
The principal band in the chromatogram obtained with greater than the area of the peak in the chromatogram
solution (1) corresponds to that in the chromatogram ed with solution (2) (0.05%, calculated with reference
obtained with solution (2). The principal band in the tacose content).
chromatogram obtained with solution (3) appears as a single,
compact band.
B. Carry out the method for liguid chromatography,
(1) Dilute a quantity of the infusion, if necessary, with water
of Ciprofloxacin.
(2) 0.07% w/v of lithium lactate BPCRS in water.
mobile phase.
CHROMATOGRAPHIC CONDITIONS (3) Dilute 1 volume of
(a) Use a stainless steel column (30 cm x 7.8 mm) packed mobile phase and further d
ss ead with a strong cation-exchange resin of sulfonated, cross- the mobile phase.
linked styrene-divinylbenzene copolymer in the hydrogen form ) volumes with the
(7 to 11 um) (Aminex HPX-87H is suitable). mobile phase and further dilute 1 v 5 volumes with
(b) Use isocratic elution and the mobile phase described the mobile phase.
below.
The chromatographic conditions described undef’ Assay may
(d) Use a column temperature of 40°. be used.
(e) Use a detection wavelength of 208 nm. For solution (1) allow the chromatography to proceed for
(f) Inject 20 uL of each solution. twice the retention time of ciprofloxacin.
MOBILE PHASE When the chromatograms are recorded under the prescribed
15 volumes of acetonitrile and 85 volumes of 0.0025m sulfuric conditions the retention time of ciprofloxacin is about
acid. 9 minutes. Retention times relative to ciprofloxacin are:
impurity E, about 0.4; impurity F, about 0.5; impurity B,
After each analysis the column should be rinsed with a
about 0.6; impurity C, about 0.7; impurity D, about 1.2.
mixture of 0.005M sulfuric acid and acetomtrile and then
regenerated with 0.025m sulfuric acid. SYSTEM SUITABILITY
CONFIRMATION
The chromatogram obtained with solution (1) shows a peak
to ciprofloxacin impurity B and ciprofloxacin impurity C is at
due to lactate with the same retention time as the principal
least 1.3.
wae
Bae
vee wd
2016 Ciprofloxacin Preparations III-327
LIMITS IMPURITIES
Identify any peaks in the chromatogram obtained with The impurities limited by the requirements of this
solution (1) corresponding to ciprofloxacin impurities B, C, monograph include impurities B, C, D, E andF listed under
D and E using solution (2) and multiply the area of these Ciprofloxacin.
peaks by the following correction factors: 0.7, 0.6, 1.4 and
6.7 respectively.
the area of any peak corresponding to Ciprofloxacin Tablets
7-[(2-aminoethyl)amino]-1-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid (ciprofloxacin impurity C) Action and use
is not greater than the area of the principal peak in the Fluoroquinolone antibacterial.
am obtained with solution (3) (0.5%);
DEFINITION
Ciprofloxacin Tablets contain Ciprofloxacin Hydrochloride.
all the secondary peaks, excluding the with the following requirements.
floxacin impurity C,is not Content of ciprofloxacin, C;7H,3;FN3;03
IDENTIFICATION
Disregard any peak with A. Carry out the method for thin-layer chromatography,
of the principal peak in th ram obtained with
solution (4) (0.05%).
(1) Add a quantity of the powdered tablets containing the
tewaad
Bacterial endotoxins equivalent of 2 g of ciprofloxacin to 750 mL of water, mix

The endotoxin limit concentration is mL, with the aid of ultrasound for 20 minutes, add sufficient
Appendix XIV C. water to produce 1000 mL and mix. Filter a portion of the
ASSAY : | resulting suspension (Whatman GF/C filter paper is suitable)
Carry out the method for liguid chromatography, « and dilute the filtrate with sufficient water to produce a
Appendix III D, using the following solutions. solution containing the equivalent of 0.05% w/v of
ciprofloxacin.
(1) Dilute a quantity of the infusion with sufficient of
mobile phase to produce a solution containing the equiva 2) 0.058% w/v of ciprofloxacin hydrochloride BPCRS in water.
of 0.05% w/v of Ciprofloxacin. 1 volume of solution (1) and 1 volume of
(2) 0.058% w/v of ciprofloxacin hydrochloride BPCRS in the
mobile phase. TTOGRAPHIC CONDITIONS
CHROMATOGRAPHIC CONDITIONS the coating silica gel F754 (Merck silica gel 60 Fos4
with base-deactivated octadecylsilyl silica gel for chromatography
(5 um) (Nucleosil 120-C18 and LiChrospher 100 RP 18 are (c) Apply
suitable).
(d) Develop the pia
(e) After removal of
below.
15 minutes and exa
eee (c) Use a flow rate of 1.5 mL per minute. 365 nm).
etN ws
MOBILE PHASE
(e) Use a detection wavelength of 278 nm. 10 volumes of acetonitrile, 20 vol
(f) Inject 5 wL of each solution. 40 volumes of dichloromethane an of methanol.
MOBILE PHASE CONFIRMATION
13 volumes of acetonitrile and 87 volumes of a 0.245% w/v The principal bandin the chromatogram obtained with
solution of orthophosphoric acid the pH of which has been solution (1) corresponds to thatin the chrom togram
adjusted to 3.0 with triethylamine. obtained with solution (2). The principal band in the
DETERMINATION OF CONTENT chromatogram obtained with solution (3) appears as a single,
compact band.
wAe a4
awe awl
Calculate the content of C;7H,3FN30O3 in the infusion using
wen
aS
AA
a
the declared content of C;7H;sFN303,HCI in ciprofloxacin B. In the Assay, the retention time of the principal peak in
hydrochloride BPCRS. Each mg of C;7H;3sFN303,HC! is the chromatogram obtained with solution (1) is the same as
equivalent to 0.9010 mg of C,;7H;3FN3Q3. that of the principal peak in the chromatogram obtained with
solution (2).
STORAGE
Ciprofloxacin Infusion should be protected from light. TESTS
It should not be refrigerated. Dissolution
LABELLING
The quantity of active ingredient is stated in terms of the Appendix XII Bl.
equivalent amount of ciprofloxacin.
we yee
II-328 Ciprofloxacin Preparations 2016
TEST CONDITIONS the area of any peak corresponding to 1-cyclopropyl-6-fluoro-

(a) Use Apparatus 2, rotating the paddle at 50 revolutions 7-(piperazin-1-yl)quinolin-4(1H)-one (ciprofloxacin
per minute. impurity E) is not greater than 1.5 times the area of the
(b) Use 900 mL of water, at a temperature of 37°, as the principal peak in the chromatogram obtained with solution
medium. (4) (0.3%)5
PROCEDURE
(1) After 30 minutes withdraw a 10 mL sample of the solution (4) (0.2%);
suitably diluted with water, if necessary, at the maximum at
peak corresponding to ciprofloxacin impurity C, is not
276 nm, Appendix IT B, using dissolution medium in the
reference cell.
loride BPCRS in water at the maximum at
276 nm using. tion medium in the reference cell.
solution (4) (0.05%).
DETERMINATI(
ASSAY
in the medium from’tt
declared content of C,7H
solutions.
hydrochloride BPCRS. Eac
equivalent to 0.9010 mg of (1) Add a quantity of the powdered tablets containing the
equivalent of 2 g of ciprofloxacin to 750 mL of the mobile
LIMIT phase, mix with the aid of ultrasound for 20 minutes, add
ra any
The amount of ciprofloxacin rel sss than 80% of sufficient mobile phase to produce 1000 mL and mix. Filter
the stated amount. a portion of the resulting suspension (Whatman GF/Cfilter
Related substances is suitable) and dilute the filtrate with sufficient mobile phase
Carry out the method for liquid chromatography, to produce a solution containing the equivalent of 0.05% w/v
Appendix III D, using the following solutions. of ciprofloxacin.
(1) Use solution (1) as described under Assay. (2) 0.058% w/v of ciprofloxacin hydrochloride BPCRS in the
(2) 0.05% w/v of ciprofloxacin impurity standard BPCRS in, mobile phase.
mobile phase. HROMATOGRAPHIC CONDITIONS
(3) Dilute 1 volume of solution (1) to 100 volumes with the “ stainless steel column (25 cm x 4.6 mm) packed
mobile phase and further dilute 1 volume to 2 volumes. activated octadecylsilyl silica gel for chromatography
(4) Dilute 1 volume of solution (1) to 100 volumes with the icleosil 120-C18 and LiChrospher 100 RP 18 are
mobile phase and further dilute 1 volume to 5 volumes.
be used.
For solution (1) allow the chromatography to proceed for
2.3 times the retention time of ciprofloxacin. (e) Use a detection ways
When the chromatograms are recorded under the prescribed (f) Inject 5 uL of each sehut
conditions the retention time of ciprofloxacin is about MOBILE PHASE
9 minutes. Retention times relative to ciprofloxacin are: 13 volumes of acetoniurile an
impurity E, about 0.4; impurity F, about 0.5; impurity B,
about 0.6; impurity C, about 0.7; impurity D, about 1.2. adjusted to 3.0 with triethylamine.
SYSTEM SUITABILITY
to ciprofloxacin impurity B and ciprofloxacin impurityC 1s at hydrochloride BPCRS. Each mg of C,7H,sFN303,H
least 1.3. equivalent to 0.9010 mg of C,7H;gFN303.
LIMITS
LABELLING
Identify any peaks in the chromatogram obtained with The quantity of active ingredient is stated in terms of the
solution (1) corresponding to ciprofloxacin impurities B, C, equivalent amount of ciprofloxacin.
D and E using solution (2) and multiply the area of these
peaks by the following correction factors: 0.7, 0.6, 1.4 and IMPURITIES
6.7 respectively. The impurities limited by the requirements of this
monograph include impurities B, C, D, E andF listed under
Ciprofloxacin Hydrochloride.
7-[(2-aminoethyl)amino]-1-cyclopropy!-6-fluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid (ciprofloxacin impurity C)
is not greater than the area of the principal peak in the
2016 Cisplatin Preparations III-329
corresponding to sodium chloride and

Cisplatin Injection trichloroammineplatinate is at least 2.0.
Action and use LIMITS
Platinum-containing cytotoxic. In the chromatogram obtained with solution (2):
DEFINITION
trichloroammineplatinate 1s not greater than the area of the
Cisplatin Injection is a sterile solution of Cisplatin. It is either
supplied as a ready-to-use solution or it is prepared by
(1) 3.0%).
dissolving Cisplatin for Injection in the requisite amount of
Water for Injections immediately before use. Transplatin
The injection complies with the requirements stated under Not more than 2.0% when determined by the method for
Parenteral, Preparations. liquid chromatography, Appendix II D, using the following
solutions. Where specified, use as the solvent a 0.9% w/v
a ready-to-use solution, the injection complies
solution of sodium chloride (saline solution).
requirements.
(1) Add 10 mL of a 0.005% w/v solution of
transplatin BPCRS in saline solution to 25 mg of
cisplatin BPCRS, dilute to 25 mL with saline solution, shake
for 30 minutes to effect dissolution and add sufficient saline
solution to produce 50 mL (solution A). Mix 5 mL ofa
With the exception of ide freshly prepared 0.5% w/v solution of thiourea, 5 mL of
procedures protected from light. 1m hydrochloric acid and 10 mL of solution A, heat an aliquot
in a reaction vial at 60° for 1 hour and cool.
IDENTIFICATION
(2) Prepare in the same manner as solution (1) but using
10 mL of the injection diluted, if necessary with saline
Ne NS
350 nm of a solution diluted, if necessgi solution to produce a solution containing 0.05% w/v of
0.1% w/v of Cisplatin exhibits a maximuiii’s Cisplatin in place of the 10 mL of solution A.
B. In the Assay, the chromatogram obtainé: (3) Prepare in the same manner as solution (1) but using a
(2) shows a peak with the same retention tint mixture of 10 mL of a solution containing 0.005% w/v of
principal peak in the chromatogram obtained with cisplatin BPCRS in saline solution and 10 mL of a
solution (1). : 0.005% w/v solution of transplatm BPCRS in saline solution
TESTS in place of 10 mL of solution A.
Acidity MATOGRAPHIC CONDITIONS
a stainless steel column (25 cm x 4.6 mm) packed
Trichloroammineplatinate ca gel with a chemically bonded, strongly acidic
Appendix HI D, using the following solutions. Prepare the
solutions immediately before use and protect from light.
(1) Dissolve sufficient potassium
trichloroammineplatinate BPCRS in a 0.9% w/v solution of
(d) Usea co
sodium chloride to produce a solution containing 0.0015% w/v
of trichloroammineplatinate.
(2) Use the injection diluted, if necessary, with a 0.9% w/v
ANA
wet Nee
Te te
solution of sodium chloride to produce a solution containing
flow rate of 2 mL per minute for 30,minutes, at 0.5 mL per
way
0.05% w/v of Cisplatin.

minute for 30 minutes and th sat 2 mL per minute
for 30 minutes.
(h) When the chromatogram obtain
with silica gel with a chemically bonded, strongly basic
recorded under the prescribed cond
quaternary ammonium anion-exchange coating (10 pm)
(Spherisorb SAX is suitable).
adjust the composition of the mobile phase’
the column.
below.
MOBILE PHASE
Ma
rae AA
2.5% w/v solution of potassium dihydrogen orthophosphate
wen we
Neon ee (e) Use a detection wavelength of 209 nm.
SYSTEM SUITABILITY
MOBILE PHASE
the column efficiency, determined on the peak due to
0.04% w/v solution of ammonium sulfate adjusted, if transplatin in the chromatogram obtained with solution (1),
necessary, to a pH of 5.8 to 6.0. is greater than 2,500 theoretical plates per metre and unless,
SYSTEM SUITABILITY in the chromatogram obtained with solution (3);
The test is not valid unless, in the chromatogram obtained the resolution factor between the peaks corresponding to
with solution (1), the resolution factor between the peaks cisplatin and transplatin is at least 1.7.
tea
III-330 Citalopram Preparations 2016
LIMITS principal peak in the chromatogram obtained with

In the chromatogram obtained with solution (2): solution (1).
the area of any peak corresponding to the derivative of TESTS
transplatin is not greater than the area of the corresponding Acidity
peak in the chromatogram obtained with solution (1) (2%). pH of a solution containing 0.1% w/v of Cisplatin, 3.5 to
ASSAY 6.5, Appendix V L.
Carry out the method for liquid chromatography, Trichloroammineplatinate
Appendix III D, using the following solutions. Complies with the test described for the ready-to-use solution
(1) 0.1% w/v of cisplatin BPCRS in a 0.9% w/v solution of above but preparing solution (2) in the following manner.
sodium chloride. (2) Dissolve the contents of a sealed container in sufficient of
(2) Use the.anjection being examined diluted, if necessary, a 0.9% w/v solution of sodium chloride to produce a solution
with a 0% ion of sodium chloride to produce a containing 0.05% w/v of Cisplatin.
rw.
solution Cong % wiv of Cisplatin. Transplatin

(3) 0.05% wiv of ¢ésplatin BPCRS and 0.005% wiv of Complies with the test described for the ready-to-use solution
transplatin BPCRS i 9% w/v solution of sodium chloride; above.
shake for 30 minut dissolution of the transplatin. (2) Prepare in the same manner as solution (1) but using
CHROMATOGRAPHIC 10 mL of a solution prepared by shaking the contents of a
sealed container with sufficient saline solution for 30 minutes
(a) Use a stainless steel c m x 4.6 mm) packed
to produce a solution containing 0.1% w/v of Cisplatin in
with particles of silica the sur hich has been modified
place of 10 mL of the solution of transplatin BPCRS and
by chemically bonded amine gr
cisplatin BPCRS.
NH, is suitable).
(b) Use isocratic elution and the mobil ASSAY
below. Carry out the method described for the ready-to-use
(c) Use a flow rate of 1.5 mL per minute. formulation above. For solution (2) dissolve the contents of a
sealed container in sufficient of a 0.9% w/v solution of sodium
chloride solution to produce a solution containing 0.1% w/v of
(e) Use a detection wavelength of 220 nm. Cisplatin.
(f) Inject 20 pL of each solution. Calculate the content of Cl,AH,N>Pt in the sealed container
(g) Ignore any peak with a long retention time. sing the declared content of Cl,AHgN>»Pt in cisplatin BPCRS.
MOBILE PHASE
the procedure with a further nine sealed containers.
téthe average content of Cl,H;N>Pt per container
SYSTEM SUITABILITY .

to transplatin and cisplatin is at least 3.5.
Calculate the content of Cl,H,N>Pt in the injection using the
declared content of Cl,AH,gN>Pt in cisplatin BPCRS.
Citalopram Ora
STORAGE
When supplied as a ready-to-use solution, Cisplatin Injection Action and use
should be protected from light. It should not be refrigerated. Selective serotonin reuptake 1
DEFINITION
CISPLATIN FOR INJECTION Citalopram Oral Drops contain Citalopr.
DEFINITION a suitable vehicle.
Cisplatin for Injection is a sterile material consisting of The oral drops comply with the requirements stat
Cisplatin with Mannitol and Sodium Chloride. It is supplied Liquids and with the following requirements.
in a sealed container. Content of citalopram, C,)H,,FN,O
The contents of the sealed container comply with the requirements 95.0 to 105.0% of the stated amount.
for Powders for Injections or Infusions stated under Parenteral.
IDENTIFICATION
A. Dilute the oral drops with sufficient methanol to produce a
Content of cisplatin, Cl.H,;N>Pt solution containing the equivalent of 0.001% w/v of
95.0 to 105.0% of the stated amount. citalopram. The light absorption of the resulting solution,
With the exception of identification test A, carry out the procedures Appendix II B, in the range 200 to 400 nm exhibits a
protected from light. : maximum at about 239 nm and a minimum at about
IDENTIFICATION 223 nm.
A. The light absorption, Appendix II B, in the range 230 to B. In the Assay, the principal peak in the chromatogram
350 nm of a solution containing 0.1% w/v of Cisplatin in obtained with solution (1) shows a peak with the same
0.1m hydrochloric acid exhibits a maximum only at 300 nm. retention time as the principal peak in the chromatogram
B. In the Assay, the chromatogram obtained with solution obtained with solution (2).
2016 Citalopram Preparations IIJ-331
TESTS ASSAY
Acidity Carry out the method for liquid chromatography,
pH, 4.0 to 6.5, Appendix V L. Appendix III D, using the following solutions in
Related substances 0.1m hydrochloric acid.
Carry out the method for liguid chromatography, (1) Dilute a weighed quantity of the oral drops containing
Appendix III D, using the following solutions in mobile the equivalent of 20 mg of citalopram to 100 mL.
phase A. (2) 0.025% w/v citalopram hydrobromide BPCRS.
(1) Dilute a suitable volume of the oral drops containing the CHROMATOGRAPHIC CONDITIONS
equivalent of 100 mg of citalopram to 50 mL.
(2) Dilute 1 volume of solution (1) to 100 volumes. Dilute with octadecylsilyl siica gel for chromatography (5 um) (Waters
1 volume of the resulting solution to 10 volumes. Symmetry C18 is suitable).
HIC CONDITIONS below.
“ss steel column (25 cm x 4.6 mm) packed (c) Use a flow rate of 1 mL per minute.
decylsilyl silica gel for chromatography (d) Use an ambient column temperature.
MOBILE PHASE
50 volumes of methanol and 50 volumes of a solution
containing 0.5 volumes of triethylamine and 100 volumes of
(e) Use a detection waveleng 0.6% w/v of anhydrous sodium dihydrogen orthophosphate,
(f) Inject 40 wL of each solution adjusted to pH 6.5 with 5m hydrochloric acid.
Mobile phase A 30 volumes of acetonitril The test is not valid unless, in the chromatogram obtained
a solution containing 1 volume of glacial acetg with solution (2), the retention time of the peak due to
250 volumes of water adjusted to pH 4.5 with 5x citalopram is between 7 and 11 minutes.
hydroxide. DETERMINATION OF CONTENT
Mobile phase B 30 volumes of a solution containing Determine the weight per mL of the oral solution,
1 volume of glacial acetic acid and 250 volumes of wate 0 endix V G, and calculate the content of Cz9H,,FN.2O,
adjusted to pH 4.5 with 5M sodium hydroxide, and 70 volu it in volume, using the declared content of
of acetonitrile. FN,O in citalopram hydrobromide BPCRS

0-15 95 5 isocratic

Citalopram
aN a
we Ne A
ve ae en Action and use ¢
Selective serotonin reuptake inhibiter; antidepressant.
aan
woe erie

conditions the retention time of impurity D relative to DEFINITION 3
citalopram (retention time, about 9.3 minutes) is about 0.9. Citalopram Tablets contain Citalopram Hydrobromide.
SYSTEM SUITABILITY The tablets comply with the requirements
The test is not valid unless, in the chromatogram obtained with the following requirements.
with solution (3), the resolution between the peaks due to Content of citalopram, C,)H,,;FN,O
impurity D and citalopram is at least 2.0. 95.0 to 105.0% of the stated amount.
LIMITS IDENTIFICATION
In the chromatogram obtained with solution (1): To a quantity of powdered tablets containing the equivalent
~w ae
hat
aes
Fa a
wwe we
the area of any secondary peak is not greater than twice the of 50 mg of citalopram, add 30 mL of water and filter.
area of the principal peak in the chromatogram obtained with To the filtrate, add 1 mL of 0.1m sodium hydroxide and
solution (2) (0.2%); extract with two 25-mL quantities of cyclohexane. Filter the
combined extract through silica treated filter paper
(Whatman 1PS is suitable), evaporate the filtrate to dryness
at 80° under nitrogen for approximately 1 hour. The infrared
absorption spectrum, Appendix II A, is concordant with the
Disregard any peak with an area less than the area of the reference spectrum of citalopram (RS 471).
vere d
(2) (0.1%).
II-332 Citalopram Preparations 2016
TESTS Time Mobile phase A Mobile phase B Comment

Dissolution (Minutes) (% viv) (% viv)
Comply with the dissolution test for tablets and capsules, 0-15 95 5 isocratic
wae ee
Appendix XII B1. 15-45 95-5 5-95 linear gradient
TEST CONDITIONS 45-55 5 95 isocratic
(a) Use Apparatus 2, rotating the paddles at 50 revolutions 55-60 5->95 95-5 linear gradient
per minute. 60-65 95 5 re-equilibration
PROCEDURE
conditions the retention times relative to citalopram
1inutes withdraw a sample of the medium and (retention time, about 9.3 minutes) are: impurity A, about
‘Awe
filter. Meg =the absorbance of the filtered medium, diluted 0.4 and impurity D, about 0.9.
¢ acid, if necessary, to produce a solution
SYSTEM SUITABILITY
Saw as
alent of 0.00056% w/v of citalopram, at

impurity D and citalopram is at least 2.0.
LIMITS
reference cell. In the chromatogram obtained with solution (1):
DETERMINATION OF CONT the area of the peak due to impurityA is not greater than
the medium from the absorbanc | obtained with solution (2) (0.3%);
declared content of C,)H»,FN2O, in citalo l the area of any other secondary peak is not greater than twice
hydrobromide BPCRS. : the area of the principal peak in the chromatogram obtained
LIMITS
The amount of citalopram released is not less tha 7
of the stated amount.
Related substances
LD isregard any peak with an area lessthan the area of the
phase A.
(1) Disperse a quantity of powdered tablets containing the
equivalent of 100 mg of citalopram in 40 mL of mobile sowder 20 tablets. Carry out the method for
phase A, mix with the aid of ultrasound for 10 minutes, tography, Appendix 'III D, using the following
shake for a further 10 minutes and dilute to produce 50 mL.
Centrifuge and use the supernatant liquid.
(2) Dilute 1 volume of solution (1) to 100 volumes. Dilute
1 volume of the resulting solution to 10 volumes.
15 minutes, shakefot | r+ 15 minutes and dilute to
(3) 0.0014% w/v of citalopram impurity standard BPCRS.
100 mL with 0.1m hydroehle id. Centrifuge and use the
CHROMATOGRAPHIC CONDITIONS supernatant liquid.
any ea

a ae
ye aw (2) 0.025% w/v citalopram hydrébromide BPCRS.

AN AY
CHROMATOGRAPHIC CONDITIONS -
(a) Use a stainless steel column (15 Q : -Semm) packed
with octadecylsilyl silica gel for chromatography
below.
Symmetry C18 is suitable).
(b) Use isocratic elution and the mobile phase di
below.
(e) Use a detection wavelength of 238 nm. (c) Use a flow rate of 1 mL per minute.
(f) Inject 40 pL of each solution. (d) Use an ambient column temperature.
Poarenare MOBILE PHASE (e) Use a detection wavelength of 240 nm.
ae Fa

wene
an 7
a solution containing | volume of glacial acetic acid and

MOBILE PHASE
250 volumes of water adjusted to pH 4.5 with 5m sodium
hydroxide. 50 volumes of methanol and 50 volumes of a solution
containing 100 volumes of 0.6% w/v of anhydrous sodium
Mobile phase B30 volumes of a solution containing
dihydrogen orthophosphate and 0.5 volumes of triethylamine
1 volume of glacial acetic acid and 250 volumes of water
adjusted to pH 6.5 with 5m hydrochloric acid.
adjusted to pH 4.5 with 5m sodium hydroxide, and 70 volumes
of acetonitrile. SYSTEM SUITABILITY
with solution (2), the retention time of the peak due to
citalopram is between 7 and 11 minutes.
maw en
2016 Clarithromycin Preparations IJI-333
DETERMINATION OF CONTENT (d) Use a column temperature of 40°.

Calculate the content of C2)H2,FN-,O in the tablets using (e) Use a detection wavelength of 205 nm.
the declared content of C.,)H2;FN,O in citalopram (f) Inject 10 wL of each solution.
hydrobromide BPCRS.
MOBILE PHASE
LABELLING
Mobile phase A A 0.476% w/v solution of potassium
The quantity of active ingredient is stated in terms of the dihydrogen orthophosphate, adjusted to pH 4.4 with either
equivalent amount of citalopram. 2M orthophosphoric acid or a 4.5% w/v solution of potassium
hydroxide, filtered through a C18 filtration kit (3M Empore is
suitable).
Clarithromycin for Infusion Mobile phase B- acetomtrile R1.

ea

Clarithromycin Wit
sealed container. 36-42 75 25 re-equilibration
The contents of the sealed

for Powders for Injections When the chromatograms are recorded using the prescribed
Preparations and with the fo conditions the retention times relative to clarithromycin
Content of clarithromycin, 5 ; (retention time = about 11 minutes) are:
95.0 to 105.0% of the stated amount. impurity I = about 0.38; impurity A = about 0.42;
impurity J= about 0.63; impurity L = about 0.74;
IDENTIFICATION
impurity B = about 0.79; impurity M = about 0.81;
Shake a quantity of the contents of a sealec impurity C = about 0.89; impurity D = about 0.96;
containing 0.5 g of Clarithromycin with 10 mL
impurity N = about 1.15; impurity E = about 1.27;
extract with 20 mL of dichloromethane. Separate’ impurity F = about 1.33; impurity P = about 1.35;
dichloromethane layer, wash with 5 mL of water, fi
impurity O = about 1.41; impurity K = about 1.59;
through anhydrous sodium sulfate and evaporate the filtr impurity G = about 1.72; impurity H = about 1.82.
dryness under a stream of nitrogen. The infrared absorpti a
EM SUITABILITY
spectrum of the residue, Appendix II A, is concordant with“
the reference spectrum of clarithromycin (RS 424). t is not valid unless:
TESTS hromatogram obtained with solution (2), the

factor of the peak due to clarithromycin is less than
Acidity
pH of a solution containing 5% w/v of Clarithromycin, 4.0 to
6.0, Appendix V L. rath obtained with solution (4), the peak-to-
t 3.0 where H, is the height above the
baseline of thé pe > to impurity D and H, is the height
A solution containing 5% w/v of Clarithromycin in carbon
above the baselifie ¢ &lowest point of the curve separating
dioxide-free water is not more opalescent than reference
this peak from the o clarithromycin;
suspension IT, Appendix IV A, and not more intensely
coloured than reference solution Y7, Appendix IV B, the chromatogram obtaifie h solution (4), closely
Method II. resembles the chromatog# supplied with clarithromycin for
peak identification EPCRS.
Related substances
LIMITS
Appendix III D, using the following solutions. Identify any peaks in the chromato
(1) Dissolve a quantity of the contents of a sealed container solution (1) corresponding to impuriti
containing 75 mg of Clarithromycin in 25 mL of water, mix solution (4) and multiply the areas of the :
with the aid of ultrasound and add sufficient acetomtrile R1 to corresponding correction factors; impurity €
impurity H, 0.15.
produce 50 mL.
mixture of equal volumes of acetonitrile RI and water. the area of any secondary peak is not greater than twice the
mixture of equal volumes of acetonitrile R1 and water. solution (3) (1%);
(4) 0.15% w/v of clarithromycin for peak identification EPC.RS not more than four such peaks have an area greater than
in a mixture of equal volumes of acetonitrile R1 and water.
(a) Use a stainless steel column (10 cm x 4.6 mm) packed than 7 times the area of the principal peak in the
with octadecylsilyl sihca gel for chromatography (3 um) chromatogram obtained with solution (3) (3.5%).
(Phenomenex Hypersil BDS is suitable). Disregard any peak with an area less than 0.2 times the area
(b) Use gradient elution and the mobile phase described of the principal peak in the chromatogram obtained with
below. solution (3) (0.1%). Disregard any peaks eluting before
(c) Use a flow rate of 1.1 mL per minute. impurity I and after impurity H.
IW-334 Clarithromycin Preparations 2016
Water IDENTIFICATION
Not more than 3.0% w/w, Appendix IX C. Use 0.5 g. Shake a quantity of the powdered tablets containing 0.5 g of
ay wns
wie wtetl
ASSAY Clarithromycin with 10 mL of water and extract with 20 mL

of dichloromethane. Separate the lower dichloromethane layer
and centrifuge. Filter the supernatant (Whatman GEF/C is
suitable) and evaporate to dryness. The infrared absorption
spectrum of the residue, Appendix II A, after drying under
vacuum at room temperature for 2 hours, is concordant with
the reference spectrum of clarithromycin (RS 424).
(1) Dissolve a quantity of the mixed contents of the 10
TESTS
containers containing 0.5 g of Clarithromycin in 10 mL of
water; add 50 mL ofwater and 25 mL of methanol and mix Dissolution
eee ad
Carry out the dissolution test for tablets and capsules,
Appendix XII BI.
we Nee
enw jlumes of the resulting solution to

obile phase, mix well and filter. TEST CONDITIONS

clarithromycin BPCR , per minute.
mobile phase. (b) Use 900 mL of a solution containing 1000 volumes of a
1.361% w/v solution of sodium acetate and 350 volumes of
0.1M acetic acid, adjusted to pH 5.0 with 0.1m acetic acid, at a
temperature of 37° + 0.5°, as the medium.
woos et
PROCEDURE
with end-capped octadecylsilyl silica gel fo After 45 minutes, withdraw a sample of the medium and
(5 um) (Nucleosil C18 is suitable). filter. Carry out the method for liguid chromatography,
(b) Use isocratic elution and the mobile pha Appendix III D, using the following solutions.
below. (1) Use the filtered dissolution medium, diluted with mobile
(c) Use a flow rate of 1 mL per minute. phase if necessary, to produce a solution expected to contain
0.011% w/v of Clarithromycin.
(2) 0.011% wywv of clarithromycin BPCRS in the mobile phase.
3) 0.011% w/v of each of clarithromycin BPCRS and
vithromycin impurity E BPCRSin the mobile phase.
MOBILE PHASE
GRAPHIC CONDITIONS
40 volumes of 0.067M potassium dihydrogen orthophosphate and
inless steel column (15 cm x 4.6 mm) packed
60 volumes of methanol, adjusted to pH 3.5 with
d octadecylsilyl silica gel for chromatography
ODS2 is suitable).
SYSTEM SUITABILITY
neand the mobile phase described
The assay is not valid unless:
in the chromatogram obtained with solution (2), the mL per minute.
symmetry factor of the peak corresponding to clarithromycin is
(d) Use a column tertiperaturé, of 50°.
between 0.8 and 2.0;
(e) Use a detection waveleng 10 nm.
factor between the two principal peaks is at least 2.0. (f) Inject 50 wL of each solution.
MOBILE PHASE
Calculate the content of clarithromycin, C3gH¢9NOj,3, in a 35 volumes of 0.067M potassium dihy ogen hophosphate and
container of average content weight from the chromatograms 65 volumes of methanol adjusted to pH#.G
obtained and from the declared content of C33H¢9.NOj3 in orthophosphonic acid.
clarithromycin BPCRS. When the chromatograms are recorded unde
conditions the approximate retention times for cl;
and clarithromycin impurity E are 4 and 6 minutes.
respectively.
Clarithromycin Tablets SYSTEM SUITABILITY

lr ree
sean
ra .
Action and use
Macrolide antibacterial. principal peaks is at least 2.0.
DEFINITION
Calculate the total content of clarithromycin, C3gH¢9NO};;3,
Clarithromycin Tablets contain Clarithromycin.
in the medium using the declared content of C3gHg9NOj,3 in
The tablets comply with the requirements stated under Tablets and clarithromycin BPCRS.
Related substances
Content of clarithromycin, C3,H,9NO;3 Carry out the method for liguid chromatography,
95.0 to 105.0% of the stated amount. Appendix III D, using the following solutions.
2016 Clarithromycin Preparations III-335
(1) Disperse a quantity of powdered tablets containing 75 mg LIMITS

of Clarithromycin in 40 mL of a mixture of equal volumes of Identify any peaks in the chromatogram obtained with
acetonitrile R1 and water (solution A), mix with the aid of solution (1) corresponding to impurities G and H using
ultrasound, add sufficient solution A to produce 50 mL and solution (4) and multiply the areas of these peaks by the
filter through a Whatman GF/C filter and then through a corresponding correction factors; impurity G, 0.27;
0.45-um PTFE filter. impurity H, 0.15.
(2) Dilute 5 volumes of solution (1) to 100 volumes with In the chromatogram obtained with solution (1):
solution A. the area of any secondary peak is not greater than twice the
(3) Dilute 10 volumes of solution (2) to 100 volumes with area of the principal peak in the chromatogram obtained with
solution A. solution (3) (1%) and not more than four such peaks have
(4) 0.15% w/v of clarithromycin for peak identification EPCRS an area greater than 0.8 times the area of the principal peak
; jon A.
RAPHIC CONDITIONS the sum of the areas of all the secondary peaks is not greater
ss steel column (10 cm x 4.6 mm) packed
chromatogram obtained with solution (3) 3.5%).
aca gel for chromatography (3 um)
solution (3) (0.1%). Disregard any peaks eluting before
impurity I and after impurity H.
ASSAY
(1) Finely powder a quantity of tablets containing 2 g of
MOBILE PHASE Clarithromycin and quantitatively transfer the powder to a
volumetric flask using about 350 mL of methanol. Mix with
the aid of ultrasound for 15 minutes, shake vigorously for
15 minutes, allow to cool, add sufficient methanol to produce
500 mL and mix. Filter the solution (Whatman GF/C paper
suitable). is suitable), dilute 1 volume of the filtrate to 40 volumes with
Mobile phase B_ acetonitrile R1. mobile phase and filter through a 0.45-um filter.
*Q.01% wiv of clarithromycin BPCRS in the mobile phase.
0.01% w/v of each of clarithromycin BPCRS and
(Minutes) (% v/v) (% viv)


grams are recorded under the prescribed
imate retention times for clarithromycin
When the chromatograms are recorded using the prescribed

tye conditions the retention times relative to clarithromycin
(retention time = about 11 minutes) are:
impurity I = about 0.38; impurity A = about 0.42;
impurity J = about 0.63; impurity L = about 0.74;
impurity B = about 0.79; impurity M = about 0.81; DETERMINATION OF CONTENT
impurity C = about 0.89; impurity D = about 0.96;
impurity F = about 1.33; impurity P = about 1.35;
impurity G = about 1.72; impurity H = about 1.82.
aye
Te
Pv
ete
AY
aww nS
ALN AN?
SYSTEM SUITABILITY Prolonged-release Clarithromycin Tablets
vane sn
Ne
Action and use

in the chromatogram obtained with solution (2) the symmetry Macrolide antibacterial.
factor of the peak due to clarithromycin is less than 1.75;
Prolonged-release Clarithromycin Tablets from different
in the chromatogram obtained with solution (4) the peak-to- manufacturers, whilst complying with the requirements of the
valley ratio is at least 3.0 where H, is the height above the monograph, are not interchangeable unless otherwise justified and
baseline of the peak due to impurity D and H, is the height authorised.
this peak from the peak due to clarithromycin; DEFINITION
the chromatogram obtained with solution (4) closely Prolonged-release Clarithromycin Tablets contain
resembles the chromatogram supplied with clarithromycin for Clarithromycin. They are formulated so that the medicament
peak identification EPCRS. is released over a period of several hours.
II-336 Clarithromycin Preparations 2016
PRODUCTION When the chromatograms are recorded using the prescribed

A suitable dissolution test is carried out to demonstrate the conditions the retention times relative to clarithromycin
appropriate release of Clarithromycin. The dissolution profile (retention time = about 11 minutes) are:
reflects the in vivo performance which in turn is compatible impurity I = about 0.38; impurity A = about 0.42;
with the dosage schedule recommended by the manufacturer. impurityJ= about 0.63; impurity L = about 0.74;
The tablets comply with the requirements stated under Tablets and impurity B = about 0.79; impurity M = about 0.81;
with the following requirements. impurity C = about 0.89; impurity D = about 0.96;
Content of clarithromycin, C33,H<¢9.NO;3
impurity F = about 1.33; impurity P = about 1.35;
IDENTIFICATION impurity G = about 1.72; impurity H = about 1.82.
Shake a quantity of the powdered tablets containing 0.5 g of SYSTEM SUITABILITY
Clarithromyé with 10 mL of water and extract with 20 mL
of dichloromethang,<Separate the lower dichloromethane layer
and centrifiige r the supernatant (Whatman GF/Cis in the chromatogram obtained with solution (2) the symmetry
suitable) and€\ ite to dryness. The infrared absorption factor of the peak due to clarithromycin is less than 1.75;
yppendix II A, after drying under in the chromatogram obtained with solution (4) the peak-to-
vacuum at room t or 2 hours, is concordant with valley ratio is at least 3.0 where Hy, is the height above the
the reference spectrum omycin (RS 424). baseline of the peak due to impurity D and H,, is the height
TESTS
this peak from the peak due to clarithromycin;
Related substances
resembles the chromatogram supplied with clarithromycin for
peak identification EPCRS.
(1) Disperse a quantity of oowdered tablets ¢
of Clarithromycin in 40 mL of a mixture @ LIMITS
acetonitrile R1 and water (solution A), mix wil Identify any peaks in the chromatogram obtained with
ultrasound, add sufficient solution A to produ solution (1) corresponding to impurities G and H using
filter through a Whatman GF/C filter and then solution (4) and multiply the areas of these peaks by the
0.45-um PTFE filter. corresponding correction factors; impurity G, 0.27;
(2) Dilute 5 volumes of solution (1) to 100 volumes wit impurity H, 0.15.
solution A. n the chromatogram obtained with solution (1):
(3) Dilute 10 volumes of solution (2) to 100 volumes with : of any secondary peakis not greater than twice the
solution A. @ principal peakin the chromatogram obtained with
(4) 0.15% w/v of clanthromycin for peak identification EPCRS (1%) and not more than four such peaks have
in solution A. ater than 0.8 times the area of the pn peak
(Phenomenex Hypersil BDS is suitable).
romatogram obtained with
below.
peaks eluting before
oles (c) Use a flow rate of 1.1 mL per minute.
MN (d) Use a column temperature of 40°.
a (e) Use a detection wavelength of 205 nm.
MOBILE PHASE
Mobile phase A A 0.476% w/v solution of potassium
dihydrogen orthophosphate, adjusted to pH 4.4 with either 2m
orthophosphoric acid or a 4.5% w/v solution of potassium
hydroxide, filtered through a C18 filtration kit (3M Empore is 15 minutes, allow to cool, add sufficient methanol to produce
oe suitable). 500 mL and mix. Filter the suspension (Whatman GF/C
erg Mobi B ‘trile R1. paper is suitable), dilute 1 volume of the filtrate to
59 obile phase acetonitrile 40 volumes with mobile phase and filter through a 0.45-um
Leg Use the following gradient. filter.
oO (2) 0.01% w/v of clarithromycin BPCRS in the mobile phase.

Time Mobile phase A Mobile phase B Comment (3) 0.01% w/v of each of clarithromycin BPCRS and
(Minutes) (% viv) (% viv) clarithromycin impurity E BPCRS in the mobile phase.
. 9, 9 ° e . ° . °
0-32 7540 25-60 linear gradient CHROMATOGRAPHIC CONDITIONS
32-34 40 60 isocratic (a) Usea stainless steel column (15 cm x 4.6 mm) packed
Soe 34-36 4075 60-25 linear gradient with end-capped octadecylsilyl silica gel for chromatography
2 36-42 75 25 re-equilibration (5 um) (Superspher ODS2 is suitable).
“ 4
caw os
Aen
ae aN
2016 Clemastine Preparations III-337
(b) Use isocratic elution and the mobile phase described (b) Use isocratic elution and the mobile phase described
below. below.
(c) Use a flow rate of 1.5 mL per minute. (c) Use a flow rate of 1 mL per minute.
wintet |
(d) Use a column temperature of 50°. (d) Use an ambient column temperature.
(e) Use a detection wavelength of 210 nm. (e) Use a detection wavelength of 220 nm.
(f) Inject 50 uwL of each solution. (f) Inject 10 wL of each solution.
35 volumes of 0.067M potassium dihydrogen orthophosphate and 0.1 volume of orthophosphoric acid, 45 volumes of acetonitrile
65 volumes ofmethanol adjusted to pH 4.0 with and 55 volumes of a 1% w/v solution of ammonium
SYSTEM SUITABILITY
peaks due to clemastine fumarate and 1-(4-chloropheny]l)-1-
phenylethanol in the chromatogram obtained with solution
(3) is at least 2.2.
The test is not va the chromatogram obtained LIMITS
with solution (3), the tor between the two In the chromatogram obtained with solution (1):
the area of any peak corresponding to 1-(4-chlorophenyl)-1-
phenylethanol is not greater than the area of the peak in the
sme la
twa N ee
Related substances
(1) Add 20 mL of water, 20 mL of a saturated solution of
Clemastine Oral Solution sodium chlonde and 2 mL of 13.5M ammonia to a quantity of
the oral solution containing the equivalent of 8 mg of
Action and use clemastine, extract with four 40 mL quantities of
Histamine H, receptor antagonist; antihistamine. dichloromethane, washing each extract with the same 40 mL
DEFINITION
Clemastine Oral Solution contains Clemastine Fumarate in
suitable vehicle. eé to dryness under the same conditions and dissolve
The oral solution complies with the requirements stated under Oral uein 4 mL ofmethanol.
Content of clemastine, C,,H,,CINO
IDENTIFICATION
A. In the test for Related substances, the principal spot in the
Saal
chromatogram obtained with solution (2) corresponds to that (6) 0.0054% w/v of 2-(2 dro ethyl)-1-
in the chromatogram obtained with solution (3). methylpyrroldine BPCRS.
B. In the Assay, the retention time of the principal peak in CHROMATOGRAPHIC CONDITIO
(a) Use as the coating silica gel 6 :
(b) Use the mobile phase as described, bel
Le nee
solution (2).
TESTS
_ (d) Develop the plate to 15 cm.
1-(4-Chlorophenyl)-1-phenylethanol
Carry out the method for higuid chromatography, (e) After removal of the plate, dry it in a current’of cold air
Appendix III D, using the following solutions in a mixture of for 5 minutes, spray with a freshly prepared mixture of
25 volumes of acetonitrile and 75 volumes of a 1% w/v 1 volume of potassium iodobismuthate solution and 10 volumes
ete solution of ammonium dihydrogen orthophosphate. of 2M acetic acid and then with hydrogen peroxide solution
Awad
(10 vol). Cover the plate immediately with a glass plate of

(1) Dilute a quantity of the oral solution containing the
the same size and examine the chromatograms after
equivalent of 0.5 mg of clemastine to 25 mL.
2 minutes.
(2) 0.00008% w/v of 1-(4-chlorophenyl)-1-
MOBILE PHASE
phenylethanol BPCRS.
(3) 0.000335% w/v of clemastine fumarate BPCRS and 1 volume of 13.5mM ammonia, 20 volumes of methanol and
0.00008% w/v of 1-(4-chlorophenyl)-1-phenylethanol BPCRS. 80 volumes of stabiliser-free tetrahydrofuran.
SYSTEM SUITABILITY
(a) A stainless steel column (10 cm x 4.6 mm) packed with The test is not valid unless the chromatogram obtained with
end-capped octadecylsilyl silica gel for chromatography (5 wm) solution (5) shows two clearly separated spots.
4
—
IlI-338 Clemastine Preparations 2016
In the chromatogram obtained with solution (1): A. In the test for Related substances, the principal spot in the
we te!
any spot corresponding to 2-(2-hydroxyethyl)-1- chromatogram obtained with solution (2) corresponds to that
methylpyrrolidine is not more intense than the spot in the in the chromatogram obtained with solution (3).
chromatogram obtained with solution (6) (2%, with reference B. In the test for 1-(4-Chlorophenyl)-1-phenylethanol, the
to clemastine fumarate); retention time of the principal peak in the chromatogram
any orange-brown secondary spot is not more intense than the obtained with solution (1) is the same as that of the peak in
spot in the chromatogram obtained with solution (4) (0.5%, the chromatogram obtained with solution (3).
with reference to clemastine fumarate). TESTS
Disregard any spot remaining on the line of application and 1-(4-Chloropheny]l)-1-phenylethanol
ith an Rf value greater than that of the principal Carry out the method for liguid chromatography,
(1) Add to a quantity of the powdered tablets, containing the
equivalent of 10 mg of clemastine, 200 mL of a mixture of
solution of ammonium dihydrogen orthophosphate, shake
vigorously for 45 minutes, centrifuge at a speed of at least
ine to 20 mL with a mixture
4000 revolutions per minute for 10 minutes and use the
79. volumes of a 1% w/v
cA we t
supernatant liquid.
solution of ammoniumdihyd 6
(2) 0.0000335% w/v of 1-(4-chlorophenyl)-1-
(2) 0.00335% w/v of clemasti
phenylethanol BPCRS in a mixture of 25 volumes of
acetonitrile and 75 volumes of a 1% w/v solution of
ammonium dihydrogen orthophosphate.
(3) 0.0067% w/v of clemastine fumarate BPCRS in a mixture
(a) A stainless steel column (10 cm x 4.6 mr of 25 volumes of acetonitrile and 75 volumes of a 1% w/v
end-capped octadecylsilyl silica gel for chromatograp solution of ammonium dihydrogen orthophosphate.
(Nucleosil C18 is suitable). |
(4) 0.000335% w/v of clemastine fumarate BPCRS and
(b) Use isocratic elution and the mobile phase describ | 0.000064% w/v of 1-(4-chlorophenyl)-1-phenylethanol BPCRS
below. nm a mixture of 25 volumes of acetonitrile and 75 volumes of a
(c) Use a flow rate of 1 mL per minute. solution of ammonium dihydrogen orthophosphate.
(d) Use an ambient column temperature. OGRAPHIC CONDITIONS
(e) Use a detection wavelength of 220 nm. atographic conditions described under Assay may
MOBILE PHASE
0.1 volume of orthophosphoric acid, 45 volumes of acetonitrile

and 55 volumes of a 1% w/v solution of ammonium peaks due len
dihydrogen orthophosphate. phenylethanol in th matogram obtained with solution
(4) is at least 2.2.
Determine the weight per mL of the oral solution, LIMITS
Appendix V G, and calculate the content of C2.;H».CINO, In the chromatogram o solution (1):
weight in volume, using the declared content of the area of any peak correspo: ig to 1-(4-chloropheny])-1-
C,,;H26CINO in clemastine fumarate BPCRS. phenylethanol is not greater thansthes of the peak in the
LABELLING chromatogram obtained with solution (2 %, calculated
The quantity of the active ingredient is stated in terms of the with reference to clemastine fumarate)””
equivalent amount of clemastine. Related substances
Carry out the method for thin-layer chromatog;
Appendix III A, using the following solutions. «
equivalent of 8 mg of clemastine with 4 mL of methanol for
Clemastine Tablets 15 minutes, centrifuge at 4000 revolutions per minute for
10 minutes and use the supernatant liquid.
tw Ae
Action and use

Histamine H, receptor antagonist; antihistamine. (2) Dilute 1 volume of solution (1) to 10 volumes with
methanol.
DEFINITION (3) 0.027% w/v of clemastine fumarate BPCRS in methanol.
Clemastine Tablets contain Clemastine Fumarate. (4) 0.00135% w/v of clemastine fumarate BPCRS in methanol.
The tablets comply with the requirements stated under Tablets and (5) 0.0135% w/v of each of clemastine fumarate BPCRS and
with the following requirements. diphenhydramine hydrochloride BPCRS in methanol.
Content of clemastine, C,,H>,CINO (6) 0.00135% w/v of 2-(2-hydroxyethyl)-1-
93.0 to 105.0% of the stated amount. methylpyrrolidine BPCRS in methanol.
Nw AS
Baton te
2016 Clindamycin Preparations ITI-339

(a) Use as the coating silica gel 60 F,5, (Merck plates are Calculate the content of C,;H2.CINO in each tablet using
ste we
suitable). the declared content of C,;H2,CINO in clemastine
Amn e ae
(b) Use the mobile phase as described below. fumarate BPCRS.

(c) Apply 20 wL of each solution. ASSAY
(d) Develop the plate to 15 cm. For tablets containing the equivalent of less than 2 mg
(e) After removal of the plate, dry in a current of cold air for and/or less than 2% w/w of clemastine
5 minutes, spray with a freshly prepared mixture of 1 volume Use the average of the individual results obtained in the test
of potassium todobismuthate solution and 10 volumes of for Uniformity of content.
2M acetic acid and then with hydrogen peroxide solution For tablets containing the equivalent of 2 mg or more
Cover the plate immediately with a glass plate of and 2% w/w or more of clemastine
eTetes ate
ee
solutions.
a,
(1) Add to a quantity of the powdered tablets containing the

80 volumes of
equivalent of 10 mg of clemastine 200 mL of a mixture of
SYSTEM SUITABI solution of ammonium dihydrogen orthophosphate, shake
The test is not valid vigorously for 45 minutes, centrifuge at a speed of at least
solution (5) shows two c 4000 revolutions per minute for 10 minutes and use the
LIMITS supernatant liquid.
of 25 volumes of acetonitrile and 75 volumes of a 1% w/v
solution of ammonium dihydrogen orthophosphate.
methylpyrrolidine is not more intense
chromatogram obtained with solution ( CHROMATOGRAPHIC CONDITIONS
reference to clemastine fumarate); (a) Use a stainless steel column (10 cm x 4.6 mm) packed
(5 um) (Nucleosil C18 is suitable),
with reference to clemastine fumarate). (b) Use isocratic elution and the mobile phase described
Disregard any spot remaining on the line of application
any spot with an Rf value greater than that of the principa se a flow rate of 1 mL per minute.
spot.
Tablets contaming the equivalent of less than 2 mg and/or
less than 2% w/w of clemastine comply with the
requirements stated under Tablets using the following
method of analysis. Carry out the method for liquid vophosphoric acid, 45 volumes of acetonitrile
chromatography, Appendix III D, using the following % wiv solution of ammonium
solutions.
(1) Vigorously shake one tablet with 40 mL of a mixture of
25 volumes of acetonitrile and 75 volumes of a 1% w/v Calculate the content of iH CINO in the tablets using
solution of ammonium dihydrogen orthophosphate for the declared content of 4,,CINO in clemastine
45 minutes and centrifuge until a clear supernatant liquid is fumarate BPCRS.
obtained.
LABELLING
The quantity of the active ingredient stated.in terms of the
of 25 volumes of acetonitrile and 75 volumes of a 1% w/v
equivalent amount of clemastine.
solution of ammonium dihydrogen orthophosphate.
(5 um) (Nucleosil C18 is suitable). Clindamycin Capsules
Action and use
below.
Lincosamide antibacterial.
(d) Use an ambient column temperature. DEFINITION
(e) Use a detection wavelength of 220 nm. Clindamycin Capsules contain Clindamycin Hydrochloride.
(f) Inject 10 wL of each solution. The capsules comply with the requirements stated under Capsules
MOBILE PHASE
Content of clindamycin, C,;3H33;CIN,O,;S
0.1 volume of orthophosphoric acid, 50 volumes of acetonitrile
Ne and 50 volumes of a 1% w/v solution of ammonium
IW-340 Clindamycin Preparations 2016
IDENTIFICATION the sum of the areas of all the secondary peaks is not greater
A. Shake a quantity of the contents of the capsules than 3 times the area of the principal peak in the
containing the equivalent of 30 mg of clindamycin with chromatogram obtained with solution (2) (6%).
15 mL of chloroform, filter and evaporate the filtrate to Disregard any peak with an area less than 0.025 times the
dryness. The zfrared absorption spectrum of the residue, area of the principal peak in the chromatogram obtained with
Appendix IT A, is concordant with the reference spectrum of solution (2) (0.05%).
clindamycin hydrochloride (RS 064).
Water
B. In the Assay, the chromatogram obtained with solution The contents of the capsules contain not more than 7.0%
(1) shows a peak with the same retention time as the w/w of water, Appendix [IX C. Use 1 g.
solution (2). ASSAY
rays
SS (1) Shake a quantity of the mixed contents of 20 capsules

containing the equivalent of 50 mg of clindamycin with
50 mL of the mobile phase for 15 minutes and filter
(1) Shake a quantity
ui (Whatman GF/C filter is suitable).
containing the eq
(2) 0.11% w/v of chndamycin hydrochloride EPCRS in the
mobile phase.
oe (Whatman GF/C filter issu
ane (2) Dilute 1 volume of solutii
Oe mobile phase. The chromatographic conditions described under Related
wae wid
Net ow
(3) 0.1% w/v of clindamycin hyd
mobile phase. DETERMINATION OF CONTENT
CHROMATOGRAPHIC CONDITIONS Calculate the content of C;gH33CIN2OsS in the capsules

using the declared content of C;3H33CIN,O;5S,HCI in
(a) Use a stainless steel column (25 cm x 4.4
clindamycin hydrochloride EPCRS. Each mg of
with octadecylsilyl silica gel for chromatography (5°
, C,3H33CIN20O5S,HCI is equivalent to 0.9209 mg of
BDS 5 um is suitable).
C,3H33CIN2O5S.
below. LABELLING
(c) Use a flow rate of 1 mL per minute. The quantity of active ingredient is stated in terms of the
amount of clindamycin.
(e) Use a detection wavelength of 210 nm. TES
ities limited by the requirements of this
(f) Inject 20 pl of each solution.
y include those listed under Clindamycin
(g) For solution (1), allow the chromatography to proceed Hydr
for at least twice the retention time of the principal peak. .
MOBILE PHASE
| solution of potassium dihydrogen orthophosphate adjusted to : . ee
2 pH 7.5 with a 25% w/v solution of potassium hydroxide. Clindamycin In
oh When the chromatograms are recorded under the prescribed Action and use
oe conditions the retention time of clindamycin is about Lincosamide antibacterial.
10 minutes.
nen 4
is SYSTEM SUITABILITY DEFINITION

Clindamycin Injection is a sterile so
oe The test is not valid unless the chromatogram obtained with
Phosphate in Water for Injections.
ni solution (3) shows peaks with retention times relative to
clindamycin of about 0.4 [Ph Eur impurity A (lincomycin)], The injection complies with the requirements stateg'und
about 0.65 [Ph Eur impurity B (clindamycin B)] and about Parenteral Preparations and with the following requig
0.8 [Ph Eur impurity C (7-epiclindamycin)]. Content of clindamycin, C,;3;H3;CIN,O-;S
LIMITS
Bey In the chromatogram obtained with solution (1): CHARACTERISTICS
aol the area of any peak corresponding to impurity B is not An almost colourless solution.
greater than the area of the principal peak in the IDENTIFICATION
chromatogram obtained with solution (2) (2%); A. Carry out the method for thin-layer chromatography,
the area of any peak corresponding to impurity C is not Appendix III A, using the following solutions.
greater than twice the area of the principal peak in the (1) Dilute a volume of the injection containing the equivalent
chromatogram obtained with solution (2) (4%); of 50 mg of clindamycin to 10 mL with methanol.
noe the area of any other secondary peak is not greater than half (2) 0.5% wy of clindamycin phosphate EPCRS in methanol.
Soh the area of the principal peak in the chromatogram obtained
oe with solution (2) (1%): CHROMATOGRAPHIC CONDITIONS
rato (a) Use as the coating silica gel GF 254.
TS (b) Use the mobile phase as described below.
— pn nr
2016 Clobazam Preparations III-341
(c) Apply 10 wL of each solution. CHROMATOGRAPHIC CONDITIONS
(d) Develop the plate to 15 cm. (a) Use a stainless steel column (25 cm x 4.6 mm) packed
(e) After removal of the plate, allow it to dry in air and spray with octylsilyl silica gel for chromatography (5 um) (Zorbax C8
sea
eaten A with dilute potassium todobismuthate solution. is suitable).
MOBILE PHASE
below.
1.5 volumes of 18m ammonia, 30 volumes of toluene and
CONFIRMATION
solution (1) corresponds to that in the chromatogram (f) Inject 20 wL of each solution.
obtained with solution (2). (g) Allow the chromatography to proceed for 3 times the
retention time of the peak due to clindamycin.
The order of elution of the peaks in the chromatogram
Fae” aa
obtained with solution (3) is: lincomycin hydrochloride,

clindamycin phosphate and benzyl alcohol.
MOBILE PHASE
25 volumes of acetonitrile R1 and 75 volumes of a 1.36% w/v
solution of potassium dihydrogen orthophosphate adjusted to
pH 2.5 with orthophosphoric acid.
SYSTEM SUITABILITY
afficient mobile with solution (3), the resolution factor between the peaks due
“ivalent of to lincomycin hydrochloride and clindamycin phosphate is at
0.3% w/v of clindamycin. least 7.7.
(2) 0.012% w/v of lincomycin hydrochloride B, DETERMINATION OF CONTENT
0.024% w/v of chndamycin phosphate EPCRS an Calculate the content of C,3H33CIN.O;S in the injection
0.0015% v/v of benzyl alcoholin the mobile phasé using the declared content of C;3H3,CIN,O¢PS in
CHROMATOGRAPHIC CONDITIONS chndamycin phosphate EPCRS. Each mg of C;3H34CIN2,OsPS
The chromatographic conditions described under Assay is equivalent to 0.8416 mg of C,;gH33CIN,O;S.
be used.
The order of elution of the peaks in the chromatogram ycin Injection should be stored at a temperature not
obtained with solution (2) is: lincomycin hydrochloride, 30°. It should not be refrigerated and it should not
clindamycin phosphate and benzyl alcohol.
SYSTEM SUITABILITY
to lincomycin hydrochloride and clindamycin phosphate is at
least 7.7.
LIMITS

8.0% by normahsation. complying with the requirements of hem
menograph, may not be
Disregard any peak due to benzyl alcohol. interchangeable.
Action and use
Benzodiazepine.
Dilute the injection in water BET to give a solution
containing the equivalent of 10 mg of clindamycin per mL DEFINITION
(solution A). The endotoxin limit concentration of solution A
Clobazam Oral Suspension is a suspension containing
is 6 IU of endotoxin per mL.
Clobazam in a suitable flavoured vehicle.
ASSAY The oral suspension complies with the requirements stated under
Carry out the method for guid chromatography, Oral Liguids and with the following requirements.
Content of clobazam, C,;H,3;CIN,O,
(1) Dilute a volume of the injection with sufficient mobile 95.0 to 105.0% of the stated amount.
phase to produce a solution containing the equivalent of
0.015% w/v of clindamycin. IDENTIFICATION
(2) 0.018% w/v of chndamycin phosphate EPCRS in the
mobile phase.
(1) Dilute a quantity of the oral suspension containing 10 mg
(3) 0.012% w/v of lincomycin hydrochloride BPCRS,
of Clobazam to 100 mL with methanol.
0.024% w/v of clindamycin phosphate EPCRS and
0.0015% v/v of benzyl alcohol in the mobile phase. (2) 0.01% w/v of clobazam BPCRS in methanol.
mS
my
8
take
- oe,
,
toy
IWI-342 Clobazam Preparations 2016

weet
te
oe
so
,
.
.
yO,
an
CHROMATOGRAPHIC CONDITIONS the area of any peak corresponding to desmethylclobazam is

(a) Use as the coating silica gel F54. not greater than the area of the principal peak in the
cae
(b) Use the mobile phase as described below. chromatogram obtained with solution (2) (0.5%);
ete Na
(c) Apply 10 uL of each solution. the area of any other secondary peak is not greater than the
the sum of the areas of all the secondary peaks, other than the
peak corresponding to desmethylclobazam, is not greater
MOBILE PHASE than five times the area of the principal peak in the
35 volumes of acetonitrile and 65 volumes of water. chromatogram obtained with solution (3) (1.0%).
CONFIRMATION Disregard any peak due to propyl hydroxybenzoate and any
peak with an area less than 0.5 times the area of the principal
spot in the chromatogram obtained with
AemN te
award
peak in the chromatogram obtained with solution (3) (0.1%).
ASSAY
(1) To a weighed quantity of the oral suspension containing
solution (2). 5 mg of Clobazam add 50 mL of the mobile phase and shake
TESTS vigorously for 20 minutes. Mix with the aid of ultrasound for
Acidity 40 minutes and further shake for 40 minutes. Add sufficient
pH, 4.5 to 5.5, Appendix mobile phase to produce 100 mL, centrifuge and use the
supernatant liquid.
Related substances
(2) To 25 mg of clobazam BPCRS add 25 mL of the mobile
awa
Carry out the method for liquid chromatography

phase and shake for 15 minutes. Add sufficient mobile phase
Appendix III D, using the following solut
to produce 50 mL and further dilute 10 volumes of this
(1) To a quantity of the oral suspension cont; solution to 100 volumes with the mobile phase.
Clobazam add 25 mL of the mobile phase and a
(3) 0.005% w/v of 7-chloro-1,5-dihydro-5-phenyl-1,5-
15 minutes. Mix with the aid of ultrasound for 15 nit
benzodiazepine-2,4(3H)-dione BPCRS (desmethylclobazam)
and shake for 15 minutes. Add sufficient mobile phase
and 0.05% w/v of propyl hydroxybenzoate in the mobile phase.
produce 50 mL, centrifuge and use the supernatant liqui
(2) Dilute 2.5 volumes of a 0.01% w/v solution of 7-chlo
1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione BPCRS™ stainless steel column (15 cm x 2.0 mm) packed
(desmethylclobazam) in methanol to 100 volumes with the apped octadecylsilyl silica gel for chromatography
mobile phase. ucleosil C18 is suitable).
(3) Dilute 2 volumes of solution (1) to 100 volumes with the ratic elution and the mobile phase described
mobile phase. Further dilute 10 volumes of this solution to
(4) 0.005% w/v of 7-chloro-1,5-dihydro-5-phenyl-1,5-
benzodiazepine-2,4(3H)-dione BPCRS (desmethylclobazam)
and 0.05% w/v of propyl hydroxybenzoate in the mobile phase.
MOBILE PHASE
aauvasn 30 volumes of acetonitrile a
we ete
SYSTEM SUITABILITY
we aes

below.
3.0.
Determine the weight per mL of the oral suspensiofi,
Appendix V G, and calculate the content of C;,H,3CIN,O,,
(g) For solution (1), allow the chromatography to proceed weight in volume, using the declared content of
ae AN
for twice the retention time of clobazam. C,6H,3CIN2O, in clobazam BPCRS.
MOBILE PHASE
STORAGE
30 volumes of acetonitrile and 70 volumes of water. Clobazam Oral Suspension should be protected from light.
SYSTEM SUITABILITY

propyl hydroxybenzoate and desmethylclobazam is at least
3.0.
LIMITS
ae
ee Ay
BaF Act
a
aw ae!
el
eh 8
2016 Clobazam Preparations III-343

Clobazam Tablets mobile phase. Further dilute 1 volume of this solution to
Clobazam Tablets from different manufacturers, whilst complying 10 volumes with the mobile phase.
with the requirements of the monograph, may not be
(3) Dilute 2.5 volumes of a 0.01% w/v solution of 7-chloro-
interchangeable.
1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione BPCRS
Action and use in methanol to 100 volumes with the mobile phase.
Benzodiazepine. (4) Dilute 1 volume of a 0.01% w/v solution of 7-chloro-1,5-
dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione BPCRS in
DEFINITION methanol to 2 volumes with a 0.1% w/v solution of
Clobazam Tablets contain Clobazam. clobazam BPCRS in mobile phase.
The tablets comply with the requirements stated under Tablets and (5) Dilute 1 volume of solution (2) to 2 volumes with
with the following requirements. methanol.

A. Shake a quantity e powdered tablets containing (3 um) (Nucleosil C18 is suitable).
20 mg of Clobazam w40
ith. . mL of dichloromethane, filter and (b) Use isocratic elution and the mobile phase described
evaporate the filtrate todry ess. Dissolve the residuein the below.
minimum amount of 7% “evaporate to dryness and dry (c) Use a flow rate of 0.25 mL per minute.
the residue at 105° for 1 The infrared absorption (d) Use a column temperature of 40°.
spectrum of the residue, Appe is concordant with
the reference spectrum of cloba ) |
B. In the Assay, the retention time e principal peak.in
the chromatogram obtained with solutic similar to (g) Allow the chromatography to proceed for twice the
that of the principal peak in the chromate retention time of clobazam.
solution (2). MOBILE PHASE
TESTS 30 volumes of acetonitrile and 70 volumes of water.

Dissolution SYSTEM SUITABILITY
Comply with the requirements in the dissolution test je The test is not valid unless, in the chromatogram obtained
TEST CONDITIONS -1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-
(a) Use Apparatus 2, rotating the paddle at 75 revolutions d'clobazam is at least 3.0.
per minute.
(b) Use 500 mL of 0.1m hydrochloric acid, at a temperature of matogram obtainedwith solution (1):
PROCEDURE épine-2,4(3H)-dioneiis not greater than
Carry out the method for liguid chromatography, ] peakin the chromatogram obtained
filter. Use the filtered medium, diluted with acetonitrile if area of the principal : eak
necessary, to produce a solution expected to contain solution (2) (0.2%);
0.001% w/v of Clobazam. the sum of the impurities
(2) 0.001% w/v of clobazam BPCRS in a mixture of equal Disregard any peak with an area
volumes of acetonitrile and water. principal peak in the chromatogr
CHROMATOGRAPHIC CONDITIONS solution (5) (0.1%).
The chromatographic conditions described under Related ASSAY
substances may be used. Inject 50 uL of each solution.
liquid chromatography,Appendix III D, using t fi
solutions.
Calculate the total content of clobazam, C,;¢.H,3CIN2Oz,, in
the medium using the declared content of C,;gH,3CIN2O> in (1) To a quantity of the powdered tablets containing 20 mg
clobazam BPCRS. of Clobazam add 80 mL of the mobile phase, mix with the
aid of ultrasound, add sufficient mobile phase to produce
LIMITS 100 mL and centrifuge. Dilute 1 volume of the supernatant
The amount of clobazam, C,.H,3CIN2O> released is not less liquid to 10 volumes with the mobile phase.
than 75% (Q) of the stated amount. (2) 0.002% w/v of clobazam BPCRS in the mobile phase.
Related substances (3) Dilute 1 volume of a 0.01% w/v solution of 7-chloro-1,5-
Carry out the method for liquid chromatography, dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione BPCRS in
Appendix III D, using the following solutions. the mobile phase to 2 volumes with a 0.1% w/v solution of
(1) To a quantity of the powdered tablets containing 25 mg clobazam BPCRS in the mobile phase.
of Clobazam add 25 mL of the mobile phase and mix with
the aid of ultrasound. Add sufficient mobile phase to produce
50 mL, centrifuge and use the supernatant liquid.
II-344 Clobetasol Preparations 2016
CHROMATOGRAPHIC CONDITIONS due to clobetasol propionate in the chromatogram obtained

The chromatographic conditions described under Related with solution (1).
,v and
AUN
Aw aN
FLAS
ASSAY
SYSTEM SUITABILITY CAUTION Carry out the preparation of solutions (2) and (3) with
The Assay is not valid unless, in the chromatogram obtained full facial protection and wearing heat-resistant gloves.
with solution (3), the resolution between the peaks due to Carry out the method for liguid chromatography,
7-chloro-1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3.H)- Appendix III D, using the following solutions. Solution (1)
dione and clobazam is at least 3.0. contains 0.005% w/w of clobetasol propionate BPCRS and
0.01% w/v of beclometasone dipropionate BPCRS (internal
standard) in ethanol (50%). For solution (2) add 10 mL of
Calculate the content of C;5H,3CIN2O, in the tablets using
absolute ethanol to a quantity of the cream containing 1 mg of
the declared content of C,¢H,3CIN2O, in clobazam BPCRS.
Clobetasol Propionate, stopper firmly using a plastic stopper,
heat on a water bath with intermittent shaking until the
by the requirements of this cream is completely dispersed. Cool the contents in ice for
30 minutes, centrifuge and dilute 5 mL of the supernatant
A. 7-Chloro-1,3=dih -5-phenyl-1,5-benzodiazepine- liquid to 10 mL with water. Prepare solution (3) in the same
2,4(3H)-dione; 7- -phenyl-1,5-dihydro-3H-1,5- manner as solution (2) but add 5 mL of a 0.04% wiv
benzodiazepine-2,4- lesmethylclobazam; European solution of beclometasone dipropionate BPCRS in absolute
Pharmacopoeia impurity ethanol and 5 mL of absolute ethanol. Solutions (2) and (3)
may assume a gel-like appearance.
stationary phase C (5 um) (Spherisorb ODS 1 is suitable) and
Clobetasol Cream
eR AS
wes el
swine
maintained at 60°, (b) as the mobile phase with a flow rate of
2 mL per minute a mixture of 45 volumes of absolute ethanol
Action and use
and 55 volumes of water and (c) a detection wavelength of
Glucocorticoid.
240 nm.
DEFINITION Calculate the content of C,5;H3,CIFOs using peak areas and
Clobetasol Cream contains Clobetasol Propionate in the declared content of C,;H3,CIFOs in clobetasol
suitable basis.
Content of clobetasol propionate, C,;H;,CIFO;
IDENTIFICATION
Appendix III A, using silica gel GF 54 as the coating
substance and a mixture of 5 volumes of absolute ethanol,
10 volumes of acetone and 100 volumes of dichloromethane as Action and use
the mobile phase. Apply separately to the plate 10 pL of each Glucocorticoid.
of the following solutions. Prepare solution (1) in the
following manner. Transfer a quantity of the cream DEFINITION
containing 0.75 mg of Clobetasol Propionate to a 25-mL Clobetaso!l Cutaneous Foa ins Clobetasol Propionate
centrifuge tube, add 10 mL of methanol and heat in a water- in a suitable basis in a suitabl 48)
bath at 60° for 4 minutes. Remove from the water-bath and The cutaneous foam complies with the’
shake vigorously. Repeat the heating and shaking, cool to Medicated Foams and with the followi
room temperature, add 3.5 mL of water and mix. Centrifuge Content of clobetasol propionate, C,
for 10 minutes. Transfer 10 mL of the clear supernatant 95.0 to 105.0% of the stated amount.
liquid to a 100-mL separating funnel, add 1 g of sodium
IDENTIFICATION
chloride and 10 mL of water and mix. Add 5 mL of
dichloromethane and shake for 1 minute. Evaporate the hy,
dichloromethane layer to dryness in a current of nitrogen Appendix III A, using the following solutions.
oNwad
with gentle heating and dissolve the residue in 0.5 mL of (1) Transfer a quantity of the cutaneous foam containing
ae.
we ww 4
dichloromethane. Solution (2) contains 0.05% w/v of clobetasol 0.5 mg of Clobetasol Propionate to a 25-mL centrifuge tube,
ALN alte
ware 4
propionate BPCRS in dichloromethane. Solution (3) is a add 10 mL of methanol and heat in a water bath at 70° for
mixture of equal volumes of solutions (1) and (2). After 4 minutes. Remove from the water bath and shake
removal of the plate, allow it to dry in air and examine under vigorously. Repeat the heating and shaking, cool in ice for
ultraviolet light (254 nm). The principal spot in the 5 minutes and centrifuge. Evaporate 10 mL of the clear
chromatogram obtained with solution (1) corresponds to that supernatant liquid to dryness and dissolve the residue in
in the chromatogram obtained with solution (2). 1 mL of dichloromethane.
The principal spot in the chromatogram obtained with (2) 0.05% w/v of clobetasol propionate BPCRS in
solution (3) appears as a single compact spot. dichloromethane.
Nw
B. In the Assay, the chromatogram obtained with solution (3) Equal volumes of solutions (1) and (2).
2016 Clobetasol Preparations III-345

(a) Use as the coating silica gel F254. The test is not valid unless, in the chromatogram obtained
seme
LeAN (b) Use the mobile phase as described below.

impurity C and clobetasol propionate is at least 1.5.
tN et

(d) Develop the plate to 15 cm. LIMITS
(e) After removal of the plate, dry in air and examine under Use the chromatogram obtained with solution (3) to identify
ultraviolet light (254 nm). any peaks due to impurity F and impurity B and multiply the
areas of these peaks by the corresponding correction factors;
MOBILE PHASE
impurity F, 0.6 and impurity B, 0.7.
5 volumes of absolute ethanol, 10 volumes of acetone and In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity E is not
id unless the chromatogram obtained with chromatogram obtained with solution (2) (0.7%);
lars as a single compact spot. the area of any secondary peak is not greater than 0.5 times
solution (2). 2.5 tumes the area of the principal peak in the chromatogram
im obtained with solution obtained with solution (2) (2.5%).
(1) shows a peak withthe : : ation time as the peak Disregard any peak with an area less than the area of the
due to clobetasol propionate principal peak in the chromatogram obtained with solution
with solution (2). : (4) (0.1%).
TESTS ASSAY
Related substances Carry out the method for liquid chromatography,
Carry out the method for liquid chromatograp Appendix III D, using the following solutions.
Appendix III D, using the following solutions® Solution A Prepare a 0.04% w/v solution of beclometasone
phase. dipropionate BPCRS (internal standard) in ethanol (50%).
(1) Add 10 mL of mobile phase to a quantity of thé (1) Add 5 mL of absolute ethanol and 5 mL of solution A to a
cutaneous foam containing 1 mg of Clobetasol Propiofiat quantity of the cutaneous foam containing 1 mg of
heat on a water-bath with intermittent shaking until the “s asol Propionate, heat on a water-bath with intermittent
cutaneous foam is completely dispersed. Cool the contents in : until the cutaneous foam is completely dispersed.
ice for 30 minutes, centrifuge and dilute 5 mL of the contents in ice for 30 minutes, centrifuge and dilute
supernatant liquid to 10 mL. the supernatant liquid to 10 mL with water.
(2) Dilute 1 volume of solution (1) to 100 volumes. /v of clobetasol propionate BPCRS in a mixture
(3) 0.025% w/v of clobetasol for peak identification EPCRS. solution A and 3 volumes of ethanol (50%).
(4) Dilute 1 volume of solution (2) to 10 volumes. tition in the same manner as solution (1)
Solution (1) may assume a gel-like appearance.

verve
with octadecylsilyl silica gel for chromatography (3.5 um)
(Kromasil C18 is suitable).
below. (Spherisorb ODS1 is suitable)
(c) Use a flow rate of 1.0 mL per minute. (b) Use isocratic elution and the
below.
for 3 times the retention time of the principal peak. (f) Inject 20 nL of each solution.
Liwte ted
MLAS
ete
ee ae
50 volumes of acetonitrile and 50 volumes of a solution 45 volumes of absolute ethanol and 55 volumes of water.
containing 0.025mM ammonium acetate previously adjusted to SYSTEM SUITABILITY
pH 4.0 with glacial acetic acid. The test is not valid unless, in the chromatogram obtained
When the chromatograms are recorded under the prescribed with solution (2), the resolution between the peaks due to
conditions the retention times relative to clobetasol (retention clobetasol propionate and beclometasone dipropionate is at
time, about 9 minutes) are: impurity F, about 0.3; least 4.0.
impurity B, about 0.6, impurity C, about 0.9 and impurity E,
about 2.0.
Calculate the content of C,;H3.CIFOs; in the cutaneous
ean
foam using the ratios of the peak areas and the declared
sth
enw e
ao
A
content of C,;H32CIFOs in clobetasol propionate BPCRS.
IlI-346 Clobetasol Preparations 2016
IMPURITIES standard) in ethanol (50%). For solution (2) add 10 mL of

The impurities limited by the requirements of this absolute ethanol to a quantity of the ointment containing 1 mg
rR sla
Weve aw monograph include impurities A to G and J listed under of Clobetasol Propionate, stopper firmly usinga plastic
‘ways
ae el
Clobetasol Propionate and: stopper, heat on a water-bath with intermittent shaking until
the ointment is completely dispersed. Cool the contents in
ice for 30 minutes, centrifuge and dilute 5 mL of the
supernatant liquid to 10 mL with water. Prepare solution (3)
in the same manner as solution (2) but add 5 mL ofa
0.04% w/v solution of beclometasone dipropionate BPCRS in
absolute ethanol and 5 mL of absolute ethanol. Solutions (2)
and (3) may assume a gel-like appearance.
octadecylsilyl sitca gel for chromatography (5 wm) (Spherisorb
teewand
1.2 1-deo opanoylbetamethasone

ODS 1is suitable) and maintained at 60°, (b) as the mobile
45 volumes of absolute ethanol and 55 volumes of water and
(c) a detection wavelength of 240 nm.
Clobetasol Ointmen Calculate the content of C25H3.CIFOs using peak areas and
the declared content of C25H3.,CIFOs; in clobetasol
Action and use propionate BPCRS.
Glucocorticoid.
STORAGE
DEFINITION Clobetasol Ointment should be stored at a temperature not
Clobetasol Ointment contains Clobetasol ate ina exceeding 30°.
suitable basis. ‘
The omtment complies with the requirements stated

Semi-solid Preparations and with the following requi¥
Content of clobetasol propionate, C,;H3;,CIFO; Clobetasol Scalp Application
IDENTIFICATION
Appendix III A, using silica gel GF254 as the coating
10 volumes of acetone and 100 volumes of dichloromethane as
the mobile phase. Apply separately to the plate 10 wL of each
of the following solutions. Prepare solution (1) in the
following manner. Transfer a quantity of the ointment
containing 0.5 mg of Clobetasol Propionate to a 25-mL ropionate, C,;H3;,CIFO;
centrifuge tube, add 10 mL of methanol and heat in a water ted amount.
bath at 70° for 4 minutes. Remove from the water bath and
shake vigorously. Repeat the heating and shaking, cool in ice yyer chromatography,
for 5 minutes and centrifuge for 10 minutes. Transfer 5 mL solutions.
of the clear supernatant liquid to a suitable vial, evaporate to
ication containing
dryness in a current of nitrogen and dissolve the residue in
0.5 mL of dichloromethane. Solution (2) contains 0.05% w/v
of clobetasol propionate BPCRS in dichloromethane. Solution (3)
is a mixture of equal volumes of solutions (1) and (2). After
removal of the plate, allow it to dry in air and examine under
ultraviolet light (254 nm). The principal spot in the
The principal spot in the chromatogram obtained with (2) 0.05% w/v of clobetasol propionate BPCRS in
ways
solution (3) appears as a single compact spot. dichloromethane.
(3) Equal volumes of solutions (1) and (2).
‘2 Tw
wm eed

(2) shows a peak with the same retention time as the peak CHROMATOGRAPHIC CONDITIONS
due to clobetasol propionate in the chromatogram obtained (a) Use as the coating silica gel F54.
with solution (1).
ASSAY (c) Apply 10 pL of each solution.
CAUTION Carry out the preparation of solutions (2) and (3) with (d) Develop the plate to 15 cm.
full facial protection and wearing heat-resistant gloves.
Carry out the method for liquid chromatography, ultraviolet ight (254 nm).
Appendix III D, using the following solutions. Solution (1)
contains 0.005% w/v of clobetasol propionate BPCRS and
0.01% w/v of beclometasone dipropionate BPCRS (internal
2016 Clobetasol Preparations III-347
MOBILE PHASE the area of any peak corresponding to impurity E is not

5 volumes of absolute ethanol, 10 volumes of acetone and greater than 0.7 times the area of the principal peak in the
5
100 volumes of dichloromethane. chromatogram obtained with solution (2) (0.7%);
SYSTEM SUITABILITY the area of any peak corresponding to impurity F is not
solution (3) appears as a single compact spot.
CONFIRMATION
The principal spot in the chromatogram obtained with obtained with solution (2) (0.5%);
(4) (0.1%).
ASSAY
Prepare a 0.04% w/v solution of beclometasone
dipropionate BPCRS (internal standard) in ethanol (50%)
Appendix III D, tho
(solution A).
phase.
(1) Add 5 mL of absolute ethanol and 5 mL of solution A to a
quantity of the scalp application containing 1 mg of
application is completely dispersed. Cog
Clobetasol Propionate, heat on a water-bath with intermittent
for 30 minutes, centrifuge and dilute 5
shaking until the cutaneous foam is completely dispersed.
supernatant liquid to 10 mL.
Cool the contents in ice for 30 minutes, centrifuge and dilute
(2) Dilute 1 volume of solution (1) to 100 volumes
5 mL of the supernatant liquid to 10 mL with water.
(3) 0.025% w/v of clobetasol for peak identification
(2) 0.005% w/v of clobetasol propionate BPCRS in a mixture
(4) Dilute 1 volume of solution (2) to 10 volumes. of 1 volume of solution A and 3 volumes of ethanol (50%).
Solution (1) may assume a gel-like appearance. Prepare the solution in the same manner as solution (1)
CHROMATOGRAPHIC CONDITIONS tus, 5 mL of ethanol (50%) in place of 5 mL of solution
with octadecylsilyl sihca gel for chromatography (3.5 wm)
(Kromasil C18 is suitable).
below. with octadeey[silyl sé
(c) Use a flow rate of 1.0 mL per minute. (Spherisorb ODS
(d) Use a column temperature of 60°. (b) Use isocratic ef
(e) Use a detection wavelength of 240 nm. below.
MOBILE PHASE
50 volumes of acetonitrile and 50 volumes of a solution (e) Use a detection wavelength» ot
containing 0.025mM ammonium acetate previously adjusted to (f) Inject 20 pL of each solution.
pH 4.0 with glacial acetic acid. MOBILE PHASE
conditions the retention times relative to clobetasol (retention
SYSTEM SUITABILITY
time, about 9 minutes) are: impurity F, about 0.3;
impurity B, about 0.6, impurity C, about 0.9 and impurity E, The test is not valid unless, in the chromatograrti obtained
about 2.0. with solution (2), the resolution between the peaks due to
clobetasol propionate and beclometasone dipropionate is at
SYSTEM SUITABILITY
eh
wen least 4.0.
~AN AW
terntet el
impurity C and clobetasol propionate is at least 1.5. Calculate the content of C2;H3.CIFOs in the scalp
application using the ratios of the peak areas and the
LIMITS
declared content of C25H32CIFOS in clobetasol
Use the chromatogram obtained with solution (3) to identify propionate BPCRS.
any peaks due to impurity F and impurity B and multiply the
IMPURITIES
areas of these peaks by the corresponding correction factors;
impurity F, 0.6 and impurity B, 0.7. The impurities limited by the requirements of this
monograph include impurities A to G and J listed under
Clobetasol Propionate and:
II-348 Clobetasol Preparations 2016
TESTS
Related substances
phase.
(1) Add 10 mL of mobile phase to a quantity of the
shampoo containing 1 mg of Clobetasol Propionate, heat on
a water-bath with intermittent shaking until the shampoo is
completely dispersed. Cool the contents in ice for
liquid to 10 mL.
(3) 0.025% w/v of clobetasol for peak identification EPCRS.
(4) 0.00002% w/v of clobetasol impurity # EPCRS.
Action and (5) Dilute 1 volume of solution (2) to 10 volumes.
Glucocorticoid.
Solution (1) may assume a gel-like appearance.
DEFINITION CHROMATOGRAPHIC CONDITIONS
Clobetasol Shampoo co etasol Propionate in a (a) Use a stainless steel column (15 cm x 4.6 mm) packed
suitable basis. with octadecylsilyl silica gel for chromatography (3.5 um)
The shampoo complies with the (Kromasil C18 is suitable).
Cutaneous Application and with # (b) Use isocratic elution and the mobile phase described
Content of clobetasol propionate, €> below.
95.0 to 105.0% of the stated amount. (c) Use a flow rate of 1.0 mL per minute.
IDENTIFICATION (d) Use a column temperature of 60°.
A. Carry out the method for thin-layer chromatogya (e) Use a detection wavelength of 240 nm.
Appendix ITI A, using the following solutions. (f) Inject 40 uL of each solution.
(1) Transfer a quantity of the shampoo containing 0.4:mg MOBILE PHASE
Clobetasol Propionate to a 25-mL centrifuge tube, add
50 volumes of acetonitrile and 50 volumes of a solution
10 mL of methanol and heat in a water bath at 70° for
ming 0.025mM ammonium acetate previously adjusted to
4 minutes. Remove from the water bath and shake
4:0 vaith glacial acetic acid.
vigorously. Repeat the heating and shaking, cool in ice for
5 minutes and centrifuge. Evaporate 10 mL of the clear chromatograms are recorded under the prescribed
supernatant liquid to dryness and dissolve the residue in e retention times relative to clobetasol (retention
1 mL of dichloromethane. minutes) are: impurity F, about 0.3;
(2) 0.05% w/v of clobetasol propionate BPCRS in

dichloromethane.
(3) Equal volumes of solutions (1) and (2).
(a) Use as the coating silica gel F254. impurity C and clobeta
(b) Use the mobile phase as described below. LIMITS
(d) Develop the plate to 15 cm. : y.B and multiply the
(e) After removal of the plate, dry in air and examine under areas of these peaks by the correspondi ection factors;
ultraviolet ight (254 nm). impurity F, 0.6 and impurity B, 0.7.
MOBILE PHASE In the chromatogram obtained with solutio
5 volumes of absolute ethanol, 10 volumes of acetone and the area of any peak corresponding to impurity:
100 volumes of dichloromethane. greater than 0.7 times the area of the principal pe&k in the
SYSTEM SUITABILITY
the area of any peak corresponding to impurity J is not
CONFIRMATION
The principal spot in the chromatogram obtained with 0.5 times the area of the principal peak in the chromatogram
solution (1) corresponds in position and colour to that in the obtained with solution (2) (0.5%);
chromatogram obtained with solution (2). the sum of the areas of any other secondary peaks is not
B. In the Assay, the chromatogram obtained with solution greater than twice the area of the principal peak in the
(1) shows a peak with the same retention time as the peak chromatogram obtained with solution (2) (2.0%).
due to clobetasol propionate in the chromatogram obtained Disregard any peak with an area less than the area of the
with solution (2). principal peak in the chromatogram obtained with solution
(4) (0.1%).
2016 Clobetasone Preparations III-349
ASSAY
Prepare a 0.04% w/v solution of beclometasone
Clobetasone Cream
dipropionate BPCRS (internal standard) in ethanol (50%) Action and use
(solution A). Glucocorticoid.
Appendix III D, using the following solutions. DEFINITION
(1) Add 5 mL of absolute ethanol and 5 mL of solution A to a Clobetasone Cream contains Clobetasone Butyrate in a
quantity of the shampoo containing 1 mg of Clobetasol suitable basis.
Propionate, heat on a water-bath with intermittent shaking The cream complies with the requirements stated under Topical
until the cutaneous foam is completely dispersed. Cool the Semi-solid Preparations and with the following requirements.
contents in ice for 30 minutes, centrifuge and dilute 5 mL of Content of clobetasone butyrate, C,,H3;,CIFO,
IDENTIFICATION
Appendix III A, using silica gel 60 GF 54 as the coating
10 volumes of acetone and 100 volumes of chloroform as the
mobile phase. Apply separately to the plate 10 wL of each of
the following solutions. For solution (1) disperse a quantity
of the cream containing 0.5 mg of Clobetasone Butyrate in a
mixture of 5 volumes of ethanol (80%) and 10 volumes of n-
hexane, taking 15 mL of the solvent mixture for each g of
teen
(Spherisorb ODS1is suitable). cream. Shake the mixture, allow to separate, filter the
(b) Use isocratic elution and the mobil aqueous layer and add 1 mL of water for every 10 mL of n-
below. hexane used. Cool the solution in ice for 30 minutes,
(c) Use a flow rate of 2 mL per minute. centrifuge, filter the supernatant liquid and dilute with
(d) Use a column temperature of 60°. 10 mL of water for every 10 mL of n-hexane used. Add 1 g
(e) Use a detection wavelength of 240 nm. of sodium chloride for every 10 mL of water used and extract
with 5 mL of chloroform for every 10 mL of water used.
Evaporate the chloroform layer to dryness in a current of dry
MOBILE PHASE gen with gentle heating and dissolve the residue in
45 volumes of absolute ethanol and 55 volumes of water. eof chloroform. Solution (2) contains 0.1% w/v of
SYSTEM SUITABILITY
e butyrate BPCRS in chloroform. Solution (3)
* mixture of equal volumes of solutions (1) and (2).
clobetasol propionate and beclometasone dipropionate 1s at
taixied with solution (1) corresponds to that
least 4.0. |
yerdneobtained with solution (2).
DETERMINATION OF CONTENT e chromatogram obtained with
Calculate the content of C2;H3,CIFOs; in the shampoo using gle compact spot.
the ratios of the peak areas and the declared content of tegram obtained with solution
C35H3,CIFOs in clobetasol propionate BPCRS.
IMPURITIES due to clobetasone butyra
The impurities limited by the requirements of this with solution (1).
monograph include impurities A to G and J listed under ASSAY
Clobetasol Propionate and: CAUTION Carry out the preparation of solutions ( and (3) with
We
full facial protection and wearing heat-resistas DES.
contains 0.004% w/v of clobetasone butyrate BPCRS and

0.0028% w/v of clobetasol propionate BPCRS (internal
standard) in ethanol (50%). For solution (2) add 10 mL of
absolute ethanol to a quantity of the cream containing 1 mg of
Clobetasone Butyrate. Stopper firmly using a plastic stopper
and heat on a water-bath with intermittent shaking until the
cream is completely dispersed. Cool the contents in ice for
1. 21-deoxy-17-O-propanoylbetamethasone.
liquid to 10 mL with water. Prepare solution (3) in the same
manner as solution (2) but adding 5 mL of absolute ethanol
and 5 mL of a 0.014% w/v solution of the internal standard
in absolute ethanol. Solutions (2) and (3) may assumeagel-
like appearance.
IWI-350 Clobetasone Preparations 2016
octadecylsilyl silica gel for chromatography (5 wm) (Spherisorb 0.0028% w/v of clobetasol propionate BPCRS (internal
ODS1is suitable) and maintained at 60°, (b) as the mobile standard) in ethanol (50%). For solution (2) add 10 mL of
phase with a flow rate of 2 mL per minute a mixture of absolute ethanol to a quantity of the ointment containing 1 mg
eM ee
40 volumes of absolute ethanol and 60 volumes of water and of Clobetasone Butyrate. Stopper firmly using a plastic
(c) a detection wavelength of 241 nm. The proportions of stopper and heat on a water-bath with intermittent shaking
the mobile phase may be adjusted to give a retention time for until the ointment is completely dispersed. Cool the contents
clobetasone butyrate of about 5.5 minutes. in ice for 30 minutes, centrifuge and dilute 5 mL of the
Calculate the content of C2,H32,CIFOs; in the cream using supernatant liquid to 10 mL with water. Prepare solution (3)
peak areas and the declared content of C2,H32CIFOs; in in the same manner as solution (2) but adding 5 mL of
clobetasone butyrate BPCRS. absolute ethanol and 5 mL of a 0.014% w/v solution of the
internal standard in absolute ethanol. Solutions (2) and (3)
may assumea gel-like appearance.
should be stored at a temperature not
octadecylsilyl silica gel for chromatography (5 um) (Spherisorb
ODS 1 is suitable) and maintained at 60°, (b) as the mobile
Clobetasone 40 volumes of absolute ethanol and 60 volumes of water and
(c) a detection wavelength of 241 nm. The proportions of
Action and use the mobile phase may be adjusted to give a retention time for
Glucocorticoid. clobetasone butyrate of about 5.5 minutes.
Calculate the content of C.,H32,CIFO; in the ointment using
DEFINITION
peak areas and the declared content of C,,H;,CIFO, in
Clobetasone Ointment contains Clobé ‘Butyrate in a clobetasone butyrate BPCRS.
suitable basis.
STORAGE
The ointment complies with the requirements stat, ey Topical
Clobetasone Ointment should be stored at a temperature not
Semi-solid Preparations and with the following requixeme
exceeding 30°.
Content of clobetasone butyrate, C,,H;2CIFO,
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, zimine Capsules
Appendix III A, using silica gel 60 GF54 as the coating
10 volumes of acetone and 100 volumes of chloroform as the
mobile phase. Apply separately to the plate 10 uL of each of
the following solutions. For solution (1) disperse a quantity
of the ointment containing 0.5 mg of Clobetasone Butyrate ntain Clofazimine.
in a mixture of 5 volumes of ethanol (80%) and 10 volumes the requirements stated under Capsules
of n-hexane, taking 15 mL of the solvent mixture for each g
of ointment. Shake the mixture, allow to separate, filter the
aqueous layer and add 10 mL of water and 1 g of sodium
chloride for every 15 mL of the solvent mixture used. Extract
95.0% to 105.0% of thes
the resulting aqueous solution with 5 mL of chloroform for IDENTIFICATION
each g of sodium chloride used and evaporate the chloroform
layer to dryness in a current of dry nitrogen with gentle
heating. Dissolve the residue in 0.5 mL of chloroform. two maxima, at 289 nm and 491 nine:
Solution (2) contains 0.1% w/v of clobetasone butyrate BPCRS B. Dissolve a quantity of the contents
in chloroform. Solution (3) contains a mixture of equal
volumes of solutions (1) and (2). After removal of the plate, 0.1 mL of hydrochloric acid; an intense violet colgur
allow it to dry in air and examine under ultraviolet light produced. Add 0.5 mL of 5m sodium hydroxide; tk
(254 nm). The principal spot in the chromatogram obtained changes to orange-red.
with solution (1) corresponds to that in the chromatogram
obtained with solution (2). The principal spot in the TEST
chromatogram obtained with solution (3) appears as a single Related substances
compact spot. Carry out the method for liquid chromatography,
Appendix ITI D, using the following solutions. For solution
(1) dissolve a quantity of the contents of the capsules
containing 0.5 g of Clofazimine in 100 mL of the mobile
due to clobetasone butyrate in the chromatogram obtained
phase, filter and dilute 1 volume of this solution to
with solution (1).
100 volumes with the mobile phase. Solution (2) contains
ASSAY 0.0000125% w/v of tminophenazine BPCRS in the mobile
CAUTION Carry out the preparation of solutions (2) and (3) with phase. Solution (3) contains 0.0005% w/v of
full facial protection and wearing heat-resistant gloves. clofazimine BPCRS and 0.0005% w/v of
Carry out the method for liquid chromatography, wminophenazine BPCRS in the mobile phase.
vate a Appendix III D, using the following solutions. Solution (1) The chromatographic procedure may be carried out using
contains 0.004% w/v of clobetasone butyrate BPCRS and (a) a stainless column (25 cm x 4.6 mm) packed with
2016 Clofibrate Preparations TII-351
octylsilyl silica gel for chromatography (5 wm) (Nucleosil C8 is maxima, at 280 nm and 288 nm. The A(1%, 1 cm) at the
AN
suitable), (b) as the mobile phase with a flow rate of 1.5 mL maxima are about 44 and about 31, respectively.
wet Se
per minute a mixture of 35 volumes of a solution prepared

Swane
TESTS
by dissolving 2.25 g of sodium dodecyl sulfate, 0.85 g of
Acidity
tetrabutylammonium hydrogen sulfate and 0.885 g of disodium
Add 10 mL of the contents of the capsules to 100 mL of
hydrogen orthophosphate in 500 mL of water and adjusting the
ethanol (96%) previously neutralised to phenolphthalein
PH to 3.0 with orthophosphoric acid and 65 volumes of
solution R1 with 0.1m sodium hydroxide VS and titrate with
acetonitrile and (c) a detection wavelength of 280 nm.
0.1m sodium hydroxide VS. Not more than 2.5 mL is required
Inject 20 uwL of solution (3). The test is not valid unless the to change the colour of the solution.
resolution factor between the two principal peaks 1s at least 2,
Refractive index
the retention time of iminophenazine relative to that of
1.500 to 1.505, determined on the contents of the capsules,
clofazimine.is about 0.7 and the column efficiency, determined
Appendix V E.
on the e.to clofazimine is at least 3000 theoretical
plates. : Relative density
In the chr obtained with solution (1) the area of 1.138 to 1.147, determined on the contents of the capsules,
any secondary peaks greater than the area of the Appendix V G.
principal peak in atogram obtained with solution 4-Chlorophenol
(2) (0.25%) and the areas of any such peaks is Carry out the method for gas chromatography,
not greater than twice't “of the peak in the Appendix III B.
chromatogram obtained \ on (2) (0.5%). (1) Extract a volume of the contents of the capsules
ASSAY containing 10.0 g of Clofibrate with 20 mL of 1M sodium
hydroxide, wash the lower layer with 5 mL of water, add the
washings to the aqueous layer and reserve the organic layer
(1) add 100 mL of the mobile phase to for the test for Volatile related substances. Extract the
mixed contents of 20 capsules containing; combined aqueous layer and washings with two 5-mL
quantities of chloroform, discard the chloroform and acidify
100 volumes with the mobile phase. Solution¢ the aqueous layer by the drop wise addition of hydrochloric
0.005% w/v of clofazimine BPCRS in the mobile p acid. Extract with three 3-mL quantities of chloroform,
Solution (3) contains 0.0005% w/v of clofazimine BPER combine the organic extracts and dilute to 10 mL with
0.0005% w/v of iminophenazine BPCRS in the mobile pk chloroform.
The chromatographic procedure described under Relate 2) 0.0025% w/v of 4-chlorophenol in chloroform.
substances may be used. TOGRAPHIC CONDITIONS
Inject 20 uL of solution (3). The test is not valid unless the a column (1.5m x 4 mm) packed with either acid-
resolution factor between the two principal peaks is at least 2, ed, silamsed diatomaceous support (Chromosorb
the retention time of iminophenazine relative to that of [ is suitable) (40 to 60 mesh) impregnated with
clofazimine is about 0.7 and the column efficiency, determined ethyl silicone fluid (SE-30 ise suitable) or
on the peak due to clofazimine is at least 3000 theoretical dedhatomaceous support (80 to 100 mesh)
plates. | wivg.of dimethyl silicone
fluid.
Calculate the percentage content of C27H22.CI,N, in the
capsules using the declared content of C27H2.CI1,N, in
clofazimine BPCRS.
(f) Inject 2 uL of each solutio L,
Clofibrate Capsules
LIMITS
In the chromatogram obtained wi

Action and use the area of any peak corresponding to 4
Fibrate; lipid-regulating drug. greater than the area of the peak in the chr
obtained with solution (2) (25 ppm).
DEFINITION
Volatile related substances
Clofibrate Capsules contain Clofibrate. Carry out the method for gas chromatography,
The capsules comply with the requirements stated under Capsules Appendix III B.
and with the following requirements. (1) Dry the organic layer reserved in the test for
IDENTIFICATION 4-Chlorophenol with anhydrous sodium sulfate.
The contents of the capsules comply with the following tests. (2) A solution of the contents of the capsules in chloroform
A. The infrared absorption spectrum, Appendix II A, is containing 0.012% w/v of Clofibrate.
concordant with the spectrum of clofibrate EPCRS. (3) 0.012% w/v solution of methyl 2-(4-chlorophenoxy)-2-
B. The light absorption, Appendix II B, in the range 220 to methylpropionate EPCRS in the contents of the capsules.
250 nm of a 0.001% w/v solution in methanol exhibits a CHROMATOGRAPHIC CONDITIONS
maximum only at 226 nm. The A(1%, 1 cm) at the
The chromatographic conditions described under
maximum is about 460.
4-Chlorophenol may be used.
:
tae
r
C. The light absorption, Appendix II B, in the range 250 to
te Ae
350 nm of a 0.01% w/v solution in methanol exhibits two
Paws
II-352 Clomethiazole Preparations 2016
SYSTEM SUITABILITY C. Mix a quantity of the contents of the capsules containing

In the chromatogram obtained with solution (3) measure 0.1 g of Clomethiazole with 0.2 g of powdered sodium
from the baseline the height of the peak corresponding to hydroxide, heat to fusion and continue heating for a further
methyl 2-(4-chlorophenoxy)-2-methylpropionate (a) and the few seconds. Cool, add 0.5 mL of water anda slight excess
height of the lowest part of the curve separating this peak of 2m hydrochloric acid and warm. Any fumes evolved do not
from the peak corresponding to clofibrate (6). The test 1s not turn moistened starch 1odate paper blue (distinction from
valid unless a is equal to at least 30% of full-scale deflection clomethiazole edisilate).
and a-b is greater than 75% of a. TEST
In the chromatogram obtained with solution (1): Carry out the method for liguid chromatography,
(1) Add 100 mL of 1m sulfuric acid to whole capsules
yew ay
containing a total of 0.96 g of Clomethiazole, immerse in a
water bath for 20 seconds, remove from the bath and shake
vigorously. Repeat this treatment until the capsule shells have
Carry out thet i!
dissolved without exceeding a total heating time of 1 minute.
described under Caps
Cool, centrifuge, filter the aqueous layer (Whatman GF/C
contents of the 20 ¢
paper is suitable) and dilute 5 mL of the filtrate to 50 mL
weight of Clofibrate.
with the mobile phase.
Clofibrate, C,2H,sClO3 cece:
Not less than 97.0% w/w when de ined by the following
mobile phase.
method. To a weighed quantit < contents of
(3) Dilute 1 volume of a 0.030% w/v solution of 4-methyl-5-
10 capsules containing 1 g of 25 mL of
0.5m ethanolic potassium hydroxide andieat ait a reflux vinylthiazole edisilate BPCRS in methanol (solution A) to
(4) Dilute 1 volume of a 0.020% w/v solution of
5-(2-chloroethyl) -4-methyl-3-[2-(4-methylthtazol-5-
with 0.2m hydrochloric acid VS using 1 mL of phenolpk yb) ethyl]thiazolium chloride BPCRS (quaternary dimer) in
solution R1 as indicator. Repeat the operation witho methanol (solution B) to 50 volumes with the mobile phase.
contents of the capsules. The difference between the (5) Dilute 1 volume of a 0.020% w/v solution of 4-methyl-5-
titrations represents the amount of hydrochloric acid 2-hydroxyethyl) thiazole BPCRS 1n methanol (solution C) to
required. Each mL of 0.2m hydrochloric acid VS is equivale ‘ames with the mobile phase.
to 48.54 mg of C,.H;5ClO3. mL each of solutions A, B and C to 5 mL of the
ained in the preparation of solution (2) and dilute
Clomethiazole Capsules
Action and use
Hypnotic.
(b) Use isocratic eltitic
DEFINITION below. ‘
Clomethiazole Capsules contain a solution of Clomethiazole
ay?
maw a4
in a suitable fixed oil. (d) Use an ambient colum

‘
:
a
Naat
flerd tee: 7 ee : ae:

te
(e) Use a detection wavelength 6

et

ia

!
pf.
Content of clomethiazole, C;HsCINS

eye
MOBILE PHASE
oe

ie?
ey
30 volumes of methanol and 70 volumes of agsolut

fot
.
IDENTIFICATION containing 0.13% w/v of sodium hexanesulfonate, % wiv

:
ee
ee
A. Shake a quantity of the contents of the capsules of tetramethylammonium hydrogen sulfate, adjusted té° pH 2.0
as CVNet tt,
containing 20 mg of Clomethiazole with 70 mL of with 5m sodium hydroxide.

toy ‘
Cee .
.
0.1m hydrochloric acid for 15 minutes and dilute to 100 mL SYSTEM SUITABILITY
© eas
with the same solvent. Filter and dilute 10 mL of the filtrate

Ceres,
get,
CRSeRasee 7
The test is not valid unless in the chromatogram obtained

Nibeas
to 50 mL with 0.1m hydrochloric acid. The light absorption of

CPSP
with solution (6) baseline separation is achieved between the

thos
the resulting solution, Appendix II B, in the range 230 to

peaks due to the three specified impurities and also between
350 nm exhibits a maximum only at 257 nm.
each of these peaks and the principal peak.
B. To a quantity of the contents of the capsules containing
0.3 g of Clomethiazole add 10 mL of 0.1m hydrochloric acid LIMITS
and shake. To the aqueous layer add 5 mL of 1m sodium Calculate the content of each of the specified impurities with
hydroxide, mix and extract with 15 mL of chloroform. Dry the reference to the stated content of Clomethiazole in the
chloroform layer with anhydrous sodium sulfate, filter and capsules expressing the content of 4-methyl-5-vinyl-thiazole
evaporate to remove the solvent. The infrared absorption as the base (1 mg of 4-methyl-5-vinylthiazole edisilate 1s
spectrum of a thin film of the residue, Appendix II A, is equivalent to 0.568 mg of its base). Calculate the content of
tare concordant with the reference spectrum of clomethiazole each of any other impurities from the areas of their peaks in
the chromatogram obtained with solution (1) using the
alas
tg ite
(RS 051).
oye
,
t
ee
tas.
.
.
.
peg
Lf
LO"
.
-
Oi",
2016 Clomethiazole Preparations III-353
principal peak in the chromatogram obtained with solution MOBILE PHASE

(2) as reference and assuming the same response as 5 volumes of water, 10 volumes of 13.5mM ammonia,
clomethiazole. 20 volumes of butan-1-ol and 65 volumes of acetone.
The content of each of the three specified impurities is not CONFIRMATION
greater than 1.5% and the content of any other impurity is
not greater than 0.5%. The total content of all the impurities
is not greater than 3.0%.
ASSAY
TESTS
Carry out Method I for non-aqueous titration,
Appendix VIII A, using a quantity of the mixed contents of
pH of the infusion, 5.0 to 7.5, Appendix V L.
Related substances
(1) Dilute a volume of the infusion with the mobile phase to
produce a solution containing 0.04% w/v of Clomethiazole
Edisilate.
Clomethiazo (2) Dilute 1 volume of solution (1) to 200 volumes with the
Clomethiazole Intrave! mobile phase.
Action and use
vinylthiazole edisilate BPC'RS in methanol (solution A) to
Hypnotic.
DEFINITION ' (4) Dilute 1 volume of a 0.020% w/v solution of
Clomethiazole Infusion is a sterile solution: 5-(2-chloroethyl)-4-methyl-3-[2-(4-methylthiazol-5-
Clomethiazole Edisilate. It is supplied as a4 wethyl]thiazolium chloride BPCRS (quaternary dimer) in
solution. methanol (solution B) to 50 volumes with the mobile phase.
Parenteral Preparations and with the following requiremey (2-hydroxyethyl) thiazole BPCRS in methanol (solution C) to
Content of clomethiazole edisilate,
(CgHsCINS)2,C,H.O¢S2 Add 1 mL each of solutions A, B and C to 5 mL of the
92.5 to 107.5% of the stated amount. ‘éobtained in the preparation of solution (2) and dilute
IDENTIFICATION
OGRAPHIC CONDITIONS
A. To a volume of the infusion containing 40 mg of
Clomethiazole Edisilate add 4 mL of 2m sodium hydroxide,
mix and extract with 25 mL of dichloromethane. Dry the
extract with anhydrous sodium sulfate, filter and evaporate to Suitable).
dryness. The infrared absorption spectrum of the residue, (b) Use iso fon and the mobile phase described
Appendix II A, is concordant with the reference spectrum of below.
clomethiazole (RS 051).
B. Carry out the method for thin-layer chromatography, (d) Use an ambient c
(e) Use a detection wavel
(1) Add 90 mL of acetone to a volume of the preparation
containing about 50 mg of Clomethiazole Edisilate, mix and
centrifuge. Wash the oily residue with three 10-mL quantities
of acetone and then with three 10-mL quantities of ether.
Dry the residue with a current of warm air and then dry
under reduced pressure at 35° for 30 minutes. Dissolve the
residue in 1 mL of 1M acetic acid, dilute to 5 mL with with 5m sodium hydroxide.
methanol, mix and filter through a 0.45-um membrane filter. SYSTEM SUITABILITY
(2) Dissolve 0.1 g of disodium ethanedisulfonate in 5 mL of The test is not valid unless in the chromatogram obtained
1M acetic acid and dilute to 25 mL with methanol. with solution (6) baseline separation is achieved between the
CHROMATOGRAPHIC CONDITIONS peaks due to the three specified impurities and also between
(a) Use as the coating silica gel. each of these peaks and the principal peak.
(b) Use the mobile phase as described below. LIMITS
(c) Apply 10 uwL of each solution. Calculate the content of each of the specified impurities with
(d) Develop the plate to 15 cm. reference to the stated content of clomethiazole in the
infusion (1 mg of clomethiazole edisilate is equivalent to
(e) After removal of the plate, dry it in a current of air until
0.629 mg of base) and expressing 4-methyl]-5-vinyl-thiazole
the ammonia is removed and spray with a 0.1% w/v solution
as the base (1 mg of 4-methyl-5-vinylthiazole edisilate is
of bromocresol purple in ethanol (96%) previously adjusted to a
equivalent to 0.568 mg of its base). Calculate the content of
purple colour with 2M ammonia and examine immediately.
each of any other impurities from the areas of their peaks in
the chromatogram obtained with solution (1) using the
III-354 Clomethiazole Preparations 2016
(2) as reference and assuming the same response as TEST

clomethiazole. Related substances
In the chromatogram obtained with solution (1): Complies with the test prescribed under Clomethiazole
the area of the peak corresponding to impurity A is not Capsules, calculating the content of each of the stated
greater than the area of the corresponding peak in the impurities with reference to the equivalent content of
chromatogram obtained with solution (3) (1.5%); clomethiazole in the oral solution (1 mg of clomethiazole
edisilate is equivalent to 0.629 mg of base) and using the
the area of the peak corresponding to impurity B is not
following solution as solution (1). Dilute a volume of the oral
greater than the area of the corresponding peak in the
solution with the mobile phase to produce a solution
containing 0.05% w/v of Clomethiazole Edisilate.
the area of the peak corresponding to impurity C is not
greater than,the area of the corresponding peak in the ASSAY
Carry out the Assay described under Clomethiazole
Intravenous Infusion.
‘ r secondary peak is not greater than the
area of the chromatogram obtained with solution STORAGE
(2) (0.5%); Clomethiazole Oral Solution should be stored at a
temperature of 2° to 8°.
yw et
Appendix III D, using the fo

Clomifene Tablets
(1) Dilute a volume of the prepara Action and use
to produce a solution containing 0.01% Estrogen receptor modulator.
Edisilate.
(2) 0.01% w/v of clomethiazole edisilate B DEFINITION
phase. Clomifene Tablets contain Clomifene Citrate.
CHROMATOGRAPHIC CONDITIONS The tablets comply with the requirements stated under Tablets and
substances may be used. Content of clomifene citrate, C,,;H,,;CINO,C;H;,0,
Calculate the content of (CgHgCINS)2,C,H,O,S. from the ICATION
declared content of (CgsHgCINS).,C,H,O¢S>2 in clomethiazole ht absorption, Appendix II B, in the range 220 to
edisilate BPCRS. he solution obtained in the Assay exhibits two
235 nm and 292 nm.
STORAGE
ntity of the powdered tablets containing
Clomethiazole Infusion should be stored at a temperature of
2° to 8°.
5 mg of Clé Citrate in 5 mL of a mixture of 1 volume
of acetic anhyi volumes of pyridine and heat in a
water bath. A dark red olour is produced.
TESTS
Dissolution
eeanet Clomethiazole Oral Solution Comply with the requiremer ts for Monographs of the British
Pharmacopoeia in the dissolu test for tablets and capsules,
Action and use
Appendix XII Bl.
Hypnotic.
TEST CONDITIONS
DEFINITION (a) Use Apparatus 1, rotating the basket, at
Clomethiazole Oral Solution is a solution of Clomethiazole per minute.
Edisilate in a suitable flavoured vehicle. (b) Use 900 mL of water, at a temperature of 3
The oral solution complies with the requirements stated under Oral medium. |
Liquids and with the following requirements. PROCEDURE
Content of clomethiazole edisilate, (1) After 45 minutes withdraw a sample of the medium and
(CZ5HsCINS)2,C,H,O,S, filter.
awa
wt oe
(2) Measure the absorbance of a layer of suitable thickness of
TAN ela
wr
IDENTIFICATION the filtered sample, suitably diluted, if necessary, with

A. To a volume of the oral solution containing 0.1 g of 0.1m hydrochloric acid, at the maximum at 232 nm,
Clomethiazole Edisilate add 4 mL of 2m sodium hydroxide, Appendix II B.
mix and extract with 25 mL of dichloromethane. Dry the DETERMINATION OF CONTENT
extract with anhydrous sodium sulfate, filter and evaporate to
Calculate the total content of clomifene citrate,
C,6H2sCINO,C,H,O-, in the medium taking 317 as the
clomethiazole (RS 051).
a
wt
ae
te
B. Complies with test B for Identification described under Z-Isomer
Vere as
|
raw ad
Clomethiazole Intravenous Infusion.
Appendix III D, using the following solution.
2016 Clomipramine Preparations TIT-355

50 mg of Clomifene Citrate with 50 mL of 0.1m hydrochloric
Clomipramine Capsules
acid for 10 minutes and filter. To 25 mL of the filtrate add
<Nta ae
Action and use

5 mL of 1M sodium hydroxide and extract with three 25-mL
we ne 4

quantities of ethanol-free chloroform. Wash the combined
extracts with 10 mL of water, dry over anhydrous sodium DEFINITION
sulfate and add sufficient ethanol-free chloroform to produce Clomipramine Capsules contain Clomipramine
100 mL. To 20 mL of the solution add 0.1 mL of Hydrochloride.
triethylamine and sufficient hexane to produce 100 mL.
CHROMATOGRAPHIC CONDITIONS and with the following requirements.
(a) Use a stainless steel column (30 cm x 4 mm) packed Content of clomipramine hydrochloride,
with sic jor chromatography (10 um) (Porasilis suitable). C,9H23CIN2,HC1
eo eS
‘ution and the mobile phase described 95.0 to 105.0% of the stated amount.
ren Note
bile phase through the system until IDENTIFICATION

Triturate a quantity of the contents of the capsules
containing 0.15 g of Clomipramine Hydrochloride with
10 mL of chloroform, filter and evaporate the filtrate to
Appendix II A, after recrystallisation from hot acetone and
drying at 110° for 30 minutes, is concordant with the
reference spectrum of clomipramine hydrochloride (RS 069).
due to Z-clomifene. TESTS

Related substances
MOBILE PHASE
A mixture of ethanol-free chloroform and he Appendix II D, using the following solutions.
containing 0.10% v/v of triethylamine, adjustes
(1) Disperse a quantity of the mixed contents of 20 capsules
baseline separation is obtained between E- and Z-
containing 40 mg of Clomipramine Hydrochloride with
(20 volumes of ethanol-free chloroform and 80 volut
15 mL of mobile phase A with the aid of ultrasound for
hexane is usually suitable).
15 minutes, cool, dilute to 20 mL with the same solvent and
SYSTEM SUITABILITY hrough a 0.45 um PTFE filter.
The test is not valid unless baseline separation is achieved e 1 volume of solution (1) to 100 volumes with
between E- and Z-clomifene and the column efficiency is
greater than 10,000 theoretical plates per metre determined
using the peak due to the E-isomer.
LIMIT
30.0 to 50.0% of the content of clomifene citrate as
determined in the Assay.
Calculate the percentage of Z-isomer from the expression
100A7/(1.08Ap+ Az) where Az and Ap are the areas of the
peaks due to the Z- and E-isomers, respectively.
ASSAY (a) Use a stainless steel column (25.0 cm x 4.6 mm) packed
Weigh and powder 20 tablets. Shake a quantity of the with cyanopropylsilyl silica ge chromatography (5 wm)
powder containing 50 mg of Clomifene Citrate for (Hypersil BDS CN is suitable)”
30 minutes with 70 mL of 0.1m hydrochloric acid prepared (b) Use gradient elution and the righ: ases described
using a 30% v/v solution of propan-2-ol as solvent, dilute to below.
100 mL with the propanolic hydrochloric acid and filter. (c) Use a flow rate of 1.5 mL per min
Dilute 5 mL of the filtrate to 100 mL with 0.1m hydrochloric
acid and measure the absorbance of the resulting solution at
the maximum at 292 nm, Appendix IT B, using in the (e) Use a detection wavelength of 254 nm.
reference cell a solution prepared by diluting 5 mL of the (f) Inject 20 uL of each solution.
propanolic hydrochloric acid to 100 mL with MOBILE PHASE
0.1m hydrochloric acid. Calculate the content of
Mobile phase A Dissolve 1.2 g of sodium dihydrogen
C,6H2gCINO,C.gHgO7 taking 175 as the value of
orthophosphate in 950 mL of water, add 1.1 mL of nonylamine,
adjust to pH 3.0 with orthophosphoric acid and add sufficient
STORAGE water to produce 1000 mL (solution A). Mix 75 volumes of
Clomifene Tablets should be protected from light. solution A with 25 volumes of acetonitrile.
Mobile phase B_ Mix 65 volumes of solution A and
IWI-356 Clomipramine Preparations 2016
Time Mobile phase A Mobile phase B Comment Cl

wen ws
weal
( NON y OF
oo
C, 3-(3-chloro-5H-dibenzo[6,f]azepin-5-yl)-N,N-
The retention times relative to clomipramine are about 0.5, dimethylpropan-1-amine,
j 3 3.4 and 4.3 for impurities A, B, C, D, E,
rete tN
AN a
with solution (4), ¢

to clomipramine
LIMITS
D. R1 = R3 = Cl, R2 = CH,-CH,-CH>»-N(CH3),: 3-(,7-

dichloro-10,11-dihydro-5H-dibenzo[b,f/Jazepin-5-yl)-N,N-
dimethylpropan-1-amine,
E. Rl = R2 = R3 = H: 10,11-dihydro-5H-dibenzo[b,f|azepine
CGminodibenzyl),
the area of any peak corresponding to impurity F i F, R1 = Cl, R2=R3=H:
greater than the area of the corresponding peak in ¢ 3-chloro-10,11-dihydro-5H-dibenzo[6,/]azepine,
chromatogram obtained with solution (3) (0.2%); G. R1 = Cl, R2 =CH,-CH=CH), R3 = H:
the area of any other secondary peak is not greater than 3-chloro-5- (prop-2-enyl)-10,11-dihydro-5.H-
0.2 times the area of the principal peak in the chromatogr o[6,flazepine.
and the sum of the areas of any such secondary peaks is not
The sum of the impurities is not greater than 1.0%.
Disregard any peak with an area not greater than 0.01 times
the area of the principal peak in the chromatogram obtained monograph, aré
with solution (2) (0.01%). authorised.
ASSAY
Action and use
Shake a quantity of the mixed contents of 20 capsules
containing 50 mg of Clomipramine Hydrochloride with
200 mL of 0.1m hydrochloric acid for 1 hour, dilute to
250 mL with 0.1m hydrochloric acid and filter. Dilute 15 mL
of the filtrate to 100 mL with 0.1m hydrochloric acid and Clomipramine Hydrochloride.They
measure the absorbance of the resulting solution at the the medicament is released over a perio
maximum at 252 nm, Appendix II B. Calculate the content
of Cy9H23CIN>,HCI taking 226 as the value of A(1%, 1 cm) PRODUCTION
appropriate release of Clomipramine Hydrochloride.
IMPURITIES The dissolution profile reflects the im vivo performance which
in turn is compatible with the dosage schedule recommended
by the manufacturer.
sewed
Aa es
ewe awd
Content of clomipramine hydrochloride,
C,9H23CIN,,HCl
IDENTIFICATION
Shake a quantity of powdered tablets containing 0.15 g of
A. N-[3-(@-chloro-10,11-dihydro-5.H-dibenzo[b,/]azepin-5- Clomipramine Hydrochloride with 10 mL of dichloromethane,
yl)propyl!]-N,N’,N’-trimethylpropane-1,3-diamine, filter and evaporate the filtrate to dryness. The infrared
absorption spectrum of the residue, Appendix II A, after
B. imipramine,
recrystallisation from hot acetone and drying at 105° for
te ie
ee a
2016 Clomipramine Preparations III-357
30 minutes, is concordant with the reference spectrum of the area of any peak corresponding to clomipramine
“Nw ai
clomipramine hydrochloride (RS 069). impurity B is not greater than the area of the corresponding
peak in the chromatogram obtained with solution (3) (1%);
TESTS
eae4
the area of any peak corresponding to impurity C,

aae adt
Related substances
Carry out the method for liguid chromatography, impurity D or impurity F 1s not greater than the area of the
Appendix III D, using the following solutions in mobile corresponding peak in the chromatogram obtained with
phase A. solution (3) (0.2%);
(1) Disperse a quantity of powdered tablets containing 40 mg the area of any other secondary peak is not greater than
of Clomipramine Hydrochloride in 15 mL with the aid of 0.2 times the area of the principal peak in the chromatogram
ultrasound for 15 minutes, cool, dilute to 20 mL and filter obtained with solution (2) (0.2%);
fclomipramine impurity B BPCRS and
sof clomipramine impurity C BPCRS, the total impurity content is not greater than 2.0%.
(4) 0.005% w/v of ‘tion (5) (0.1%).
0.0015% w/v of clomii ASSAY
solutions in the mobile phase.
(a) Use a stainless steel colunin :
with cyanopropylsilyl silica gel for chroy (1) Disperse a quantity of powdered tablets containing 40 mg
(Hypersil BDS CN 1s suitable). of Clomipramine Hydrochloride in 15 mL with the aid of
ultrasound for 15 minutes, cool, dilute to 20 mL and filter
through a 0.45-um PTFE filter. Dilute 1 volume to
below.
10 volumes.
(2) 0.02% w/v of clomipramine hydrochloride BPCRS.
(3) 0.005% w/v of clomipramine hydrochloride BPCRS and
(e) Use a detection wavelength of 254 nm. 0.0015% w/v of clomipramine impunty C BPCRS.
(f) Inject 20 uL of each solution. MATOGRAPHIC CONDITIONS
MOBILE PHASE stainless steel column (25.0 cm x 4.6 mm) packed
Mobile phase A Dissolve 1.2 g of sodium dihydrogen propyisilyl silica gel for chromatography (5 um)
orthophosphate in 950 mL of water, add 1.1 mL of nonylamine, DS CN is suitable).
adjust to pH 3.0 with orthophosphoric acid and add sufficient elution and the mobile phase described
water to produce 1000 mL (solution A). Mix 75 volumes of
solution A with 25 volumes of acetonitrile.
£5 mL per minute.
Mobile phase B35 volumes of acetonitrile and 65 volumes of
erature of 30°.
solution A.
(f) Inject 20 uL of ea
Time Mobile Mobile Comments
MOBILE PHASE
(minutes) phase A phase B
% %
10 — 20 100 > 0 0 > 100 linear gradient
1000 mL (solution A). Mix 75 volum
20 - 32 0 100 isocratic
32 — 34 0 > 100 100 > 0 linear gradient
34 — 44 100 0 isocratic When the chromatograms are recorded u
conditions the retention time of clomipramine 1
8 minutes.
sold
oe yt
SYSTEM SUITABILITY
conditions the retention times relative to clomipramine The test is not valid unless, in the chromatogram obtained
EMA
(retention time = about 8 minutes) are: impurity A = about with solution (3), the resolution factor between the peaks due
Ew
Saas
0.5; impurity B = about 0.7; impurity C = about 0.9; to clomipramine impurity C and clomipramine is at least 1.5.
impurity D = about 1.7; impurity E = about 2.5; impurity F
a
Bete
= about 3.4 and impurity G = about 4.3.

a
Calculate the content of C;9H23CIN2,HCI in the tablets

er
SYSTEM SUITABILITY
using the declared content of Cj9)H23CIN2,HCI in
The test is not valid unless, in the chromatogram obtained clomipramine hydrochloride BPCRS.
peck
cr
to clomipramine impurity C and clomipramine is at least 3.0. IMPURITIES

LIMITS
monograph include those listed in the monograph for
grtdse

Oe
Clomipramine Hydrochloride.
t
>. ude
ekg
wan
IWI-358 Clonazepam Preparations 2016
extract separately with the same 10 mL volume of water,

Clonazepam Injection combine the extracts and add sufficient chloroform to produce
Action and use 10 mL.
Benzodiazepine. (2) 0.0005% w/v of 3-amino-4-(2-chlorophenyl) -6-nitroquinolin-
2(1H)-one BPCRS in chloroform.
DEFINITION (3) 0.0002% w/v of 3-amino-4-(2-chlorophenyl) -6-nitroquinolin-
Clonazepam Injection is a sterile solution of Clonazepam. 2(1H)-one BPCRS in chloroform.
It is prepared immediately before use by diluting Sterile
Clonazepam Concentrate with Water for Injections in
accordance with the manufacturer’s instructions. (a) Use as the coating silica gel G.
The injection complies with the requirements stated under (b) Use the mobile phases as described below.
Parenteral arations. (c) Apply 50 uL of each solution.
AN ALS
(e) After the first development, remove the plate and dry in a
current of cool air. After the second development, remove
the plate, heat at a pressure of 2kPa at 120° for 3 hours,
allow to cool and spray with a 10% w/v solution of zinc
chloride in 0.1m hydrochloric acid. Allow the plate to dry in air
and visualise by Method I, Appendix III A, beginning at the
words ‘expose to nitrous fumes ...’.
and with the following requiremén
MOBILE PHASE
Content of clonazepam, C,;] ig
For the first development 20 volumes of chloroform and
95.0 to 105.0% of the stated amount
80 volumes of ether.
CHARACTERISTICS For the second development 10 volumes of ether and
A clear, colourless or slightly greenish yellov 90 volumes of nitromethane.
IDENTIFICATION . | Under the prescribed conditions the Rf value of clonazepam
Carry out the method for thin-layer chromatography,: is about 0.35; 3-amino-4-(2-chlorophenyl) -6-nitroquinolin-
Appendix III A, using the following solutions. 2(1H)-one (carbostyril impurity), about 0.45; 2-amino-2'-
(1) Dilute a volume of the injection containing 3 mg of chloro-5-nitrobenzophenone (nitrobenzophenone impurity),
Clonazepam in a stoppered tube with an equal volume of about 0.75.
water, shake with 1 mL of chloroform, allow to separate and
use the chloroform layer. omatogram obtained with solution (1):
(2) Dissolve 3 mg of clonazepam BPCRS in 1 mL of responding to the nitrobenzophenone impurity is
chloroform. se than the spot in the chromatogram
CHROMATOGRAPHIC CONDITIONS tion (3) (0.2%);
(a) Use as the coating silica gel F254 (Merck silica gel 60 F554 ‘to the carbostyril impurity is not
plates are suitable). more intense than ot in the chromatograms obtained
(b) Use the mobile phase as described below. with solutions (3) (0.2%
(c) Apply 10 pL of each solution. any other secondary spoj'is not more intense than the spot in
the chromatogram obtained olution (2) (0.5%).
(e) After removal of the plate, dry it in a current of cold air, ASSAY ,
spray with 2m sodium hydroxide and heat at 120° for Protect the solutions from light. ‘To ume of the injection
15 minutes. containing 20 mg of Clonazepam ficient propan-2-ol to
produce 100 mL and dilute 10 mL textQO’mL with propan-
MOBILE PHASE
2-ol. Measure the absorbance of the resulting solution at the
2 volumes of 13.5M ammonia, 15 volumes of n-heptane, maximum at 310 nm, Appendix II B. Ca
30 volumes of nitromethane and 60 volumes of ether. of C;5H, 9CIN30; taking 364 as the value ofA
CONFIRMATION the maximum at 310 nm.
The principal spot in the chromatogram obtained with STORAGE
solution (1) corresponds in position and colour to that in the Clonazepam Injection should be protected from light.
chromatogram obtained with solution (2). Spots due to
LABELLING
excipients may also be observed.
wane
aN 4
The label states (1) ‘Sterile Clonazepam Concentrate’;

TESTS (2) that the diluted injection is to be given by intravenous
Acidity injection.
Related substances
Appendix III A, using the following solutions protected from
light.
(1) Dilute, if necessary, a volume of the injection containing
10 mg of Clonazepam to 20 mL with water and extract with
three 3-mL quantities of chloroform. Wash each chloroform
2016 Clonazepam Preparations III-359

Clonazepam Oral Suspension solution A.
NOTE: Clonazepam Oral Suspension 1s not currently licensed 1n the
United Kingdom.
solution A.
Action and use (4) Dissolve 5 mg of (2-amino-5-
Benzodiazepine. nitrophenyl) (2-chlorophenyl) methanone BPCRS in 2 mL of
tetrahydrofuran and dilute to 10 mL with methanol. Dilute
DEFINITION
1 volume of this solution to 100 volumes with solution A and
Clonazepam Oral Suspension is a suspension of Clonazepam further dilute 1 volume of the resulting solution to
in a suitable flavoured aqueous vehicle. 50 volumes with solution A.
The oral suspension complies with the requirements stated under (5) Dissolve 5 mg of 3-amino-4-(2-chlorophenyl)
-6-
Oral Ligttds, the requirements stated under Unlicensed Medicines nitroquinolin-2(1H)-one BPCRS in 2 mL of tetrahydrofuran
and and dilute to 10 mL with methanol. Dilute 1 volume of this
solution to 100 volumes with solution A and further dilute
1 volume of the resulting solution to 50 volumes with
solution A.
(6) Dissolve 5 mg of clonazepam BPCRS and 5 mg of
flumitrazepam BPCRS in 9.5 mL of tetrahydrofuran.
Add 37.5 mL of methanol and dilute to 100 mL with water.
centrifuge; three layers may solution A.
dichloromethane layer, dry CHROMATOGRAPHIC CONDITIONS
with end-capped octylsilyl silica gel for chromatography (5 um)
(3) 0.01% wiv of each of clonazepam BPGR (Symmetry C8 is suitable).
flunmitrazepam BPCRS in dichloromethane. (b) Use isocratic elution and the mobile phase described
CHROMATOGRAPHIC CONDITIONS below.
(a) Use as the coating silica gel F254 (Merck silica ge!’60 (c) Use a flow rate of 1 mL per minute.
plates are suitable). (d) Use an ambient column temperature.
(b) Use the mobile phase as described below. Jse a detection wavelength of 220 nm.
_of tetrahydrofuran, 37.5 volumes of methanol and
> solution containing 0.66% w/v of
MOBILE PHASE lrogen orthophosphate previously adjusted to
10 volumes of acetone and 90 volumes of dichloromethane. %.w/v solution of sodium hydroxide or dilute
SYSTEM SUITABILITY phosphoric acid
The test is not valid unless the chromatogram obtained with SYSTEM SUITAB
solution (3) shows two clearly separated spots. The test is not valid’ he chromatogram obtained
CONFIRMATION with solution (6), the resefution factor between the two
The principal spot in the chromatogram obtained with principal peaks is at least “sé.”
solution (1) corresponds in position and size to that in the LIMITS |
chromatogram obtained with solution (2). In the chromatogram obtained w
B. In the Assay, the retention time of the principal peak in the area of any peak corresponding t
the chromatogram obtained with solution (1) is the same as nitrophenyl) (2-chlorophenyl)methanone ‘(in
that of the principal peak in the chromatogram obtained with greater than the area of the principal peak in
solution (2). chromatogram obtained with solution (4) (1-0
TESTS the area of any peak corresponding to 3-amino-4-
Dissolution (2-chlorophenyl)-6-nitroquinolin-2(1H)-one (impurity B) is
Complies with the requirements stated under Unlicensed not greater than the area of the principal peak in the
Medicines, Oral Suspensions. Use a volume of the oral chromatogram obtained with solution (5) (1.0%);
a
tbat
fe
Related substances area of the principal peak in the chromatogram obtained with
te

vo

ete

oan
the sum of the areas of any such peaks is not greater than the
a
light. Prepare a mixture of 9.5 volumes of tetrahydrofuran,

Se

me
37.5 volumes of methanol and 53 volumes of water (solution solution (2) (2.0%).
A).
.?
le
(1) To a volume of the oral suspension containing 1 mg of

ee

.
een ey ht ce
wifey ae.
Clonazepam, add 9.5 mL of tetrahydrofuran and 37.5 mL of (7) (0.1%).

yer ey
Sy
methanol; shake, dilute to 100 mL with water and filter

cyte
TN

ve
Fe
5
III-360 Clonazepam Preparations 2016
ASSAY TEST CONDITIONS

Carry out the method for liguid chromatography, (a) Use Apparatus 1, rotating the basket at 100 revolutions
Appendix III D, using the following solutions protected from per minute.
light. (b) Use 900 mL of water, at a temperature of 37°, as the
(1) To a weighed quantity of the oral suspension containing dissolution medium.
1 mg of Clonazepam, add 9.5 mL of tetrahydrofuran and
PROCEDURE
37.5 mL of methanol; shake, dilute to 100 mL with water and
filter through a 0.45-um filter.
(2) 0.001% w/v of clonazepam BPCRS in solution A
described under Related substances.
filter. Use the filtered medium, diluted with water if
0.00005% w/v of Clonazepam.
kanol and dilute to 100 mL with water.
(2) 0.00005% w/v of clonazepam BPCRS.
js. CONDITIONS
with octadecylsilyl sihca gel for chromatography (5 «wm).
romatogram obtained below.
with solution (3), the resolutn between the two
principal peaks is at least 1.8
DETERMINATION OF CONTEN
Determine the weight per mL of the oral’suspensi
Appendix V G, and calculate the content.¢f C,
weight in volume, using the declared conte MOBILE PHASE
C,5H;9CIN3Q03 in clonazepam BPCRS. 30 volumes of acetonitrile, 30 volumes of methanol and
STORAGE 40 volumes of water.
Clonazepam Oral Suspension should be protected fro DETERMINATION OF CONTENT
IMPURITIES alculate the total content of clonazepam, C,5;H)9CIN30O3;,

The impurities limited by the requirements of this medium from the chromatograms obtained and using
monograph include impurities A and B listed under lared content of C)5H,9CIN3O3 in
Clonazepam.
Clonazepam Tablets
ollowi
‘
..
Clonazepam Tablets from different manufacturers, whilst

Pon
Lo
prepare samples imme y before use. Use low-actinic

:
complying with the requirements of the monograph, may not be

oe
. :
glassware. Prepare a mii re of 10 volumes of

ay
interchangeable.
:
tetrahydrofuran, 42 volut ‘OLgnethanol and 48 volumes of

tions
ee
water (solution A). Carry out the method for hquid

ee
Action and use

DE
aera
wee
chromatography, Appendix II ng the following

CES gy
Benzodiazepine.
“met
soa
solutions. &
r+,
loos
DEFINITION (1) Shake a quantity of the powdered t containing

.
Clonazepam Tablets contain Clonazepam. 10 mg of Clonazepam with 1 mL of tetreéhydrofuran and

The tablets comply with the requirements stated under Tablets and 4 mL of methanol, add sufficient water to ©20 mL,
with the following requirements. mix and filter.
Content of clonazepam, C,;H, 9CIN3;0;3 (2) Dilute 1 volume of solution (1) to 100 volurties
95.0 to 105.0% of the stated amount. solution A and further dilute 2 volumes of this soltition to
10 volumes with solution A.
IDENTIFICATION
(3) 0.005% w/v each of clonazepam BPCRS and
Extract a quantity of the powdered tablets containing 10 mg
flunitrazepam BPCRS in solution A.
of Clonazepam with 25 mL of dichloromethane, centrifuge,
AS
ary Bh katy
filter the supernatant liquid, evaporate to dryness and dry the (4) 0.0005% w/v of 3-amino-4-(2-chlorophenyl) -6-nitroquinolin-
a“
2(1H)-one BPCRS in solution A.

.
residue at 60° at a pressure not exceeding 0.7 kPa. The

.
aN
.
infrared absorption spectrum of the residue, Appendix II A, is (5) Dilute 1 volume of solution (2) to 2 volumes with
te
:
‘ poe
concordant with the reference spectrum of clonazepam solution A.

toes
‘
et eR
(RS 432).
a
Set
Tg
.
TESTS (a) Use a stainless steel column (15 cm x 3.9 mm) packed
et
.
.
-¢
Dissolution with end-capped octylsilyl silica gel for chromatography (5 um)

rt
PD
.
Carry out the following procedure protected from light. (Symmetry C8 is suitable).
.
Gd ee? Aue, i
,
tye Ne ¢ eee.
Comply with the requirements in the dissolution test for tablets (b) Use isocratic elution and the mobile phase described
ote teitey:
Sree
gt!
sis seh Ye,
and capsules, Appendix XII B1. below.

Ver
.
2016 Clonidine Preparations ITI-361
(c) Use a flow rate of 1 mL per minute. SYSTEM SUITABILITY

(d) Use an ambient column temperature. The test 1s not valid unless, in the chromatogram obtained
(e) Use a detection wavelength of 254 nm. with solution (3), the resolution between the two principal
peaks is at least 1.8.
retention time of clonazepam. Calculate the content of C;;H; 9CIN303 in the tablets from
the chromatograms obtained and using the declared content
MOBILE PHASE
of C,5H;9CIN303 in clonazepam BPCRS.
48 volumes of a 0.66% w/v solution of diammonium hydrogen
orthophosphate, previously adjusted to pH 8.0 with a ASSAY
4.0% w/v solution of sodium hydroxide or dilute phosphoric For tablets containing less than 2 mg and/or less than
acid, mes of tetrahydrofuran and 42 volumes of 2% w/w of Clonazepam
ntion times relative to clonazepam For tablets containing 2 mg or more and 2% w/w or
(retention time, out. 7 minutes) are: 3-amino-4- more of Clonazepam
(2-chlorophenyl), yuinolin-2(1H)-one, about 2.1 and Prepare a mixture of 10 volumes of tetrahydrofuran,
(2-amino-5-nitrop chlorophenyl)methanone, 42 volumes of methanol and 48 volumes of water
about 2.4. (solution A). Carry out the following procedure protected
from light and prepare the solutions immediately before use.
SYSTEM SUITABILITY
The test is not valid unless omatogram obtained Appendix III D, using the following solutions.
with solution (3), the resolutip ; two principal
AULA
peaks is not less than 1.8.
10 mg of Clonazepam with 10 mL of tetrahydrofuran and
LIMITS 7 40 mL of methanol, add sufficient water to produce 100 mL,
In the chromatogram obtained with soluth mix and filter.
the area of any peak corresponding to 3-amino-4- .<. (2) 0.01% w/v of clonazepam BPCRS in solution A.
(2-chlorophenyl)-6-nitroquinolin-2(1H)-one is net (3) 0.005% w/v each of clonazepam BPCRS and
than the area of the principal peak in the chromatogram flunitrazepam BPCRS in solution A.
the area of any peak corresponding to (2-amino-5-
hromatographic conditions described under Related
nitrophenyl) (2-chlorophenyl)methanone is not greater tha
stances may be used.
solution (2) (0.2 %).
The sum of the impurities is not more than 2%.
Disregard any peak with an area less than that of the area of
the principal peak in the chromatogram obtained with taified and using the declared content
solution (5) (0.1%). of C 15H 9CIN303 1 BPCRS.
Uniformity of content STORAGE
Tablets containing less than 2 mg and/or less than 2% w/w Clonazepam Tablets should
of Clonazepam comply with the requirements stated under
IMPURITIES
Tablets using the following method of analysis. Prepare a
mixture of 10 volumes of tetrahydrofuran, 42 volumes of
methanol and 48 volumes of water (solution A). Carry out the
following procedure protected from light and prepare the
solutions immediately before use. Carry out the method for
liqud chromatography, Appendix III D, using the following
solutions in solution A. Clonidine Injection
(1) Shake a whole tablet with 1 mL of tetrahydrofuran and
4 mL of methanol, add sufficient water to produce 10 mL, Action and use
mix and filter. Dilute the filtrate, if necessary with sufficient Alpha,-adrenoceptor agonist; treatment of hypertension.
solution A to produce a solution expected to contain
0.001% w/v of Clonazepam. DEFINITION
(2) 0.001% w/v of clonazepam BPCRS. Clonidine Injection is a sterile solution of Clonidine
Hydrochloride in Water for Injections.
(3) 0.0005% w/v each of clonazepam BPCRS and
flunttrazepam BPCRS. The injection complies with the requirements stated under
Content of clonidine hydrochloride, C,H )CI,N3,HCl
CHARACTERISTICS
IiI-362 Clonidine Preparations 2016
IDENTIFICATION
A. Dilute a volume containing 0.3 mg of Clonidine
Clonidine Tablets
Hydrochloride to 5 mL with 0.01m hydrochloric acid. The light Action and use
absorption of the resulting solution, Appendix II B, in the Alphay-adrenoceptor agonist; treatment of hypertension.
range 245 to 350 nm exhibits maxima at 272 nm and
279 nm and an inflection at 265 nm. DEFINITION
B. To a volume containing 0.15 mg of Clonidine Clonidine Tablets contain Clonidine Hydrochloride.
Hydrochloride add 1 mL of a 10% w/v solution of ammonium The tablets comply with the requirements stated under Tablets and
reineckate and allow to stand for 5 minutes. A pink precipitate with the following requirements.
is produced.
Content of clonidine hydrochloride, C,H »CI,N;,HCl
TESTS 90.0 to 110.0% of the stated amount.
Acidity
;
IDENTIFICATION
pH, 4.0:
To a quantity of the powdered tablets containing 0.5 mg of
Clonidine Hydrochloride add 30 mL of water and 5 mL of
Carry out the méthox 1M sodium hydroxide. Swirl gently and extract with 20 mL of
Appendix II A, usi chloroform. Centrifuge the chloroform layer, dry with
volume of the injection anhydrous sodium sulfate, filter and evaporate the filtrate to
containing 0.75 mg of Ci ‘Hydrochloride, evaporate to dryness. Dissolve the residue in 8 mL of 0.01m hydrochloric
dryness and dissolve the res mL of methanol. acid. The resulting solution complies with the following tests.
(2) Dilute 1 volume of soluti 0 volumes with A. The light absorption, Appendix II B, in the range 245 to
methanol. 350 nm exhibits maxima at 272 nm and 279 nm and an
inflection at 265 nm.
(a) Use as the coating silica gel G. . B. Add 1 mL of a 10% w/v solution of ammonium reineckate
and allow to stand for 5 minutes. A pink precipitate is
(b) Use the mobile phase as described below
produced.
TEST
(e) After removal of the plate, allow it to dryin air and spray Tablets containing less than 2 mg and/or less than 2% w/w
with potassium todobismuthate solution R2. Allow to dryin ag yf Clonidine Hydrochloride comply with thereduiements
for 1 hour, spray again with the same reagent and
immediately spray with a 5% w/v solution of sodium nitrite.
MOBILE PHASE
The filtered upper layer of a mixture obtained by shaking
together 10 volumes of glacial acetic acid, 40 volumes of uffer pH 7.6, if necessary, to give a solution
butan-1-ol and 50 volumes of water and allowing the layers to 0015% wiv of Clonidine Hydrochloride.
separate.
LIMITS
anhydrous sodium
and allow to separate.
absorbent cotton and di
with boric acid solution.
ASSAY layer of the resulting solutio
To a volume containing 0.15 mg of Clonidine Hydrochloride
add 25 mL of citro-phosphate buffer pH 7.6. Add 5 mL of
water and 1 mL of a solution containing 0.15% w/v of
bromothymol blue and 0.15% w/v of anhydrous sodium
carbonate. Add 30 mL of chloroform, shake for 1 minute and
centrifuge. To 15 mL of the chloroform layer add 10 mL of
boric acid solution and measure the absorbance of the resulting pH 7.6, transferring 5 mL to a separating funnel'and®”
solution at the maximum at 420 nm, Appendix II B, using in completing the procedure described above, beginning at the
the reference cell a solution prepared by diluting 10 mL of words ‘add 1 mL ofa solution ...’ and using the declared
boric acid solution to 25 mL with chloroform. Repeat the content of CgHo9Cl2N3,HCl in clonidine hydrochloride BPCRS.
operation using 5 mL of a 0.003% w/v solution of clonidine For tablets containing less than 0.3 mg of Clonidine
hydrochloride BPCRS, adding 20 mL of citro-phosphate buffer Hydrochloride, use the same procedure but with a
pH 7.6 and completing the procedure described above, concentration of 0.001% w/v or 0.0005% w/v of Clonidine
beginning at the words ‘Add 5 mL of water ...’. Calculate the Hydrochloride as appropriate and with correspondingly
content of CgH»Cl,N3,HCl in the injection using the smaller concentrations of clonidine hydrochloride BPCRS.
declared content of CgHoCl,N3,HCl in clonidine
ASSAY
hydrochlonde BPCRS.
containing 0.15 mg of Clonidine Hydrochloride add 25 mL
of citro-phosphate buffer pH 7.6 and shake for 15 minutes.
Add 5 mL of water and 1 mL of a solution containing
0.15% w/v of bromothymol blue and 0.15% w/v of anhydrous
2016 Clotrimazole Preparations III-363
sodium carbonate and shake to disperse. Add 30 mL of Remove from the water bath, shake the mixture vigorously
chloroform, shake continuously for 1 minute and centrifuge. while cooling to room temperature, cool in ice for
To 15 mL of the chloroform layer add 10 mL of boric acid 15 minutes, centrifuge for 5 minutes and decant the
i
solution and measure the absorbance of the resulting solution supernatant liquid. Repeat the extraction with two further
at the maximum at 420 nm, Appendix II B, using in the 20-mL quantities of methanol. To the combined methanol
reference cell a solution prepared by diluting 10 mL of boric extracts add 10 mL of methanol and dilute to 100 mL with
acid solution to 25 mL with chloroform. Repeat the operation water. Cool in ice and filter through a glass microfibre filter
using 5 mL of a 0.003% w/v solution of clonidine paper (Whatman GF/C is suitable).
hydrochloride BPCRS, adding 20 mL of citro-phosphate buffer (2) 0.0002% w/v of 2-chlorotritanol BPCRS in a mixture of
pH 7.6 and completing the procedure described above, 3 volumes of water and 7 volumes of methanol R1.
beginning at the words ‘Add 5 mL of water ...’. Calculate
t of CgH,CI,N3,HCI in the tablets using the
mixture of 3 volumes of water and 7 volumes of methanol R1.
of CoH oCl,N3,HCl in clonidine
we Ne

(Lichrosorb RP-18 or Spherisorb ODS 1 is suitable).
Action and use below.
Antifungal. (c) Use a flow rate of 1.5 mL per minute.
DEFINITION &
Clotrimazole Cream contaifi
|
The cream complies with the requirement
Semt-solid Preparations and with the follou (g) For solution (1), allow the chromatography to proceed
Content of clotrimazole, C,H, ,CIN;
30 volumes of 0.02m orthophosphoric acid and 70 volumes of

IDENTIFICATION “ g methanol R1, the pH of the mixture being adjusted to 7.5
A. Carry out the method for thin-layer chromatography
with a 10% v/v solution of triethylamine in methanol R1.
EM SUITABILITY
(1) Shake a quantity of the cream containing 20 mg of
Clotrimazole with 4 mL of dichloromethane for 30 minutes, chromatogram obtained with solution (3):
centrifuge and use the supernatant liquid. mn efficiency, determined using the principal peak,
(2) 0.5% w/v of clotrrmazole BPCRS in dichloromethane. e at least 9000 theoretical plates per metre.
(a) Use a silica gel precoated plate (Merck silica gel 60 plates
are suitable). sak corresponding to 2-chlorotritanol is not
(b) Use the mobile phase as described below in a greater than of the peak in the chromatogram
chromatography tank containing 25 mL of 13.5mM ammonia in obtained with soluti
a beaker.
(d) Develop the plate to 15 cm. Appendix III D, using thé
€reati
(e) After removal of the plate, allow it to dry in a current of (1) Extract a quantity of the
air and spray with dilute potassium todobismuthate solution.
MOBILE PHASE
di-isopropyl ether. room temperature, cool in ice for 15 ming

CONFIRMATION 5 minutes and decant the supernatant liquid :
The principal spot in the chromatogram obtained with extraction with two further 20-mL quantities of methanol.
solution (1) is reddish brown and corresponds to the To the combined methanol extracts add 10 mL of methanol
principal spot in the chromatogram obtained with and dilute to 100 mL with water. Cool in ice and filter
solution (2). through a glass microfibre filter paper (Whatman GF/Cis
B. In the Assay, the retention time of the principal peak in suitable). Dilute 1 volume of the filtrate to 5 volumes with a
the chromatogram obtained with solution (1) is similar to mixture of 3 volumes of water and 7 volumes of methanol.
that of the peak due to Clotrimazole in the chromatogram (2) Dissolve 20 mg of clotrimazole BPCRS in 70 mL of
obtained with solution (2). methanol, add sufficient water to produce 100 mL and dilute
1 volume of the resulting solution to 5 volumes with a
TESTS
mixture of 3 volumes of water and 7 volumes of methanol.
2-Chlorotritanol (Impurity A)
Carry out the method for liguid chromatography, CHROMATOGRAPHIC CONDITIONS
Appendix III D, using the following solutions. The chromatographic conditions described under
(1) Extract a quantity of the cream containing 20 mg of 2-Chlorotritanol may be used.
Clotrimazole by warming with 20 mL of methanol R1 in a
water bath at 50° for 5 minutes, shaking occasionally.
IlI-364 Clotrimazole Preparations 2016
SYSTEM SUITABILITY (1) Dilute a quantity of the eye drops containing 0.1g to
The column efficiency, determined using the peak in the produce 100 mL.
chromatogram obtained with solution (2), should be at least (2) 0.0002% w/v of 2-chlorotritanol BPCRS (impurity A).
9000 theoretical plates per metre. CHROMATOGRAPHIC CONDITIONS
Calculate the content of C2.H;7CIN>2 in the cream using the with octadecylsilyl silica gel for chromatography (10 um) (Partisil
declared content of C,,H,7CIN2 in clotrimazole BPCRS. ODS-1 is suitable).
IMPURITIES (b) Use isocratic elution and the mobile phase described
The impurities limited by the requirements of this below.
monograph include: (c) Use a flow rate of 2 mL per minute.
2-Chlorotrit#xol (Impurity A listed under Clotrimazole). (d) Use an ambient column temperature.
MOBILE PHASE
Clotrimazole
Mix 800 mL of a 0.025m phosphate buffer solution,
NOTE: Clotrimazole Eve save not currently licensed in the
prepared by dissolving 5.7 g of dipotassium hydrogen
United Kingdom.
orthophosphate trihydrate in 1000 mL of water, with 1200 mL
Action and use of methanol.
Antifungal. LIMITS
DEFINITION . In the chromatogram obtained with solution (1):

Clotrimazole Eye Drops area sterile sok on,of Clotrimazole the area of any peak corresponding to 2-chlorotritanol
in a suitable oily vehicle. é (impurity A) is not greater than the area of the principal peak
The eye drops comply with the requirements state in the chromatogram obtained with solution (2) (0.2%).
Preparations, the requirements stated under Unli ASSAY
and with the following requirements. Carry out the method for liquid chromatography,
Content of clotrimazole, C,,H,7CIN, Appendix III D, using the following solutions in a mixture of
95.0 to 105.0% of the stated amount. 0 volumes of chloroform and 30 volumes of methanol.
IDENTIFICATION Dilute a quantity of the eye drops containing 0.1g to
A. Carry out the method for thin-layer chromatography, 0 mL.
Appendix III A, using the following solutions. /v of clotrimazole BPCRS.
(1) Shake a quantity of the eye drops with an equal volume MSRAPHIC CONDITIONS
of dichloromethane and, if necessary, dilute the solution to
contain 0.5% w/v of clotrimazole.
(2) 0.5% w/v of clotrimazole BPCRS in dichloromethane.
22H 7CIN> in the eye drops using
(a) Use as the coating silica gel (Merck silica gel 60 plates are 7CIN> in clotrimazole BPCRS.
suitable).
STORAGE
(b) Use the mobile phase as described below in a
chromatography tank containing 25 mL of 13.5M ammonia in Clotrimazole Eye Drops
2° to 8°.
a beaker.
(c) Apply 10 uL of each solution. IMPURITIES .
(d) Develop the plate to 15 cm. The impurities limited by the requir
monograph include:
air and spray with dilute potassium 1odobismuthate solution. 2-Chlorotritanol (Impurity A listed unde
MOBILE PHASE
di-isopropyl ether.
CONFIRMATION

Clotrimazole Pessaries
solution (1) is reddish brown and corresponds to the
Action and use
ws
Antifungal.
solution (2).
B. In the Assay, the chromatogram obtained with solution DEFINITION
(1) shows a peak with the same retention time as the peak Clotrimazole Pessaries are moulded pessaries containing
due to clotrimazole in the chromatogram obtained with Clotrimazole.
solution (2). The Pessaries comply with the requirements stated under Vaginal
TESTS Preparations and with the following requirements.
2-Chlorotritanol (Impurity A) Content of clotrimazole, C,,H,7CIN,
Carry out the method for liquid chromatography, 95.0 to 105.0% of the stated amount.
ha Pay
aNd
Poa
10 volumes of chloroform and 30 volumes of methanol.
2016 Clotrimazole Preparations IJ-365

A. Carry out the method for thin-layer chromatography, 30 volumes of 0.02m orthophosphoric acid and 70 volumes of
Appendix III A, using the following solutions. methanol, adjust the pH of the mixture to 7.5 with a 10% v/v
(1) Shake a quantity of the pessaries, cut into small pieces, solution of triethylamine in methanol.
containing 20 mg of Clotrimazole with 4 mL of SYSTEM SUITABILITY
dichloromethane for 30 minutes, centrifuge and use the
The column efficiency, determined using the principal peak in
supernatant liquid.
the chromatogram obtained with solution (3), should be at
(2) 0.5% w/v of clotrimazole BPCRS in dichloromethane. least 9000 theoretical plates per metre.
CHROMATOGRAPHIC CONDITIONS LIMITS
(a) Use a silica gel precoated plate (Merck silica gel 60 plates In the chromatogram obtained with solution (1):
are suitable).
vile phase as described below in a the principal peak in the chromatogram obtained with
ASSAY
ate, allow it to dry in a current of Carry out the method for liquid chromatography,
air and spray with di um iodobismuthate solution. Appendix III D, using the following solutions.
MOBILE PHASE (1) Weigh 20 pessaries and cut into small pieces. To a
di-tsopropyl ether. quantity of the pessaries containing 0.1 g of Clotrimazole add
CONFIRMATION
50 mL of methanol and shake for 20 minutes. Dilute to
250 mL with methanol, filter and to 10 mL of the filtrate add
60 mL of methanol and sufficient water to produce 100 mL.
solution (1) is reddish brown and corr
principal spot in the chromatogram obta1 (2) Dissolve 20 mg of clotrimazole BPCRS in 70 mL of
solution (2). methanol, add sufficient water to produce 100 mL and dilute
B. In the Assay, the chromatogram obtained w
(1) shows a principal peak with the same retentio
the principal peak in the chromatogram obtained with CHROMATOGRAPHIC CONDITIONS
solution (2). ze chromatographic conditions described under Related
abstances may be used.
TESTS
Related substances SUITABILITY
Carry out the method for liquid chromatography, umn efficiency, determined using the peak in the
Appendix III D, using the following solutions. tegram obtained with solution (2), should be at least
(1) Cut a suitable amount of pessaries into small pieces.
Add 50 mL of methanol to a quantity of the pessaries
containing 0.1 g of Clotrimazole and shake for 20 minutes.
Dilute to 100 mL with methanol and filter. To 20 mL of the ed and using the declared content
filtrate add 50 mL of methanol and sufficient water to zole BPCRS.
produce 100 mL.
(2) 0.0002% w/v of 2-chlorotritanol BPCRS in a mixture of
mixture of 3 volumes of water and 7 volumes of methanol. Clotrimazole Vagin
(4) Dilute 1 volume of solution (3) to 40 volumes with a Action and use
mixture of 3 volumes of water and 7 volumes of methanol. Antifungal.
DEFINITION
with octadecylsilyl silica gel for chromatography (5 wm) Clotrimazole Vaginal Tablets are vaginal tablets containing
(Lichrosorb RP-18 or Spherisorb ODS1is suitable). Clotrimazole.
(b) Use isocratic elution and the mobile phase described The Vaginal Tablets comply with the requirements stated under
below. Vaginal Preparanons and with the following requirements.
(c) Use a flow rate of 1.5 mL per minute. Content of clotrimazole, C,,H,7CIN;
(e) Use a detection wavelength of 215 nm. IDENTIFICATION
(f) Inject 20 pL of each solution. A. Carry out the method for thin-layer chromatography,
for 1.5 times the retention time of the principal peak. (1) Shake a quantity of the powdered tablets containing
20 mg of Clotrimazole with 4 mL of dichloromethane for
30 minutes, centrifuge and use the supernatant liquid.
(2) 0.5% w/v of clotrimazole BPCRS in dichloromethane.
III-366 Clotrimazole Preparations 2016
CHROMATOGRAPHIC CONDITIONS the area of any secondary peak is not greater than the area of
(a) Use a silica gel precoated plate (Merck silica gel 60 plates the principal peak in the chromatogram obtained with
are suitable). solution (2) (1.0%).
(b) Use the mobile phase as described below in a Disregard any peak with an area less than the area of the
chromatography tank containing 25 mL of 13.5mM ammonia in principal peak in the chromatogram obtained with
a beaker. solution (4) (0.05%).
(c) Apply 10 ywL of each solution. ASSAY
(d) Develop the plate to 15 cm. Carry out the method for liquid chromatography,
(e) After removal of the plate, allow it to dry in a current of Appendix III D, using the following solutions.
air and spray with dilute potassium 1odobismuthate solution. (1) Weigh and powder 20 tablets. To a quantity of the
powder containing 0.1 g of Clotrimazole add 50 mL of
methanol and shake for 20 minutes. Dilute to 250 mL with
methanol, filter and to 10 mL of the filtrate add 60 mL of
methanol and sufficient water to produce 100 mL.
chromatogram obtained with (2) Dissolve 20 mg of clotrimazole BPCRS in 70 mL of
and corresponds to the methanol, add sufficient water to produce 100 mL and dilute
principal spot in the thrématé am obtained with 1 volume of the resulting solution to 5 volumes with a
solution (2). mixture of 30 volumes of water and 70 volumes of methanol.
B. In the Assay, the chroma tained with solution CHROMATOGRAPHIC CONDITIONS
(1) shows a principal peak withthe s retention time as
the principal peak in the chrom tained with
solution (2).
SYSTEM SUITABILITY
TESTS
The column efficiency, determined using the peak in the
Related substances |
chromatogram obtained with solution (2), should be at least
Carry out the method for liquid chromatography
9000 theoretical plates per metre.
(1) Add 50 mL of methanol to a quantity of the powdére
tablets containing 0.1 g of Clotrimazole and shake for < Calculate the content of C2.H,7CIN> in the tablets from the
20 minutes. Dilute to 100 mL with methanol and filter. hromatograms obtained and using the declared content of
To 20 mL of the filtrate add 50 mL of methanol and 99H, 7CIN> in clotrimazole BPCRS.
sufficient water to produce 100 mL.
(2) 0.0002% w/v of 2-chlorotritanol BPCRS in a mixture of
mixture of 3 volumes of water and 7 volumes of methanol. Action and use’ 4
CHROMATOGRAPHIC CONDITIONS Antifungal and corti
DEFINITION
Clotrimazole and Hydrocort etate Cream contains
(Lichrosorb RP-18 or Spherisorb ODS 1 is suitable).
under Topical
below.
trements.
Content of clotrimazole, C,,H,7CIN,
Content of hydrocortisone, C,;H390;
(f) Inject 20 uL of each solution. 90.0 to 110.0% of the stated amount.
IDENTIFICATION
MOBILE PHASE
30 volumes of 0.02m orthophosphoric acid and 70 volumes of (1) Shake a quantity of the cream containing 20 mg of
methanol; adjust the pH of the mixture to 7.5 with a 10% viv Clotrimazole with 4 mL of dichloromethane for 30 minutes.
solution of triethylamine in methanol. Centrifuge and use the supernatant liquid.
SYSTEM SUITABILITY (2) 0.5% w/v of clotrimazole BPCRS in dichloromethane.
The column efficiency, determined using the principal peak in CHROMATOGRAPHIC CONDITIONS
the chromatogram obtained with solution (3), should be at
least 9000 theoretical plates per metre.
suitable).
LIMITS
2016 Clotrimazole Preparations II-367
(e) After removal of the plate, dry in air and then spray with 5 minutes, filter through a 0.45-um membrane filter and use
dilute potassium todobismuthate solution. the filtrate.
MOBILE PHASE (3) 0.00015% w/v of 2-chlorotritanol BPCRS.
di-isopropyl ether. At the bottom of the chromatography tank, (4) 0.000168% w/v of hydrocortisone acetate BPCRS.
place a beaker containing 25 mL of 13.5mM ammonia. (5) 0.0168% w/v of hydrocortisone acetate BPCRS and
CONFIRMATION 0.000084% w/v of prednisolone acetate BPCRS.
The principal spot in the chromatogram obtained with (6) Dilute 1 volume of solution (3) to 10 volumes.
solution (1) is reddish-brown and corresponds in position CHROMATOGRAPHIC CONDITIONS
and colour to that in the chromatogram obtained with (a) Use a stainless steel column (25 cm x 4.6 mm) packed
solution (2). with octadecylsilyl silica gel (5 um) (Waters X-Bridge C18 is
B. Carry*gut the method for thin-layer chromatography, suitable).
iC using the following solutions. (b) Use gradient elution and the mobile phase described
ity of the cream containing the equivalent of below.
cane and shake. Discard the upper layer,
um sulfate to the lower layer, mix
MOBILE PHASE
Mobile phase A 1.5 g/L of potassium dihydrogen
hydrocortisone acetate BPCRS§ in: orthophosphate in water adjusted to pH 3.0 with 10% v/v
CHROMATOGRAPHIC CONDITION
c Mobile phase B acetomitrile R1.
(a) Use as the coating silica gel (Mer 60 plates are
suitable). Mobile phase C_ methanol.
(b) Use the mobile phase as described below
(c) Apply 5 uL of each solution. Time Mobile Mobile Mobile Comment
(Minutes) phase A phase B phase C
(% viv) (% viv) (% viv)
(e) After removal of the plate, dry in air and then sp
0-2 90 10 0 isocratic
alkaline tetrazolium blue solution.
MOBILE PHASE
75 0 isocratic
1.2 volumes of water, 8 volumes of methanol, 15 volumes of
ether and 77 volumes of dichloromethane.
50 50 isocratic
CONFIRMATION
50310 © 50-0 linear gradient
re-equilibration
solution (1) corresponds in position to that in the
chromatogram obtained with solution (2). The principal spot
in solution (3) appears as a single, compact spot.
are recorded under the prescribed
C. In the Assay for clotrimazole, the chromatogram obtained conditions the reten relative to hydrocortisone
with solution (1) shows a peak with the same retention time acetate (retention time,
as the peak due to clotrimazole in the chromatogram
D. In the Assay for hydrocortisone acetate, the
chromatogram obtained with solution (2) shows a peak with
the same retention time as the peak due to hydrocortisone clotrimazole, about 1.1 and 2-chlorott
acetate in the chromatogram obtained with solution (3). impurity A), about 1.6.
TESTS SYSTEM SUITABILITY
Related substances The test is not valid unless, in the chromatogram obtained
Carry out the method for liguid chromatography, with solution (5), the peak-to-valley ratio between
Appendix III D, using the following solutions in solvent A. prednisolone acetate and hydrocortisone acetate is at least 12.
Solvent A 50 volumes of acetonitrile R1 and 50 volumes of LIMITS
methanol.
For Clotrimazole at 210 nm _ In the chromatogram obtained
(1) Add 30 mL of Solvent A to a quantity of the cream with solution (1):
containing 7.5 mg of Clotrimazole and heat at 40° until fully the area of any peak corresponding to 2-chlorotritanol is not
dispersed. Allow the mixture to return to room temperature greater than 2 times the area of the principal peak in the
and dilute to 50 mL. Cool in ice for 5 minutes, filter through chromatogram obtained with solution (3) (2%).
a 0.45-um membrane filter and use the filtrate.
For Hydrocortisone Acetate at 245 nm In the chromatogram
(2) Add 30 mL of Solvent A to a quantity of the cream obtained with solution (2):
containing the equivalent of 7.5 mg of hydrocortisone and
the area of any peak corresponding to hydrocortisone is not
heat at 40° until fully dispersed. Allow the mixture to return
vain wy
to room temperature and dilute to 50 mL. Cool in ice for

III-368 Clozapine Preparations 2016
the area of any peak corresponding to ep:-hydrocortisone

ene ml
acetate is not greater than 1.5 times the area of the principal
Clozapine Oral Suspension
aN we
peak in the chromatogram obtained with solution (4) (1.5%); Action and use
men
the area of any peak corresponding to prednisolone acetate is Dopamine Dy, receptor antagonist; neuroleptic.
not greater than 0.6 times the area of the principal peak in
the chromatogram obtained with solution (4) (0.6%) DEFINITION
the area of any other secondary peak is not greater than half Clozapine Oral Suspension is a suspension of Clozapine in a
the area of the principal peak in the chromatogram obtained suitable flavoured vehicle.
with solution (4) (0.5%); The oral suspension complies with the requirements stated under
the sum of the areas ofall secondary peaks is not greater than Oral Liguids and with the following requirements.
Content of clozapine, C;gH,9CIN,
an area less than the area of the Shake the oral suspension vigorously before carrying out the
principal pe k iv chromatogram obtained with following tests.
solution (6) (0.
IDENTIFICATION
ASSAY A. Shake a quantity of the oral suspension containing
Carry out the method romatography, 100 mg of Clozapine with 20 mL of dichloromethane for
Appendix III D, usingthe A olutionsin Solvent A, 15 minutes, filter (Whatman GF/C is suitable) and evaporate
the filtrate to dryness under a stream of nitrogen.
(1) Add 30 mL of Solvent A to The infrared absorption spectrum of the residue, Appendix II A,
containing 7.5 mg of Clotrimaz is concordant with the reference spectrum of clozapine
vtete oT
(RS 444).
solution (2).
heat at 40° until fully dispersed. Allow the mixture tre TESTS
to room temperature and dilute to 100 mL. Cool in ice, Acidity
5 minutes, filter through a 0.45-um membrane filter and u H, 4.0 to 6.0, Appendix V L.
the filtrate. |
ated: ubstances
(3) 0.0075% w/v of clotrimazole BPCRS and 0.0084% w/v of
e method for liquid chromatography,
hydrocortisone acetate BPCRS.
I D, using the following solutions.
(4) 0.0168% w/v of hydrocortisone acetate BPCRS and
0.000084% w/v of prednisolone acetate BPCRS.
CHROMATOGRAPHIC CONDITIONS |
SYSTEM SUITABILITY
with solution (4), the peak-to-valley ratio between
yaaa
prednisolone acetate and hydrocortisone acetate is at least 12.
In the chromatogram obtained at 210 nm with solution (1);
calculate the content of C,H ,7CIN> in the cream using the CHROMATOGRAPHIC CONDITIONS
declared content of C,H,7CIN> in clotrimazole BPCRS. (a) Use a stainless steel column (15 cm
In the chromatogram obtained at 245 nm with solution (2); with end-capped octadecylsilyl silica gel for chro
calculate the content of C,;H3 05 in the cream using the (5 um) (Phenomenex Luna C18 is suitable).
declared content of C23H320¢ in hydrocortisone (b) Use gradient elution and the mobile phase desctf ed
acetate BPCRS. Each mg of C,,;H3 905 using is equivalent to below.
1.12 mg of C43H3206¢. (c) Use a flow rate of 1 mL per minute.
IMPURITIES (d) Use a column temperature of 30°.
The impurities limited by the requirements of this (e) Use a detection wavelength of 257 nm.
monograph include those listed under Clotrimazole and (f) Inject 20 wL of each solution.
Hydrocortisone Acetate.
MOBILE PHASE
Mobile phase A 25 volumes of methanol and 75 volumes of a

solution prepared by dissolving 2.04 g of potassium dihydrogen
orthophosphate in 1000 mL of water and adjusting the pH to
2.0 with dilute orthophosphonc acid (solution A).
Mobile phase B 15 volumes of solution A and 85 volumes of
methanol.
2016 Co-amulofruse Preparations III-369
Time Mobile phase A Mobile phase B Comment MOBILE PHASE

(Minutes) (% viv) (% viv) 33 volumes of a 1.36% w/v solution of sodium acetate,
0-2 95 5 isocratic adjusted to pH 5.5 with glacial acetic acid, and 67 volumes of
2-29 95-5 5995 linear gradient methanol.
29-30 595 9535 linear gradient DETERMINATION OF CONTENT
30-35 95 5 re-equilibration Determine the weight per mL of the oral suspension,
Appendix V G, and calculate the content of C,gH; 9CINg,,
weight in volume, using the declared content of C;gH,9CIN,
SYSTEM SUITABILITY in clozapine BPCRS.
The test is not valid unless: STORAGE
atogram obtained with solution (3), the resolution Clozapine Oral Suspension should be protected from light.
e peaks due to clozapine and impurity C is
resembles |
Co-amilofruse Tablets
clozapine for peak, 1
Amiloride and Furosemide Tablets
LIMITS
Action and use
ities A, B, C and D using Potassium sparing diuretic + loop diuretic.
peak due to impurity D
DEFINITION
Co-amilofruse Tablets contain Amiloride Hydrochloride and
Furosemide in the proportions one part of anhydrous
the areas of any peaks corresponding amiloride hydrochloride to eight parts of Furosemide.
D are not greater than twice the area o
the area of any peak corresponding to impurity @
greater than 3 times the area of the principal pea Content of anhydrous amiloride hydrochloride,
chromatogram obtained with solution (2) (0.3%); C,HsCIN,O,HC1
the area of any other secondary peak 1s not greater than
the area of the principal peak in the chromatogram obtain tent of furosemide, C,,H,,;CIN,O;S
with solution (2) (0.2%); 0.to 105.0% of the stated amount.
(4) (0.05%).
ASSAY peaks jin the chrofn:
same as those in the
solution (4).
(1) Add 180 mL of ethanol (96%) to a weighed quantity of TEST
the oral suspension containing 20 mg of Clozapine, shake for Related substances «
15 minutes and mix with the aid of ultrasound for
15 minutes. Add sufficient ethanol (96%) to produce 200 mL
and mix; filter the final solution, if necessary, discarding the
first 10 mL of filtrate. 5 volumes of methanol and 90 volumesof
mobile phase. Apply separately to the plate 20 uLzof each of
(2) Add 90 mL of ethanol (96%) to 20 mg of
the following solutions. For solution (1) mix with the aid of
clozapine BPCRS and shake for 15 minutes; mix with the aid
ultrasound a quantity of the powdered tablets containing
of ultrasound for a further 15 minutes and add sufficient
80 mg of Furosemide with 16 mL of methanol for 5 minutes,
ethanol (96%) to produce 200 mL.
centrifuge and use the supernatant liquid. For solution (2)
CHROMATOGRAPHIC CONDITIONS dilute 1 volume of solution (1) to 10 volumes with methanol.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed For solution (3) dilute 1 volume of solution (2) to
with end-capped base-deactivated octadecylsilyl sihca gel for 20 volumes with methanol. Solution (4) contains 0.05% w/v
chromatography (5 um) (Hypersil BDS is suitable). offurosemide BPCRS in methanol. Solution (5) contains
(b) Use isocratic elution and the mobile phase described 0.00625% wiv of amiloride hydrochloride BPCRS in methanol.
below. Solution (6) contains 0.0025% w/v of 4-chloro-5-
(c) Use a flow rate of 1 mL per minute. sulfamoylanthranilic acid BPCRS in methanol. Solution (7)
contains 0.00031% w/v of methyl 3,5-diamino-6-
chloropyrazine-2-carboxylate BPCRS in methanol. After removal
ae,
(e) Use a detection wavelength of 254 nm. of the plate, dry it in a current of air and examine under
2 te oe
(f) Inject 20 wL of each solution. ultraviolet light (254 nm). In the chromatogram obtained with
“ett ht
Ae a
‘ceed
iF
solution (1) any secondary spot other than any spot remaining
II-370 Co-amiulozide Preparations 2016
on the line of application or any spots corresponding to

either of the named impurities is not more intense than the
Co-amilozide Oral Solution
2 ete ate spot in the chromatogram obtained with solution (3) (0.5%, Amiloride and Hydrochlorothiazide Oral Solution
with reference to the content of furosemide). Examine under
Action and use
ultraviolet light (365 nm). In the chromatogram obtained with
Potassium-sparing diuretic + thiazide diuretic.
solution (1) any spot corresponding to methyl 3,5-diamino-6-
chloropyrazine-2-carboxylate is not more intense than the DEFINITION
spot in the chromatogram obtained with solution (7) (0.5%,
Co-amilozide Oral Solution is a solution containing
with reference to the content of anhydrous amiloride
Amiloride Hydrochloride and Hydrochlorothiazide in the
hydrochloride). Reveal the spots by Method I. In the
proportions one part of anhydrous amiloride hydrochloride to
chromatogram obtained with solution (1) any spot
ten parts of Hydrochlorothiazide in a suitable flavoured
ing to 4-chloro-5-sulfamoylanthranilic acid is not
vehicle.
the spot in the chromatogram obtained
Content of anhydrous amiloride hydrochloride,
ASSAY
C,H,CIN,O,HC1
Weigh and powder
III D, using the following
rseé.a quantity of the Content of hydrochlorothiazide, C;HsCIN;0,S,
IDENTIFICATION
same solvent mixture, mix, filter and diltite
(1) Disperse a volume of the oral solution containing 0.1 g of
filtrate to 50 mL with the same solvent mi
Hydrochlorothiazide in methanol, dilute to 50 mL with
methanol and mix.
(2) 0.2% wiv of hydrochlorothiazide BPCRS in methanol.
6 volumes of methanol adjusted to pH 2.0 with orthop (3) 0.02% wv of amiloride hydrochloride BPCRS in methanol.
acid. Solution (4) contains 0.002% w/v of amiloride 4) Equal volumes of solutions (1), (2) and (3).
hydrochlonde BPCRS and 0.016% w/v of furosemide BPCRS TOGRAPHIC CONDITIONS
a mixture of 4 volumes of water and 6 volumes of methanol
ODS1 is suitable), (b) as the mobile phase with a flow rate of
1.2 mL per minute a 0.02 solution of sodium hexanesulfonate ultraviolet light
in a mixture of 4 volumes of water and 6 volumes of
MOBILE PHASE
methanol, the pH of the solution adjusted to 4.0 with
1M acetic acid and (c) a detection wavelength of 361 nm. 12 volumes of 3M amino: a
tetrahydrofuran. ‘
| with solution (4), the resolution factor between the peaks due CONFIRMATION
to furosemide and amiloride is at least 2.5. The principal spots in the ch ‘ogram obtained with
Calculate the content of CsHgCIN7O,HCI and solution (1) correspond in positiofY and r to those in the
C,2H;,;CIN2OsS using the declared content of
C.HsCIN7O,HC1 and C,.H,,CIN,O;5S in amiloride
hydrochloride BPCRS and furosemide BPCRS, respectively. not correspond exactly with those of the prs ts in
the chromatograms obtained with solutions (
STORAGE
chromatogram obtained with solution (4) exhibits
Co-amilofruse Tablets should be protected from light. compact spot at each of these Rf values.
LABELLING B. In the Assay, the retention times of the two principal
The quantity of Amiloride Hydrochloride is stated in terms peaks in the chromatogram obtained with solution (3)
of the equivalent amount of anhydrous amiloride correspond to those of the peaks in the chromatograms
hydrochloride. obtained with solutions (1) and (2).
TESTS
Acidity
ee
4-Amino-6-chlorobenzene-1,3-disulfonamide
(1) Disperse a volume of the oral solution contaming 50 mg
of Hydrochlorothiazide in the mobile phase, dilute to
100 mL with the mobile phase and mix.
2016 Co-amilozide Preparations III-371
(2) 0.00050% w/v of 4-amino-6-chlorobenzene-1,3- LABELLING

disulfonamide BPCRS in the mobile phase. The strength with respect to Amiloride Hydrochloride is
(3) Prepare in the same manner as solution (1) but using stated in terms of the equivalent amount of anhydrous
solution (2) in place of the mobile phase. amiloride hydrochloride in a suitable dose-volume.
(10 um) (Nucleosil C18 is suitable). Co-amilozide Tablets
(b) Use isocratic elution and the mobile phase described Amiloride and Hydrochlorothiazide Tablets
below.
Action and use
DEFINITION
Co-amilozide Tablets contain Amiloride Hydrochloride and
Hydrochlorothiazide in the proportions one part of
anhydrous amiloride hydrochloride to ten parts of
4 volumes of phosp Hydrochlorothiazide.
and 76 volumes of
Content of anhydrous amiloride hydrochloride,
C.HsgCIN,O,HC1
Content of hydrochlorothiazide, C;H;CIN;0,S,
chlorobenzene-1,3-disulfonamide. ‘The reséhutie
these two peaks may be improved by decreasi IDENTIFICATION
methanol content in the mobile phase. A. Shake a quantity of the powdered tablets containing 0.1 g
of Hydrochlorothiazide with 50 mL of acetone, filter,
LIMITS
evaporate the filtrate to dryness and dry the residue at 105°
1 hour. The infrared absorption spectrum of the dried
the area of any peak corresponding to 4-amino-6- lue, Appendix II A, is concordant with the reference
chlorobenzene-1,3-disulfonamide is not greater than the area
solution (2).
ASSAY
Appendix III D, using the following solutions. i@retention times of the two principal
(1) Disperse a volume of the oral solution containing 50 mg ogram obtained with solution (4)
of Hydrochlorothiazide in the mobile phase, dilute to correspond to“the e chromatograms obtained with
100 mL with the mobile phase and mix. solutions (2) and (
(2) Dissolve 50 mg of hydrochlorothiazide BPCRS in a TESTS
mixture of 20 mL of methanol and 4 mL of phosphate buffer Related substances
pH 3.0 and dilute to 100 mL with water. Carry out the method for thir C vomatography,
(3) Dissolve 50 mg of amiloride hydrochlonde BPCRS in Appendix III A, using szlica gel ating substance
200 mL of methanol and to 20 mL of the resulting solution and a mixture of 85 volumes of ethy, aw and 15 volumes
add 4 mL of phosphate buffer pH 3.0 and dilute to 100 mL of propan-2-ol as the mobile phase.
with methanol.
containing 50 mg of Hydrochlorothiazidewith,d
The chromatographic conditions described under 4-Amino-6-
acetone and filter. For solution (2) dilute 1 volume of solution
chlorobenzene-1,3-disulfonamide may be used but using a
(1) to 100 volumes with acetone. After removal of the plate,
detection wavelength of 286 nm.
dry it in a current of air and reveal the spots by Method I.
SYSTEM SUITABILITY Any secondary spot in the chromatogram obtained with
The assay is not valid unless the system suitability criteria of solution (1) is not more intense than the spot in the
the test for 4-Amino-6-chlorobenzene-1,3-disulfonamide are chromatogram obtained with solution (2). Disregard any spot
met. remaining on the line of application.
DETERMINATION OF CONTENT Methyl 3,5-diamino-6-chloropyrazine-2-carboxylate
Determine the weight per mL of the oral solution, Carry out the method for thin-layer chromatography,
Appendix V G, and calculate the content of Appendix III A, protected from light, using a silica gel
CsHgCIN7O,HCl and C7HgCIN30,S,, weight in volume, precoated plate (Merck silica gel 60 plates are suitable) and a
using the declared content of CgsHgCIN7O,HC]I and freshly prepared mixture of 90 volumes of 1,4-dioxan and
C7HgCIN30,8, in amilonde hydrochloride BPCRS and 12 volumes of 3M ammonia as the mobile phase. Apply
hydrochlorothiazide BPCRS respectively. separately to the plate 10 uL of each of the following
solutions. For solution (1) shake a quantity of the powdered
II-372 Co-amoxiclav Preparations 2016
tablets containing the equivalent of 17.5 mg of anhydrous

amiloride hydrochloride with 10 mL of methanol and
Co-amoxiclav Injection
temas centrifuge. Solution (2) contains 0.0010% w/v of methyl Amoxicillin and Potassium Clavulanate Injection
3,5-diamino-6-chloropyrazine-2-carboxylate BPCRS in methanol.
Action and use
Penicillin antibacterial + beta-lactamase inhibitor.
20 volumes with methanol. Solution (4) contains 0.010% w/v
of amiloride hydrochloride BPCRS in methanol. After removal DEFINITION
of the plate, allow it to dry in air and examine under
Co-amoxiclav Injection is a sterile solution of Amoxicillin
ultraviolet light (365 nm). Any spot corresponding to methyl
Sodium and Potassium Clavulanate in Water for Injections.
3,5-diamino-6-chloropyrazine-2-carboxylate in the
It is prepared by dissolving Co-amoxiclav for Injection in the
chromatogram obtained with solution (1) is not more intense
requisite amount of Water for Injections immediately before
than the spot.in the chromatogram obtained with
use.
solution {
liquid chromatographys STORAGE

solutions. Solution Co-amoxiclav Injection should be used immediately after
preparation.
CO-AMOXICLAV FOR INJECTION

200 mL, to 20 mL of the resultis DEFINITION
0.1m hydrochloric acid and dilute
For solution (3) dissolve 50 mg Co-amoxiclav for Injection is a sterile material consisting of
Amoxicillin Sodium and Potassium Clavulanate with or
0.1m hydrochlonc acid and dilute to 100 mE: without excipients. It is supplied in a sealed container.
For solution (4) add a mixture of 20 mL of 7 PRODUCTION
4 mL of 0.1m hydrochloric acid to a quantity of the The methods of production, extraction and purification of
tablets containing 50 mg of Hydrochlorothiazide, mix@ Potassium Clavulanate used in the formulation of
the aid of ultrasound for 15 minutes, dilute to 100 m Co-amoxiclav Injection are such that potasstum clavam-2-
water, mix and filter. arboxylate is eliminated or present at a level not exceeding
(a) a stainless steel column (20 cm x 4.6 mm) packed with of the sealed container comply with the requirements
end-capped octadecylsilyl silica gel for chromatography (10 um) or Injections or Infusions stated under Parenteral
(Nucleosil C18 is suitable), (b) a mixture of 76 volumes of nd with the following requirements.
water, 20 volumes of methanol and 4 volumes of phosphate
buffer pH 3.0 as the mobile phase with a flow rate of 2 mL
per minute and (c) a detection wavelength of 286 nm.
The assay is not valid unless a peak due to 4-amino-6-
chlorobenzene-1,3-disulfonamide appears immediately before
solution (1). Increase the sensitivity, if necessary, to obtain at A. Carry out the me 108
least 10% of full-scale deflection on the chart paper for this Appendix III A, using the:
peak. The assay is also not valid unless the height of the
trough separating the two peaks is less than 10% of the
height of the peak due to 4-amino-6-chlorobenzene-1,3-
disulfonamide. The resolution between the two peaks may be
improved by decreasing the methanol content of the mobile
phase. amoxicillin trihydrate BPCRS in a mixture 0
Calculate the content of CsHgCIN7O,HCI and methanol and 6 volumes of 0.1m mixed phosphate buf
C7HgCIN30,S, using the declared content of pH 7.0. *
C.e-HgCIN7O,HCl and C7HgCIN30,S>, in amiloride
hydrochloride BPCRS and hydrochlorothiazide BPCRS
respectively. (a) Use as the coating silica gel F254 (Merck silica gel 60 Fos54
plates are suitable). Impregnate the plate by spraying it with
STORAGE a 0.1% w/v solution of disodium edetate in mixed phosphate
Co-amilozide Tablets should be protected from light. buffer pH 4.0 and allow to dry overnight. Activate the plate
LABELLING by heating at 105° for 1 hour just prior to use.
The quantity of Amiloride Hydrochloride is stated in terms (b) Use the mobile phase as described below.
of the equivalent amount of anhydrous amiloride (c) Apply 1 wL of each solution.
hydrochloride. (d) Develop the plate to 15 cm.
Sten
Y
2016 Co-amoxiclav Preparations III-373
MOBILE PHASE (f) Inject 20 ul of each solution.

1 volume of butan-1-ol, 2 volumes of a 0.1% w/v solution of MOBILE PHASE
disodium edetate in mixed phosphate buffer pH 4.0, 6 volumes of Mobile phase A Dissolve 15.6 g of sodium dihydrogen
glacial acetic acid and 10 volumes of butyl acetate. orthophosphate in 1000 mL of water and adjust the pH to 4.2
CONFIRMATION with orthophosphonic acid.
The principal spots in the chromatogram obtained with Mobile phase B Mix 10 volumes of mobile phase A with
solution (1) are similar in position and colour to those in the 90 volumes of methanol.
B. In the Assay, the retention time of the two principal peaks Time Mobile Mobile Comments
in the chromatogram obtained with solution (1) correspond (minutes) phase A phase B
to those.in the chromatogram obtained with solution (2). (% viv) (% v/v)
0-4 100 0 isocratic
48 100 > 70 0 > 30 linear gradient
8 > 18 70 30 isocratic
amoxicillin, 8. » Appendix V L. 18 > 25 70 —> 100 30 > 0 linear gradient
Clavulanate polymér.and other fluorescent impurities 25 > 30 100 0 re-equilibration
Carry out the method for fluorescence spectrophotometry,
Appendix II E, using lloving freshly prepared solutions.
Identify the peaks due to amoxicillin, amoxicillin dimer and
(1) To a quantity of the ¢ |
a-penicilloic acid using solution (3) and the chromatogram
containing the equivalent o
supplied with amoxicillin impurity standard BPCRS.
50 mL of a 0.1m phosphate &
as described below, shake vigoroush SYSTEM SUITABILITY
solution (3) resembles the chromatogram supplied with
amoxicillin impurity standard BPCRS and the resolution factor
of sodium dihydrogen orthophosphate in 800 ml#o between the peaks due to amoxicillin and a-penicilloic acid is
the pH to 5.0 using 1m sodium hydroxide and ad at least 2.0.
water to produce 1000 mL.
LIMITS

sulfate BPCRS in 0.5m sulfuric acid. [NoTE: The fluorescenee.,
quinine sulfate is 118 times more intense than that of an ea of any peak due to a-penicilloic acid is not greater
equivalent concentration of clavulanate polymer.] f the area of the principal peak in the chromatogram
ith solution (2) (5%);
PROCEDURE
ny peak due to amoxicillin dimer (the peak may
Measure the fluorescence of the solutions using an excitation ublet) is not greater than half the area of the
wavelength of 360 nm and an emission wavelength of
440 nm, using the phosphate buffer solution in the reference
cell.
LIMIT
The fluorescence obtained with solution (1) is not more
intense than that obtained with solution (2) (5% w/w, ondary peaks is not greater
calculated with respect to the content of clavulanic acid). than 1.5 times the area o e°principal peak in the
Related substances chromatogram obtained wit solutiot: (2) (15%).
Carry out the method for liguid chromatography, Bacterial endotoxins
Appendix III D, using the following freshly prepared Carry out the test for bacterial endoto
solutions. Dissolve the contents of the sealed c
(1) Dilute a quantity of the contents of a sealed container
containing the equivalent of 0.1 g of amoxicillin in sufficient amoxicillin (solution A). The endotoxin limit¢on ntration
mobile phase A to produce 200 mL. of solution A is 2.5 IU of endotoxin per mL.
(2) 0.0057% w/v of amoxicillin tnhydrate BPCRS in mobile Water
phase A. Not more than 3.5% w/w, Appendix IX C. Use 0.5 g.
(3) 0.05% wy of amoxicillin impurity standard BPCRS in ASSAY
mobile phase A. Determine the weight of the contents of 10 containers as
CHROMATOGRAPHIC CONDITIONS described in the test for uniformity of weight,
(a) Use a stainless steel column (5 cm x 4.6 mm) packed Appendix XII C1, Powders for Parenteral Administration.
with octadecylsilyl silica gel for chromatography (3 wm) Carry out the method for liquid chromatography,
(Spherisorb $3 ODS2 is suitable). Appendix III D, using the following solutions.
(b) Use gradient elution and the mobile phase described (1) Dissolve, with shaking, a quantity of the mixed contents
below. of the 10 containers containing the equivalent of 0.1 g of
(c) Use a flow rate of 1.5 mL per minute. amoxicillin in sufficient water to produce 100 mL, mix and
filter.
(2) 0.11% w/v of amoxicillin trihydrate BPCRS and 0.02% wiv
of lithium clavulanate EPCRS in water.
te yet
II-374 Co-amoxiclav Preparations 2016
CHROMATOGRAPHIC CONDITIONS Content of clavulanic acid, CsH,NO,;

(a) Use a stainless steel column (25 cm x 4.6 mm) packed When freshly constituted, not more than 120.0% of the
Rte.
anes)
with octadecylsilyl silica gel for chromatography (5 um) (Hypersil stated amount. When stored at the temperature and for the
period stated on the label during which the oral suspension
whe ete
ODS is suitable).
(b) Use isocratic elution and the mobile phase described may be expected to be satisfactory for use, not less than
below. 80.0% of the stated amount.
(c) Use a flow rate of 1 mL per minute. IDENTIFICATION

(d) Use an ambient column temperature. Carry out the method for thin-layer chromatography,
(1) Disperse, with shaking, a quantity of the oral suspension
containing the equivalent of 0.4 g of clavulanic acid in
MOBILE 100 mL of a mixture of 4 volumes of methanol and
80 volume > nol and 920 volumes of a 1.56% w/v 6 volumes of 0.1 mixed phosphate buffer pH 7.0 and filter.
solution of Sodgi drogen orthophosphate in water, the pH (2) 0.4% wiv of lithium clavulanate EPCRS and 0.8% w/v of
amoxicillin trihydrate BPCRS in a mixture of 4 volumes of
methanol and 6 volumes of 0.1m mixed phosphate buffer
pH 7.0.
(a) Use a silica gel F254 precoated plate (Merck silica gel 60
DETERMINATION OF CONTEN® F554 plates are suitable). Impregnate the plate by spraying it
Calculate the content of C,gH,gN3O with a 0.1% w/v solution of disodium edetate in mixed
container of average content weight u phosphate buffer pH 4.0 and allow to dry overnight. Activate
content of CygHjgN305S in amoxicillin
tri the plate by heating at 105° for 1 hour just prior to use.
the declared content of CsHgLiNO; in lithiz (b) Use the mobile phase described below.
clavulanate EPCRS. Each mg of CgHgLiNO nt to (c) Apply 1 pL of each solution.
0.9711 mg of CgHoNOs. : (d) Develop the plate to 15 cm.
LABELLING (e) After removal of the plate, dry in air and examine under
The label of the sealed container states the quantity of ultraviolet light (254 nm).
Amoxicillin Sodium contained in it, in terms of the
equivalent amount of amoxicillin, and the quantity of
f butan-1-ol, 2 volumes of a 0.1% w/v solution of
Potassium Clavulanate, in terms of the equivalent amount of—
etate in mixed phosphate buffer pH 4.0, 6 volumes of
clavulanic acid.
acid and 10 volumes of butyl acetate.
The label of the sealed container states that the preparation
contains penicillin.
pr | in the chromatogram obtained with
solution (1) é 3
chromatogram
TESTS
Co-amoxiclav Oral Suspension Acidity or alkalinity |
Amoxicillin and Potassium Clavulanate Oral Suspension pH of a solution containitig ivalent of 2.5% w/v of
amoxicillin, 4.0 to 7.0, Appendix.¥V L.
Action and use
Penicillin antibacterial + beta-lactamase inhibitor. Clavulanate polymer and other scent impurities
DEFINITION
Co-amoxiclav Oral Suspension is a suspension containing
Amoxicillin Trihydrate and either Potassium Clavulanate or
Diluted Potassium Clavulanate in a suitable flavoured
vehicle. It is prepared by dispersing the dry ingredients in the as described below, shake vigorously for 1 minute agid then
specified volume of Water just before issue for use. shake with the aid of ultrasound for 5 minutes; add sufficient
The dry ingredients comply with the requirements for Powders and of the buffer solution to produce 100 mL and filter through a
Granules for Oral Solutions and Oral Suspensions stated under 0.45-um filter. To prepare the buffer solution dissolve 15.6 g
Oral Liquids. of sodium dihydrogen orthophosphate in 800 mL of water, adjust
For the following tests prepare the oral suspension as directed on the pH to 5.0 using 1m sodium hydroxide and add sufficient
the label. The suspension, examined immediately after preparation water to produce 1000 mL.
unless otherwise indicated, complies with the requirements stated (2) Prepare a solution containing 0.42 ug per mL of quinine
under Oral Liquids and with the following requirements. sulfate BPCRS in 0.5m sulfuric acid. [NoTe: The fluorescence of
Content of amoxicillin, C,;H,>9N3;0;S quinine sulfate is 118 times more intense than that of an
When freshly constituted, not more than 120.0% of the equivalent concentration of clavulanate polymer.]
stated amount. When stored at the temperature and for the PROCEDURE
period stated on the label during which the oral suspension Measure the fluorescence of the solutions using an excitation
may be expected to be satisfactory for use, not less than wavelength of 360 nm and an emission wavelength of
lw te
Sato"
2016 Co-amoxiclav Preparations IIJ-375
440 nm, using the phosphate buffer solution in the reference the area of any other secondary peak is not greater than the
cell. area of the principal peak in the chromatogram obtained with
LIMIT
solution (2) (1%).
The fluorescence obtained with solution (1) is not more Disregard any peak corresponding to the principal peak in
intense than that obtained with solution (2) (5% w/w, the chromatogram obtained with solution (4) and any peaks
calculated with respect to the content of clavulanic acid). due to excipients.
Related substances ASSAY “

Carry out the method for liquid chromatography, Carry out the method for liguid chromatozraphy,
Appendix III D, using the following solutions. Appendix III D, using the following solutions.
(1) Disperse, with shaking, a quantity of the oral suspension (1) Disperse, with shaking, a quantity of the oral suspension
containing the equivalent of 30 mg of amoxicillinin 15 mL containing the equivalent of 0.25 g of amoxicillin in 400 mL
hase A. Add sufficient mobile phase A to produce of water, add sufficient water to produce 500 mL, mix and
fhrough a 0.45-um membrane filter. filter.
of solution (1) to 100 volumes with (2) 0.05% w/v of amoxicillin trihydrate BPCRS and 0.02% w/v
of lithium clavulanate EPCRS in water.
(a) Use.a stainless steel column (25 cm x 4.6 mm) packed

ODS is suitable).
(b) Use: isocratic elution and the mobile phase described
below.
below. (f) Inject 20 wL of each solution.
(c) Use a flow rate of 1 mL per minute. MOBILE PHASE —
5 volumes of methanol and 95 volumes of a 0.78% wiv
(e) Use a detection wavelength of 254 nm. solution of sodium dihydrogen orthophosphate monohydrate,
(f) Inject 50 wL of each solution. sted to pH 4.4 with orthophosphonic acid.
MOBILE PHASE EM SUITABILITY
Mobile phase A 1 volume of acetomtrile and 99 volumes of a is not valid unless, in the chromatogram obtained
pH 5.0 buffer solution prepared in the following manner. juin (2), the resolution factor between the peaks due
To 250 mL of 0.2m potassium dihydrogen orthophosphate add uit and lithium clavulanate 1is at least 3.5 and the
2M sodium hydroxide until the pH reaches 5.0 and then add Synieétry
sufficient water to produce 1000 mL. most 1.5
Mobile phase B 20 volumes of acetomitrile and 80 volumes of
the pH 5.0 buffer solution.
Use the following gradient conditions:
Equilibrate the column with the mobile phase ratio
established during system suitability. Inject freshly prepared
solution (1) and immediately after the elution of the
amoxicillin peak start a linear gradient elution to reach a
mobile phase ratio A:B of 0:100 over 25 minutes. Continue
the chromatography with mobile phase B for a further
15 minutes. Equilibrate the column for 15 minutes with the
starting mobile phase ratio established during system
suitability before the next injection. satisfactory for use.
Inject mobile phase A using the same elution gradient to STORAGE
obtain a blank. The Oral Suspension should be kept at the temperature and
SYSTEM SUITABILITY used within the period stated on the label.
Equilibrate the column with a mobile phase ratio A:B of LABELLING
92:8. The test is not valid unless, in the chromatogram The quantity of Amoxicillin Trihydrate is stated in terms of
obtained with solution (3), the resolution factor between the the equivalent amount of amoxicillin, and the quantity of
peaks due to amoxicillin and cefadroxil is at least 2.0. Potassium Clavulanate is stated in terms of the equivalent
If necessary adjust the ratio A:B of the mobile phase. amount of clavulanic acid.
LIMITS The label states that the preparation contains a penicillin.
the area of any peak with a retention time relative to
amoxicillin of about 4.1 (amoxicillin dimer) is not greater
se ee IiI-376 Co-amoxiclav Preparations 2016
(1) After 45 minutes withdraw 20 mL of the medium and

Co-amoxiclav Tablets filter through a 0.45-um membrane filter, discarding the first
Amoxicillin and Potasstum Clavulanate Tablets 10 mL of filtrate. Use the filtered medium, diluted with water
Lae
if necessary, to produce a solution containing the equivalent

Action and use
of 0.025% w/v of amoxicillin.
Penicillin antibacterial + beta-lactamase inhibitor.
(2) 0.025% w/v of amoxicillin tnhydrate BPCRS and
DEFINITION 0.01% w/v of lithium clavulanate EPCRS in water.
Co-amoxiclav Tablets contain Amoxicillin Trihydrate and CHROMATOGRAPHIC CONDITIONS
either Potassium Clavulanate or Diluted Potassium The chromatographic procedure described under Assay may
Clavulanate. be used.
Calculate the total content of amoxicillin, C;,.H,;)>N30;S, and
of clavulanic acid, CgH NOs, in the medium from the
chromatograms obtained and using the declared content of
Ci6H19N305S in amoxicillin trihydrate BPCRS and the
declared content of CgHgLiNOs, in lithium
IDENTIFICATION © clavulanate EPCRS. Each mg of CgHgLiNOs is equivalent to
0.9711 mg of CgHoNOs.
Carry out the method fo
Clavulanate polymer and other fluorescent impurities
(1) Shake a quantity of the po Carry out the method for fluorescence spectrophotometry,
equivalent of 0.4 g of clavulanics if Appendix II E, using the following freshly prepared solutions.
of 4 volumes of methanol and 6 volumeg:o (1) To a quantity of the finely powdered tablets containing
the equivalent of 0.1 g of clavulanic acid add 50 mL ofa
0.1m phosphate buffer solution pH 5.0, prepared as
mixture of 4
amoxicillin trihydrate BPCRS in a described below, stir until the sample is evenly dispersed and
methanol and 6 volumes of 0.1m mixed phosphat add sufficient of the buffer solution to produce 100 mL.
pH 7.0. Shake the solution vigorously for 1 minute, shake
mechanically for 5 minutes and then with the aid of
Itrasound for 5 minutes and filter through a 0.45-um filter.
(a) Use a silica gel F.54 precoated plate (Merck silica gel pare the buffer solution dissolve 15.6 g of sodium
F554 plates are suitable). Impregnate the plate by spraying it gen orthophosphate in 800 mL of water, adjust the pH
with a 0.1% w/v solution of disodium edetate in mixed sig 1M sodium hydroxide and add sufficient water to
phosphate buffer pH 4.0 and allow to dry overnight. Activate
the plate by heating at 105° for 1 hour just prior to use. solution containing 0.42 ug per mL of quinine
(b) Use the mobile phase described below. S'1n..0.5mM sulfuric acid. [noTe: The fluorescence of
(d) Develop the plate to 15 cm. equivalent c6n,
(e) After removal of the plate, dry in air and examine under PROCEDURE
MOBILE PHASE
1 volume of butan-1-ol, 2 volumes of a 0.1% w/v solution of

cell.
cowie ote disodium edetate in mixed phosphate buffer pH 4.0, 6 volumes of
glacial acetic acid and 10 volumes of butyl acetate. LIMIT “
CONFIRMATION The fluorescence obtained with soli .
intense than that obtained with solution #2) (5% w/w,
The principal spots in the chromatogram obtained with
calculated with respect to the content of ¢la:
chromatogram obtained with solution (2). Related substances
TESTS
Dissolution
(1) Disperse a quantity of the powdered tablets containing
the equivalent of 30 mg of amoxicillin in 15 mL of mobile
phase A with the aid of ultrasound for 20 minutes, with
Appendix XII B1.
occasional shaking. Add sufficient mobile phase A to produce
TEST CONDITIONS 20 mL and filter through a 0.45-um membrane filter.
(a) Use Apparatus 2, rotating the paddle at 75 revolutions (2) Dilute 1 volume of solution (1) to 100 volumes with
per minute. mobile phase A.
veins
(b) Use 900 mL of water, at a temperature of 37°, as the (3) 0.0004% w/v of cefadroxil BPCRS and 0.003% w/v of
medium. amoxicillin trihydrate BPCRS in mobile phase A.
PROCEDURE (4) 0.075% w/v of lithium clavulanate EPCRS in mobile
Carry out the method for liquid chromatography, phase A.
2016 Co-amoxiclav Preparations III-377
with octadecylsilyl silica gel for chromatography (5 um) (Hypersil (c) Use a flow rate of 2 mL per minute.
ODS is suitable). (d) Use an ambient column temperature.
(b) Use gradient elution and the mobile phase described (e) Use a detection wavelength of 220 nm.
below.
MOBILE PHASE
solution of sodium dihydrogen orthophosphate monohydrate,
(f) Inject 50 wL of each solution. adjusted to pH 4.4 with orthophosphoric acid.
SYSTEM SUITABILITY
otassium dthydrogen orthophosphate add to amoxicillin and lithium clavulanate is at least 3.5 and the
il the pH reaches 5.0 and then add symmetry factor of the peak due to lithtum clavulanate is at
most 1.5.
Calculate the content of C;6.H,;9N30;S and of CsH NOs in
the tablets using the declared content of C;,.H,;9N3035S in
amoxicillin tnhydrate BPCRS and the declared content of
CgHeLiNOs in lithium clavulanate EPCRS. Each mg of
solution (1) and immediately after t CgHeLiNOs is equivalent to 0.9711 mg of CgHoNOs.
amoxicillin peak start a lineargradient
STORAGE
Co-amoxiclav Tablets should be protected from light and
stored in an airtight container.
starting mobile phase ratio established during system, LABELLING
suitability before the next injection. The quantity of Amoxicillin Trihydrate is stated in terms of
Inject mobile phase A using the same elution gradient't the equivalent amount of amoxicillin, and the quantity of
obtain a blank. stum Clavulanate is stated in terms of the equivalent
of clavulanic acid.
SYSTEM SUITABILITY
el states that the preparation contains a penicillin.
92:8. The test is not valid unless, in the chromatogram
obtained with solution (3), the resolution factor between the
peaks due to amoxicillin and cefadroxil is at least 2.0.
If necessary adjust the ratio A:B of the mobile phase.
LIMITS

Action and use
the area of any peak with a retention time relative to
Penicillin antibacterial
amoxicillin of about 4.1 (amoxicillin dimer) is not greater
DEFINITION
area of the principal peak in the chromatogram obtained with Potassium Clavulanatein a suitable
solution (2) (1%).
The tablets comply with the requirements ‘s
Disregard any peak corresponding to the principal peak in with the following requirements.
Content of amoxicillin, C,;H;)>.N3;0;S
ASSAY 90.0 to 110.0% of the stated amount.
Weigh and powder 20 tablets. Carry out the method for Content of clavulanic acid, CgH,»NO;
oe
liquid chromatography, Appendix III D, using the following 90.0 to 110.0% of the stated amount.
.
rcbtics
solutions.
?
IDENTIFICATION
(1) Dissolve, with shaking, a quantity of the powdered tablets
containing the equivalent of 0.25 g of amoxicillin in 400 mL Carry out the method for thin-layer chromatography,
of water, add sufficient water to produce 500 mL, mix and Appendix III A, using the following solutions.
filter. (1) Shake a quantity of the powdered tablets containing the
equivalent of 0.4 g of clavulanic acid in 100 mL of a mixture
(2) 0.05% w/v of amoxicillin trihydrate BPCRS and 0.02% w/v
of lithium clavulanate EPCRSin water. of 4 volumes of methanol and 6 volumes of 0.1m mixed
phosphate buffer pH 7.0 and filter.
(2) 0.4% w/v of lithium clavulanate EPCRS and 0.8% w/v of
(a) Use a stainless steel column (25 cm x 4.6 mm) packed amoxicillin trihydrate BPCRS in a mixture of 4 volumes of
with octadecylsilyl silica gel for chromatography (5 um) (Hypersil methanol and 6 volumes of 0.1m mixed phosphate buffer
ODS 5 um is suitable). pH 7.0.
ITI-378 Co-amoxiclav Preparations 2016
CHROMATOGRAPHIC CONDITIONS (3) 0.0004% w/v of cefadroxil BPCRS and 0.003% w/v of
(a) Usea silica gel F254 precoated plate (Merck silica gel 60 amoxicillin tnhydrate BPCRS in mobile phase A.
F454 plates are suitable). Impregnate the plate by spraying it (4) 0.075% w/v of lithium clavulanate EPCRS in mobile
with a 0.1% w/v solution of disodium edetate in mixed phase A.
phosphate buffer pH 4.0 and allow to dry overnight. Activate CHROMATOGRAPHIC CONDITIONS
the plate by heating at 105° for 1 hour just prior to use.
with octadecylsilyl sihca gel for chromatography (5 um) (Hypersil
(c) Apply 1 pL of each solution. ODS is suitable).
(d) Develop the plate to 15 cm. (b) Use gradient elution and the mobile phase described
(e) After removal of the plate, dry in air and examine under below.
ultraviolet “ (254 nm). (c) Use a flow rate of 1 mL per minute.
-ol, 2 volumes of a 0.1% wi/V solution of (e) Use a detection wavelength of 254 nm.
ixed phosphate buffer pH 4.0, 6 volumes of (f) Inject 50 wL of each solution.
lumes of butyl acetate.
MOBILE PHASE
Mobile phase A 1 volume of acetonitrile and 99 volumes of a
ogram obtained with pH 5.0 buffer solution prepared in the following manner.
nd colour to thosein the To 250 mL of 0.2m potassium dihydrogen orthophosphate add
2M sodium hydroxide until the pH reaches 5.0 and then add
TESTS sufficient water to produce 1000 mL.
Disintegration Mobile phase B 20 volumes of acetonitrile and 80 volumes of
Comply with the requirements for Dispersi the pH 5.0 buffer solution.
Clavulanate polymer and other fluor Use the following gradient conditions:
Equilibrate the column with the mobile phase ratio
established during system suitability. Inject freshly prepared
solution (1) and immediately after the elution of the
the equivalent of 0.1 g of clavulanic acid add 50 mL, amoxicillin peak start a linear gradient elution to reach a
0.1m phosphate buffer solution pH 5.0, prepared as obile phase ratio A:B of 0:100 over 25 minutes. Continue
described below, stir until the sample is evenly dispersed a he chromatography with mobile phase B for a further
add sufficient of the buffer solution to produce 100 mL. utes. Equilibrate the column for 15 minutes with the
Shake the solution vigorously for 1 minute, shake iobile phase ratio established during system
mechanically for 5 minutes and then with the aid of fore the next injection.
ultrasound for 5 minutes and filter through a 0.45-pm filter.
To prepare the buffer solution dissolve 15.6 g of sodium
dihydrogen orthophosphate in 800 mL of water, adjust the pH
to 5.0 using 1m sodium hydroxide and add sufficient water to
produce 1000 mL. :newith a mobile phase ratio A:B of
id unless, in the chromatogram
(2) Prepare a solution containing 0.42 pg per mL of guinine
sulfate BPCRS in 0.5m sulfuric acid. [Note: The fluorescence of
quinine sulfate is 118 times more intensethan that of an
If necessary adjust the ratio
equivalent concentration of clavulanate polymer.
|
LIMITS
PROCEDURE
In the chromatogram obtained with
Measure the fluorescence of the solutions using an excitation
wavelength of 360 nm and an emission wavelength of the area of any peak with a retentior
440 nm, using the phosphate buffer solution in the reference
cell.
LIMIT
The fluorescence obtained with solution (1) is not more
intense than that obtained with solution (2) (56% w/w, solution (2) (1%).
calculated with respect to the content of clavulanic acid).
Disregard any peak corresponding to the principal peak in
Related substances
Nw aed

Appendix III D, using the following solutions.. ASSAY
(1) Disperse a quantity of the powdered tablets containing
liquid chromatography, Appendix ITI D, using the following
the equivalent of 30 mg of amoxicillin in 15 mL of mobile
solutions.
phase A with the aid of ultrasound for 20 minutes, with
occasional shaking. Add sufficient mobile phase A to produce (1) Dissolve, with shaking, a quantity of the powdered tablets
20 mL and filter through a 0.45-um membrane filter. containing the equivalent of 0.25 g of amoxicillin in 400 mL
of water, add sufficient water to produce 500 mL, mix and
filter.
mobile phase A. ,
(2) 0.05% w/v of amoxicillin trihydrate BPCRS and 0.02% wiv
of lithtum clavulanate EPCRS in water.
2016 Co-beneldopa Preparations III-379
CHROMATOGRAPHIC CONDITIONS (2) 0.5% w/v of levodopa BPCRS in 0.1m hydrochloric acid.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed (3) 0.142% w/v of benserazide hydrochloride BPCRS in
with octadecylsilyl silica gel for chromatography (5 um) (Hypersil 0.1m hydrochloric acid.
ODS 5 um is suitable). CHROMATOGRAPHIC CONDITIONS
(a) Use a precoated cellulose plate (Merck plates are suitable).
below.
(e) After removal of the plate, dry in a current of warm air
(f) Inject 20 uwL of each solution. for 5 minutes, spray with dilute phosphomolybdotungstic reagent,
MOBILE PH. dry in a current of warm air for 30 seconds and spray with a
5 volumesofmetfi d 95 volumes of a 0.78% w/v 10% w/v solution of sodium hydroxide.
solution of sodiitm ihydi n orthophosphate monohydrate, MOBILE PHASE
10 volumes of a 10% v/v solution of hydrochloric acid,
20 volumes of water and 70 volumes of propan-2-ol.
CONFIRMATION
to amoxicillin and lithium cla
clearly separated spots, the spot with the higher Rf value
symmetry factor of the peak due t
corresponding to the spot in the chromatogram obtained with
most 1.5.
solution (2) and the spot with the lowerRf value
DETERMINATION OF CONTENT corresponding to the spot in the chromatogram obtained with
solution (3).
amoxicillin trihydrate BPCRS and the declared co (1) exhibits two peaks with the same retention times as those
CgHgLiNOs in lithium clavulanate EPCRS. Each mg due to benserazide and levodopa in the chromatogram
CsHeLiNOs is equivalent to 0.9711 mg of CgHyNOs. obtained with solution (2).
STORAGE
Dispersible Co-amoxiclav Tablets should be protected from °
light and stored in an airtight container.
LABELLING
The quantity of Amoxicillin Trihydrate is stated in terms of
the equivalent amount of amoxicillin, and the quantity of
Potassium Clavulanate is stated in terms of the equivalent (a) Use pp
amount of clavulanic acid. per minute:
The label states that the preparation contains a penicillin. (b) Use 900 mL
PROCEDURE
Carry out the method for / atography,
Co-beneldopa Capsules solutions.
Benserazide Hydrochloride and Levodopa Capsules (1) After 45 minutes withdraw a
medium and filter. Use the filtered nied liluted with the
Action and use mobile phase if necessary, expected to c
Dopa decarboxylase inhibitor + dopamine precursor; Levodopa per mL.
treatment of Parkinson’s disease.
(2) Dilute 1 volume of a 0.1% w/v solution o
levodopa BPCRS in 0.1M orthophosphoric acid to
DEFINITION
Co-beneldopa Capsules contain Benserazide Hydrochloride
and Levodopa in the proportions, by weight, 1 part CHROMATOGRAPHIC CONDITIONS
benserazide to 4 parts levodopa. The chromatographic conditions described under Assay may
The capsules comply with the requirements stated under Capsules be used. Disregard the peak due to benserazide.
and with the following requirements. DETERMINATION OF CONTENT
Content of benserazide, C;)H,;N30; Calculate the total content of levodopa, Cy>H,,;NOx,, in the
95.0 to 105.0% of the stated amount. medium using the declared content of CgH,,;NOz, in
Content of levodopa, Co>H,,NO, levodopa BPCRS.
95.0 to 105.0% of the stated amount. Related substances
IDENTIFICATION A. Carry out the method for liquid chromatography,
A. Carry out the method for thin-layer chromatography, Appendix III D, using the following solutions prepared in
mobile phase that has been cooled to 4° and injected
immediately.
(1) Shake a quantity of the capsule contents containing 0.2 g
of Levodopa with 40 mL of 0.1m hydrochloric acid for (1) Shake a quantity of the contents of the capsules
containing the equivalent of 0.1 g of benserazide with
10 minutes, filter and use the filtrate.
III-380 Co-beneldopa Preparations 2016
100 mL, mix with the aid of ultrasound for 3 minutes, (e) After removal of the plate, dry in a current of warm air,
shaking occasionally, and filter through a 0.45-um filter, spray with a freshly prepared mixture containing equal
discarding the first 5 mL of filtrate. volumes of a 10% w/v solution of zron(im) chloride hexahydrate
and a 5% w/v solution of potassium hexacyanoferrate(im) and
sau me
(2) 0.0005% w/v of benserazide impurity A BPCRS.

wet etd
AaB Y
examine the plate immediately.

(3) 0.0005% w/v of each of benserazide hydrochloride BPCRS
and benserazide impurity A BPCRS. MOBILE PHASE
CHROMATOGRAPHIC CONDITIONS 10 volumes of a 10% v/v solution of hydrochloric acid,

20 volumes of water and 70 volumes of propan-2-ol.
(a) Use a stainless steel column (12.5 cm x 4 mm) packed
with octylsilyl silica gel for chromatography (5 um) (Lichrospher LIMITS
RP8 is suitable). Any secondary band in the chromatogram obtained with
(b) Use isocratic elution and the mobile phase described solution (1) is not more intense than the band in the
below. chromatogram obtained with solution (2) (0.5%). The test is
not valid unless the chromatogram obtained with solution (3)
we ay
shows a distinct band, at a higher Rf value than the principal

band, which is more intense than the band in the
(e) Use a dete chromatogram obtained with solution (2).
ASSAY
(g) For solution (1)allo Carry out the method for liquid chromatography,
nine times the retention Appendix III D, using the following solutions.
MOBILE PHASE (1) Shake a quantity of the mixed contents of 20 capsules
Dissolve 4.76 g of potassium dihvds en eythophosphatein containing 0.1 g of Levodopa with 80 mL of
Fete tS
800 mL of water, adding 200 mi cetonitile and 1. 22 g of 0.1m orthophosphoric acid for 5 minutes, mix with the aid of
svn wd
aw Nee 4
sodium decanesulfonate and adjusting the pH ultrasound for 30 minutes, cool, add sufficient
orthophosphoric acid. 0.1m orthophosphoric acid to produce 100 mL and mix. Filter
SYSTEM SUITABILITY the resulting solution through a 0.45-um filter (Whatman
GF/C is suitable), discarding the first 5 mL of filtrate, and
The test is not valid unless, in the chromatogram
dilute 10 volumes of the filtrate to 100 volumes with the
with solution (3) the resolution factor between the tw@
mobile phase.
2) Dissolve 28.7 mg of benserazide hydrochlonde BPCRS and
LIMITS
- g of levodopa BPCRSin sufficient 0.1m orthophosphonic
In the chromatogram obtained with solution (1): stexproduce 100 mL, mix and dilute 10 volumes of the
the area of any peak corresponding to benserazide impurity A solution to 100 volumes with the mobile phase.
is not greater than the area of the principal peak in the GRAPHIC CONDITIONS
area of the peak due to benserazide in the chromatogram
(b) Use isocr
the sum of the areas of any secondary peaks is not greater than below.
twice the area of the peak due to benserazide in the
of the peak due to benserazide in the chromatogram obtained
Appendix III A, using the following solutions. Dissolve 4.76 g of potasstum dihydro
(1) Prepare immediately before use; shake a quantity of the 800 mL of water, adding 200 mL of ace
contents of the capsules containing 0.1 g of Levodopa with
10 mL of a mixture of equal volumes of anhydrous formic acid orthophosphonic acid.
and methanol. DETERMINATION OF CONTENT
(2) Dilute 1 volume of solution (1) to 200 volumes with The chromatogram obtained with solution (2) shows two
methanol. principal peaks; the retention time of the peak due to
ane ate
Le ah ial
(3) Equal volumes of solution (1) and a solution prepared by benserazide is about three times that of the peak due to
swan
dissolving 30 mg of L-tyrosine in 1 mL of anhydrous formic levodopa.
as “
acid and diluting to 100 mL with methanol. Calculate the content of C;p)H,5;N3O05 and of Co>H,,;NO, in
CHROMATOGRAPHIC CONDITIONS each capsule using the declared contents of C;9)H,5N30s in
(a) Use a precoated cellulose plate (Merck plates are suitable). benserazide hydrochloride BPCRS and of Co>H,,;NO, in
(b) Use the mobile phase as described below. levodopa BPCRS.
(c) Apply separately to the plate, as bands 20 mm long, STORAGE

10 uL of each of solutions (1) and (2) and 20 uL of solution Co-beneldopa Capsules should protected from moisture.
(3) and dry in a current of air. LABELLING
cA te (d) Develop the plate to 15 cm. The quantity of Benserazide Hydrochloride is stated in terms
em
we we 4
of the equivalent amount of benserazide.
ee de ee Ur i of Sate siRes
Maule EATS Sle
OPT SOLS
GENe Te TE ee
Oe Se EET,ee
2016 Co-beneldopa Preparations III-381
Prolonged-release Co-beneldopa B. In the Assay, the chromatogram obtained with solution

(1) exhibits two peaks with the same retention times as those
Capsules due to benserazide and levodopa in the chromatogram
Prolonged-release Benserazide Hydrochloride and Levodopa obtained with solution (2).
Capsules TESTS
Prolonged-release Co-beneldopa Capsules from different Related substances
manufacturers, whilst complying with the requirements of the Carry out the method for liquid chromatography,
monograph, are not interchangeable unless otherwise justified and Appendix III D, using the following solutions. Use freshly
authonised. prepared solutions. Store and inject them at 4, using a cooled
autosampler.
Action and use
Prepare a solution containing 0.05m potassium dihydrogen
Dopa decarboxylase inhibitor + dopamine precursor;
orthophosphate and 0.005M sodium decanesulfonate, adjusted to
»f Parkinson’s disease.
tet
anal) pH 3.0 using orthophosphonic acid (buffer solution).
(1) Dissolve a quantity of the contents of the capsules
o-beneldopa Capsules contain containing the equivalent of 0.150 g of benserazide in 50 mL
Benserazide ydgochioride and Levodopa. They are of acetonitrile and 225 mL of methanol and mix for 5 minutes.
formulated so : icament is released over a period Add 600 mL of the buffer solution and mix, add 5-10 drops
of several hours. of octanol and dilute with sufficient of the buffer solution to
produce a solution containing the equivalent of 0.0150% w/v
PRODUCTION of benserazide.
A suitable dissolution test ut to demonstrate the
appropriate release of Bens and L
mobile phase. Dilute 1 volume of this solution to 5 volumes
terete
The dissolution profile reflects
tv te
in turn is compatible with the dosag¢’sc
by the manufacturer. (3) 0.05% w/v of levodopa BPCRS, 0.015% wiv of benserazide
hydrochloride BPCRS, 0.00015% w/v of benserazide
The capsules comply with the requirements
iumpurity A BPCRS and 0.0003% w/v of benserazide
impurity B BPCRS in the mobile phase.
Content of benserazide, C,9H,;N30;
(a) Use a stainless steel column (12.5 cm x 4.0 mm) packed
Content of levodopa, CoH,,;NO,
RP8 is suitable).
IDENTIFICATION Use isocratic elution and the mobile phase described
Appendix III A, using the following solutions. Carry out the
test protected from light and prepare the solutions immediately
before use.
(1) Shake a quantity of the capsule contents containing 0.2 g
of Levodopa with 40 mL of 0.1M methanolic sulfuric acid for
10 minutes, filter and use the filtrate. MOBILE PHASE
(2) 0.5% w/v of levodopa BPCRS in 0.1m methanolic sulfuric 4.5 volumes of a rile, 25 volumes of methanol and
acid. : ion of potassium dihydrogen
(3) 0.142% w/v of benserazide hydrochloride BPCRS in orthophosphate and 0.005xi of sedium decanesulfonate, adjusted
0.1M methanolic sulfuric acid.
AN A
CHROMATOGRAPHIC CONDITIONS -under the prescribed

conditions, the relative retentions ference to
(a) Use a precoated cellulose plate (Merck plates are suitable).
benserazide (retention time = about minutes) are: levodopa
(b) Use the mobile phase as described below. = about 0.3; benserazide impurity A
(c) Apply 2 wL of each solution. benserazide impurity B = about 3.2.
(e) After removal of the plate, dry in a current of warm air In the chromatogram obtained with solution (1):
for 5 minutes, spray with dilute phosphomolybdotungstic reagent,
the area of any peak corresponding to benserazide impurity A
dry in a current of warm air for 30 seconds and spray with a
10% w/v solution of sodium hydroxide.
aw ad
MOBILE PHASE
the area of any peak corresponding to benserazide impurity B
10 volumes of a 10% v/v solution of hydrochloric acid, is not greater than 0.6 times the area of the corresponding
20 volumes of water and 70 volumes of propan-2-ol. peak in the chromatogram obtained with solution (3) (1.2%)5
CONFIRMATION the area of any other secondary peak is not greater than the
The chromatogram obtained with solution (1) shows two area of the peak due to benserazide in the chromatogram
clearly separated spots, the spot with the higher Rf value obtained with solution (2) (0.2%);
corresponding to the spot in the chromatogram obtained with the total impurity content is not greater than 2.4%.
solution (2) and the spot with the lower Rf value
corresponding to the spot in the chromatogram obtained with
solution (3).
DA itn ee Co Ne IN ee de eS LU
II-382 Co-beneldopa Preparations 2016
Disregard any peak with an area less than half the area of the IDENTIFICATION
peak due to benserazide in the chromatogram obtained with A. Carry out the method for thin-layer chromatography,
solution (2) (0.1%). Appendix III A, protected from light, using a precoated
hen
whe
A wa
ete
ASSAY cellulose plate (Merck plates are suitable) and a mixture of

weve
10 volumes of a 10% v/v solution of hydrochloric acid,

Appendix III D, using the following solutions. Use freshly 20 volumes of water and 70 volumes of propan-2-ol as the
prepared solutions. Store and inject them at 4°, using a cooled mobile phase, but allowing the solvent front to ascend 10 cm
autosampler. above the line of application. Apply separately to the plate
2 uL of each of the following solutions. For solution (1)
(1) Dissolve a quantity of the mixed contents of 20 capsules
shake a quantity of the powdered tablets containing 0.2 g of
containing the equivalent of 0.125 g of benserazide in 50 mL
Levodopa with 40 mL of 0.1m hydrochloric acid for
of acetonitrile and 225 mL of methanol and mix for 5 minutes.
10 minutes, filter and use the filtrate. Solution (2) contains
Add 600 of buffer solution and mix, add 5-10 drops of
0.5% wiv of levodopa BPCRS in 0.1m hydrochloric acid.
octanol 4 with sufficient buffer solution to produce a Solution (3) contains 0.142% w/v of benserazide
ALN ALY
hydrochloride BPCRS in 0.1M hydrochloric acid. After removal

of the plate, allow it to dry in a current of warm air for
(2) 0.05% wiv dpa BPCRS, 0.015% wiv of benserazide 5 minutes, spray with dilute phosphomolybdotungstic reagent,
hydrochloride BPC. 5% wiv of benserazide dry in a current of warm air for 30 seconds and spray with a
10% w/v solution of sodium hydroxide. The chromatogram
obtained with solution (1) shows two clearly separated spots,
ce Nee
the spot with the higher Rf value corresponding to the spot
The chromatographic conditi in the chromatogram obtained with solution (2) and the spot
substances may be used. Use a with the lower Rf value corresponding to the spot in the
er aes
220 nm for benserazide and 270 nm chromatogram obtained with solution (3).
awe ye
SYSTEM SUITABILITY
The Assay is not valid unless, in the chrom due to benserazide and levodopa in the chromatogram
with solution (2), the symmetry factor of the peak.d obtained with solution (2).
levodopa is between 0.6 and 1.5. |
TESTS
Disintegration :
Calculate the content of C;j)H,;5N30;5 and of C)H,,N omply with the requirements for Dispersible Tablets.
the capsules using the declared content of C,;>H,5;N3O03; in
benserazide hydrochloride BPCRS and the declared content of °
ut the method for liquid chromatography,
CyH,;NO, in levodopa BPCRS.
III D, using the following solutions. The solutions
LABELLING epared in mobile phase that has been cooled to
The quantity of Benserazide Hydrochloride is stated in terms immediately. For solution (1) shake a
of the equivalent amount of benserazide.
IMPURITIES
d for 3 minutes, shaking
rough a 0.45-um filter, discarding
monograph include impurities A and B listed under
the first 5 mL of filtrat, :
Benserazide Hydrochloride.
of benserazide impurity z
rarwsd
Solution (3) contains 0.
aavad
hydrochloride BPCRS and ben:
the mobile phase.
Dispersible Co-beneldopa Tablets
Dispersible Benserazide Hydrochloride and Levodopa (a) a stainless steel column (12.5 c
Tablets octylsilyl silica gel for chromatography (5 um
Action and use

Dopa decarboxylase inhibitor + dopamine precursor; of potassium dihydrogen orthophosphatein 800 ml. Q Avater,
treatment of Parkinson’s disease. adding 200 mL of acetonitrile and 1.22 g of sodium
decanesulfonate and adjusting the pH to 3.5 with
DEFINITION orthophosphoric acid and (c) a detection wavelength of
Dispersible Co-beneldopa Tablets contain Benserazide
Ueawasl
woe
Ae ay
220 nm.
Hydrochloride and Levodopa in the proportions, by weight,
vw we A
Inject 20 wL of each solution. The test is not valid unless, in

1 part benserazide to 4 parts levodopa in a suitable the chromatogram obtained with solution (3), the resolution
dispersible basis. factor between the two principal peaks is at least 2.0.
The tablets comply with the requirements stated under Tablets and For solution (1) allow the chromatography to proceed for
with the following requirements. nine times the retention time of benserazide. In the
Content of benserazide, C,,~)H,;N30; chromatogram obtained with solution (1) the area of any
93.0 to 105.0% of the stated amount. peak corresponding to benserazide impurity A is not greater
Content of levodopa, C,H,,NO, than the area of the principal peak in the chromatogram
95.0 to 105.0% of the stated amount. obtained with solution (2) (0.5%), the area of any other
secondary peak is not greater than the area of the peak due to
BN a
2016 Cocaine Preparations III-383
benserazide in the chromatogram obtained with solution (3) Calculate the content of CjgH,5N305 and of Co5H,,;NO, in
(0.5%) and the sum of the areas of any such peaks is not each tablet using the declared contents of Cj9H,5N305 in
greater than twice the area of the peak due to benserazide in benserazide hydrochlonde BPCRS and of CgH,,;NO, in
the chromatogram obtained with solution (3) (1%). levodopa BPCRS.
STORAGE
of the peak due to benserazide in the chromatogram obtained
Dispersible Co-beneldopa Tablets should be protected from
moisture.
Appendix III A, using a precoated cellulose plate (Merck LABELLING
plates are suitable) and a mixture of 10 volumes of a 10% v/v The quantity of Benserazide Hydrochloride is stated in terms
solution of hydrochloric acid, 20 volumes of water and of the equivalent amount of benserazide.
f propan-2-ol as the mobile phase. Apply
te, as bands 20 mm long, 10 wL of each
*(2) and 20 uL of solution (3) and dry in
ion (1) should be prepared immediately
(1) shake a quantity of the powdered
Cocaine Eye Drops
Levodopa with 10 mL ofa Action and use
mixture of equal v6: nhydrous formic acid and Local anaesthetic.
methanol, filter and us
1 volume of solution (1) DEFINITION
Solution (3) is a mixture Cocaine Eye Drops area sterile solution of Cocaine
and a solution prepared by Hydrochloride in Purified Water.
1 mL of anhydrous formic acid. 100 mL with
toodry i
1 na
containing equal volumes of a 10% w/v so Content of cocaine hydrochloride, C,,H,,;,NO,,HCl

chloride hexahydrate and a 5% w/v solution 95.0 to 105.0% of the stated amount.
hexacyanoferrate(im) and examine the plateiimmé IDENTIFICATION
secondary band i1 n the chromatogram obtained with« A. Add 5 mL of 0.2m ammonia to a volume of the eye drops
containing 40 mg of Cocaine Hydrochloride and extract with
obtained with solution (2) (0.5%). The test is not valid wo 5-mL quantities of dichloromethane, filter the extracts
unless the chromatogram obtained with solution (3) show gh a phase separating paper (Whatman IPS is suitable)
distinct band, at a higher Rf value than the principal band, orate to dryness. The infrared absorption spectrum of
which is more intense than the band in the chromatogram e, Appendix IT A, is concordant with the reference
obtained with solution (2). cocaine (RS 071).
ASSAY tion A characteristic of chlorides, Appendix VI.
solutions. For solution (1) shake a quantity of the powdered
tablets containing 0.1 g of Levodopa with 80 mL of
0.1m orthophosphoric acid for 5 minutes, mix with the aid of Related substance
ultrasound for 30 minutes, cool, add sufficient Carry out the method
0.1m orthophosphoric acid to produce 100 mL and mix. Filter Appendix III D, using t g solutions. For solution
(1) dilute a volume ofthe fe ps with sufficient mobile
the resulting solution through a 0.45-ym filter (Whatman
GF/C is suitable), discarding the first 5 mL of filtrate, and 04% wiv of Cocaine
dilute 10 volumes of the filtrate to 100 volumes with the 8% wiv of
mobile phase. For solution (2) dissolve 28.7 mg of olution (3)
benserazide hydrochloride BPCRS and 0.1 g of levodopa BPCRS
in sufficient 0.1m orthophosphoric acid to produce 100 mL,
mix and dilute 10 volumes of the resulting solution to
100 volumes with the mobile phase. The chromatographic procedure maybe carr
The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm x 4.6 mm) packed with
(a) a stainless steel column (25 cm x 4 mm) packed with octadecylsilyl silica gel for chromatography (10 um) (Partisil 10
octylsilyl silica gel for chromatography (5 um) (Lichrospher RP8 ODS is suitable), (b) as the mobile phase with a flow rate of
is suitable), (b) as the mobile phase with a flow rate of 2 mL per minute a mixture of 1 volume of 9m perchloric acid,
1.2 mL per minute a mixture prepared by dissolving 4.76 g 35 volumes of methanol and 64 volumes of water and (c) a
of potassium dihydrogen orthophosphate in 800 mL of water, detection wavelength of 240 nm.
adding 200 mL of acetonitrile and 1.22 g of sodium The test is not valid unless, in the chromatogram obtained
decanesulfonate and adjusting the pH to 3.5 with with solution (4), the resolution factor between the peaks
orthophosphoric acid and (c) a detection wavelength of corresponding to benzoylecgonine and benzoic acid is at least
220 nm. Inject 20 uL of each solution. 2.0.
The chromatogram obtained with solution (2) shows two In the chromatogram obtained with solution (1) the area of
principal peaks; the retention time of the peak due to any peak corresponding to benzoylecgonine is not greater
benserazide is about three times that of the peak due to than the area of the principal peak in the chromatogram
levodopa. obtained with solution (2) (2%), the area of any peak
corresponding to benzoic acid is not greater than the area of
tN
II-384 Cocaine Preparations 2016
the principal peak in the chromatogram obtained with IDENTIFICATION

solution (3) (2%) and the sum of the two impurities is not A. Carry out the method for thin-layer chromatography,
eA
te NA
a
greater than 2%. Appendix III A, using the following solutions.
Ava
Peni
tees
AN ANS ASSAY (1) Add 4 mL of methanol to a quantity of the paste
containing 5 mg of Cocaine Hydrochloride, stir well and mix
es]

Appendix III D, using the following solutions. For solution with the aid of ultrasound for 30 minutes. If any of the paste
(1) dilute a volume of the eye drops containing 40 mg of has not dissolved, centrifuge the mixture at 3000 rpm for
Cocaine Hydrochloride with sufficient water to produce 5 minutes. Decant the supernatant liquid and add sufficient
100 mL. Solution (2) contains 0.04% w/v of cocaine methanol to produce 5 mL.
hydrochloride BPCRS. Solution (3) contains 0.0008% w/v (2) 0.1% w/v of cocaine hydrochloride BPCRS in methanol.
each of benzoylecgonine hydrate and benzoic acid in (3) A mixture of equal volumes of solutions (1) and (2).
solution (1).
(a) Use as the coating silica gel F254 (Merck silica gel 60 Fos4
yeas A

|

from the chromatograms obi ultraviolet light (254 nm).
content of C,7H2,;NO,,HCI1
MOBILE PHASE
STORAGE é 5 volumes of dimethylamine, 20 volumes of toluene and
Cocaine Eye Drops should be prot 65 volumes of hexane.
IMPURITIES SYSTEM SUITABILITY
The impurities limited by the requirement The test is not valid unless the principal spot in the
monograph include: chromatogram obtained with solution (3) appears as a single,
compact spot.
+
CONFIRMATION
fs" COOH The principal spot in the chromatogram obtained with
n (1) corresponds to thatin the chromatogram
with solution (2).
O
A. Benzoylecgonine the following solutions.

quantity of the paste containing 0.4 g
COOH
wwe AN |
re-suspending the solution edéh®

extracts and dilute to 100 mLvith
B. Benzoic acid
phase.
(3) 0.0008% w/v of benzoic acid in the mobi
Cocaine Paste (4) 0.0008% w/v of each of benzoylecgonine hydrate

benzoic acidin solution (1). :
NOTE: Cocaine Paste 1s not currently licensed in the United
Kingdom. CHROMATOGRAPHIC CONDITIONS
S A
AS es
. i Ne
wane
Action and use with octadecylsilyl silica gel for chromatography (10 wm) (Partisil
gee hd
eaves
Local anaesthetic. 10 ODS is suitable).
DEFINITION
below.
Cocaine Paste contains Cocaine Hydrochloride in a suitable
basis. It is intended for intranasal administration. (c) Use a flow rate of 2 mL per minute.
The paste complies with the requirements stated under Topical (d) Use an ambient column temperature.
Semi-solid Preparations, the requirements stated under Unlicensed (e) Use a detection wavelength of 240 nm.
Medicines and with the following requirements. (f) Inject 20 wL of each solution.
Content of cocaine hydrochloride, C,,H,,NO,,HCI
2016 Co-careldopa Preparations TT-385
MOBILE PHASE
1 volume of 9m perchloric acid, 35 volumes of methanol and

Co-careldopa Tablets
Levodopa and Carbidopa Tablets
SYSTEM SUITABILITY Action and use
The test is not valid unless, in the chromatogram obtained Dopa decarboxylase inhibitor + dopamine precursor;
with solution (4), the resolution factor between the peaks treatment of Parkinson’s disease.
2.0. DEFINITION
Co-careldopa Tablets contain Carbidopa and Levodopa.
LIMITS
the area,of any peak corresponding to benzoylecgonineis not
Content of anhydrous carbidopa, C;)H,,N,04
greatet rea ofthe principal peakinthe
Content of levodopa, CoH,,NO,
éak corresponding to benzoic acid is not
of the principal peak in the
IDENTIFICATION
due to carbidopa and levodopa in the chromatogram
B. To a quantity of the powdered tablets containing the
containing 0.4 g equivalent of 1 mg of anhydrous carbidopa add 5 mL of
ater; stir
$ and 0.05m sulfuric acid, shake for 2 minutes and filter. Add 5 mL
of dimethylaminobenzaldehyde reagent to the filtrate. A yellow
and collect the aqueous layer.Repeat t
the. colour is produced.
further three 10-mL quantities of water,re:
C. To a quantity of the powdered tablets containing 50 mg
shaking the solution each time. Combine th
of Levodopa add 4 mL of ethanol (96%) and 1 mL of
extracts and dilute to 100 mL with water. Filter
4
Im sulfuric acid and shake for 2 minutes. Add 2 mL of
the solution and dilute 10 mL to 100 mL with wate
cinnamaldehyde, allow to stand for 20 minutes, add 50 mL of
(2) 0.04% w/v of cocaine hydrochoride BPCRS in water. 0.1m hydrochloric acid, shake for 2 minutes and allow to
(3) 0.0008% w/v of each of benzoylecgonine hydrate and a, Filter the aqueous layer obtained and to 5 mL add
benzoic acid in solution (1). mil. of iron(1u) chloride solution R1. To half of the solution
CHROMATOGRAPHIC CONDITIONS. cess of 5M ammonia; a purple colour is produced.
The chromatographic conditions described under Related mainder add an excess of 2m sodium hydroxide;
substances may be used. edeolour is produced.
SYSTEM SUITABILITY
Dissolution
Comply with 4 € reguirements for Monographs of the British
Pharmacopoeiai in Ssolution test for tablets and capsules,
Appendix XII Bl.
2.0.
TEST CONDITIONS
(a) Use Apparatus 1, rotatin fine basket at 50 revolutions per
Calculate the content of C;7H2;NO,,HCI in the paste using
minute. &
the declared content of C;7H2;NO.,HCl in cocaine
hydrochoride BPCRS. (b) Use 750 mL of 0.1M nydroch .at a temperature of
IMPURITIES
PROCEDURE
monograph include: Carry out the method for liguid chromatograp
(1) After 45 minutes withdraw a sample of the edium and
N.jis = COOH filter. Use the filtered medium, diluted with 0.1m hydrochloric
acid if necessary, expected to contain 0.005% of Levodopa
O and 0.00054% w/v of Carbidopa.
4 0 (2) 0.0050% w/v of levodopa BPCRS and 0.00054% w/v of
carbidopa BPCRS in 0.1m hydrochloric acid.
1. Benzoylecgonine, CHROMATOGRAPHIC CONDITIONS

COOH with octylsilyl silica gel for chromatography (10 um) (Lichrosorb
RP8 is suitable).
oar Cy (b) Use isocratic elution and the mobile phase described
a below.
2 (c) Use a flow rate of 1.5 mL per minute.
ven 2. Benzoic acid.
tm
III-386 Co-codamol Preparations 2016
(d) Use an ambient column temperature. 90 volumes of dichloromethane as the mobile phase. Apply
(e) Use a detection wavelength of 282 nm. separately to the plate 10 pL of each of the following
solutions. For solution (1) shake a quantity of the contents of
the capsules containing 24 mg of Codeine Phosphate with
MOBILE PHASE 30 mL of water for 1 minute and centrifuge. Decant, add
0.1m potasstum dihydrogen orthophosphate adjusted to pH 3.0 10 mL of 1m sodium hydroxide and 30 mL of dichloromethane
with 1m orthophosphoric acid. to the supernatant liquid, shake for 1 minute and filter the
DETERMINATION OF CONTENT dichloromethane layer through glass-fibre paper (Whatman
GF/C is suitable). Solution (2) contains 0.08% w/v of codeine
Calculate the total content of Cj~H,4N2O, and of
phosphate BPCRS in methanol (50%). Solution (3) contains
CyH,,;NO,, in the medium using the declared contents of
0.08% w/v of codeine phosphate BPCRS and dihydrocodeine
Ci oH 14N20,4 in carbidopa BPCRS and of CoH, iNO, in
tartrate BPCRS in methanol (50%). After removal of the plate,
levodopa BPC’
allow it to dry in air, spray with ethanolic tron(1m) chloride
ASSAY solution and heat at 105° for 10 minutes. The principal spot
Weigh and powder blets. Carry out the method for in the chromatogram obtained with solution (1) corresponds
liquid chromatograps ndix III D, using the following in position and colour to that in the chromatogram obtained
solutions. with solution (2). The test is not valid unless the
(1) Shake a quantity of chromatogram obtained with solution (3) shows two clearly
Levodopa with 60 mL of separated spots of different colours.
15 minutes, add sufficient 0.T C. In the Assay for codeine phosphate, the chromatogram
100 mL and filter. Dilute 10 obtained with solution (2) shows a peak with the same
50 mL with 0.1m hydrochloric acid. & retention time as the principal peak in the chromatogram
(2) 0.050% w/v of levodopa BPCR obtained with solution (1).
carbidopa BPCRS in 0.1m hydrochloric acid. TESTS
CHROMATOGRAPHIC CONDITIONS Dissolution
The chromatographic conditions described un Comply with the requirements for Monographs of the British
may be used. Pharmacopoeia in the dissolution test for tablets and capsules
with respect to the content of Paracetamol,
Appendix XII Bl, using Apparatus 2. Use as the medium
Calculate the content of C;9H,4N2O. and of CoH, ,;NO,ir QO mL of phosphate buffer pH 5.8 and rotate the paddle at
the tablets using the declared contents of Cj>)H,4N2O,in volutions per minute. Withdraw a sample of 20 mL of
carbidopa BPCRS and of CgH,;NO, in levodopa BPCRS. nd filter. Dilute the filtrate with 0.1m sodium
LABELLING ive a solution expected to contain about
The quantity of Carbidopa is stated in terms of the of Paracetamol. Measure the absorbance of this
equivalent amount of anhydrous carbidopa.
content
715 as the valu
257 nm.
Co-codamol Capsules 4-Aminophenol
Codeine Phosphate and Paracetamol Capsules Carry out the method
lutions. Solution (1)
Action and use
Opioid analgesic + analgesic; antipyretic.
tents of the
DEFINITION
Co-codamol Capsules contain Codeine Phosphate and
Paracetamol.
Content of codeine phosphate, mixture of 0.4 volume of formic acid, 15 volumes of #iethanol
C,3H,;NO3,H3P0,,'2H,O and 85 volumes of water as the mobile phase with a flow rate
95.0 to 105.0% of the stated amount. of 2 mL per minute and (c) a detection wavelength of
Content of paracetamol, CsH»NO, 272 nm.
95.0 to 105.0% of the stated amount. In the chromatogram obtained with solution (2) the area of
IDENTIFICATION any peak corresponding to 4-aminophenol is not greater than
A. Shake a quantity of the contents of the capsules the area of the principal peak in the chromatogram obtained
containing 0.5 g of Paracetamol with 20 mL of acetone, filter with solution (1) (0.1%). In the chromatogram obtained with
and evaporate the filtrate to dryness. The infrared absorption solution (2) peaks with a long retention time may occur due
spectrum of the residue, Appendix IT A, is concordant with to excipients.
the reference spectrum of paracetamol (RS 258). Related substances
B. Carry out the method for thin-layer chromatography, A. Carry out the method for thin-layer chromatography,
Appendix ITI A, usinga silica gel F554 precoated plate Appendix III A, using silica gel G as the coating substance
(Merck silica gel 60 F.5,4 plates are suitable) and a mixture of and a mixture of 6 volumes of 13.5m ammonia, 30 volumes
1 volume of 13.5mM ammonia, 10 volumes of methanol and of cyclohexane and 72 volumes of absolute ethanol as the
2016 Co-codamol Preparations III-387
mobile phase. Apply separately to the plate 20 wL of each of The chromatographic procedure may be carried out using
Swe el
the following solutions. For solution (1) shake a quantity of (a) a stainless steel column (10 cm x 4.6 mm) packed with
the contents of the capsules containing 50 mg of Codeine octadecylsilyl silica gel for chromatography (5 um) (Nucleosil
Phosphate with 50 mL of 0.1m hydrochloric acid for C18 is suitable), (b) as the mobile phase with a flow rate of
10 minutes and filter. Make the filtrate alkaline with 1.5 mL per minute 0.01M sodium pentanesulfonate in a
5m sodium hydroxide and extract with two 40 mL quantities of mixture of 22 volumes of methanol and 78 volumes of water,
dichloromethane. Wash the combined extracts with 10 mL of the pH of the solution being adjusted to 2.8 using
water, filter through a layer of anhydrous sodium sulfate on an 2m hydrochloric acid, and (c) a detection wavelength of
absorbent cotton plug moistened with dichloromethane, 220 nm.
evaporate the filtrate to dryness at a temperature not Calculate the content of C;gH2;NO3,H3PO,,/2H.20O in each
exceeding 45° using a rotary evaporator and dissolve the capsule using the declared content of
residue in 2 mL of dichloromethane. For solution (2) dilute C1i3sH21NO3,H3PO0.,/2H20 in codeine phosphate BPCRS.
lution (1) to 100 volumes with
ASSAY
“For solution (3) dilute 1 volume of solution
For codeine phosphate
NN
s with dichloromethane. After removal of the

Weigh the contents of 20 capsules. Carry out the method for
solutions. Solution (1) contains 0.004% w/w of codeine
phosphate BPCRS in the mobile phase. For solution (2) shake
(1.5%) and not more th a quantity of the contents of the capsules containing 8 mg of
higher than that of the pri Codeine Phosphate with 100 mL of the mobile phase for
10 minutes, dilute to 200 mL with the same solvent, filter
through a glass-fibre filter (Whatman GF/C is suitable) and
use the filtrate.
25 volumes of acetone and 65 vohamegy 3 of content may be used.
the mobile phase. Pour the mobile phase Calculate the content of C;gH2,;,NO3,H3PO,4,42H,O using
the declared content of C;gH.;NO3,H3PO0,4,'’2H,0O in codeine
the tank and allow the solvent front to ascend 14:¢m_ phosphate BPCRS.
the line of application. Apply separately to the plate®200 x For paracetamol
of solution (1) and 40 uL of each of solutions (2), (3) # Weigh the contents of 20 capsules. Carry out the method for
(4). For solution (1) transfer a quantity of the contents oi
capsules containing 1.0 g of Paracetamol to a ground-glass-' s. Solution (1) contains 0.005% w/v of
stoppered 15 mL centrifuge tube, add 5 mL of peroxide-free mol BPCRS in the mobile phase. For solution (2)
ether, shake mechanically for 30 minutes, centrifuge at quantity of the contents of the capsules containing
1000 revolutions per minute for 15 minutes or until a clear of Paracetamol with 100 mL of the mobile phase for
supernatant liquid is obtained and use the supernatant liquid.
For solution (2) dilute 1 mL of solution (1) to 10 mL with
ethanol (96%). Solution (3) contains 0.0050% w/v of 4’- dilute 5 mis | rate to 250 mL with the mobile phase.
chloroacetantde in ethanol (96%). For solution (4) dissolve The chromatographic conditions described under Uniformity
0.25 g of 4’-chloroacetanilide and 0.10 g of paracetamol in
of content may bé it with a detection wavelength of
sufficient ethanol (96%) to produce 100 mL. After removal of
243 nm.
the plate, dry it in a current of warm air and examine under
Calculate the content o O, using the declared
ultraviolet ght (254 nm). Any spot corresponding to
content of CgH NO, in pe tamol BPCRS.
4’'-chloroacetanilide in the chromatogram obtained with
solution (1) is not more intense than the spot in the LABELLING .
chromatogram obtained with solution (3) (0.005%). Any The label states the quantities of Godel hosphate and of
secondary spot in the chromatogram obtained with solution (2) Paracetamol in each capsule.
with an Rf value lower than that of 4’-chloroacetanilide is When Co-codamol Capsules are pres manded no
not more intense than the spot in the chromatogram
obtained with solution (3) (0.25%). The test is not valid
unless the chromatogram obtained with solution (4) shows supplied.
two clearly separated principal spots, the spot corresponding
to 4’~chloroacetanilide having the higher Rf value.
eA wd
Capsules containing less than 2 mg and/or less than 2% w/w

of Codeine Phosphate comply with the requirements stated Co-codamol Tablets
under Capsules using the following method of analysis. Carry Codeine Phosphate and Paracetamol Tablets
out the method for liguid chromatography, Appendix III D,
using the following solutions. Solution (1) contains Action and use
0.004% w/v of codeine phosphate BPCRS in the mobile phase. Opioid analgesic + analgesic; antipyretic.
For solution (2) add 100 mL of the mobile phase to the
DEFINITION
contents of the capsules and mix with the aid of ultrasound
until completely dispersed. Shake for 10 minutes, dilute to Co-codamol Tablets contain Codeine Phosphate and
200 mL with the mobile phase, filter through a glass-fibre Paracetamol.
filter (Whatman GF/C is suitable) and use the filtrate.
tA AS
III-388 Co-codamol Preparations 2016
The tablets comply with the requirements stated under Tablets and The chromatographic procedure may be carried out using
wee
with the following requirements. (a) a stainless steel column (20 cm x 4.6 mm) packed with
octadecylsilyl silica gel for chromatography (10 um) (Nucleosil
TAN
Content of codeine phosphate,

C18 is suitable), (b) 0.01M sodium butanesulfonate in a
eA Ne
C,3H,,NO3,H3PQ0,,'2H,O
95.0 to 105.0% of the stated amount. mixture of 0.4 volume offormic acid, 15 volumes of methanol
and 85 volumes of water as the mobile phase with a flow rate
Content of paracetamol, CsH,»NO,
of 2 mL per minute and (c) a detection wavelength of
272 nm.
IDENTIFICATION In the chromatogram obtained with solution (2) the area of
A. Shake a quantity of the powdered tablets containing 0.5 g any peak corresponding to 4-aminophenol is not greater than
of Paracetamol with 20 mL of acetone, filter and evaporate the area of the peak in the chromatogram obtained with
the filtrate to See TTA,The infrared absorption spectrum of the solution (1) (0.1%). In the chromatogram obtained with
yawns
solution (2) peaks with a long retention time may occur due
raw aa to excipients.
Related substances
lica gel F254 precoated plate A. Carry out the method for thin-layer chromatography,
lates are suitable) and a mixture of Appendix III A, using silica gel G as the coating substance
and a mixture of 6 volumes of 13.5mM ammonia, 30 volumes
e mobile phase.
eh ofthe followinApply
of cyclohexane and 72 volumes of absolute ethanol as the
separately to the plate 10 LE g mobile phase. Apply separately to the plate 20 uL of each of
solutions. For solution (1) sl the following solutions. For solution (1) shake a quantity of
tablets containing 24 mg of C the powdered tablets containing 50 mg of Codeine
rene
of water for 1 minute and centrif Phosphate with 50 mL of 0.1m hydrochloric acid for
1m sodium hydroxide and 30 mL of chla form O the 10 minutes and filter. Make the filtrate alkaline with
supernatant liquid, shake for 1 minute ang filtér’t
NN
5M sodium hydroxide and extract with two 40 mL quantities of

chloroform. Wash the combined extracts with 10 mL of water,
filter through a layer of anhydrous sodium sulfate on an
phosphate BPCRS in methanol (50%). Solution (3 absorbent cotton plug moistened with chloroform, evaporate
0.08% w/v each of codeine phosphate BPCRS and the filtrate to dryness at a temperature not exceeding 45°
dthydrocodeine tartrate BPCRS in methanol (50%). Aft sing a rotary evaporator and dissolve the residue in 2 mL of
removal of the plate, allow it to dry in air, spray with hloroform. For solution (2) dilute 1.5 volumes of solution (1)
ethanolic tron() chloride solution and heat at 105° for volumes with chloroform. For solution (3) dilute
10 minutes. The principal spot in the chromatogram ‘Oltame of solution (1) to 100 volumes with chloroform.
obtained with solution (1) corresponds in position and colour
to that in the chromatogram obtained with solution (2).
solution (3) shows two clearly separated spots of different
colours. not more than one such spot with
C. In the Assay for codeine phosphate, the chromatogram hat of the principal spot is more
obtained with solution (2) shows a peak with the same intense than the spot e chromatogram obtained with
retention time as the principal peak in the chromatogram solution (3) (1%).
TESTS Appendix III A, using silica
Dissolution substance and a mixture of
Pharmacopoeia in the dissolution test for tablets and capsules
with respect to the content of Paracetamol, immediately place the prepared plat
Appendix XII B1, using Apparatus 2. Use as the medium tank and allow the solvent front to asce
900 mL of phosphate buffer pH 5.8 and rotate the paddle at
50 revolutions per minute. Withdraw a sample of 20 mL of
the medium and filter. Dilute the filtrate with 0.1m sodium
hydroxide to give a solution expected to contain about tablets containing 1.0 g of Paracetamol to a ground-glass-
0.00075% w/v of Paracetamol. Measure the absorbance of this stoppered 15 mL centrifuge tube, add 5 mL of peroxide-free
solution, Appendix IT B, at the maximum at 257 nm using ether, shake mechanically for 30 minutes, centrifuge at
1000 revolutions per minute for 15 minutes or until a clear
NY
0.1M sodium hydroxide in the reference cell. Calculate the total

supernatant liquid is obtained and use the supernatant liquid.
weit eA
content of paracetamol, CgHaNO, in the medium taking 715

as the value of A(1%, 1 cm) at the maximum at 257 nm. For solution (2) dilute 1 mL of solution (1) to 10 mL with
ethanol (96%). Solution (3) contains 0.0050% w/v of
4-Aminophenol
4'-chloroacetanilide in ethanol (96%). For solution (4) dissolve
0.25 g of 4'-chloroacetanilide and 0.10 g of paracetamol in
sufficient ethanol (96%) to produce 100 mL. After removal of
contains 0.001% w/v of 4-aminophenol in the mobile phase.
the plate, dry it in a current of warm air and examine under
For solution (2) shake a quantity of the powdered tablets
ultraviolet light (254 nm). Any spot corresponding to
containing 0.5 g of Paracetamol with 50 mL of the mobile
4'-chloroacetanilide in the chromatogram obtained with
phase for 10 minutes and filter.
Varela
chromatogram obtained with solution (3) (0.005%). Any
SNe
wee
2016 Co-codamol Preparations III-389
secondary spot in the chromatogram obtained with solution (2) LABELLING

with an Rf value lower than that of 4’-chloroacetanilide is The label states the quantities of Codeine Phosphate and of
not more intense than the spot in the chromatogram Paracetamol in each tablet.
obtained with solution (3) (0.25%). The test is not valid When Co-codamol Tablets are prescribed or demanded no
unless the chromatogram obtained with solution (4) shows strength being stated, tablets containing 8 mg of Codeine
two clearly separated principal spots, the spot corresponding Phosphate and 500 mg of Paracetamol shall be dispensed or
to 4’-chloroacetanilide having the higher Rf value. supplied.
of Codeine Phosphate comply with the requirements stated
under Tablets using the following method of analysis. Carry
thod for liquid chromatography, Appendix III D,
Effervescent Co-codamol Tablets
Codeine Phosphate and Paracetamol Effervescent Tablets
leine phosphate BPCRS in the mobile phase.
100 mL of the mobile phase to one Action and use
e aid of ultrasound until completely Opioid analgesic + analgesic; antipyretic.
DEFINITION
Effervescent Co-codamol Tablets contain Codeine Phosphate
and Paracetamol in a suitable soluble, effervescent basis.
(a) a stainless steel colum 4.6 mm) packed with
octadecylsilyl silica gel for chro rum) (Nucleosil
C18 is suitable), (b) as then ith a flow rate of Content of codeine phosphate, C,;;H,,NO3,H3PQu,,
1.5 mL per minute 0.01M sodium pésita Hfonate in a 1,H,O
mixture of 78 volumes of water and 22: 1€& of methanol, 92.5 to 107.5% of the stated amount.
the pH of the solution being adjusted to’ Content of paracetamol, CsH »NO,
2M hydrochloric acid, and (c) a detection wave 95.0 to 105.0% of the stated amount.
220 nm.
IDENTIFICATION
Calculate the content of CieH»1NO3,H3;PO.,/%2H> A. Carry out the method for thin-layer chromatography,
tablet using the declared content of é Appendix III A, using a TLC silica gel Fy54 plate (Merck
C,3H2,;NO3,H3PO0,,/2H,0O in codeine phosphate BPCRS are suitable) and a mixture of 1 volume of
ASSAY mmonia, 10 volumes of methanol and 90 volumes of
For codeine phosphate methane as the mobile phase. Apply separately to the
Weigh and powder 20 tablets. Carry out the method for L of each of the following solutions. For solution
liquid chromatography, Appendix III D, using the following quantity of the powdered tablets containing 24 mg
solutions. Solution (1) contains 0.004% w/v of codeine sphate in 30 mL of water until effervescence
phosphate BPCRS in the mobile phase. For solution (2) shake
a quantity of the powdered tablets containing 8 mg of
Codeine Phosphate with 100 mL of the mobile phase for
through a glass-fibre filter (Whatman GF/C is suitable) and phosphate BPCRS
in‘met
use the filtrate. 0.08% w/v each of code
ethanolic iron() chloride solurién at 105° for
Calculate the content of C;3H.;NO3,H3PO,,’/2H.O using
10 minutes. The principal spot in.th matogram
the declared content of C;gsH2,;,NO3,H3PO,4,2H.20 in codeine
obtained with solution (1) correspon ition and colour
phosphate BPCRS.
to that in the chromatogram obtained “8 ion (2).
For paracetamol The test is not valid unless the chromatogg obtained with
Weigh and powder 20 tablets. Carry out the method for solution (3) shows two clearly separated spots'o ferent
liquid chromatography, Appendix III D, using the following colours.
solutions. Solution (1) contains 0.005% w/v of
B. In the Assay for codeine phosphate, the chromatogram
paracetamol BPCRS in the mobile phase. For solution (2)
shake a quantity of the powdered tablets containing 500 mg retention time as the principal peak in the chromatogram
of Paracetamol with 100 mL of the mobile phase for
through a glass-fibre filter (Whatman GF/C is suitable) and TESTS
dilute 5 mL of the filtrate to 250 mL with the mobile phase. 4-Aminophenol
The chromatographic conditions described under Uniformity Carry out the method for guid chromatography,
of content may be used but with a detection wavelength of Appendix III D, using the following solutions. Solution (1)
243 nm. contains 0.001% w/v of 4-aminophenol in the mobile phase.
For solution (2) stir a quantity of the powdered tablets
Calculate the content of CgH,NO, using the declared
containing 0.5 g of Paracetamol with 50 mL of the mobile
content of CgHaNO>z in paracetamol BPCRS.
phase for 10 minutes and filter.
IWI-390 Co-codaprin Preparations 2016
octadecylsilyl silica gel for chromatography (10 um) CNucleosil ASSAY

C18 is suitable), (b) 0.01M sodium butanesulfonate in a For codeine phosphate
mixture of 0.4 volume of formic acid, 15 volumes of methanol Use the average of the 10 individual results determined in
vw end
and 85 volumes of water as the mobile phase with a flow rate the test for Uniformity of content.
of 2 mL per minute and (c) a detection wavelength of For paracetamol
272 nm. Weigh and powder 20 tablets. Carry out the method for
In the chromatogram obtained with solution (2) the area of liquid chromatography, Appendix III D, using the following
any peak corresponding to 4-aminophenol is not greater than solutions. Solution (1) contains 0.005% w/v of
the area of the peak in the chromatogram obtained with paracetamol BPCRS in the mobile phase. For solution (2) mix
solution (1) (0.1%). In the chromatogram obtained with a quantity of the powdered tablets containing 0.5 g of
solution (2) peaks with a long retention time may occur due Paracetamol with 100 mL of the mobile phase for
through a glass-fibre filter (Whatman GF/C is suitable) and
thod for thin-layer chromatography, dilute 5 mL of the filtrate to 250 mL with the mobile phase.
a TLC silica gel G plate (Analtech The chromatographic conditions described under Uniformity
mixture of 6 volumes of of content may be used but with a detection wavelength of
243 nm.
Calculate the content of CgH,NO, using the declared
the plate 20 wL of each ¢ the following solutions. content of CgHaNOz in paracetamol BPCRS.
For solution (1) carefully m ity of the powdered
tablets containing 50 mg o osphate with 50 mL STORAGE
of 0.1m hydrochloric acid for 10 Effervescent Co-codamol Tablets should be protected from
moisture.
40-mL quantities of dichloromethane. Wash LABELLING
extracts with 10 mL of water, filter throug The label states the quantities of Codeine Phosphate and of
anhydrous sodium sulfate on an absorbent cot Paracetamol in each tablet.
moistened with dichloromethane, evaporate the fi
When Co-codamol Effervescent Tablets are prescribed or
dryness at a temperature not exceeding 45° using a
demanded no strength being stated, tablets containing 8 mg
evaporator and dissolve the residue in 2 mL of
of Codeine Phosphate and 500 mg of Paracetamol shall be
dichloromethane. For solution (2) dilute 1.5 volumes of
dispensed or supplied.
solution (1) to 100 volumes with dichloromethane.
100 volumes with dichloromethane. After removal of the plate,
allow it to dry in air and spray with potassium todobismuthate
solution. Any secondary spot in the chromatogram obtained
chromatogram obtained with solution (2) (1.5%) and not
more than one such spot with an Rf value higher than that of
the principal spot is more intense than the spot in the Opioid analges yretic; analgesic; anti-inflammatory.
Uniformity of content DEFINITION
Tablets containing less than 2 mg and/or less than 2% w/w Co-codaprin Tablets co eine Phosphate and Aspirin
of Codeine Phosphate comply with the requirements stated in the proportions, by to 50 parts.
under Tablets using the following method of analysis. Carry The tablets comply with the reqix: ents stated under Tablets and
out the method for liguid chromatography, Appendix III D, with the following requirements.
using the following solutions. Solution (1) contains Content of codeine phosphate, C,3H
0.004% w/v of codeine phosphate BPCRS in the mobile phase. 1,H,O
For solution (2) add mobile phase to one tablet and mix with 90.0 to 110.0% of the stated amount.
the aid of ultrasound until completely dispersed. Shake for
Content of aspirin, Co.H;O,
10 minutes, dilute with sufficient mobile phase to produce a
solution containing 0.004% w/v of Codeine Phosphate, filter
through a glass-fibre filter (Whatman GF/C is suitable) and IDENTIFICATION
use the filtrate. A. Boil 1 g of the powdered tablets with 10 mL of 1M sodium
one AT The chromatographic procedure may be carried out using hydroxide, cool and filter. Acidify the filtrate with 1m sulfuric
Tey wte
am ae |
(a) a stainless steel column (10 cm x 4.6 mm) packed with acid; a white precipitate is produced. To a solution of the
octadecylsilyl silica gel for chromatography (5 um) (Nucleosil precipitate add iron(1) chloride solution R1; a deep violet
C18 is suitable), (b) as the mobile phase with a flow rate of colour is produced.
1.5 mL per minute 0.01M sodium pentanesulfonate in a B. Shake 1 g of the powdered tablets with a mixture of
mixture of 78 volumes of water and 22 volumes of methanol, 20 mL of water and 1 mL of 1M sulfuric acid for 5 minutes
eeveed
the pH of the solution being adjusted to 2.8 using and filter. Reserve the residue for test C. The filtrate yields
2M hydrochloric acid, and (c) a detection wavelength of the reactions characteristic of phosphates, Appendix VI. Make
220 nm. the remainder of the filtrate alkaline with 5m ammonia,
Calculate the content of C;gH.,;NO3,H3PO,, ¥2H.2O in each extract with dichloromethane, separate the dichloromethane
twee ad
tablet using the declared content of C;3H2.;NO3,H3POu,, layer and evaporate the dichloromethane. Place a small
quantity of the residue on the surface of a drop of nitric acid;
a eon A
¥2HO in codeine phosphate BPCRS.

a yellow, but no red, colour is produced.
we oe
Nowe
jap“ ddaegaitadaa
oe ta
2016 Co-codaprin Preparations II-391
C. Dissolve 0.1 g of the residue obtained in test B in 1 mL the principal spot is more intense than the spot in the
of sulfuric acid, add 0.05 mL of zron(im) chloride solution R1 or chromatogram obtained with solution (3) (1%).
0.05 mL of ammonium molybdate-sulfuric acid solution and Salicylic acid
warm gently. A bluish violet colour is produced which To a quantity of the powdered tablets containing 0.50 g of
changes to red on the addition of 0.05 mL of 2m mitnc acid. Aspirin add 50 mL of dichloromethane and 10 mL of water,
TESTS shake well and allow toseparate. Filter the dichloromethane
Dissolution layer through a dry filter paper and evaporate 10 mL of the
Comply with the requirements for Monographs of the British filtrate to dryness at room temperature using a rotary
Pharmacopoeia in the dissolution test for tablets and capsules evaporator. To the residue add 4 mL of ethanol (96%), stir
with respect to the content of Aspirin, Appendix XII B1. well, dilute to 100 mL with water at a temperature not
exceeding 10°, filter immediately and rapidly transfer 50 mL
TEST CONDITIONS
to a Nessler cylinder. Add 1 mL of freshly prepared ammonium
2, rotating the paddle at 50 revolutions tron(1m) sulfate solution R1, mix and allow to stand for
1 minute. Anyviolet colour produced is not more intense
(b) Use 500 x€.pH 4.5 buffer prepared by mixing 29.9 g than that obtained by adding 1 mL of freshly prepared
of sodium acet 16.6 mL of glacial acetic acid with ammonium tron(u) sulfate solution R1 to a mixture of 3 mL of
sufficient water a freshly prepared 0.050% w/v solution of salicylic acid in
as the medium. ethanol (96%) and sufficient water to produce 50 mL
PROCEDURE contained in a second Nessler cylinder (3.0%).
ASSAY
For codeine phosphate
the maximum at 265 nm, Appen To a quantity of the powder containing 24 mg of Codeine
in the reference cell. Phosphate add 5 mL of 5M sodium hydroxide and 15 mL of
(2) Measure the absorbance of a suitableso water, shake for 2 minutes and extract with three 50-mL
aspirin BPCRS using pH 4.5 buffer in the f quantities of dichloromethane. Wash each extract with the
DETERMINATION OF CONTENT same 10 mL of water, filter through absorbent cotton
previously moistened with dichloromethane and evaporate the
Calculate the total content of aspirin, CpHgQOx,, 1
combined extracts to about 60 mL on a water bath in a
current of air. Cool, add 25 mL of water, 5 mL of acetate
declared content of CgHgO, in aspirin BPCRS.
ar pH 2.8 and 5 mL of dimethyl yellow and oracet blue 2R
Foreign alkaloids sand titrate with 0.01mM dioctyl sodium sulfosuccinate VS
Carry out the method for thin-layer chromatography, igorous swirling until near the end point, then add the
Appendix III A, using the following solutions. ‘Op wise and, after each addition, swirl vigorously,
50 mg of Codeine Phosphate with 50 mL of 0.1m hydrochloric
acid, filter and make the filtrate alkaline with 5m sodium
hydroxide. Extract with two 40-mL quantities of
dichloromethane and wash the combined extracts with 10 mL
of water. Filter through a layer of anhydrous sodium sulfate on
an absorbent cotton plug moistened with dichloromethane.
Evaporate the filtrate to dryness and dissolve the residue in
2 mL of dichloromethane.
(2) Dilute 1.5 volumes of solution (1) to 100 volumes with
dichloromethane.
dichloromethane.
C 1 gH» 1NO3,H3POs,, VY, H,0 in codeine pho.
(a) Use as the coating silica gel. For aspirin

To a quantity of the powder containing 0.8 g o
20 mL of water and 2 g of sodium citrate and boil under a
(c) Apply 20 uL of each solution. reflux condenser for 30 minutes. Cool, wash the condenser
(d) Develop the plate to 15 cm. with 30 mL of warm water and titrate with 0.5m sodium
(e) After removal of the plate, dry in air, spray with potassium hydroxide VS using phenolphthalein solution R1 as indicator.
todobismuthate solution. Each mL of 0.5m sodium hydroxide VS is equivalent to
45.04 mg of CoHgQxq.
MOBILE PHASE
6 volumes of 13.5M ammonia, 30 volumes of cyclohexane and STORAGE

72 volumes of absolute ethanol. Co-codaprin Tablets should be protected from light.
LIMITS LABELLING
Any secondary spot in the chromatogram obtained with The label states that the tablets contain Aspirin, unless this
solution (1) is not more intense than the spot in the word appears in the name of the tablets (this requirement
chromatogram obtained with solution (2) (1.5%) and not does not apply in countries where exclusive proprietary rights
more than one such spot with an Rf value higher than that of in the name Aspirin are claimed).
ere l
IlI-392 Co-codaprin Preparations 2016
5 mL of 5m sodium hydroxide and 15 mL of water, shake for

Dispersible Co-codaprin Tablets 2 minutes and extract with three 50 mL quantities of
Dispersible Aspirin and Codeine Tablets dichloromethane. Wash each extract with the same 10 mL of
nee Ne
water, filter through absorbent cotton previously moistened
Action and use
with dichloromethane and evaporate the combined extracts to
Opioid analgesic + antipyretic; analgesic; anti-inflammatory.
about 60 mL on a water bath in a current of air. Cool, add
DEFINITION 25 mL of water, 5 mL of acetate buffer pH 2.8 and 5 mL of
dimethyl yellow and oracet blue 2R solution and titrate with
Dispersible Co-codaprin Tablets contain Codeine Phosphate
0.01M dioctyl sodium sulfosuccinate VS with vigorous swirling
and Aspirin in the proportions, by weight, 1 part to 50 parts
until near the end point, then add the titrant drop wise and,
in a suitable dispersible basis.
after each addition, swirl vigorously, allow to separate and
The tablets comply with the requirements stated under Tablets and swirl gently for 5 seconds. The end point is indicated by the
with the folleging requirements. appearance of a permanent pinkish grey colour in the
dichloromethane layer. Repeat the operation without the
ween 4
see as
yer Ne
powdered tablets. The difference between the titrations
represents the amount of dioctyl sodium sulfosuccinate
required.
Dissolve 40 mg of codeine phosphate BPCRS in 25 mL of
water and 5 mL of acetate buffer pH 2.8, add 60 mL of
dichloromethane and 5 mL of dimethyl yellow and oracet blue 2R
A. Effervesce on the additié
solution, shake well to dissolve the codeine phosphate and
B. Boil 1 g of the powdered tab complete the method described above beginning at the words
hydroxide, cool and filter. Acidi ‘and titrate ...’ Calculate the content of
CigH213NO3,H3PO0,,/2H,O using the declared content of
C,3H»,;NO3,H3PO0,,'/2H.0 in codeine phosphate BPCRS.
colour is produced.
For aspirin
C. Shake 1 g of the powdered tablets with
To a quantity of the powder containing 0.8 g of Aspirin add
15 mL of water and swirl until effervescence ceases.
Add 5 mL of 0.5m sulfuric acid and extract with 50 mL of
the reactions characteristic ofphosphates, Appendix
ether followed by three 30-mL quantities of ether. Wash the
the remainder of the filtrate alkaline with 5m ammonia,
ombined extracts with 10 mL of water, filter through
extract with dichloromethane, separate the dichloromethane
nt cotton previously moistened with ether, washing
layer and evaporate the dichloromethane. Place a small
arating funnel and filter with ether. Evaporate the
quantity of the residue on the surface of a drop of mitric acid;
ater bath at 30° in a current of air. Dissolve the
a yellow but no red colour is produced. L of acetone and evaporate in a water bath at
D. Dissolve 0.1 g of the residue obtained in test C in 1 mL solve the residue in 5 mL of acetone and
of sulfuric acid, add 0.05 mL of tron(i) chloride solution R1 or @ water bath at 30°. Dissolve the residue in
0.05 mL of ammonium molybdate-sulfuric acid solution and
warm gently. A bluish violet colour is produced which solution and tite ith 0.1m sodium hydroxide VS using
changes to red on the addition of 0.05 mL of 2m mitric acid. phenol red solution gs ator. Each mL of 0.1m sodium
TEST hydroxide VS is equiva x1 8.02 mg of CyHgOg.
Salicylic acid STORAGE |

To a quantity of the powdered tablets containing 0.50 g of Dispersible Co-codaprin ‘Tablets sk uld be protected from
Aspirin add 50 mL of dichloromethane and a mixture of 2 mL light.
Nw ane
of 1m hydrochloric acid and 8 mL of water, shake well and
LABELLING ©
allow to separate. Filter the dichloromethane layer through a
dry filter paper and evaporate 10 mL of the filtrate to dryness The label states that the tablets cont rin, unless this
at room temperature using a rotary evaporator. To the word appears in the name of the tablets is r uirement
residue add 4 mL of ethanol (96%), stir well, dilute to does not apply in countries where exclus
100 mL with water at a temperature not exceeding 10°, filter in the name Aspirin are claimed).
immediately and rapidly transfer 50 mL to a Nessler cylinder.
Add 1 mL of freshly prepared ammonium iron(1m) sulfate
solution .R1, mix and allow to stand for 1 minute. Any violet
colour produced is not more intense than that obtained by Co-danthrusate Capsules
ane adding 1 mL of freshly prepared ammonium iron(im) sulfate Dantron and Docusate Sodium Capsules
eNews
solution R1 to a mixture of 3 mL of a freshly prepared
0.050% w/v solution of salicylic acid in ethanol (96%) and Action and use
sufficient water to produce 50 mL contained in a second Stimulant laxative.
Nessler cylinder (3.0%).
DEFINITION
ASSAY Co-danthrusate Capsules contain Dantron and Docusate
Weigh and powder 20 tablets. Sodium in the proportions, by weight, 5 parts to 6 parts.
For codeine phosphate The capsules comply with the requirements stated under Capsules
To a quantity of the powder containing 16 mg of Codeine and with the following requirements.
Phosphate add 20 mL of water and 1 g of disodium edetate,
Content of dantron, C,,Hs;O,
oat
swirl gently until effervescence ceases, shake to dissolve, add
oe” ee ar a
i i
2016 Codeine Preparations III-393
Content of docusate sodium, C,).H3,Na0O-S (g) For solution (2), allow the chromatography to proceed
90.0 to 110.0% of the stated amount. for 1.5 times the retention time of the principal peak.
A. Carry out the method for thin-layer chromatography, 2.5 volumes of glacial acetic acid, 40 volumes of
Appendix III A, using the following solutions. tetrahydrofuran and 60 volumes of water.
(1) Shake a quantity of the contents of the capsules SYSTEM SUITABILITY
containing 50 mg of Dantron with 10 mL of dichloromethane,
filter and dilute 2 mL of the filtrate to 20 mL with
with solution (3):
dichloromethane.
a peak due to 1-hydroxyanthraquinone appears immediately
(2) 0.06% w/v of docusate sodium BPCRS in dichloromethane.
before the principal peak, as indicated in the reference
(3) 0.05% w/v of dantron BPCRS in dichloromethane. chromatogram supplied with dantron
impurity standard BPCRS;
the height of the trough separating the two peaks is not
greater than one third of the height of the peak due to
(b) Usethe 1-hydroxyanthraquinone.
(c) Apply 10 pL: LIMITS
(d) Develop the plate In the chromatogram obtained with solution (1):
(e) After removal of the area of any peak corresponding to
with ethanolic sulfuric acid 1-hydroxyanthraquinone is not greater than 2.5 times the
15 minutes. Examine in da area of the principal peak in the chromatogram obtained with
solution (2) (3.3% taking into account the correction factor
MOBILE PHASE
for the impurity);
15 volumes of methanol and 85 volutn
CONFIRMATION greater than the area of the principal peak in the
Disregard any peak with a retention time less than one third
chromatograms obtained with solutions (2) and @). of that of the principal peak.
B. Shake a quantity of the contents of the capsules ASSAY
containing 60 mg of Docusate Sodium with 50 mL of*w
For dantron
To 5 mL of this mixture add 1 mL of 2m sulfuric acid, 10m,
quantity of the mixed contents of 20 capsules
of dichloromethane and 0.2 mL of dimethyl yellow solution an
ring 35 mg of Dantron add 50 mL of absolute ethanol,
mix; a red colour is produced in the dichloromethane layer.
water bath for 30 minutes and cool. Add sufficient
Add 50 mg of cetrimide and mix; the dichloromethane layer i
ethanol to produce 100 mL and filter through glass-
yellow.
paperWhatman GF/C is suitable). Dilute 5 mL of the
C. To a quantity of the contents of the capsules containing
50 mg of Dantron add 10 mL of dichloromethane and 5 mL
of 1M ammonia and mix. A red colour is produced in the 1B. Calculate the content of
aqueous layer. ; value of A(1%, 1 cm) at the
TEST
Related substances For docusate sodiu
Carry out the method for liguid chromatography, Toa quantity of the mix
containing 50 mg of Dantron with 20 mL of tetrahydrofuran
for 5 minutes and dilute to 100 mL with the mobile phase.
mobile phase.
sulfan blue mixed solution as indicator, to the2 f t appearance
(3) Dissolve 50 mg of dantron impurity standard BPCRS in
of a green colourin the chloroform layer and shaking
20 mL of tetrahydrofuran and dilute to 100 mL with the
vigorously towards the end point. Each mL of
mobile phase.
0.004m benzethonium chloride VS is equivalent to 1.778 mg of
CHROMATOGRAPHIC CONDITIONS C.0H37Na0O-S.
below.
Codeine Phosphate Injection
(c) Use a flow rate of 1 mL per minute. Action and use
(d) Use an ambient column temperature. Opioid receptor agonist; analgesic.
cee es
DEFINITION
ney (f) Inject 20 wL of each solution. Codeine Phosphate Injection is a sterile solution of Codeine
4
Fo win Phosphate in Water for Injections.
fate We et ee et
II-394 Codeine Preparations 2016
The injection comphes with the requirements stated under

Codeine Phosphate Oral Solution
Content of codeine phosphate, ~ Action and use |
C,3H2,:NO3,H3PO0,,'2H,O - Opioid receptor agonist; cough suppressant.
DEFINITION
IDENTIFICATION | ,
Codeine Phosphate Oral Solution contains Codeine
A. To a volume of the injection containing 60 mg of Codeine
Phosphate or Codeine Phosphate Sesquihydrate in a suitable
Phosphate add 0.05 mL of hydrochloric acid and sufficient
flavoured vehicle.
water to produce 7.5 mL. Shake with three 10-mL quantities
of chloroform and discard the chloroform. Add sufficient The oral solution complies with the requirements stated under Oral
6M ammonia to make the aqueous solution alkaline to litmus Liguids and with the following requirements.
paper, extr with three 10-mL quantities of chloroform, Content of codeine phosphate C,,;H,,NO3,H3POu,,
HO
nered
IDENTIFICATION
spectrum of codéin
To a quantity of the oral solution containing 60 mg of
B. Yields reaction Codeine Phosphate add 20 mL of water and 30 mL of
Appendix VI. chloroform, shake and discard the chloroform layer. To the
TESTS aqueous layer add 10 mL of 1M sodium hydroxide and extract
Acidity with 30 mL of chloroform. Wash the chloroform layer with
pH, 3.0 to 6.0, Appendix Vv & | two 10-mL quantities of 0.1m sodium hydroxide followed by
10 mL of water. Dry the chloroform layer with anhydrous
Related substances
Sanur.
sodium sulfate and filter. Evaporate the filtrate to dryness and
Carry out the method for liquid chrométogra,;
dry the residue at 60°. The infrared absorption spectrum of the
Appendix III D, using the following solutis 16) olution
residue, Appendix II A, is concordant with the reference
(1) dilute, if necessary, the injection with m
spectrum of codeine (RS 072).
producea solution containing 0.6% w/v of Coé
Phosphate. For solution (2) dilute 1 volume of solut Related substances
to 100 volumes with methanol (60%). | Carry out the method for thin-layer chromatography,
Appendix III A, using the following solutions in chloroform.
The chromatographic procedure may be carried out usin
(a) a stainless steel column (10 cm x 4.6 mm) packed (1) To a quantity of the oral solution containing 60 mg of
octadecylsilyl silica gel for chromatography (5 um) (Nucleosil ne Phosphate add 20 mL of water and 2 mL of
C18 is suitable), (b) as the mobile phase with a flow rate of onia and extract with two 20-mL quantities of
2 mL per minute a mixture prepared by adding 600 mL of Dry the combined extracts with anhydrous sodium
methanol containing 2.22 g of dioctyl sodium sulfosuccinate to evaporate the filtrate to dryness and dissolve the
100 mL of water containing 1.36 g of sodium acetate, diluting
to 1 litre with water and adjusting the pH to 5.5 with glacial
acetic acid and (c) a detection wavelength of 285 nm. (3) Dilute C
For solution (1) allow the chromatography to proceed for CHROMATOGRA
2.5 times the retention time of the principal peak.
The sum of the areas of any secondary peaks in the are suitable).
chromatogram obtained with solution (1) is not greater than
twice the area of the principal peak in the chromatogram
Te OtNS
obtained with solution (2) (2%). (c) Apply 10 WL of each solu

“©
plate to 15 cm.
ASSAY (d) Develop the
Carry out the method for guid shromatosraphy, (e) After removal of the plate, dry i
Appendix III D, using the following solutions. Solution (1) potassium 1odobismuthate solution.
contains 0.06% w/v of codeine phosphate BPCRS in methanol MOBILE PHASE
(60%). For solution (2) dilute the injection, if necessary, with 6 volumes of 13.5m ammonia, 30 volumes ofcyG he and
methanol (60%) to produce a solution containing 0.06% w/v 72 volumes of ethanol (96%).
of Codeine Phosphate.
LIMITS
hel ae
Calculate the content of C;3sH»,;NO3,H3PO,,/2H.O in the

wis
avd
wo
injection using the declared content of
CigH21;NO3,H3PO0,4,/2H2O in codeine phosphate BPCRS. not more than one such spot with an Rf value higher than
that of the principal spot is more intense than the spot in the
STORAGE chromatogram obtained with solution (3) (1%).
Codeine Phosphate Injection should be protected from light.
ASSAY
15 mg of Codeine Phosphate, if necessary, with sufficient
water to produce a 0.06% w/v of Codeine Phosphate.
a
2016 Codeine Preparations ITIT-395
(2) 0.06% w/v of codeine phosphate BPCRS in water. surface of a drop of nitric acid. A yellow but no red colour is
CHROMATOGRAPHIC CONDITIONS produced (distinction from morphine).
(a) Use a stainless steel column (20 cm x 4.6 mm) packed B. Heat 10 mg of the residue obtained in test A on a water
with end-capped octadecylsilyl silica gel for chromatography bath with 1 mL of sulfuric acid and 0.05 mL of tron(am)
(5 um) (Nucleosil C18 is suitable). chloride solution R1. A blue colour is produced which changes
to red on the addition of 0.05 mL of mitric acid.
below. C. Extract the powdered tablets with water and filter.
The filtrate yields reaction B characteristic of phosphates,
Appendix VI.
TESTS
Foreign alkaloids
of each solution. Carry out the method for thin-layer chromatography,
t@.to sodium benzoate may be present. Appendix III A, using silica gel G as the coating substance
with the peak due to codeine phosphate and a mixture of 6 volumes of 13.5mM ammonia, 30 volumes
phic conditions to achieve a of cyclohexane and 72 volumes of absolute ethanol as the
satisfactory separatieti. An increase in the content of water in mobile phase. Apply separately to the plate 20 wL of each of
the mobile phase of.an ificrease in the concentration of the following solutions. For solution (1) shake a quantity of
sodium octanesulfo rease the retention time of the the powdered tablets containing 0.25 g of codeine phosphate
peak due to codeine pho: relative to that of the peak or its equivalent with 10 mL of a mixture of 4 volumes of
due to sodium benzoate. 0.01mM hydrochloric acid and 1 volume of absolute ethanol for
MOBILE PHASE 15 minutes and filter. For solution (2) dilute 1.5 volumes of
0.01M sodium octanesulfonatein %tr solution (1) to 100 volumes with a mixture of 4 volumes of
volume of
0.01mM hydrochloric acid and 1 volume of absolute ethanol.
glacial acetic acid, 45 volumes ofmeth 4 and 55 volumes of
water. For solution (3) dilute 1 volume of solution (1) to
100 volumes with a mixture of 4 volumes of
DETERMINATION OF CONTENT 0.01Mm hydrochloric acid and 1 volume of absolute ethanol. After
Determine the weight per mL of the oral solution removal of the plate, allow it to dry in air and spray with
Appendix V G, and calculate the content of | potassium todobismuthate solution. Any secondary spot in the
CisH»,;,NO3,H3PO0,,/2H,0, weightin volume,using the: chromatogram obtained with solution (1) is not more intense
declared content of C;gH,;NO3,H3PO,, “2H,Oin coder than the spot in the chromatogram obtained with solution (2)
phosphate BPCRS. (1.5%) and not more than one such spot with an Rf value
STORAGE n that of the principal spot is more intense than the
Codeine Phosphate Oral Solution should be protected from
light.
LABELLING
When the active ingredient is codeine phosphate
sesquihydrate, the quantity is stated in terms of the
equivalent amount of codeine phosphate.
When Codeine Linctus is prescribed or demanded, Codeine
Phosphate 0.3% w/v Oral Solution shall be dispensed or
supplied.
Codeine Phosphate Tablets

Action and use
Opioid receptor agonist; analgesic. 0. 1m sodium hydroxide VS using methyl red so a
indicator. Each mL of 0.1m hydrochloric acid VS*is
DEFINITION
to 40.64 mg of Ci8gH»,,;,NO3,H3PO0,,'/2H,0.
Codeine Phosphate Tablets contain Codeine Phosphate or
Codeine Phosphate Sesquihydrate. STORAGE
The tablets comply with the requirements stated under Tablets and Codeine Phosphate Tablets should be protected from light.
with the following requirements. LABELLING
Content of codeine phosphate, When the active ingredient is codeine phosphate
C,3H,,NO3,H3PQ0,,'2H,O sesquihydrate, the quantity is stated in terms of the
92.5 to 107.5% of the stated amount. equivalent amount of codeine phosphate.
IDENTIFICATION
A. Macerate a quantity of the powdered tablets containing
50 mg of codeine phosphate or its equivalent with 5 mL of
1m sulfuric acid and 15 mL of water. Filter, make alkaline
with 5M ammonia, extract with successive quantities of
chloroform and evaporate the chloroform extracts on a water
bath. Place a few mg of the residue, in powder, on the
IWI-396 Co-dydramol Preparations 2016
with respect to the content of Paracetamol,

Co-dydramol Tablets Appendix XII B1.
Dihydrocodeine and Paracetamol Tablets
TAN
aaa
N
TEST CONDITIONS
Action and use (a) Use Apparatus 2, rotating the paddle at 50 revolutions
vate Tete
Opioid analgesic + analgesic; antipyretic. per minute.

(b) Use 900 mL of phosphate buffer pH 5.8, at a temperature
DEFINITION of 37°, as the medium.
Co-dydramol Tablets contain Dihydrocodeine Tartrate and
PROCEDURE
Paracetamol in the proportions, by weight, 1 part to 50 parts.
The tablets comply with the requirements stated under Tablets and (1) After 45 minutes withdraw a 20 mL sample of the
with the following requirements. medium and measure the absorbance of the filtered sample,
suitably diluted with 0.1m sodium hydroxide to give a solution
Content of:dihydrocodeine tartrate, C,;;H,3NO3,C,H;O, expected to contain about 0.00075% w/v of Paracetamol, at
aye Nw
95.0 tot he stated amount. the maximum at 257 nm, Appendix II B using 0.1m sodium
hydroxide in the reference cell.
Calculate the total content of paracetamol, CgH »NOsz, in the
medium taking 715 as the value of A(1%, 1 cm) at the
maximum at 257 nm.
the filtrate to dryness. T bsorption spectrum of the
4-Aminophenol
residue, Appendix II A, is cé ith the reference
wae
30 mg of Dihydrocodeine Tartrate with 10 mL (2) 0.001% w/v of 4-aminophenol in the mobile phase.
1 minute and centrifuge. Decant, add 10 mL
shake for 1 minute and filter the chloroform layer thiro (a) Use a stainless steel column (20 cm x 4.6 mm) packed
glass-fibre paper (Whatman GF/C is suitable). with octadecylsilyl silica gel for chromatography (10 um)
(2) 0.1% w/v of dihydrocodeine tartrate BPCRS in methano Nucleosil C18 is suitable).
(50%).
(3) 0.1% w/v of codeine phosphate BPCRS in methanol (50%).
(a) Use as the coating silica gel F254 precoated plate (Merck
silica gel 60 F554 plates are suitable).
(d) Develop the plate to 15 cm. formic acid, 15 volum
(e) After removal of the plate, dry in air, spray with ethanolic LIMITS
ste
tron(il) chloride solution and heat at 105° for 10 minutes. In the chromatogram obtai solution (1):
MOBILE PHASE the area of any peak correspond ing aminophenol is not
1 volume of 13.5mM ammonia, 10 volumes of methanol and
90 volumes of dichloromethane. chromatogram obtained with solutio
SYSTEM SUITABILITY
In the chromatogram obtained with solutions(1)<
long retention time may occur due to excipiex
solution (4) shows two clearly separated spots of different Related substances :
colours. A. Carry out the method for thin-layer chromatograp
CONFIRMATION
rae
50 mg of Dihydrocodeine Tartrate with 0.5m hydrochloric

solution (1) corresponds in position and colour to that in the acid, filter, make the filtrate alkaline with 5m sodium hydroxide
chromatogram obtained with solution (2). and extract with four 25 mL quantities of chloroform. Wash
C. In the Assay for dihydrocodeine tartrate, the each chloroform extract with 10 mL of each of 0.01M sodium
chromatogram obtained with solution (2) shows a peak with hydroxide and water, filter the combined chloroform extracts,
the same retention time as the principal peak in the evaporate the filtrate to dryness at a temperature not
chromatogram obtained with solution (1). exceeding 45° and dissolve the residue in 2 mL of chloroform.
TESTS (2) Dilute 1 volume of solution (1) to 100 volumes with
Dissolution chloroform.
ye Ne Comply with the requirements for Monographs of the British (3) Dilute 1 volume of solution (1) to 200 volumes with
‘Away
awe te
ye Aw
2a te
Pharmacopoeia in the dissolution test for tablets and capsules chloroform.
wn we
Aye Ax
a aoe
2016 Co-dydramol Preparations III-397
CHROMATOGRAPHIC CONDITIONS (1) Add 50 mL of methanol to one tablet and mix with the
(a) Use as the coating silica gel GF 254. aid of ultrasound until completely dispersed. Add 100 mL of
wee ad
wane! (b) Use the mobile phase as described below. water, Shake for 10 minutes, dilute to 200 mL with water,
filter through glass-fibre paper (Whatman GF/C is suitable)
i
PUN LY
weernva

and use the filtrate.
(d) Develop the plate to 15 cm. |
(2) 0.005% wiv of dihydrocodeine tartrate BPCRS in methanol
(e) After removal of the plate, dry in air and spray with dilute (25%).
potassium iodobismuthate solution.
MOBILE PHASE
1 volume of 13.5mM ammonia, 10 volumes of methanol and with octadecylsilyl silica gel for chromatography (5 um)
90 volumes of dichloromethane. (Nucleosil C18 is suitable).
FM AGN
wane
below.
yt more intense than the spot in the (c) Use a flow rate of 1.5 mL per minute.
or Stained with solution (2) (1%) and not more (d) Use an ambient column temperature.
than one sue ..more intense than the spot in the
B. Carry out the met
Appendix III A, using. th MOBILE PHASE
ely-powdered tablets 0.01M sodium pentanesulfonate in a mixture of 22 volumes of

containing 1.0 g of Paraceta |.¢0°%, ground-glass-stoppered methanol and 78 volumes of water, the pH of the solution
15 mL centrifuge tube, add ssx1de-free ether, shake being adjusted to 2.8 using 2m hydrochloric acid.
mechanically for 30 minute t,1000 revolutions DETERMINATION OF CONTENT
per minute for 15 minutes or until “a
Calculate the content of CjgH23NO3,C,H,O,¢ in each tablet
is obtained and use the supernatant liquid
using the declared content of C;g3H.3NO3,C,H,6O¢ in
(2) Dilute 1 mL of solution (1) to 10 mI® , dithydrocodeine tartrate BPCRS.
(3) 0.0050% w/v of 4'-chloroacetanilide in ethatiol (26° ASSAY
(4) Dissolve 0.25 g of 4'-chloroacetanilide and 0.10 For dihydrocodeine tartrate
paracetamol in sufficient ethanol (96%) to produce I* Weigh and powder 20 tablets. Carry out the method for
CHROMATOGRAPHIC CONDITIONS liquid chromatography, Appendix III D, using the following
(a) Use as the coating silica gel GF 254. t1ons.
(b) Use the mobile phase as described below. Shake a quantity of the powdered tablets containing
f Dihydrocodeine Tartrate with 50 mL of methanol
(c) Apply 200 uL of solution (1). Apply 40 pL each of
inute, add 100 mL of water and shake for a further
solutions (2), (3) and (4).
(d) Pour the mobile phase into an unlined tank, immediately
place the prepared plate in the tank and close the tank. filtrate. ©
Develop the plate to 14 cm.
(2) 0.005% *
(e) After removal of the plate, dry in air and examine under (25%).
MOBILE PHASE
The chromatographic co
10 volumes of toluene, 25 volumes of acetone and 65 volumes of content may be used.
of chloroform.
MOBILE PHASE
SYSTEM SUITABILITY
0.01M sodium pentanesulfonate in’ eof 22 volumes of
The test is not valid unless the chromatogram obtained with methanol and 78 volumes of water, the’pH of the solution
solution (4) shows two clearly separated spots, the spot being adjusted to 2.8 using 2m hydrochle
corresponding to 4’-chloroacetanilide having the
DETERMINATION OF CONTENT |
higher Rf value.
Calculate the content of C;gH23NO3,C4H,O, inthe tablets
LIMITS
using the declared content of C,gH»3NO3,C,H6O,¢ in
Any spot corresponding to 4’-chloroacetanilide in the dithydrocodeine tartrate BPCRS.
chromatogram obtained with solution (1) is not more intense
For paracetamol
we ny
than the spot in the chromatogram obtained with solution (3)
(0.005%). Any secondary spot in the chromatogram obtained
with solution (2) with an Rf value lower than that of
4’'-chloroacetanilide is not more intense than the spot in the (1) Dilute 1 volume of solution (1) obtained in the Assay for
chromatogram obtained with solution (3) (0.25%). dihydrocodeine tartrate to 50 volumes with water.
Uniformity of content (2) 0.005% w/v of paracetamol BPCRS in water.
Tablets containing less than 2 mg and/or less than 2% w/w CHROMATOGRAPHIC CONDITIONS
of Dihydrocodeine Tartrate comply with the requirements The chromatographic conditions described under Uniformity
stated under Tablets using the following method of analysis. of content may be used but with a detection wavelength of
Carry out the method for liguid chromatography, 243 nm.
1. r
st oe
~~ we
III-398 Co-fluampicil Preparations 2016
MOBILE PHASE After removal of the plate, allow it to dry in air, expose to
0.01m sodium pentanesulfonate in a mixture of 22 volumes of 10dine vapour until the spots appear and examine in daylight.
methanol and 78 volumes of water, the pH of the solution In the chromatogram obtained with solution (1) the spot
being adjusted to 2.8 using 2m hydrochloric acid. with the lower Rf value corresponds to the principal spot in
the chromatogram obtained with solution (3) and the spot
with the higher Rf value corresponds to the principal spot in
Calculate the content of CgHaNO>z in the tablets using the the chromatogram obtained with solution (2). The test is not
declared content of CgH)NO> in paracetamol BPCRS. valid unless the chromatogram obtained with solution (4)
shows three clearly separated principal spots.
C. In the Assay, the retention times of the two principal
peaks in the chromatogram obtained with solution (1)
correspond to those of the principal peaks in the
Flucloxacilliff'® chromatograms obtained with solutions (2) and (3).
ASSAY
Action and use ¢ Carry out the method for liquid chromatography,
Penicillin antibacter Appendix III D, using the following freshly prepared
solutions. For solution (1) add a quantity of the mixed
DEFINITION
contents of 20 capsules containing the equivalent of 0.25 g of
Co-fluampicil Capsules contain F cloxacillin Sodium and each of ampicillin and flucloxacillin to 350 mL of water, mix
Ampicillin Trihydrate, in the "pr e 8; by weight, 1 part with the aid of ultrasound for 15 minutes, cool and dilute to
flucloxacillin to 1 part ampicilli 500 mL with water, filter through glass-fibre paper
The capsules comply with the requiremé under Capsules (Whatman GF/C is suitable) and use the filtrate. Solution (2)
and with the following requirements. « contains 0.05% w/v of anhydrous ampicillin BPCRS. Solution
Content of ampicillin, C;;H,9N;0,S (3) contains 0.056% w/v offlucloxacillin sodium BPCRS.
92.5 to 107.5% of the stated amount. The chromatographic procedure may be carried out using
Content of flucloxacillin, C,,)H,,CIFN3;0,;S (a) a stainless steel column (25 cm x 4.6 mm) packed with
92.5 to 107.5% of the stated amount. octadecylsilyl silica gel for chromatography (5 um) (Spherisorb
ODS 1 is suitable), (b) as the mobile phase with a flow rate
IDENTIFICATION : of 1.5 mL per minute a mixture of 50 volumes of methanol
A. Carry out the method for thin-layer chromatography, 0 volumes of a buffer solution containing
Appendix III A, usinga silanised silica gel precoated plate diammonium hydrogen orthophosphate and
(Merck silanised silica gel 60 F,5,, (RP-18) plates are ibutylammonium hydroxide, the pH of the solution
suitable) and a mixture 10 volumes of acetone and o 7.0 with ormhophosphionic acid and (c) a
90 volumes of a 15.4% w/v solution of ammonium acetate
adjusted to pH 5.0 with glacial acetic acid as the mobile
phase. Apply separately to the plate 1 uL of each of the
following solutions. For solution (1) shake a quantity of the
contents of the capsules containing the equivalent of 0.125 g
IFN3NaO3S in flucloxacillin
of each of ampicillin and flucloxacillin with 50 mL of
y C,9H)¢CIFN3NaO;5S is
phosphate buffer pH 7.0 and filter through glass-fibre paper
(Whatman GF/C is suitable). Solution (2) contains
0.28% w/v of ampicillin trihydrate BPCRS in phosphate buffer LABELLING
pH 7.0. Solution (3) contains 0.26% w/v offlucloxacillin The quantity of Ampicillin Ti s stated in terms of
sodium BPCRS in phosphate buffer pH 7.0. Solution (4) the equivalent amount of ampicil d the quantity of
contains 0.28% w/v of each of amoxicillin trihydrate BPCRS Flucloxacillin Sodium is stated in f.the equivalent
and ampicilhn trihydrate BPCRS in phosphate buffer pH 7.0. amount of flucloxacillin.
After removal of the plate, allow it to dry in air, expose to The label states that the preparation co
iodine vapour until the spots appear and examine in daylight.
In the chromatogram obtained with solution (1) the spot
with the lower Rf value corresponds to the principal spot in
with the higher Rf value corresponds to the principal spot in Co-fluampicil Oral Suspension
the chromatogram obtained with solution (2). The test is not Flucloxacillin and Ampicillin Oral Suspension
valid unless the chromatogram obtained with solution (4)
shows two clearly separated principal spots. Action and use
B. Carry out the method for thin-layer chromatography, Penicillin antibacterial.
Appendix III A, using a silanised silica gel precoated plate
DEFINITION
(Merck silanised silica gel 60 F54, (RP-18) plates are
suitable) and a mixture of 30 volumes of acetone and Co-fluampicil Oral Suspension is a suspension containing
70 volumes of a 15.4% w/v solution of ammonium acetate equal amounts of Flucloxacillin Magnesium Octahydrate and
adjusted to pH 5.0 with glacial acetic acid as the mobile Ampicillin Trihydrate in a suitable flavoured vehicle. It is
phase. Apply separately to the plate 1 uL of each of the prepared by dispersing the dry ingredients in the specified
following solutions. For solutions (1) to (3) use the solutions volume of water just before issue for use.
described under test A. Solution (4) contains 0.26% w/v of
each of cloxacillin sodium BPCRS, dicloxacillin sodium BPCRS
and flucloxacillin sodium BPCRS in phosphate buffer pH 7.0.
2016 Co-fluampicil Preparations II-399
The dry ingredients comply with the requirements for Powders and TESTS
Granules for Oral Solutions and Oral Suspensions stated under Acidity
Oral Liquids. pH, 4.8 to 5.6, Appendix V L.
For the following tests prepare the oral suspension as directed on ASSAY
the label. The suspension examined immediately after preparation, To a weighed quantity of the oral suspension containing the
unless otherwise indicated, complies with the requirements stated equivalent of 0.1 g of each of ampicillin and flucloxacillin
under Oral Liquids and with the following requirements. add sufficient water to produce 100 mL (solution A).
Content of ampicillin, C;;H,.N3;0,S For ampicillin
When freshly constituted, not more than 120.0% of the Dilute 2 mL of solution A to 50 mL with buffered copper
stated amount. When stored at the temperature and for the sulfate solution pH 5.2, transfer 10 mL to a stoppered test
period stated on the label during which the oral suspension tube and heat in a water bath at 75° for 30 minutes. Rapidly
cool to room temperature, dilute to 20 mL with buffered
copper sulfate solution pH 5.2 and measure the absorbance of
Appendix II B, using in the reference cell a solution prepared
stated amount. by diluting 2 mL of solution A to 100 mL with buffered
period stated on ‘tk copper sulfate solution pH 5.2. Calculate the content of
C16H ,9N30,4S from the absorbance obtained by carrying out
ted ani
80. 0% of the sta the operation at the same time using 2 mL of a solution
IDENTIFICATION prepared by dissolving 0.1 g of anhydrous ampicillin BPCRS
in 100 mL of water, diluting to 50 mL with buffered copper
sulfate solution pH 5.2 and beginning at the words ‘transfer
Appendix III A, using a silanised:si
10 mL ...’ and from the declared content of C;gH,9N30,S
(Merck silanised silica gel 60 Fy54, @
in anhydrous ampicillin BPCRS. Determine the weight per mL
suitable) and a mixture of 10 volumes&
of the oral suspension, Appendix V G, and calculate the
90 volumes of a 15.4% w/v solution of af
content of C,;sH;9N304S, weight in volume.
adjusted to pH 5.0 with glacial acetic acid as‘
phase. Apply separately to the plate 1 wL of each Repeat the procedure using a portion of the oral suspension
following solutions. For solution (1) dilute a quaiitity,<¢ that has been stored at the temperature and for the period
oral suspension containing the equivalent of 0.125 g°of each... stated on the label during which it may be expected to be
of ampicillin and flucloxacillin to 50 mL with phosphatée’ satisfactory for use.
pH 7.0. Solution (2) contains 0.28% w/v of ampicillin ucloxacillin
trihydrate BPCRS in phosphate buffer pH 7.0. Solution (3) mL of solution A to 100 mL with 1m hydrochloric
contains 0.26% w/v of flucloxacillin sodium BPCRS in asure the absorbance of the resulting solution at the
phosphate buffer pH 7.0. Solution (4) contains 0.28% w/v of at 352 nm, Appendix II B, after exactly
each of amoxicillin trihydrate BPCRS and ampicillin using 1m hydrochloric acid in the reference cell.
trihydrate BPCRS in phosphate buffer pH 7.0. After removal of
the plate, allow it to dry in air, expose to iodine vapour until by carrying out the operation at the same
the spots appear and examine in daylight. In the time using 2 olution prepared by dissolving 0.11 g
chromatogram obtained with solution (1) the spot with the offlucloxacillin*sodiugs BPCRS in 100 mL of water and from
lower Rf value corresponds to the principal spot in the the declared content, 9H 6CIFN3NaOsS ii n flucloxacillin
chromatogram obtained with solution (3) and the spot with sodium BPCRS. Eact 9H, .<CIFN3Na0;Sis
the higher Rf value corresponds to the principal spot in the equivalent to 0.9538 17CIFN30;S. Determine
chromatogram obtained with solution (2). The test is not the weight per mL of the oral.stispension, Appendix V G, and
valid unless the chromatogram obtained with solution (4) calculate the content of C 19HygC (N2O5S, weight in volume.
shows two clearly separated principal spots. Repeat the procedure using a port on e oral suspension
B. Carry out the method for thin-layer chromatography, for the period
Appendix III A, usinga silanised silica gel precoated plate stated on the label during which it mayb pected to be
(Merck silanised silica gel 60 Fy54, CRP-18) plates are satisfactory for use.
suitable) and a mixture of 30 volumes of acetone and
STORAGE
70 volumes of a 15.4% w/v solution of ammonium acetate
The oral suspension should be stored at the teniperature and
adjusted to pH 5.0 with glacial acetic acid as the mobile
used within the period stated on the label.
following solutions. For solutions (1) to (3) use the solutions LABELLING
described under test A. Solution (4) contains 0.26% w/v of The quantity of Ampicillin Trihydrate is stated in terms of
each of cloxacillin sodium BPCRS, dicloxacillin sodium BPCRS the equivalent amount of ampicillin and the quantity of
oe
%
c
and flucloxacillin sodium BPCRS in phosphate buffer pH 7.0. Flucloxacillin Magnesium Octahydrate is stated in terms of
.
an.
After removal of the plate, allow it to dry in air, expose to the equivalent amount of flucloxacillin.
Le
.
iodine vapour until the spots appear and examine in daylight.

rn)
The label states that the preparation contains a penicillin.

eet
;

tat
eeu4 Pi Tab
an
with the lowerRf value corresponds to the principal spot in

Dot

with the higher Rf value corresponds to the principal spot in
va
the chromatogram obtained with solution (2). The test is not

.
OS
ybetity et,
«
valid unless the chromatogram obtained with solution (4)

>
shows three clearly separated principal spots.

TR
ye
BE :
IWI-400 Colchicine Preparations 2016
(4) Dissolve 5 mg of colchicine for system suitability EPCRS in

Colchicine Tablets 5 mL.
Colchicine Tablets contain Colchicine.
The tablets comply with the requirements stated under Tablets and with octylsilyl silica gel for chromatography (5m) (Lichrosorb
with the following requirements. RP8 is suitable).
Content of colchicine, C,,H,;NO, (b) Use gradient elution and the mobile phase described
95.0 to 105.0% of the stated amount. below.
IDENTIFICATION (c) Use a flow rate of 1 mL per minute.
A. Extract a quantity of the powdered tablets containing (d) Use an ambient column temperature.
through 4: m nylon filter and dilute 10 mL of the filtrate
to 100 r ‘pet anol (50%). The light absorption,
MOBILE PHASE |
maxima, at Mobile phase A water.
Mobile phase B_ methanol.
that of the principal peal n hromatogram obtained with conditions the retention time relative to colchicine (retention
solution (2). time about 13 minutes) are: impurity A, about 0.9.
TESTS
Dissolution Time Mobile phase A Mobile phase B Comment
Comply with the dissolution test for (Minutes) (% viv) (% viv)
Appendix XII Bl. 0-12 52 48 isocratic
TEST CONDITIONS 12-25 52-20 48-80 linear gradient
(a) Use Apparatus 2, rotating the paddle at 7 25-30 20 80 isocratic

per minute. 30-32 20-52 8048 linear gradient
(b) Use 500 mL of a pH 6.8 buffer prepared by mixing 32-38 52 48 re-equilibration
3.52 g of sodium dihydrogen orthophosphate monohydrate ‘ind
4.35 g of disodium hydrogen orthophosphate dihydrate with
YSTEM SUITABILITY
sufficient water to produce 1000 mL, at a temperature of 3
as the medium. testis not valid unless, in the chromatogram obtained
n (4), the resolution between impurity A and
PROCEDURE

Appendix III D, using the following solutions protected from ge tam obtained with
solution (1):
light.
(1) After 45 minutes withdraw a 10—mL sample of the k gotresponding to impurity A is not
medium and filter. Use the filtered medium, diluted with the ae area of the principal peak in the
dissolution medium if necessary, to produce a solution
expected to contain 0.0001% w/v of colchicine. peak is not greater than the
(2) 0.0001% w/v of colchicine BPCRS in the dissolution area of the principal pe: omatogram obtained with
medium. solution (2) (1%);
vrtore CHROMATOGRAPHIC CONDITIONS

substances may be used. Inject 50 wL of each solution and
use a detection wavelength of 243 nm.
principal peak in the chromatogram obtaineé
DETERMINATION OF CONTENT (3) (0.1%).
Calculate the total content of colchicine, C,,H»;NOg¢, in the Uniformity of content
medium from the chromatograms obtained and using the Tablets containing less than 2 mg and/or less than
declared content of C,H ,5NOg, in colchicine BPCRS. of Colchicine comply with the requirements stated under
LIMITS Tablets using the following method of analysis. Carry out the
The amount of colchicine released is not less than 75% (Q) method for liquid chromatography, Appendix III D, using the
of the stated amount. following solutions in methanol (50%) protected from light.
Related substances (1) Transfer 1 tablet to a 5 mL volumetric flask. Add about
Carry out the method for liquid chromatography, 4 mL, extract with the aid of ultrasound, dilute to volume
Appendix III D, using the following solutions in methanol and filter through a 0.2-m membrane filter.
(50%) protected from light. (2) 0.01% w/v of colchicine BPCRS.
(1) Extract a quantity of the powdered tablets containing (3) Dissolve 5 mg of colchicine for system suitability EPCRS in
5.0 mg of Colchicine in 40 mL with the aid of ultrasound, 5 mL.
dilute to 50 mL and filter through a 0.2-um membrane filter. CHROMATOGRAPHIC CONDITIONS
(2) Dilute 1 volume of solution (1) to 100 volumes. The chromatographic conditions described under Related
(3) Dilute 1 volume of solution (2) to 10 volumes. substances may be used.
Nae as Soe RO eed ha te
2016 Colecalciferol Preparations III-401
SYSTEM SUITABILITY When calciferol injection is prescribed or demanded,

The test is not valid unless, in the chromatogram obtained Colecalciferol Injection or Ergocalciferol Injection shall be
wea
with solution (3), the resolution between impurity A and dispensed or supplied.
Na!
aL ay1
awes
colchicine is at least 1.5.
Calculate the content of C,2.H»5;NO,¢ in each tablet using the

declared content of C.,H»5NOg¢ in colchicine BPCRS. Colecalciferol Tablets
ASSAY
Action and use
Use the average of the 10 results obtained in the test for
Vitamin D analogue (Vitamin D3).
Uniformity of content.
DEFINITION
awe x
ete ited by the requirements of this Colecalciferol Tablets contain Colecalciferol.
Lwesy
e those listed under Colchicine. The tablets comply with the requirements stated under Tablets and
one
Colchicine Tabl d be protected from light. Content of colecalciferol, C,,H,,0

an
‘ -

an
.
:
IDENTIFICATION
:
.
t 2
yet
A. In the test for Uniformity of content, the chromatogram

ae
Colecalciferol Injecti
et tsee

roe
ro

Geos
aoe,
Action and use obtained with solution (2).

Se
or fee
Vitamin D analogue (Vitamin D3). B. Extract one tablet, in powder, with 5 mL of ethanol-free
sow
chloroform, filter and to 1 mL of the filtrate add 9 mL of

. Le
DEFINITION antimony trichloride solution. A brownish red colour is

‘
we
Colecalciferol Injection is a sterile solution congaini produced.

0.75% w/v of Colecalciferol in Ethyl Oleate. &
TESTS
The injection complies with the requirements stated underé Uniformity of content
Parenteral Preparations and with the following requiremen Tablets containing less than 2 mg and/or less than 2% w/w
Content of colecalciferol, C,,H,,0 ecalciferol comply with the requirements stated under
0.67 to 0.83% wiv.
CHARACTERISTICS
A pale yellow, oily liquid.
IDENTIFICATION
To 1 mL of a 0.2% v/v solution of the injection in ethanol- slowing manner. Add 4 mL of water to one
free chloroform add 9 mL of antimony trichloride solution. The “flask and disperse with the aid of
light absorption of the resulting solution, Appendix IT B,
exhibits a maximum at 500 nm. with 100 mL of nth
ASSAY the hexane layer and
Carry out the following procedure in subdued light. Dilute For tablets containin
0.1 g of the injection to 50 mL with dry 1,2-dichloroethane procedure but using 2 m
that has been purified by passing it through a column of silica and 25 mL of hexane.
gel. To 1 mL of this solution add rapidly 9 mL of antimony
trichloride in dichloroethane solution and measure the absorbance
of the solution at 500 and 550 nm, Appendix II B, 90 to
120 seconds after adding the reagent. Repeat the operation phase; heat under a reflux condenser in a y
using | mL of a 0.002% w/v solution of colecalciferol BPCRS for 45 minutes and cool.
in the dry, purified 1,2-dichloroethane, beginning at the
words ‘add rapidly 9 mL of ...’. Calculate the result of the
assay from the difference between the absorbances at 500 (a) Use a stainless steel column (20 cm x 4.6 mm) packed
and 550 nm and using the declared content of Cz7H4,O in with silica gel for chromatography (5 um) (Partisil is suitable).
colecalciferol BPCRS. Calculate the percentage w/v of (b) Use isocratic elution and the mobile phase described
colecalciferol taking 0.87 g as the value of the weight per mL below.
of the injection. (c) Use a flow rate of 2 mL per minute.
STORAGE (d) Use an ambient column temperature.
Colecalciferol injection should be protected from light. (e) Use a detection wavelength of 254 nm.
LABELLING (f) Inject 20 wL of each solution.
The label states (1) that the preparation is for intramuscular MOBILE PHASE
use only; (2) the equivalent number of IU (units) of 8 volumes of pentan-1-ol and 992 volumes of hexane.
antirachitic activity (vitamin D) in 1 mL.
When the chromatogram is recorded under the prescribed
te 4
Each pg of Colecalciferol is equivalent to 40 IU of conditions, approximate retention times relative to
er hd

Bm es
IW-402 Colestipol Preparations 2016
colecalciferol are 0.4 for precolecalciferol and 0.5 for trans- To prepare the sample, mix 1 part of n-etcosane and 4 parts
tN ee
colecalciferol. of the granules and grind the mixture in a mortar with
chloroform until the preparation being examined is uniformly
2 Ne A
SYSTEM SUITABILITY
coated with the v-eicosane. Prepare the standard in the same
1 we Nw

manner but adding 4 parts of colestipol hydrochloride BPCRS
in place of the preparation being examined. Load the sample
corresponding to precolecalciferol and trans-colecalciferol is at
and the standard separately into the pyrolysis unit.
least 1.0. If necessary, adjust the proportions of the
constituents and the flow rate of the mobile phase to obtain The chromatographic procedure may be carried out using a
this resolution. glass column (1.8 m x 3 mm) packed with acid-washed,
silanised diatomaceous support (80 to 100 mesh) (Chromosorb
DETERMINATION OF CONTENT W is suitable) coated with 0.25% w/w of potassium hydroxide
-we ad
and 5% w/w of polyethylene glycol 20,000 (Carbowax 20M is
anead
ete Net
suitable) maintained at about 85° with the detector at about
270°. The pyrolysis unit is capable of attaining a temperature
of about 1000° when fitted with a platinum ribbon probe and
using helium as the carrier gas with a flow rate of 60 mL per
re if necessary. To a quantity of minute. Operate the unit in accordance with the
manufacturer’s instructions to obtain a pyrogram for colestipol
hydrochloride BPCRS that is similar to that supplied with the
under a reflux condenser reference material.
ly;.add 110 mL of water The pyrogram obtained with the substance being examined is
concordant with that obtained with colestipol
Cool and add sufficient ethanol'(9 hydrochloride BPCRS.
aN 4
Shake 5 mL with 25 mL of petroleum « TESTS

to 60°) for 3 minutes and evaporate dup Acidity or alkalinity
Shake a suspension containing 10% w/w of colestipol
hydrochloride in a stoppered vial at approximately 10-minute
intervals for 1 hour, and centrifuge. Transfer a portion of the
clear supernatant liquid to a suitable container and record
120 seconds after adding the reagent, Appendix II B. 4 the pH as soon as the reading has stabilised. The pH is
the operation using duplicate 1 mL portions of a solutio 5.3 to 7.5,» Appendix VL.
containing a known amount of colecalciferol BPCRS in
ethanol-free chloroform and beginning at the words ‘add rapidly
‘with the test for Uniformity of weight for
9 mL of antimony tnchloride solution ...’. Subtract the
granules described under Granules.
absorbance at 550 nm from that at 500 nm and calculate the
content of colecalciferol in mg from the average value so
obtained and from the amount of colecalciferol in the
reference solution using the declared content of C27H4,O in
colecalciferol BPCRS.
LABELLING
colestipol hydrochl ¢
The label states the equivalent number of IU (units) of
80 g of water. Cover
antirachitic activity (vitamin D) per tablet.
suspension to equilibra fours. Filter the resulting
Each pg of Colecalciferol is equivalent to 40 IU of ity fritted-glass funnel
we Nate
ee Nee
slurry through a medium-p
antirachitic activity (vitamin D). ressure of 2 kPa;
When calciferol tablets are prescribed or demanded, ‘ner, disconnecting
Tete ON
Colecalciferol Tablets or Ergocalciferol Tablets shall be elast portion of
the test.
Colestipol Granules Cholate binding capacity
en we
et tee Action and use A quantity of the granules containing 1 g of colestipol
vaeen
Stele ete
Lipid-regulating drug. hydrochloride binds not less than 1.1 mEq and not more
than 1.6 mEq of sodium cholate, determined by the
2a as
award
DEFINITION following method. Prepare a solution containing 1.0% w/v of

Colestipol Granules contain Colestipol Hydrochloride with or sodium cholate and 0.9% w/v of sodium chloride in water
without suitable excipients. containing 1.8% v/v of 1M sodium hydroxide (solution A).
The granules comply with the requirements stated under Granules Carry out the method for liguid chromatography,
and with the following requirements. Appendix III D, using the following solutions. For solution
(1) dilute 1 volume of solution A with 1 volume of the
IDENTIFICATION mobile phase. For solution (2) transfer a quantity of the
wer aed
Carry out the method for gas chromatography, granules containing 1 g of colestipol hydrochloride to a
‘Awan
Appendix III B, using a suitable gas chromatograph fitted ground-glass-stoppered flask, add 100 mL of solution A and
with a pyrolysis unit.
PAE aN
shake vigorously for 90 minutes with the flask positioned

awh ee
ye ee
. Pew wot be
Te Ee Ts te he ect eae
ered
~ ened
2016 Colistimethate Preparations III-403
horizontally. Remove the flask from the shaker, allow the of 2 mL per minute and (c) a detection wavelength of
Ne A
contents to settle for 5 minutes and filter through a 0.45-um 254 nm.
eed
filter, discarding the first 5 mL of filtrate. Dilute 1 volume of Inject separately 20 wL of each solution. In the
the filtrate with 1 volume of the mobile phase. Solution (3) chromatogram obtained with solution (1) the area of any
contains 0.45% w/v of cholic acid BPCRS in a solution peak corresponding to styrene is not greater than the area of
prepared by mixing equal volumes of acetonitrile containing the principal peak in the chromatogram obtained with
2 mL per litre of orthophosphoric acid and water. solution (2) (1 ppm).
ASSAY
Prepare a solution of sodium glycocholate by dissolving 1.5 g in
end-capped octylsilyl silica gel for chromatography (5 mm)
40 mL of hot water, cooling and diluting to 50 mL with
(Zorbax C8 is suitable), (b) as the mobile phase with a flow
water (solution A). To a quantity of the powder containing
mL per minute a mixture of a solution containing
the equivalent of about 0.1 g of anhydrous colestyramine add
25 mL of water and shake for 15 minutes. Centrifuge and
carefully decant and discard the liquid layer. Repeat the
procedure with a further 25 mL of water. Dry the washed
residue at 100° for 2 hours. To the residue add 10 mL of
Inject 20 uL of solution A, shake mechanically for 2 hours and then
due to cholic ac minutes. From the chromato- centrifuge (solution B). Prepare solution C in the same
“exact concentration of sodium manner using 0.11 g of colestyramine BPCRS, beginning at
the words ‘add 10.0 mL of solution A...’. Dilute, separately,
declared content of cholic a¢ 2 mL of solution A, 2 mL of solution B and 2 mL of
taking each g of cholic acid t solution C to 200 mL with water. To 1 mL of each solution
sodium cholate. The cholate in separate 10 mL graduated flasks add 4 mL of sulfuric acid
determined by the expression: (80%). Loosely stopper the flasks and heat at 60° for
(x — y) x 0.2325 15 minutes, cool and dilute to volume with sulfuric acid
concentration of sodium cholate in solutiof (80%). Allow the solutions to stand for 1 hour. Measure the
concentration of sodium cholate in solution (2 absorbance of each solution at the maximum at about
318 nm, Appendix II B, using water in the reference cell.
Calculate the quantity of colestyramine in the powder using
the following expression:
Colestyramine Oral Powder M(A, ~ A, WW;

Action and use 2(A; — A3)W>
Lipid-regulating drug.
DEFINITION stated value, in g, of sodium glycocholate

Colestyramine Oral Powder contains Colestyramine with
suitable excipients.
The oral powder complies with the requirements stated under Oral
Powders and with the following requirements.
Content of anhydrous colestyramine being examined,
85.0 to 115.0% of the stated amount. = average weight of content of sachet.
IDENTIFICATION LABELLING »
To a quantity of the powder containing the equivalent of The quantity of the active ingredient is.
0.5 g of anhydrous colestyramine add 100 mL of equivalent amount of anhydrous ciiélesg
0.1m hydrochloric acid, stir and heat on a water bath for
10 minutes. Filter, wash the residue with three 50 mL
quantities of water and dry at 70° at a pressure not exceeding
7 kPa for 16 hours. The infrared absorption spectrum of the
dried residue, Appendix II A, is concordant with the reference Colistimethate Injection
eee ed
spectrum of colestyramine (RS 369).
Action and use
TESTS Antibacterial.
Styrene
Carry out the method for liquid chromatography, DEFINITION
Appendix III D, using the following solutions. For solution Colistimethate Injection is a sterile solution of Colistimethate
(1) shake a quantity of the powder containing the equivalent Sodium in Sodium Chloride Infusion. It is prepared by
of 2 g of anhydrous colestyramine with 10 mL of acetone for dissolving Colistimethate Sodium for Injection in the
30 minutes, centrifuge and use the supernatant liquid. requisite amount of Sodium Chloride Infusion.
Solution (2) contains 0.00002% w/v of styrene in acetone. The injection complies with the requirements stated under
The chromatographic procedure may be carried out using Parenteral Preparations.
STORAGE
end-capped octadecylsilyl silica gel for chromatography (10 wm)
(uBondapak C18 is suitable), (b) a mixture of equal volumes Colistimethate Injection should be used immediately after
of acetonitrile and water as the mobile phase with a flow rate preparation but, in any case, within the period recommended
IlI-404 Colistimethate Preparations 2016
by the manufacturer when prepared and stored strictly in TESTS

accordance with the manufacturer’s instructions. Acidity or alkalinity
aN AY
Dissolve a quantity in sufficient carbon dioxide-free water to
COLISTIMETHATE SODIUM FOR produce a solution containing 125,000 IU per mL. The pH
anual
we yee
of the resulting solution, measured 30 minutes after

INJECTION preparation, is 6.5 to 8.5, Appendix V L.
DEFINITION Free colistin
Colistimethate Sodium for Injection is a sterile material Dissolve a quantity containing 1,000,000 IU in 3 mL of
consisting of Colistimethate Sodium with or without water, add 0.1 mL of a 10% w/v solution of sthcotungstic acid
excipients. It is supplied in a sealed container. and allow to stand for 10 to 20 seconds. The resulting
The contents of the sealed container comply with the requirements solution is not more opalescent than reference suspension II,
fer Injections or Infusions stated under Parenteral Appendix IV A.
eaves
ate we
Loss on drying
Fm as
When dried over phosphorus pentoxide at 60° at a pressure not
exceeding 0.7 kPa for 3 hours, lose not more than 5.0% of
Appendix III A their weight. Use 1 g.
solutions in water. © Bacterial endotoxins
Carry out the test for bacterial endotoxins, Appendix XIV C,
mixture of equal volume using method D. Dissolve the contents of the sealed
at 135° in a sealed tube for ‘ container in water BET to give a solution containing
250,000 IU per mL (solution A). The endotoxin limit
concentration of solution A is 43.75 IU of endotoxin per mL.
0.5 mL of water.
rae ey
ASSAY
(2) 0.2% w/v of leucine. Determine the weight of the contents of 10 containers as
(3) 0.2% w/v of threonine. described in the test for uniformity of weight,
(4) 0.2% w/v of phenylalanine. Appendix XII C1, Powders for Parenteral Administration.
(5) 0.2% w/v of serine. Mix the contents of the 10 containers and carry out the
microbiological assay of antibiotics, Appendix XIV A.
The precision of the assay is such that the fiducial limits of
(a) Use as the coating silica gel G. rror are not less than 95% and not more than 105% of the
(c) Apply 5 uL of each solution, as 10-mm bands.
(d) Place the plate in the chromatographic tank so that it is
not in contact with the mobile phase. Allow the plate to
become impregnated with the vapour of the solvent for at
least 12 hours and develop over a path of 12 cm using the
same mobile phase.
(e) After removal of the plate, dry at 100° to 105°, spray with The label of the ea
ninhydrin solution RI and heat at 110° for 5 minutes. of IU (units) conta
MOBILE PHASE
25 parts of water and 75 parts of phenol.

Me ene
CONFIRMATION
The chromatogram obtained with solution (1) shows zones
corresponding to those in the chromatograms obtained with
solutions (2) and (3) but shows no zones corresponding to
Nebuliser Solution
those in the chromatograms obtained with solutions (4) and Colistimethate Nebuliser Solution
(5). The chromatogram obtained with solution (1) also
Action and use
shows a zone with a very low Rf value (2,4-diaminobutyric
Antibacterial.
acid).
B. Dissolve a quantity containing 125,000 IU in 5 mL of DEFINITION
ear en
water. Heat 0.5 mL of the solution with 0.5 mL of Colistimethate Sodium Powder for Nebuliser Solution
aww vo
chromotropic acid—sulfuric acid solution at 100° for 30 minutes. consists of Colistimethate Sodium with or without excipients.
A purple colour is produced (distinction from colistin It is supplied in a sealed container.
sulfate).
C. Dissolve a quantity containing 625,000 IU in 1 mL of stated under Preparations for Inhalation and with following
1m hydrochloric acid and add 0.5 mL of 0.01M todine. requirements.
The colour is discharged (distinction from colistin sulfate)
and the resulting solution yields reaction A characteristic of IDENTIFICATION
sulfates, Appendix VI. A. Carry out the method for thin-layer chromatography,
Appendix III A, protected from light, using the following
D. Yield reaction B characteristic of sodium salts,
solutions in water.
woe es
Appendix VI.
+e wa
(1) Dissolve a quantity containing 62,500 IU in 1 mL of a
mixture of equal volumes of hydrochloric acid and water, heat
viata ee
are
ca awe
oe 2016 Colistin Preparations TI-405
at 135° in a sealed tube for 5 hours, evaporate to dryness on error are not less than 95% and not more than 105% of the
a water-bath, continue the heating until any residual estimated potency.
hydrochloric acid has evaporated and dissolve the residue in The upper fiducial limit of error is not less than 95.0% and
0.5 mL of water. the lower fiducial limit of error is not more than 115.0% of
(2) 0.2% w/v of leucine. the stated number of IU.
(3) 0.2% w/v of threonine. STORAGE
(4) 0.2% w/v of phenylalanine. The sealed container should be protected from light.
(5) 0.2% w/v of serine. LABELLING
CHROMATOGRAPHIC CONDITIONS The label of the sealed container states the total number
(a) Use as the coating silica gel. of IU (units) contained in it.
obile phase as described below.
seach solution, as 10-mm bands.
Colistin Tablets
Action and use
same mobile phase. Antibacterial.
(e) After removal of the" at 100° to 105°, spray with DEFINITION

ninhydrin solution R1 and | O° for 5 minutes.
Colistin Tablets contain Colistin Sulfate.
MOBILE PHASE
25 parts of water and 75 pa with the following requirements
CONFIRMATION IDENTIFICATION
To a quantity of the powdered tablets containing 200,000 IU
add 10 mL of water, shake and filter. Use the filtrate for the
following tests. :
(5). The chromatogram obtained with solution (1) al Appendix III A, protected from light using the following
shows a zone with a very lowRf value (2,4-diaminobuty solutions.
acid).
dd 0.5 mL of hydrochloric acid to 0.5 mL of the filtrate,
B. Dissolve a quantity containing 125,000 IU in 5 mL of "a sealed tube at 135° for 5 hours, evaporate to
water. Heat 0.5 mL of the solution with 0.5 mL of a water bath, continue to heat until any residual
chromotropic acid—sulfuric acid solution at 100° for 30 minutes. hloride has been removed, dissolve the residue in
A purple colour is produced (distinction from colistin Li of.eater and centrifuge, if necessary.
sulfate).
C. Dissolve a quantity containing 625,000 [U in 1 mL of
1m hydrochloric acid and add 0.5 mL of 0.01M iodine.
The colour is discharged (distinction from colistin sulfate) (4) 0.25% wiv of
and the resulting solution yields reaction A characteristic of (5) 0.25% wiv of
sulfates, Appendix VI.
D. Yield reaction B characteristic of sodium salts,
Appendix VI.
TESTS
Dissolve a quantity in sufficient carbon dioxide-free water to
produce a solution containing 125,000 IU per mL. The pH (d) After exposure of the plate to the mobi
of the resulting solution, measured 30 minutes after for at least 12 hours, develop to 12 cm.
preparation, is 6.5 to 8.5, Appendix V L.
(e) Remove the plate, heat it at 100° to 105°, spe
Free colistin ninhydrin solution R1 and heat at 110° for 5 minutes.
Dissolve a quantity containing 1,000,000 IU in 3 mL of
MOBILE PHASE
water, add 0.1 mL of a 10% w/v solution of szlicotungstic acid
and allow to stand for 10 to 20 seconds. The resulting 25 volumes of water and 75 volumes of phenol.
solution is not more opalescent than reference suspension II, CONFIRMATION
Appendix IV A. The bands in the chromatogram obtained with solution (1)
Loss on drying correspond to those in the chromatograms obtained with
When dried over phosphorus pentoxide at 60° at a pressure not solutions (2) and (3) and do not correspond to those in the
exceeding 0.7 kPa for 3 hours, lose not more than 5.0% of chromatograms obtained with solutions (4) and (5).
their weight. Use 1 g. The chromatogram obtained with solution (1) also shows a
band with a very low Rf value (2,4-diaminobutanoic acid).
ASSAY
Mix the contents of 10 containers and carry out the B. Heat 0.5 mL of the filtrate with 0.5 mL of chromotropic
microbiological assay of antibiotics, Appendix XIV A. acid-sulfuric acid solution at 100° for 30 minutes. No purple
The precision of the assay is such that the fiducial limits of colour is produced (distinction from colistin sulfomethate).
ay . 2 Tap a
tet es ee ee ee a a a ee ee eee a
ae ee Re EA
II-406 Collodion 2016
C. The filtrate yields reaction A characteristic of sulfates, the sum of the contents of polymyxin El, polymyxin E2,
Appendix VI. polymyxin E3, polymyxin E1-I and polymyxin E1-7MOA is
ne ava
Anwss!
Composition not less than 77.0%.
Carry out the method for liguid chromatography, Related substances
Appendix III D, using the following solutions. Carry out the method for liquid chromatography,
(1) Shake a quantity of the powdered tablets containing Appendix III D, using the following solutions.
500,000 IU with 40 mL of water for 20 minutes, add (1) Shake a quantity of the powdered tablets containing
sufficient acetonitrile to produce 50 mL and filter through a 500,000 IU with 40 mL of water for 20 minutes, add
Whatman GF/C filter and then though a 0.45-um nylon sufficient acetonitrile to produce 50 mL and filter through a
filter. Whatman GF/C filter and then though a 0.45-um nylon
(2) Dissolve 25 mg of colistin sulfate EPCRS in 40 mL of filter.
water and ad. sufficient acetonitrile to produce 50 mL. (2) Dissolve 25 mg of colistin sulfate EPCRS in 40 mL of
CHROMA\ HTC CONDITIONS water and add sufficient acetonitrile to produce 50 mL. Dilute
(a) Use a stain el column (15 cm x 4.6 mm) packed
mixture of 20 volumes of acetonitrile and 80 volumes of water.
with end-cappeg déeylsilyl silica gel for chromatography
(3.5 um) (SunFire Cl d Symmetry C18 are suitable). CHROMATOGRAPHIC CONDITIONS
(b) Use isocratic e mobile phase described The chromatographic conditions described under
below. @ Composition may be used.
(c) Use a flow rate of 1 m “LIMITS
(d) Use a column temperatureof 30°" In the chromatogram obtained with solution (1):
(e) Use a detection wavelength: the area of any secondary peak is not greater than 4.0% by
eA ead
(f) Inject 20 uL of each solution. <¢ normalisation;

(g) For solution (1) allow the chromatog: to: roceed for the sum of the areas of all secondary peaks is not greater than
1.5 times the retention time of polymyxin 23.0% by normalisation.
MOBILE PHASE
peak due to polymyxin E1 in the chromatogram obtained
22 volumes of acetonitrile and 78 volumes of a solutién
with solution (2) (1%) and any peaks due to polymyxins El,
prepared by dissolving 4.46 g of anhydrous sodium sulfate i
E2, E3, El-I and El1-7MOA.
900 mL of water, adjusting the pH to 2.4 with dilute
orthophosphoric acid and adding sufficient water to produce
1000 mL. d powder 20 tablets. Dissolve a suitable quantity of
Use the chromatogram supplied with colstin sulfate EPCRS to rin phosphate buffer pH 6.0 and carry out the
identify the peaks due to polymyxins El, E2, E3, El-I and cal assay of antibiotics, Appendix XIV A.
E1-7MOA. n of the assay is such that the fiducial limits of
conditions the retention time of polymyxin E]1 is about
16 minutes. The retention times relative to polymyxin El
are: polymyxin E2, about 0.45; polymyxin E3, about 0.5;
polymyxin E1-I, about 0.8; polymyxin E1-7MOA, about 1.1. STORAGE
Colistin Tablets shoul
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained LABELLING

with solution (2): The strength is stated as t aber of TU (units) in each
the resolution factor between the peaks due to polymyxins E2 tablet.
and El is at least 8.0;
the resolution factor between the peaks due to polymyxins E2
and E1-I is at least 6.0;
the resolution factor between the peaks due to polymyxins E1-I Flexible Collodion
and E] is at least 2.5;
the resolution factor between the peaks due to polymyxins El Action and use
and E1l-7MOA is at least 1.5. Skin protective.
avasd
we
DETERMINATION OF CONTENT DEFINITION
Calculate the content of polymyxin E3, polymyxin E1-I and Flexible Collodion is a solution of Colophony in a mixture of
A Ae
tN eae
polymyxin E1-7MOA and the sum of the contents of Virgin Castor Oil and Collodion.
polymyxins El, E2, E3, E1-I and E1-7MOA using the Extemporaneous preparation
declared contents of polymyxins E1, E2, E3, El-I and The following formula and directions apply.
E1-7MOA in colistin sulfate EPCRS. Colophony 25g
LIMITS Virgin Castor Oil 25 g
The content of polymyxin E1-I is not more than 10.0%; Collodion Sufficient to produce 1000 mL
the content of polymyxin E1-7MOA is not more than 10.0%; Mix the ingredients and stir until the colophony has
yw ae]
the content of polymyxin E3 is not more than 10.0%; dissolved; allow any deposit to settle and decant the clear
raw A
liquid.
sae
2016 Co-magaldrox Preparations III-407
Flexible collodion complies with the requirements stated under In making Collodion the ethanol (90 per cent) may be replaced by
Liquids for Cutaneous Application and with the following industrial methylated spirit diluted so as to be of equivalent
requirements. alcoholic strength, provided that the law and the statutory
regulations governing the use of industrial methylated spirit are
teu as IDENTIFICATION
observed.
A. Expose a thin layer to the air. A thin, tenacious film is left
which, when ignited, burns rapidly with a yellow flame. CHARACTERISTICS 7
B. Mix with an equal volume of water. A white, viscid, A clear, viscid, colourless or pale straw-coloured liquid.
stringy mass is obtained. TESTS
Ethanol content Weight per mL
20 to 23% when determined by the following method. 0.785 to 0.795 g, Appendix V G.
Carry out the method for gas chromatography, Appendix TI B Kinematic viscosity
using th: ing solutions in ether. 405 to 700 mm? s”, when determined using afalling sphere
viscometer complying with British Standard 188: 1977
(internal Stasi (Methods for. the determination of viscosity of liquids). Fill
(2) 20% viv & J the fall tube with the collodion to about 10 mm above the
220 mm mark, place vertically in the bath and allow to stand
(3) 20% v/vofthe su
for air bubbles to clear and for temperature equilibrium to be
the internal standai
attained. Clean the sphere, immerse it.in a portion of the
CHROMATOGRAPHIC liquid being examined maintained at a temperature of 19.9°
(a) Use a glass column (1% to 20.1° and when it is at this temperature introduce it,
polymer beads (100 to 120 without wiping, into the delivery tube, Observe the time for
(b) Use nitrogen as the carriersgas per minute. the lowest part of the sphere to pass through the planes of
the tops of the 175-mm mark and the 25-mm mark, using a
(c) Use isothermal conditions mainta 120°.
telescope or other suitable device to avoid errors due to
(d) Use a flame ionisation detector. parallax. The average of three readings concordant to within
(e) Inject 1 wL of each solution. 0.5% is taken as the time of fall. Calculate the kinematic
DETERMINATION OF CONTENT viscosity (v) in square millimetres per second (mm? s") from
the expression:
Calculate the content of C;H,O from the areas ofthe,
due to ethanol and acetonitrile in the chromatogram
20 8 .
obtained with solution (1) and solution (3).
For preparations in which industrial methylated spinit has bee
y=8
£ 0-2) 9867
O.18ep 7
used, determine the content of ethanol as described above.
Determine the concentration of methanol in the following the diameter of the sphere in cm,
manner. Carry out the chromatographic procedure described density of the sphere in g cm”,
above but using the following solutions. density of the collodion being
(1) 0.25% viv of methanol and 0.25% viv of acetonitrile xamined in g cm”,
(anternal standard). “velocity ofthe fall in cms”,
(2) Dilute a volume of the preparation being examined with ocal acceleration due to gravity in cm
ether to contain between 0.2% and 0.3% v/v of methanol.
(3) Prepare in the same manner as solution (2) but adding When Collodion is pi ed or demanded, Flexible
sufficient of the internal standard to producea final Collodion shall be dispi upplied.
concentration of 0.25% v/v.
LIMIT
The sum of the contents of ethanol and methanol is 20 to
23% v/v and the ratio of the content of methanol to that of Co-magaldrox Oral Susp
ethanol is commensurate with industrial methylated spirit Magnesium Hydroxide and Aluminiu Oral
having been used. Suspension — |
Action and use
COLLODION FOR THE PREPARATION OF
Antacid.
FLEXIBLE COLLODION
Collodion is a solution of Pyroxylin in a mixture of Ether and Co-magaldrox Oral Suspension is a suspension containing
Ethanol (90 per cent). Magnesium Hydroxide and Dried Aluminium Hydroxide in a
suitable flavoured vehicle. The amount of dried aluminium
PRODUCTION hydroxide is adjusted to give the required content of Al,O3.
It may be prepared by adding 100 g of pyroxylin to 900 mL
of a mixture of 3 volumes of solvent ether and 1 volume of
ethanol (90 per cent) and agitating continuously until
dissolved. The viscosity of the resulting solution is Content of magnesium hydroxide, Mg(OH)>,
determined and the solution is diluted with the solvent 90.0 to 110.0% of the stated amount.
mixture until 1t complies with the requirement for kinematic Content of Al,O3
viscosity. 45.4 to 58.8% of the stated amount of dried aluminium
hydroxide.
SIDR ye ‘
Be ee
ty ty “ope bo ee . noe wo r
fe a ee a a me
IlI-408 Co-magaldrox Preparations 2016
IDENTIFICATION For magnesium hydroxide

A. Mix 5 mL with 10 mL of 2m hydrochloric acid, add To a volume of the solution reserved in the Assay for Al,O;
we Ne 4
5 drops of methyl red solution and heat to boiling. containing about 40 mg of magnesium hydroxide add
we Nw
Add 6M ammonia until the solution becomes yellow, continue 200 mL of water and 20 mL of triethanolamine and stir.
boiling for 2 minutes and filter. To 1 mL of the filtrate add Add 10 mL of ammonia buffer pH 10.9 and cool the solution
1 mL of 6M ammonia and 1 mL of 2M ammonium chloride; to between 3° and 4° by immersion in iced water. Titrate the
no precipitate is produced. Add 0.25m disodium hydrogen cooled solution with 0.05m disodium edetate VS using mordant
orthophosphate; a white, crystalline precipitate is produced black 11 solution as indicator. Each mL of 0.05m disodium
which is insoluble in 6M ammonia. | edetate VS 1s equivalent to 2.916 mg of Mg(OH),. Using the
B. To 5 mL add 10 mL of 2m hydrochloric acid. The solution weight per mL of the suspension, calculate the percentage
yields the reaction characteristic of aluminium salts, content of Mg(OH),, weight in volume.
Appendix, VI. STORAGE
Co-magaldrox Oral Suspension should not be allowed to
freeze.
20 mL of 3m hydrochloric acid with

ary and add sufficient water to
Co-magaldrox Tablets
Magnesium Hydroxide and Aluminium Hydroxide Tablets
Action and use

Antacid.
DEFINITION
Co-magaldrox Tablets contain Magnesium Hydroxide and
Dried Aluminium Hydroxide. The amount of Dried
Aluminium Hydroxide is adjusted to give the required
content of Al,O3.
‘add sufficient water to produce 40 mL ...’ (standard
solution). The colour of the standard solution is not as
intense as that of a solution prepared at the same time and entent of magnesium hydroxide, Mg(OH),
the same manner but using a mixture of 25 mL of solution A 110.0% of the stated amount.
and 2 mL of lead standard solution (20 ppm Pb) adjusted to a
pH between 3.0 and 4.0 using either 1M acetic acid or
6M ammonia and beginning at the words ‘add sufficient water
to produce 40 mL ...’.
Microbial contamination
Carry out a quantitative evaluation for enterobacteria and
certain other Gram-negative bacteria, Appendix XVI B1.
0.01 mL of the preparation gives a negative result, Table I
(most probable number of bacteria per gram fewer than 10°).
ASSAY 2M ammonium chloride;
For ALO3 sodium hydrogen
To a weighed quantity containing 1.5 g of dried aluminium
hydroxide add 20 mL of water, stir and slowly add 10 mL of
hydrochloric acid. Heat gently, if necessary, to aid solution,
cool, filter, wash the filter well with water, dilute the
combined filtrate and washings to 200 mL with water and
mix. Reserve a portion of the solution for the Assay for characteristic of aluminium salts, Appendix VI.
magnesium hydroxide. To 10 mL add 20 mL of water and, ASSAY
with continuous stirring, 25 mL of 0.05m disodium edetate VS
For ALO3
followed by 20 mL of a mixture of equal volumes of
Weigh and powder 20 tablets. To a quantity of the powdered
ene a
2M ammonium acetate and 2M acetic acid. Heat near the
tablets containing 1.5 g of dried aluminium hydroxide add
boiling point for 5 minutes, cool, add 50 mL of absolute
ee
20 mL of water, stir and slowly add 30 mL of 3m hydrochloric

ethanol and 3 mL of a freshly prepared 0.025% w/v solution
acid. Heat gently, if necessary, to aid solution, cool, filter,
of dithizone in absolute ethanol. Titrate the excess of disodium
wash the filter well with water, dilute the combined filtrate
edetate with 0.05m zinc sulfate VS until the colour of the
and washings to 200 mL with water and mix. Reserve a
solution changes from greenish blue to reddish violet. Each
portion of the solution for the Assay for magnestum
hydroxide. To 10 mL add 20 mL of water and, with
Al,O3. Determine the weight per mL of the suspension,
continuous stirring, 25 mL of 0.05m disodium edetate VS
Appendix V G, and calculate the percentage content of
followed by 20 mL of a mixture of equal volumes of
Al,O3, weight in volume.
2M ammonium acetate and 2M acetic acid. Heat near the
boiling point for 5 minutes, cool, add 50 mL of absolute
ethanol and 3 mL of a freshly prepared 0.025% w/v solution
pot ore
he
oe Ea DEA
noe
al SE CUR
Ee SL ALG
:
ee OROIE ee
SEO OONLRi
POLO OO OL
LEP EL
ee eeOER
FIA OI IE PO
OLEToe NL
PD he EP
OE Cat AVye En
IR FR
OLE
tt
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2016 Co-proxamol Preparations III-409
of dithizone in absolute ethanol. 'Titrate the excess of disod1um TEST CONDITIONS

edetate with 0.05m zinc sulfate VS until the colour of the (a) Use Apparatus 2, rotating the paddle at 50 revolutions
solution changes from greenish blue to reddish violet. Each per minute.
TA aN
mL of 0.05m disodium edetate VS is equivalent to 2.549 mg of (b) Use 900 mL of phosphate buffer pH 5.8, at a temperature
Al,O3. of 37°, as the medium.
For magnesium hydroxide PROCEDURE
To a volume of the solution reserved in the Assay for Al,O,
After 45 minutes withdraw a 20 mL sample of the medium
containing about 40 mg of magnesium hydroxide add
and filter. Dilute the filtrate with 0.1M sodium hydroxide, if
200 mL of water and 20 mL of triethanolamine and stir.
necessary, to give a solution expected to contain about
Add 10 mL of ammonia buffer pH 10.9 and cool the solution
0.00075% w/v of Paracetamol. Measure the absorbance of this
to between 3° and 4° *y immersion in iced water._Titrate the
solution, Appendix II B, at the maximum at 257 nm using
0.1m sodium hydroxide in the reference cell.
Calculate the total content of paracetamol, CgH »NOz, in the
medium taking 715 as the value of A(1%, 1 cm) at the
maximum at 257 nm.
Co-proxame 4-Aminophenol
Dextropropoxyphene oct eride and Paracetamol Tablets
NOTE: Co-proxamol Tablets ently licensed 1n the United
Kingdom. :
Action and use
Opioid analgesic + analgesic; antipyret (2) 0.001% w/v of 4-aminophenol in the mobile phase.
DEFINITION
Co-proxamol Tablets contain Dextropropoxyy <
Hydrochloride and Paracetamol in the proportiog
weight, 1 part to 10 parts.
The tablets comply with the requirements stated under Table
below.
requirements stated under Unlicensed Medicines and with th
following requirements. Use a flow rate of 2 mL per minute.
an ambient column temperature.
Content of dextropropoxyphene hydrochloride,
C,2H,.NO,,HCl detection wavelength of 272 nm.
95.0 to 105.0% of the stated amount. ) wL of each solution.
Content of paracetamol, C3;H,NO,
IDENTIFICATION
A. Shake a quantity of the powdered tablets containing 0.1 g
of Dextropropoxyphene Hydrochloride with 20 mL of
0.1M hydrochloric acid for 5 minutes and filter. To the filtrate
add 5 mL of 2m sodium hydroxide, extract with two 25-mL
quantities of dichloromethane, wash the combined extracts
with 10 mL of water, shake with anhydrous sodium sulfate,
filter and evaporate the filtrate to dryness. Dissolve the Peaks with a long retention time cur due to
residue in 2 mL of dichloromethane and add 50 uL, drop wise, excipients.
onto the surface of a disc prepared from about 0.3 g of Related substances
potassium bromide, allowing the solvent to evaporate between
applications; dry the disc at 50° for 2 minutes. The infrared
absorption spectrum of the resulting thin film, Appendix II A, ntaining
is concordant with the reference spectrum of 25 mg of Dextropropoxyphene Hydrochloride with 5 mL of
dextropropoxyphene (RS 091). acetonitrile for 2 minutes, add 5 mL of water, shake for a
B. Shake a quantity of the powdered tablets containing further 5 minutes, dilute to 25 mL with water, mix and filter
0.325 g of Paracetamol with 10 mL of acetone for 5 minutes, (Whatman GF’F filter paper is suitable).
filter and evaporate the filtrate to dryness. The infrared (2) 0.0005% w/v of 4-dimethylamino-3-methyl-1,2-
absorption spectrum of the residue, Appendix II A, is diphenylbutan-2-ol hydrochloride BPCRS and 0.0005% w/v of
concordant with the reference spectrum of paracetamol (1S,2R)-1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl
(RS 258). acetate BPCRS in a mixture of 1 volume of acetonitrile and
TESTS 4 volumes of water.
Dissolution CHROMATOGRAPHIC CONDITIONS
Comply with the requirements for Monographs of the British (a) Use a stainless steel column (25 cm x 4.6 mm) packed
Pharmacopoeia in the dissolution test for tablets and capsules, with octadecylsilyl sthca gel for chromatography (5 um)
Appendix XII B1. (Nucleosil C18 is suitable).
er re Ro Ae ey es yn ee ae oe Be a eG Fe
wee a ts ot et a tel a ee le nate ae era
II-410 Co-proxamol Preparations 2016
(b) Use isocratic elution and the mobile phase described any secondary spot with an Rf value lower than that of
below. 4'-chloroacetanilide is not more intense than the spot in the
arvwvad (c) Use a flow rate of 2 mL per minute. chromatogram obtained with solution (3) (0.25%).
(d) Use an ambient column temperature. ASSAY
(e) Use a detection wavelength of 215 nm. Weigh and powder 20 tablets.
(f) Inject 20 wL of each solution. For dextropropoxyphene hydrochloride
MOBILE PHASE
40 volumes of acetonitrile and 60 volumes of 0.2m sodium
perchlorate, previously adjusted to pH 2.0 using (1) Disperse a quantity of the powdered tablets containing
32.5 mg of Dextropropoxyphene Hydrochloride in 100 mL
of 0.02m hydrochloric acid, mix with the aid of ultrasound for
rder of emergence, are due to
15 minutes, allow to cool, dilute to 500 mL with a mixture
se A
of equal volumes of acetonitrile and 0.02m hydrochloric acid
and filter (Whatman GF/C filter paper is suitable).
we neol
(2) 0.0065% w/v of dextropropoxyphene hydrochloride BPCRS

SYSTEM SUITABiLIT
in a mixture of 40 volumes of acetonitrile and 60 volumes of
The test is not vali 0.02m hydrochloric acid.
with solution (2), the res@iution factor between the two peaks (3) 0.0005% w/v of 4-dimethylamino-3-methyl-1,2-
is at least 1.5. * diphenylbutan-2-ol hydrochloride BPCRS and 0.0005% w/v of
LIMITS (1S, 2R) -1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl
In the chromatogram obtaine acetate BPCRS in a mixture of 1 volume of acetonitrile and
4 volumes of water.
the areas of any peaks correspor
oem ee methyl-1,2-diphenylbutan-2-ol hydroch CHROMATOGRAPHIC CONDITIONS
benzyl-3-dimethylamino-2-methyl-1-pheny (a) Use a stainless steel column (25 cm x 4.6 mm) packed
not greater than the areas of the respective p with octadecylsilyl sihca gel for chromatography (5 um)
chromatogram obtained with solution (2) (0.5% (Nucleosil C18 is suitable).
B. Carry out the method for thin-layer chromatograph : (b) Use isocratic elution and the mobile phase described
Appendix II A, using the following solutions. below.
(1) Transfer a quantity of the finely-powdered tablets c) Use a flow rate of 2 mL per minute.
containing 1.0 g of Paracetamol to a ground-glass-stoppere ' n ambient column temperature.
15 mL centrifuge tube, add 5 mL of peroxide-free ether, shake
etection wavelength of 215 nm.
for 30 minutes, centrifuge at 1000 revolutions per minute for
15 minutes or until a clear supernatant liquid is obtained and
use the supernatant liquid.
(2) Dilute 1 mL of solution (1) to 10 mL with ethanol (96%).
(3) 0.0050% w/v of 4'-chloroacetanilide in ethanol (96%).
(4) Dissolve 0.25 g of 4'-chloroacetanilide and 0.10 g of
paracetamol in sufficient ethanol (96%) to produce 100 mL.
CHROMATOGRAPHIC CONDITIONS The test is not valid ‘unless,
(a) Use as the coating silica gel F254. with solution (3), the re
is at least 1.5.
DETERMINATION OF CONT
(c) Apply 200 uL of solution (1) and 40 uL of each of
solutions (2), (3) and (4). Calculate the content of C.,H Nt |
the declared content of C22H2.NO.;HG]I 1
dextropropoxyphene hydrochloride BPCRS.
ultraviolet light (254 nm). For paracetamol
MOBILE PHASE
10 volumes of toluene, 25 volumes of acetone and 65 volumes methanol and shake. Add 300 mL of water, shake for
of chloroform. 5 minutes, allow to cool, dilute to 500 mL with water, mix
SYSTEM SUITABILITY and filter. Dilute 5 mL of the filtrate to 250 mL with
wae 4
+ bes reel
0.01mM sodium hydroxide and measure the absorbance of the
we A
Alt ate
waned
aN
solution (4) shows two clearly separated principal spots, the
Appendix II B. Calculate the content of CgH »NO, in the
spot corresponding to 4’-chloroacetanilide having the
tablets taking 715 as the value of A(1%, 1 cm) at the
higher Rf value.
maximum at 257 nm.
LIMITS
STORAGE
Co-proxamol Tablets should be protected from light.
any spot corresponding to 4’-chloroacetanilide is not more
-y AN
anv
solution (3) (0.005%).
mee
ste”oe
ww
le,
|
wan 4 al
POT I AA MOLT OE LT be ES Te EO EE i te feat
eo ee a a a a a Goes noe
aT Matton tal Ma ta tirade
* de Meeseler
Py bs a aRe ee
oe te Dk LA
ke ~ AB ths 0
Le le Baw
ta e ted ae)
the
2016 Cortisone Preparations III-411

are
Cortisone Tablets with solution (3), the resolution factor between the peaks due
Action and use to hydrocortisone acetate and cortisone acetate is at least 4.2;
if necessary, adjust the concentration of acetonitrile in the
AAS
"eee al
aA
Corticosteroid.
mobile phase.
DEFINITION LIMITS
Cortisone Tablets contain Cortisone Acetate in fine powder. In the chromatogram obtained with solution (1):
The tablets comply with the requirements stated under Tablets and the area of any secondary peak is not greater than half the area
with the following requirements. of the principal peak in the chromatogram obtained with
Content of cortisone acetate, C,3;H3,0¢ solution (2) (0.5%);
90.0 to 110.0% of the stated amount. the sum of the areas of all the secondary peaks is not greater
wae
eS
aaa
of the powdered tablets containing 0.1 g of chromatogram obtained with solution (2) (1.5%).
f e.with 5 mL of chloroform, filter and Disregard any peak with an area less than 0.05 times the area
evaporate the’chl of the principal peak in the chromatogram obtained with
following tests. solution (2) (0.05%).
Dissolution
Use the same method Appendix XII B1.
at fer the tablet extract.
TEST CONDITIONS
Prepare potassium bromide dis¢s.
vee
B. Complies with the test for zdentif
per minute.
Appendix III A, using impregnating sol mobile
phase B. | (b) Use 900 mL of a 0.3% w/v solution of sodium dodecyl
TESTS
PROCEDURE
Related substances
Carry out the method for liguid chromatography, (1) After 45 minutes withdraw a 10 mL sample of the
Appendix III D, using the following solutions prepared: medium and measure the absorbance of the filtered sample at
immediately before use. the maximum at 242 nm, Appendix II B using a 0.3% w/v
tion of sodium dodecyl sulfate in the reference cell.
(1) Mix a quantity of the powdered tablets containing 25 m
of Cortisone Acetate with 10 mL of the mobile phase, place sure the absorbance of a 0.0028% w/v solution of
in an ultrasonic bath for 10 minutes and filter (Whatman etate BPCRS using a 0.3% w/v solution of sodium
GF/C filter is suitable). ate in the reference cell.
(2) Dilute 1 volume of solution (1) to 100 volumes with the N OF CONTENT
mobile phase. ral gontent of C23H3 0,, in the medium

(3) 0.002% w/v each of cortisone acetate BPCRS and aces obtained and using the declared
hydrocortisone acetate BPCRS in the mobile phase. content of C4 . 65 In cortisone acetate BPCRS.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed Weigh and powder 2 arry out the method for
with octadecylsilyl silica gel for chromatography (5 um) (Hypersil = IlD, using the follo
wing
yee
ODS is suitable).
(b) Use isocratic elution and the mobile phase described 1 anol containing
below. 0.02% w/v each of cortisone aceta tR&.and prednisolone to
100 mL with water.
(g) Continue the chromatography for twice the retention time CHROMATOGRAPHIC CONDITIONS
of the principal peak.
tree
Neer
MOBILE PHASE with end-capped octadecylsilyl silica gel for chromatography
(5 um) (Hypersil ODS is suitable).
wenn
(Aree
Mix 400 mL of acetonitrile with 550 mL of water, allow to
equilibrate and adjust the volume to 1000 mL with water. (b) Use isocratic elution and the mobile phase described
SYSTEM SUITABILITY below.
Equilibrate the column with the mobile phase at a flow rate (c) Use a flow rate of 1.5 mL per minute.
of 1 mL per minute for about 30 minutes. (d) Use an ambient column temperature.
Inject solution (3). When the chromatograms are recorded in (e) Use a detection wavelength of 240 nm.
the prescribed conditions the retention times are: (f) Inject 20 wL of each solution.
hydrocortisone acetate, about 10 minutes and cortisone
MOBILE PHASE
acetate, about 12 minutes.
wae
II-412 Co-tenidone Preparations 2016
SYSTEM SUITABILITY through a suitable filter (Whatman No 1 is suitable) and use

The Assay is not valid unless, in the chromatogram obtained the filtrate.
with solution (1), the resolution factor between the peaks due (2) Dilute 1 volume of solution (1) to 200 volumes with the
rate A
aN
rane A
to cortisone acetate and prednisolone is at least 5.0. mobile phase.

etek he
DETERMINATION OF CONTENT (3) Dissolve 50 mg of atenolol impurity standard BPCRS in

Calculate the content of C.3H3 0, in the tablets using the 0.1 mL of dimethyl sulfoxide, with the aid of gentle heat, and
declared content of C,3H3 90¢ in cortisone acetate BPCRS. dilute to 100 mL with the mobile phase.
(4) 0.002% w/v of 2-(4-chloro-3-sulfamoylbenzoyl) benzoic
STORAGE
acid BPCRS in the mobile phase.
Cortisone Tablets should be protected from light.
vm ee al
eee
tw Ae
Co-tenidone Tablets (b) Use isocratic elution and the mobile phase described
below.
the proportions, by weight, 4 par | MOBILE PHASE

a ateN te
arend
The tablets comply with the requirements Staite 20 volumes of tetrahydrofuran, 180 volumes of methanol and
with the following requirements. : 800 volumes of 0.025m potassium dihydrogen orthophosphate
containing 1.0 g of sodium octanesulfonate and 0.4 g of
Content of atenolol, C;,H,.N,03
tetrabutylammonium hydrogen sulfate per litre and adjusted to
Content of chlortalidone, C,,H,,;CIN,O.,S
SYSTEM SUITABILITY
IDENTIFICATION olution (3) closely resembles the reference chromatogram
A. Carry out the method for thin-layer chromatography, ied with atenolol impurity standard BPCRS and the peaks
Appendix III A, using the following solutions. responding to tertiary amine, which is usually a doublet,
(1) Remove any film coating from the tablets, powder and ether are clearly separated. If necessary, adjust the
shake a quantity of the powdered tablets containing 0.1 g of itien of sodium octanesulfonate in the mobile phase;
atenolol with 10 mL of methanol for 15 minutes and filter.
(2) 1.0% w/v of atenolol BPCRS in methanol.
(3) 0.25% w/v of chlortalidone BPCRS in methanol.

eee snd
erewad
we wed

examine under wiltraviolet light (254 nm). chromatogram obtained with solutio
MOBILE PHASE reference to the content of atenolol);
30 volumes of 18M ammonia and 150 volumes of butan-1-ol. ‘“z amine or
cipal
CONFIRMATION
peak in the chromatogram obtained with solution (2.
In the chromatogram obtained with solution (1) the two (0.25%, with reference to the content of atenolol).*
principal spots correspond in position, size and intensity to
Weve
those of the principal spots in the chromatograms obtained ASSAY

tA aS
ee ete with solutions (2) and (3). Weigh 20 tablets, remove the film coating and powder. Carry
out the method for liquid chromatography, Appendix III D,
B. In the Assay, the retention times of the two principal
we ee

correspond to those of the principal peaks in the (1) Extract a quantity of the powder containing 0.1 g of
chromatograms obtained with solutions (2) and (3). atenolol with 70 mL of the mobile phase by shaking with the
aid of ultrasound for 30 minutes, allow to cool, add sufficient
Related substances
of the mobile phase to produce 100 mL, filter and use the
filtrate.
(2) 0.1% w/v of atenolol BPCRS in the mobile phase.
(1) Remove any film coating from the tablets, powder and
shake a quantity of the powder containing 0.1 g of atenolol (3) 0.025% w/v of chlortahdone BPCRS in the mobile phase.
(and 0.025 g of chlortalidone) with 25 mL of the mobile
phase for 30 minutes with the aid of ultrasound. Filter
aw aw
2016 Co-triamterzide Preparations IIJ-413
CHROMATOGRAPHIC CONDITIONS substance. Apply separately to the plate, as 1.5-cm bands,

(a) Use a stainless steel column (20 cm x 4.6 mm) packed two 10-uL applications of each of the following four freshly
with end-capped octadecylsilyl silica gel for chromatography prepared solutions. For solution (1) shake a quantity of the
(5 um) (Nucleosil C18 is suitable). powdered tablets containing 0.10 g of triamterene with
(b) Use isocratic elution and the mobile phase described 10 mL of anhydrous formic acid for 5 minutes, centrifuge and
below. use the clear supernatant liquid. For solution (2) dissolve
5 mg of 5-nitroso-2,4,6-triaminopyrimidine EPCRS in 50 mL
of anhydrous formic acid and dilute 1 volume of the solution
(d) Use ambient column temperature. to 10 volumes with the same solvent. Prepare solution (3) in
(e) Use a detection wavelength of 275 nm. the same manner as solution (1) but shaking with 10 mL of
(f) Inject 20 wL of each solution. solution (2) in place of the formic acid. For solution (4)
dissolve 5 mg of hydrochlorothiazide BPCRS in 1 mL of
acetone.
Develop over a path of 5 cm using ether as the mobile phase,

remove the plate, allow it to dry in air and develop over a
path of 10 cm using a 0.05% w/v solution offluorescein
sodium in a mixture of 10 volumes of glacial acetic acid,
10 volumes of methanol and 80 volumes of ethyl acetate as the
Calculate the content: mobile phase. After removal of the plate, dry it in a current
C,4H,,CIN2O,S usin of air, expose to ammonia vapour for a few seconds and
examine under ultraviolet hght (254 and 365 nm). Any band
corresponding to 5-nitroso-2,4,6-triaminopyrimidine in the
When atenolol and chlorthaliio chromatogram obtained with solution (1).is not more intense
demanded, Co-tenidone Tablets shall"be dispensed or than the band in the chromatogram obtained with solution
supplied. | (2) (0.1%). The test is not valid unless, in the chromatogram
obtained with solution (3), a band corresponding to the band
due to hydrochlorothiazide (obtained with solution (4)),
appears above, and is clearly separated from, the band due to
5-nitroso-2,4,6-triaminopyrimidine.
Co-triamterzide Tablets Related substances
Triamterene and Hydrochlorothiazide Tablets A. Carry out the method for thin-layer chromatography,
sndix III A, using sidica gel G as the coating substance
Action and use
mixture of 10 volumes of 18m ammonia, 10 volumes of
and 90 volumes of ethyl acetate as the mobile phase.
DEFINITION parately to the plate 5 uL of each of the following
Co-triamterzide Tablets contain Triamterene and
Hydrochlorothiazide in the proportions, by weight, 2 parts to
1 part.
Content of triamterene, C,,H,,N,
95.0 to 105.0% of the stated amount. sufficient methanol to p (00 mL. After removal of the
Content of hydrochlorothiazide, C;H,CIN3;0,S, plate, allow it to dry in ai i the solvent has evaporated
95.0 to 105.0% of the stated amount. ‘light (365 nm). Any secondary
IDENTIFICATION
A. Shake a quantity of the powdered tablets containing
with solution (2) (0.5%, with referen
50 mg of hydrochlorothiazide with 25 mL of acetone, filter,
triamterene).
evaporate the filtrate to dryness and dry the residue at 100°
for 1 hour. The infrared absorption spectrum of the dried
residue, Appendix II A, is concordant with the reference Appendix III A, using silica gel G as the coating su
spectrum of hydrochlorothiazide (RS 178).
and a mixture of 15 volumes of propan-2-ol and 85 volumes
of ethyl acetate as the mobile phase. Apply separately to the
B. In test A for Related substances, the principal spot in the
plate 5 uL of each of the following solutions. For solution (1)
vigorously shake a quantity of the powdered tablets
containing 50 mg of hydrochlorothiazide with 50 mL of
C. In the Assay, the two principal peaks in the acetone, filter, evaporate the filtrate to dryness and dissolve
chromatogram obtained with solution (3) have the same the residue in 10 mL of acetone. For solution (2) dilute
retention times as the peak due to triamterene in the 1 volume of solution (1) to 100 volumes with acetone. After
chromatogram obtained with solution (1) and as the peak removal of the plate, dry it in a current of air and reveal the
due to hydrochlorothiazide in the chromatogram obtained spots by Method I. Any secondary spot in the chromatogram
with solution (2). obtained with solution (1) is not more intense than the spot
TESTS in the chromatogram obtained with solution (2) (1%, with
5-Nitroso-2,4,6-triaminopyrimidine reference to the content of hydrochlorothiazide). Disregard
Carry out the method for thin-layer chromatography, any spot close to the line of application.
Appendix III A, using silica gel HF 254 as the coating
IlI-414 Co-trimoxazole Preparations 2016
ASSAY The concentrate complies with the requirements for Concentrates

anew arnd
Weigh and powder 20 tablets. Carry out the method for for Injections or Infusions stated under Parenteral Preparations
liquid chromatography, Appendix III D, using the following and with the following requirements.
solutions. For solution (1) add 25 mL of acetomitrile and Content of trimethoprim, C,,H,;N,03
4 mL of glacial acetic acid to a quantity of the powdered 92.5 to 107.5% of the stated amount of trimethoprim.
tablets containing 25 mg of hydrochlorothiazide, mtx,
Content of sulfamethoxazole, C,jH,,N3;0;3S
immediately add 20 mL of water, shake for 15 minutes,
92.5 to 107.5% of the stated amount of sulfamethoxazole
dilute to 100 mL with water and filter through glass-fibre
paper (Whatman GF/A is suitable). Dilute 10 mL of the CHARACTERISTICS
filtrate to 100 mL with water. For solution (2) dissolve 50 mg A colourless or slightly yellow solution.
of triamterene BPCRS in 25 mL of acetonitrile, add 4 mL of
IDENTIFICATION
glacial acetic acid and immediately add sufficient water to
yN eae
we wea
A. Add drop wise to 75 mL of 0.1m hydrochloric acid a
volume of the sterile concentrate containing 0.8 g of
olve 25 mg of hydrochlorothiazide BPCRS
rane
Sulfamethoxazole, stirring continuously. Allow the suspension

le, add 4 mL of glacial acetic acid and
to stand for 5 minutes and filter through a sintered-glass
filter. Wash the residue with 10 mL of water, recrystallise
from ethanol (96%) and dry at 105°. Dissolve the residue in
The chromatographt lure may be carried out using the minimum volume of a 5% w/v solution of sodium
(a) a stainless steel coluf carbonate, add 1m hydrochloric acid drop wise until
end-capped octadecylsilyl silié precipitation is complete, filter, wash the residue sparingly
(uBondapak C18 is suitable} with water and dry at 105°. The infrared absorption spectrum of
methanol, 18 volumes of aceto the residue, Appendix II A, is concordant with the reference
re 0.5% w/v solution of ammoniuni che spectrum of sulfamethoxazole (RS 327).
0.01m sodium perchlorate as the mobiles
B. To a volume containing 80 mg of Trimethoprim add
of 2.0 mL per minute and (c) a detection
30 mL of 0.1m sodium hydroxide and extract with two 50 mL
273 nm.
quantities of chloroform. Wash the combined extracts with two
Calculate the content of C,,H,,N,7 and C7Het 10 mL quantities of 0.1m sodium hydroxide and then with
using the declared contents of C,H,,N7 and 10 mL of water, shake with 5 g of anhydrous sodium sulfate,
C7HgCIN30,S8, in triamterene BPCRS and filter and evaporate the filtrate to dryness using a rotary
hydrochlorothiazide BPCRS respectively. evaporator. The infrared absorption spectrum of the residue,
STORAGE ppendix II A, is concordant with the reference spectrum of
Co-triamterzide Tablets should be protected from moisture. fimetheprim (RS 354).
ut the method for thin-layer chromatography,
III A, using the following solutions.
e to dryness a volume of the sterile concentrate
of Sulfamethoxazole, shake the residue
Co-trimoxazole Infusion
Co-trimoxazole Intravenous Infusion; Trimethoprim and
Sulfamethoxazole Infusion; Trimethoprim and
Sulfamethoxazole Intravenous Infusion
Action and use

Dihydrofolate reductase inhibitor + sulfonamide antibacterial.
we eels
DEFINITION (c) Apply 5 wL of each solution ,

Co-trimoxazole Infusion is a sterile solution containing (d) Develop the plate to 15 cm. |
Trimethoprim and the sodium derivative of (e) After removal of the plate, dry 1
Sulfamethoxazole. It is prepared by diluting Sterile potassium todobismuthate solution.
Co-trimoxazole Concentrate with a suitable diluent in
MOBILE PHASE
5 volumes of dimethylformamide, 10 volumes of‘me
The infusion complies with the requirements stated under
100 volumes of chloroform. }
CONFIRMATION
fal
or es
via
STERILE CO-TRIMOXAZOLE One of the principal spots in the chromatogram obtained
oe
with solution (1) corresponds to the spot in the
see
ie ale Y
CONCENTRATE
ota
wt he nT
chromatogram obtained with solution (2) and the other

~
a ead
DEFINITION corresponds to that in the chromatogram obtained with

Sterile Co-trimoxazole Concentrate is a sterile solution of solution (3).
Trimethoprim and sulfamethoxazole sodium, prepared by the
TESTS
interaction of Sulfamethoxazole and Sodium Hydroxide, in
Alkalinity
the proportion 1 part to 5 parts, in Water for Injections
containing 40 to 45% v/v of Propylene Glycol.
Dilute the sterile concentrate with water BET to give a
ae ~
Py AN
“te,
solution containing 1 mg of Trimethoprim and 5 mg of

ava es
ee we
ne ay
woe
a te
Ne ast 2016 Co-trimoxazole Preparations III-415
Sulfamethoxazole [6 mg of co-trimoxazole] per mL (solution (1) Add 20 mL of methanol to 5 mL of the oral suspension,
A). The endotoxin limit concentration of solution A is 0.5 IU mix, shake with 10 g of anhydrous sodium sulfate, centrifuge
eaviasl per mL. and use the supernatant liquid.
ev awa
ASSAY (2) 2.0% w/v of sulfamethoxazole BPCRS in methanol.
For trimethoprim (3) 0.4% w/v of trimethoprim BPCRS in methanol.
To a volume of the sterile concentrate containing 48 mg of CHROMATOGRAPHIC CONDITIONS
Trimethoprim add 30 mL of 0.1m sodium hydroxide and
extract with four 50 mL quantities of chloroform, washing
each extract with the same two 10 mL quantities of (b) Use the mobile phase as described below.
0.1m sodium hydroxide. Combine the chloroform extracts, (c) Apply 5 wL of each solution.
extract with four 50 mL quantities of 1M acetic acid, wash the (d) Develop the plate to 15 cm.
xtracts with 5 mL of chloroform and dilute the (e) After removal of the plate, dry in air, spray with dilute
potassium 1odobismuthate solution.
ees oMe
on add 10 mL of 1M acetic acid and
MOBILE PHASE
oduce 100 mL and measure the
absorbance of ting solution at the maximum at 5 volumes of dimethylformamide, 10 volumes of methanol and
271 nm, Appen 100 volumes of chloroform.
CONFIRMATION
One of the principal spots in the chromatogram obtained
with solution (1) corresponds in position and colour to that
To a volume of the steril in the chromatogram obtained with solution (2) and the
Sulfamethoxazole add 60 m other corresponds in position and colour to that in the
hydrochloric acid. Add 3 g of ; chromatogram obtained with solution (3).
TESTS
Acidity
0.1m sodium nitrite VS is equivalent to 25.
C19H,,N303S.
ASSAY
STORAGE > é
For trimethoprim
Sterile Co-trimoxazole Concentrate should be protegfed from
Extract the chloroform solution reserved in the Assay for
light.
sulfamethoxazole with four 50 mL quantities of 1m acetic
ash the combined extracts with 5 mL of chloroform
te the aqueous extracts to 250 mL with 1M acetic
10 mL of this solution add 10 mL of 1M acetic acid
Co-trimoxazole Oral Suspension ent water to produce 100 mL and measure the
f.the resulting solution at the maximum at
‘Trimethoprim and Sulfamethoxazole Oral Suspension
Action and use 204 as the value of A(1%, 1 cm) at the

Dihydrofolate reductase inhibitor + sulfonamide antibacterial. Using the weight per mL of the oral
e content of C,,H)3N,03, weight in
DEFINITION
Co-trimoxazole Oral Suspension is a suspension containing
1.6% w/v of Trimethoprim and 8.0% w/v of
Sulfamethoxazole in a suitable flavoured vehicle. hydroxide, shake and extractwith four 50 mL quantities of
The oral suspension complies with the requirements stated under chloroform, washing each extraet wit
Oral Liquids and with the following requirements. quantities of 0.1m sodium hydroxi
Content of trimethoprim, C,4,H;3N,03 chloroform extracts for the Assay
1.44 to 1.76% ww. the combined aqueous solution and wash
with water, filter and dilute 5 mL of the .
Content of sulfamethoxazole, C;)9H,,N3;03S with water (solution A). Carry out the followingpro
7.40 to 8.60% wwv. protected from light using 2 mL of solution A. Aéid 0.
IDENTIFICATION of 4m hydrochloric acid and 1 mL of a 0.1% w/v solution of
A. To a quantity containing 50 mg of Trimethoprim add sodium nitrite and allow to stand for 2 minutes. Add 1 mL of
30 mL of 0.1m sodium hydroxide and extract with four 50 mL a 0.5% w/v solution of ammonium sulfamate and allow to
quantities of chloroform. Wash the combined extracts with two stand for 3 minutes. Add 1 mL of a 0.1% w/v solution of
10-mL quantities of 0.1m sodium hydroxide and extract with N-(1-naphthyl)ethylenediamine dihydrochloride and allow to
two 50 mL quantities of chloroform. Wash the combined stand for 10 minutes. Dilute the resulting solution to 25 mL
chloroform extracts with two 10 mL quantities of with water and measure the absorbance at 538 nm,
0.1M sodium hydroxide and then with 10 mL of water. Shake Appendix II B, using in the reference cell a solution prepared
with 5 g of anhydrous sodium sulfate, filter and evaporate to in the same manner but using 2 mL of water in place of
dryness using a rotary evaporator. The infrared absorption solution A. Dissolve 0.25 g of sulfamethoxazole BPCRS in
spectrum of the residue, Appendix II A, is concordant with 50 mL of 0.1m sodium hydroxide and dilute to 250 mL with
eae eT
set
LOY Ee
the reference spectrum of trimethoprim (RS 354). water. Dilute 5 mL of the resulting solution to 200 mL with
B. Carry out the method for thin-layer chromatography, water (solution B). Repeat the procedure using 2 mL of
TOG
Appendix III A, using the following solutions. solution B and beginning at the words ‘Add 0.5 mL of ...’.
ey
af
IlI-416 Co-trimoxazole Preparations 2016
Calculate the content of C;)H,,;N303S from the values of The tablets comply with the requirements stated under Tablets and
the absorbances obtained using the declared content of with the following requirements.
an ant
C19H,,;N303S in sulfamethoxazole BPC-RS. Determine the Content of trimethoprim, C,,H)3;N,03
weight per mL of the oral suspension, Appendix V G, and 92.5 to 107.5% of the stated amount of trimethoprim.
calculate the content of C;>H,;N303S, weight in volume.
Content of sulfamethoxazole, C;9H,,N30;3S
STORAGE 92.5 to 107.5% of the stated amount of sulfamethoxazole.
Co-trimoxazole Oral Suspension should be protected from
IDENTIFICATION
light and stored at a temperature not exceeding 30°.
A. Filter the aqueous layer reserved in the Assay for
Co-trimoxazole Oral Suspension contains, in 5 mL, 80 mg of
trimethoprim. Add, drop wise, sufficient 2m hydrochloric acid
Trimethoprim and 400 mg of Sulfamethoxazole.
to the filtrate to make it just acidic and extract with 50 mL
of ether. Wash the ether layer with 10 mL of water, shake
with 5 g of anhydrous sodium sulfate, filter and evaporate the
filtrate to dryness using a rotary evaporator. Dissolve the
‘trimoxazole Oral
Sete fy
residue in the minimum volume of a 5% w/v solution of

sodium carbonate, add 1M hydrochloric acid drop wise until
Paediatric Trimeth. nd Sulfamethoxazole Oral precipitation is complete and filter. Wash the residue
Suspension sparingly with water and dry at 105°. The infrared absorption
spectrum of the residue, Appendix IT A, is concordant with
Action and use the reference spectrum of sulfamethoxazole (RS 327).
Dihydrofolate reductase inh ulfonamide antibacterial.
B. To a quantity of the powdered tablets containing 50 mg
DEFINITION & of Trimethoprim add 30 mL of 0.1M sodium hydroxide and
extract with two 50 mL quantities of chloroform. Wash the
teen Paediatric Co-trimoxazole Oral a suspension
combined chloroform extracts with two 10-mL quantities of
containing 0.8% w/v of Trimethoprimeind 4% w/v of
0.1m sodium hydroxide and then with 10 mL of water. Shake
Sulfamethoxazole in a suitable flavoured 3
with 5 g of anhydrous sodium sulfate, filter and evaporate to
The oral suspension complies with the requirem dryness using a rotary evaporator. The infrared absorption
Oral Liquids and with the following requirements spectrum of the residue, Appendix II A, is concordant with
Content of trimethoprim, C,,H;sN,03 the reference spectrum of trimethoprim (RS 354).
0.72 to 0.88% w/v. C. Carry out the method for thin-layer chromatography,
Content of sulfamethoxazole, C;)9H,,;N3;03S Appendix III A, using the following solutions.
3.60 to 4.40% w/v.
IDENTIFICATION
Complies with the tests described under Co-trimoxazole Oral
Suspension but in test B for solution (2) use a 1.0% wiv
solution of sulfamethoxazole BPCRS in methanol and for
solution (3) use a 0.20% w/v solution of trimethoprim BPCRS
in methanol. Apply to the plate 10 wL of each of the three
solutions.
Acidity
pH, 5.0 to 6.5, Appendix V L. (d) Develop the plate t 1
ASSAY (e) After removal ofth in air and spray with dilute
Swen el
Carry out the Assays for trimethoprim and sulfamethoxazole potassium todobismuthate solution
MOBILE PHASE
yeaa
ol
described under Co-trimoxazole Oral Suspension but using

8 g of the oral suspension. 5 volumes of dimethylformamide, 10:volur of methanol and
100 volumes of chloroform. om of
STORAGE
Paediatric Co-trimoxazole Oral Suspension should be CONFIRMATION
protected from light and stored at a temperature not One of the principal spots in the chromatogr
exceeding 30°. with solution (1) corresponds to the spot in the
Paediatric Co-trimoxazole Oral Suspension contains, in chromatogram obtained with solution (2) and the*other
5 mL, 40 mg of Trimethoprim and 200 mg of corresponds to the spot in the chromatogram obtained with
Sulfamethoxazole. solution (3).
eae
ASSAY
Co-trimoxazole Tablets For trimethoprim
Trimethoprim and Sulfamethoxazole Tablets To a quantity of the powder containing 50 mg of
Action and use extract with four 50-mL quantities of chloroform, washing
Dihydrofolate reductase inhibitor + sulfonamide antibacterial. each extract with the same two 10-mL quantities of
0.1m sodium hydroxide. Reserve the aqueous layer for test A
DEFINITION for Identification. Combine the chloroform extracts and
Co-trimoxazole Tablets contain Trimethoprim and extract with four 50-mL quantities of 1M acetic acid. Wash
Sulfamethoxazole in the proportions, by weight, 1 part to 5
Ayan J
wn we 4
we Ne
a, ae
“Awe 4
the combined extracts with 5 mL of chloroform and dilute the
Pet wd
ee eed
re Ne NN parts.
yew awe
2016 Co-trimoxazole Preparations III-417
aqueous extracts to 250 mL with 1M acetic acid. To 10 mL of 20 mL of methanol and filter. Solution (2) contains 2.0% w/v
the solution add 10 mL of 1M acetic acid and sufficient water of sulfamethoxazole BPCRS in methanol. Solution (3) contains
LN ANS
to produce 100 mL and measure the absorbance of the 0.4% w/v of trimethoprim BPCRS in methanol. After removal
NAA
resulting solution at the maximum at 271 nm, of the plate, allow it to dry in air and spray with dilute
Appendix IT B. Calculate the content of C,;4H,3N,03 taking potassium todobismuthate solution. One of the principal spots in
204 as the value of A(1%, 1 cm) at the maximum at the chromatogram obtained with solution (1) corresponds to
271 nm. the spot in the chromatogram obtained with solution (2) and
For sulfamethoxazole the other corresponds to the spot in the chromatogram
Dissolve, as completely as possible, a quantity of the powder obtained with solution (3).
containing 0.5 g of Sulfamethoxazole in 60 mL of water and Disintegration
10 mL of hydrochloric acid. Add 3 g of potasstum bromide, cool The tablets disintegrate within 2 minutes when examined by
the disintegration test for tablets and capsules, Appendix XII Al,
but using water at 19° to 21°.
ASSAY
ten a

For trimethoprim
To a quantity of the powder containing 50 mg of
extract with four 50 mL quantities of chloroform, washing
eo ad
Dispersible Trimethoprim: each extract with the same two 10 mL quantities of
0.1m sodium hydroxide. Reserve the aqueous layer for test A
Action and use é for Identification. Combine the chloroform extracts and
Dihydrofolate reductase inhibito extract with four 50 mL quantities of 1m acetic acid. Wash
the combined extracts with four 5 mL quantities of chloroform
DEFINITION and dilute the aqueous extracts to 250 mL with 1M acetic
acid. To 10 mL of the solution add 10 mL of 1m acetic acid
and sufficient water to produce 100 mL and measure the
dispersible basis. 271 nm, Appendix II B. Calculate the content of
The tablets comply with the requirements stated under Table C,4H,3N,403 taking 204 as the value of A(1%, 1 cm) at the
with the following requirements. maximum at 271 nm.
Content of trimethoprim, C,,H,;N,O3 ifamethoxazole
92.5 to 107.5% of the stated amount of trimethoprim. as completely as possible, a quantity of the powder
Content of sulfamethoxazole, C;>H,,N303S ¢ 0.5 g of Sulfamethoxazole in 60 mL of water and
92.5 to 107.5% of the stated amount of sulfamethoxazole. “ydrochloric acid. Add 3 g of potassium bromide, cool
‘titrate slowly with 0.1m sodium nitrite VS, stirring
IDENTIFICATION
A. Filter the aqueous layer reserved in the Assay for Each mL 'M gedium nitrite VS is equivalent to 25.33 mg
trimethoprim. Add, drop wise, sufficient 2m hydrochloric acid of C)oH),N30,
to the filtrate to make it just acidic and extract with 50 mL
of ether. Wash the ether layer with 10 mL of water, shake
with 5 g of anhydrous sodium sulfate, filter and evaporate the
filtrate to dryness using a rotary evaporator. Dissolve the zole Table
Paediatric Co-trimox ts
wate
residue in the minimum volume of a 5% w/v solution of

sodium carbonate, add 1m hydrochloric acid drop wise until Paediatric Trimethoprim and Sul oxazole Tablets
precipitation is complete and filter. Wash the residue
sparingly with water and dry at 105°. The infrared absorption Action and use
spectrum of the residue, Appendix II A, is concordant with Dihydrofolate reductase inhibitor + su
the reference spectrum of sulfamethoxazole (RS 327).
DEFINITION
B. To a quantity of the powdered tablets containing 50 mg
of trimethoprim add 30 mL of 0.1m sodium hydroxide and
Trimethoprim and 100 mg of Sulfamethoxazole.
extract with two 50 mL quantities of chloroform. Wash the
combined chloroform extracts with two 10 mL quantities of The tablets comply with the requirements stated under Tablets and
0.1m sodium hydroxide and then with 10 mL of water. Shake with the following requirements.
with 5 g of anhydrous sodium sulfate, filter and evaporate to Content of trimethoprim, C,,H,;N,03
dryness using a rotary evaporator. The infrared absorption 0.0185 to 0.0215 g.
Content of sulfamethoxazole, C,)9H,,N3;0;3S
the reference spectrum of trimethoprim (RS 354).
0.0925 to 0.1075 g.
C. Carry out the method for thin-layer chromatography,
IDENTIFICATION
Appendix III A, using silica gel G as the coating substance
and a mixture of 100 volumes of chloroform, 10 volumes of Comply with the tests described under Co-trimoxazole
methanol and 5 volumes of dimethylformamide as the mobile Tablets.
phase. Apply separately to the plate 5 wL of each of the ASSAY
eee
~~ at
teeta
roe ee
following solutions. For solution (1) shake a quantity of the Carry out the Assays for trimethoprim and for
powdered tablets containing 0.4 g of Sulfamethoxazole with sulfamethoxazole described under Co-trimoxazole Tablets.
Te Ne a ST A tn
eal BT TG
IiI-418 Crotamiton Preparations 2016
SYSTEM SUITABILITY
Crotamiton Cream
wt. verte
Action and use

Acaricide. corresponding to the H-isomer and to crotamiton impurity A
is at least 4.5.
DEFINITION LIMITS
Crotamiton Cream contains Crotamiton in a suitable basis.
the area of any peak corresponding to crotamiton impurity A
Content of crotamiton, C,;,;H,;,NO chromatogram obtained with solution (4) (3%);
93.0 to 107.0% of the stated amount. the sum of the areas of any secondary peaks apart from any
peaks corresponding to the Z-isomer and to crotamiton
iw a
f the cream containing 0.5 g of impurity A is not greater than the sum of the areas of the
mL of water and then slowly add 50 mL peaks corresponding to the E- and Z-isomers in the
odium chloride, dry the solution (5) (0.02%) and any peak with the same retention
organic layer over anhydre sulfate, filter and time as the principal peak in the chromatogram obtained
evaporate to an oily residue: ht absorption, with solution (7).
350:nm_ of a 0.003% w/v Z-Isomer
ibits a maximum Not more than 15% of the total content of E- and Z-isomers
|
only at 242 nm. The A(1%, 1 cm) at aximum is about determined in the Assay.
315, . ASSAY
B. Carry out the method for thin-layer chrom
Appendix III A, using the following solutions Appendix III D, using the following solutions.
ethanol.
(1) 0.25% w/v of the residue obtained in test A. (1) Add 2 mL of water and 100 mL of cyclohexane to a
quantity of the preparation being examined containing 0.1 g
(2) 0.25% w/v of crotamiton BPCRS.
of Crotamiton, shake for 10 minutes and separate the lower,
(3) A mixture of equal volumes of solutions (1) and (2). us layer. Repeat the extraction using two 10 mL

cyclohexane.
(5) Dilute 1 volum ion (1) to 100 volumes with
MOBILE PHASE
cyclohexane.
Shake 98 volumes of chloroform with 2 volumes of ‘%.w/v solution of crotamiton
18m ammonia, dry over anhydrous sodium sulfate, filter and
impurity A EPCRS to 10 v
mix 97 volumes of the filtrate with 3 volumes of propan-2-ol.
eR ea
wie ne 4
(7) 0.001% w/v of methyl hy
CONFIRMATION
(a) Use a stainless steel column (25°¢ mmm) packed
with silica gel for chromatography (5 um) ‘(Lick Si60 is
obtained with solution (2), but if not, the principal spot in
suitable).
the chromatogram obtained with solution (3) appears as a
single compact spot. (b) Use isocratic elution and the mobile phas
below.
C. In the Assay, the principal peak in the chromatogram
obtained with solution (2) has the same retention time as the (c) Use a flow rate of 1 mL per minute.
principal peak in the chromatogram obtained with (d) Use an ambient column temperature.
wen ed
ree
A
solution (3). (e) Use a detection wavelength of 242 nm.
PR
ww ne A
TESTS (f) Inject 20 uwL of each solution.

Related substances MOBILE PHASE
eae
8 volumes of tetrahydrofuran and 92 volumes of cyclohexane.
Appendix III D, using solutions (1), (4), (5), (6) and (7) as
described under the Assay. For solution (1) allow the SYSTEM SUITABILITY
chromatography to proceed for 2.5 times the retention time For solutions (4) and (6), when the chromatograms are
of the principal peak. recorded under the prescribed conditions, the retention times
relative to the principal peak (E-crotamiton) are: Z-isomer,
about 0.5; N-ethyl-N-(2-methylphenyl)but-3-enamide
Use the chromatographic conditions described under Assay.
(crotamiton impurity A), about 0.8. Adjust the sensitivity of
Sew ane
2016 Cyanocobalamin Preparations III-419
the system so that the height of the principal peak in the

chromatogram obtained with solution (4) is at least 70% of
Cyanocobalamin Oral Solution
ances the full scale of the recorder. Action and use
aN wal
The test is not valid unless, in the chromatogram obtained Vitamin Bj» analogue.
corresponding to the E-isomer and to crotamiton impurity A DEFINITION
is at least 4.5. Cyanocobalamin Oral Solution contains Cyanocobalamin in
DETERMINATION OF CONTENT a suitable vehicle.
Using chromatograms (2) and (3), calculate the contents of The oral solution complies with the requirements stated under Oral
the E- and Z-isomers in the preparation being examined Liquids and with the following requirements.
using the declared contents of E- and Z-crotamiton in Content of cyanocobalamin, C.53HsgsCoN,,0,4P
PCRS and hence calculate the content of 90.0 to 115.0% of the stated amount.
IDENTIFICATION
(1) Shake a quantity of the oral solution containing 0.1 mg
of Cyanocobalamin with 10 mL of ether, allow to separate
and retain the aqueous layer. Evaporate this solution to
dryness and dissolve the residue in 0.5 mL of a mixture of
equal volumes of ethanol (96%) and water.
Crotamiton Lotion is a cuta#
(2) 0.02% w/v of cyanocobalamin BPCRS in a mixture of
Crotamiton in a suitable vehi
equal volumes of ethanol (96%) and water.
under Liquids for
Cutaneous Application and with the follows eaurements.
Content of crotamiton, C,;H,;,NO
93.0 to 107.0% of the stated amount. (b) Use the mobile phase as described below.
IDENTIFICATION
A. To a quantity of the lotion containing 0.5 g of Cret
add 30 mL of 1m hydrochloric acid and shake to produ (e) After removal of the plate, dry in air and examine in
uniform suspension. Extract with 100 mL of petroleum
(boiling range, 40° to 60°), wash the petroleum spirit layer
with 10 mL of 1m hydrochloric acid, with two 10 mL es of dilute ammonia R1, 10 volumes of methanol and
quantities of 1m sodium hydroxide and then with 10 mL ofa s of dichloromethane.
saturated solution of sodium chloride. Dry the organic layer
over anhydrous sodium sulfate, filter and evaporate to an oily
residue. The light absorption, Appendix II B, in the range
220 to 350 nm of a 0.003% w/v solution of the residue in
cyclohexane exhibits a maximum only at 242 nm. d with solution (2).
The A(1%, 1 cm) at the maximum is about 315. matogram obtained with solution
B. Carry out Identification test B described under (1) shows a peak wit same retention time as the peak
Crotamiton Cream using the residue from test A above in due to cyanocobalamin. i the:chromatogram obtained with
the preparation of solution (1). solution (2).
C. In the Assay, the principal peak in the chromatogram TESTS
obtained with solution (2) has the same retention time as the Acidity
principal peak in the chromatogram obtained with pH, 4.0 to 5.0, Appendix V L.
solution (3).
ASSAY
TESTS Carry out the procedure protected from hi
Related substances method for liguid chromatography, Appendix IID
Complies with the test described under Crotamiton Cream. following solutions in water. .
Z-tsomer (1) Dilute a weighed quantity of the oral solution with
Not more than 15% of the total content of E- and Z-isomers sufficient water to produce a solution expected to contain
determined in the Assay. 0.0005% w/v of cyanocobalamin.
ASSAY (2) 0.0005% w/v of cyanocobalamin BPCRS.
Carry out the Assay described under Crotamiton Cream CHROMATOGRAPHIC CONDITIONS
using a quantity of the lotion containing 0.1 g of Crotamiton. (a) Use a stainless steel column (15 cm x 4.6 mm) packed
with hexylsilyl silica gel for chromatography (PhenoSphere C6 is
suitable).
below.
IWI-420 Cyanocobalamin Preparations 2016
(f) Inject 100 pL of each solution. supernatant liquid with sufficient water to produce a solution
MOBILE PHASE
expected to contain 0.0005% w/v of cyanocobalamin.
1 volume of methanol and 3 volumes of a pH 3 buffer (2) 0.0005% w/v of cyanocobalamin BPCRS.
solution prepared by mixing 1000 mL of a 2.1% w/v solution CHROMATOGRAPHIC CONDITIONS
of citric acid with 250 mL of a 2.84% w/v solution of (a) Use a stainless steel column (15 cm x 4.6 mm) packed
anhydrous disodium hydrogen orthophosphate. with hexylsilyl silica gel for chromatography.
DETERMINATION OF CONTENT (b) Use isocratic elution and the mobile phase described
Calculate the content of Cgz3HgsCoN,4,0,4P in below.
_ cyanocobalamin BPCRS as specified in the leaflet which (c) Use a flow rate of 2 mL per minute.
accompanies cyanocobalamin BPCRS. (d) Use an ambient column temperature.
Append and calculate the content of cyanocobalamin,
Co3Hes ;in the oral solution using the calculated
content of C¢, 30ON ,40,4P in cyanocobalamin BPCRS. MOBILE PHASE
STORAGE 1 volume of methanol and 3 volumes of a pH 3 buffer

solution prepared by mixing 1000 mL of a 2.1% w/v solution
Cyanocobalamin
of citric acid with 250 mL of a 2.84% w/v solution of
light.
anhydrous disodium hydrogen orthophosphate.
is prescribed or demanded,
Cyanocobalamin Oral Solut _be dispensed or DETERMINATION OF CONTENT
supplied. Calculate the content of Ce3HggCoN,40,4P in
cyanocobalamin BPCRS as specified in the leaflet which
accompanies cyanocobalamin BPCRS.
Calculate the content of cyanocobalamin,
C63HgsCoN 140,4P, in each tablet using the calculated
Cyanocobalamin Tablets content of Cg3HggsCoN,40,4P in cyanocobalamin BPCRS.
Vitamin B,» analogue. Use the average of the 10 individual results obtained in the
DEFINITION
Cyanocobalamin Tablets contain Cyanocobalamin. They a
coated.
Content of cyanocobalamin, C.3;3HssCoN,40;4P
IDENTIFICATION
A. In the test for Uniformity of content, the principal peak in
the chromatogram obtained with solution (1) shows a peak
Action and use
with the same retention time as the principal peak in the
Histamine H, recept
B. Gently shake 10 tablets with 20 mL of chloroform to DEFINITION
remove the coating and dry the tablet cores in a current of
air. Transfer to a clean flask and powder with the aid of a
glass rod. To a quantity of the powdered tablet cores
containing 0.2 mg of cyanocobalamin, add 10 mL ofa
mixture of 1 volume of 2-ethoxyethanol and 3 volumes of
water, shake vigorously for 5 minutes, centrifuge at
Content of cyclizine lactate, C,,H>,N>,C3
3000 revolutions per minute for 15 minutes and filter using a
4.75 to 5.25% wy.
filter with a pore size of 0.45 um. The light absorption of the
filtrate, Appendix II B, in the range 345 to 560 nm exhibits CHARACTERISTICS
maxima at about 361 nm and 550 nm. No maximum is A clear, colourless solution.
exhibited at 351 nm (distinction from hydroxocobalamin).
IDENTIFICATION
TESTS A. To 0.5 mL add 10 mL of water followed by 5m sodium
Uniformity of content hydroxide until strongly alkaline to imus paper. Extract with
Tablets containing less than 2 mg and/or less than 2% w/w two 10-mL quantities of dichloromethane and reserve the
of Cyanocobalamin comply with the requirements stated aqueous layer for test B. Wash each dichloromethane extract
under Tablets using the following method of analysis. Carry with 5 mL of water, dry the combined extracts with
out the procedure protected from light. Carry out the anhydrous sodium sulfate, filter and evaporate the filtrate to
method for liquid chromatography, Appendix III D, using the dryness. Dissolve the residue in ethanol (96%) and evaporate
following solutions in water. to dryness. The infrared absorption spectrum of the final
ae (1) Shake one tablet with 6 mL of water for 5 minutes, dilute residue, Appendix II A, is concordant with the reference
sare to 10 mL with water and centrifuge. Dilute a quantity of the spectrum of cyclizine (RS 075).
aX eee
we aes
2016 Cyclizine Preparations III-421
B. The aqueous solution reserved in test A, after acidification the sum of the areas of all secondary peaks is not greater than
with 1m sulfuric acid, yields the reaction characteristic of 5 times the area of the principal peak in the chromatogram
lactates, Appendix VI. obtained with solution (2) (1.0%).
.
a
“4
TESTS Disregard any peak with an area less than 0.5 times that of
Acidity the peak due to cyclizine in the chromatogram obtained with
pH, 3.3 to 3.7, Appendix V L. solution (2) (0.1%).
Related substances ASSAY

Carry out the method for gas chromatography, Dilute 5 mL to 100 mL with 1m sulfuric acid. To 20 mL of
Appendix ITI B, using the following solutions in methanol the resulting solution add 2 g of sodium chloride, shake with
preparing the solutions immediately before use. two 50-mL quantities of ether, allow to separate and wash the
(1) Dilute 1 volume of the injection to 10 volumes. ether with the same two 10-mL quantities of water. To the
combined aqueous solution and washings add 20 mL of
5M sodium hydroxide and extract with three 50-mL quantities
sf the resulting solution to 5 volumes.
wae
Saw Ne
lesan
of ether. Combine the ether extracts and wash with two
of cyclizine hydrochloride BPCRS, 10-mL quantities of a saturated solution of sodium chloride.
Extract the ether layer with two 25-mL quantities of
0.05m sulfuric acid and then with two 10-mL quantities of
water. Combine the acidic and aqueous extracts and dilute to
100 mL with water. Dilute 5 mL of this solution to 200 mL
with 0.05m sulfuric acid and measure the absorbance of the
is suitable). resulting solution at the maximum at 225 nm,
Appendix II B. Calculate the content of
(b) Use helium as the carrier,g
Ci gH.2N2,C3H,.O3 taking 331 as the value of A(1%, 1 cm)
minute.
(c) Use the gradient conditions descri
LABELLING
(d) Usea split injection ratio of 1:25.
The strength is stated in terms of the amount of cyclizine
(e) Use a flame ionisation detector at 290
lactate in a suitable dose-volume.
(g) The peaks elute in the order: methanol,
1-methylpiperazine, diphenylmethanol, cyclizine.
Time Temperature Comment

(minutes)
014 100°->240° linear gradient
14516 240°->270° linear gradient
16-30 270° isocratic
SYSTEM SUITABILITY
US.
wee sy
Inject solution (3) 6 times. The relative standard deviation of

‘ ta to Oeeae ae .
each of the areas of the 3 principal peaks is not more than

wt et
5.0%.
eae
The test is not valid unless, in the chromatogram obtained area absorption spectrum of the resi
Nye
,
with solution (3); concordant with the reference spectrum

Fes
st '
the peak-to-valley ratio between methanol and Hydrochloride (RS 076).

1-methylpiperazine is at least 50; B. Extract a quantity of the powdered tablets’c
the resolution factor between diphenylmethanol and cyclizine is 0.5 g of Cyclizine Hydrochloride with 20 mL of water and
at least 18. filter. The filtrate yields reaction A characteristic of chlorides,
LIMITS
Appendix VI.
In the chromatogram obtained with solution (1): TESTS
the area of any peak corresponding to 1-methylpiperazine Related substances
(impurity A) is not greater than the peak corresponding to Carry out the method for gas chromatography,
1-methylpiperazine in solution (3) (0.5%); Appendix III B, using the following solutions prepared
the area of any peak corresponding to diphenylmethanol
(impurity B) is not greater than the peak corresponding to (1) Triturate a quantity of the powdered tablets containing
diphenylmethanol in solution (3) (0.5%); 0.20 g of Cyclizine Hydrochloride with 8 mL of methanol,
add 2 mL of 1m sodium hydroxide and filter. Dilute 1 volume
of the resulting solution to 4 volumes with methanol.
IWI-422 Cyclopenthiazide Preparations 2016
(2) Dilute 1 volume of solution (1) to 100 volumes with 0.05m sulfuric acid to produce 500 mL, filter, dilute 5 mL of
methanol and dilute 1 volume of the resulting solution to the filtrate to 100 mL with 0.05M sulfuric acid and measure
5 volumes with methanol. the absorbance of the resulting solution at the maximum at
(3) 0.0025% w/v of cychzine hydrochlonde BPCRS, 225 nm, Appendix II B. Calculate the content of
0.0025% w/v of 1-methylpiperazine BPCRS (impurity A) and C,sgH22N>,HCl taking 390 as the value of A(1%, 1 cm) at
0.0025% w/v of diphenylmethanol BPCRS (impurity B) in the maximum at 225 nm.
methanol.
(a) Use a fused silica column (25 m x 0.33 mm) coated
with a 0.5-um film of poly(dimethyl (diphenyl) siloxane (HP-5 Cyclopenthiazide Tablets
is suitable).
Action and use
Thiazide-like diuretic.
DEFINITION
Cyclopenthiazide Tablets contain Cyclopenthiazide.
(f) Inject 1 wL of eac with the following requirements.
(g) The peaks elute in ths Content of cyclopenthiazide, C,;;H,,;CIN3O,S,
1-methylpiperazine, diphem 90.0 to 110.0% of the stated amount.
IDENTIFICATION
Time Temperatur
(minutes)
(1) Shake a quantity of the powdered tablets containing 5 mg
0-14 100°—240° of Cyclopenthiazide with 5 mL of acetone and filter.
(2) 0.1% w/v of cyclopenthiazide BPCRS in acetone.
14-16 240°->270°
16-30 270° isocratic’ (a) Use as the coating silica gel GF 254.
b) Use the mobile phase as described below.
: 5 uL of each solution.
SYSTEM SUITABILITY p the plate to 15 cm.
Inject solution (3) six times. The relative standard deviation moval of the plate, dry in air, examine under
of each of the areas of the three principal peaks 1s not more t (254 nm) and then reveal the spots by
than 5.0%.
The test is not valid unless in the chromatogram obtained MOBILE’ PH.
with solution (3);
ethyl acetate.
the peak-to-valley ratio between methanol and
CONFIRMATIO
1-methylpiperazine is at least 50;
By each method of Visualisation the principal spot in the
the resolution factor between diphenylmethanol and cyclizine is
chromatogram obtained with’ selation (1) corresponds in
at least 18.
position and colour to that hromatogram obtained
LIMITS with solution (2).
nena

TESTS
the area of any peak corresponding to 1-methylpiperazine Related substances
(impurity A) is not greater than the peak corresponding to
1-methylpiperazine in solution (3) (0.5%);
the area of any peak corresponding to diphenylmethanol
(impurity B) is not greater than the peak corresponding to fil
10 mg of Cyclopenthiazide with 50 mL of acetone,
diphenylmethanol in solution (3) (0.5%); evaporate the filtrate to dryness and dissolve the residue in
fal
.
the area of any other secondary peak is not greater than the 2 mL of acetone.
area of the principal peak in the chromatogram obtained with (2) Dilute 1 volume of solution (1) to 100 volumes with
te
solution (2) (0.2%); acetone.
Nw eg
the sum of the areas of all secondary peaks is not greater than
obtained with solution (2) (1.0%). (a) Use as the coating silica gel G.
Disregard any peak with an area less than 0.5 times that of (b) Use the mobile phase as described below.
the peak due to cyclizine in the chromatogram obtained with (c) Apply 5 wL of each solution.
solution (2) (0.1%). (d) Develop the plate to 15 cm.
ASSAY (e) After removal of the plate, dry in air and reveal the spots
Weigh and powder 20 tablets. Shake a quantity of the by Method I.
ae
we
powder containing 0.125 g of Cyclizine Hydrochloride with MOBILE PHASE
400 mL of 0.05m sulfuric acid for 15 minutes. Add sufficient ethyl acetate.
2016 Cyclophosphamide Preparations III-423
LIMITS (e) After removal of the plate, dry at 120° for 5 minutes,
Any secondary spot in the chromatogram obtained with spray with ethanolic sulfuric acid (10%), heat at 120° for
wr Ned
solution (1) is not more intense than the spot in the 30 minutes and examine under wltraviolet light (365 nm).
wea i
chromatogram obtained with solution (2). MOBILE PHASE
Uniformity of content 5 volumes of 13.5M ammonia, 15 volumes of water,
Tablets containing less than 2 mg and/or less than 2% w/w 30 volumes of butyl acetate and 50 volumes of propan-2-ol.
of Cyclopenthiazide comply with the requirements stated
LIMITS
under Tablets using the following method of analysis. To one
tablet add 50 mL of methanol, shake for 20 minutes, filter Any secondary spot in the chromatogram obtained with
and measure the absorbance of the filtrate at the maximum at solution (1) is not more intense than the spot in the
273 nm, Appendix IT B. Calculate the content of chromatogram obtained with solution (2) and not more than
N30,S, taking 585 as the value of A(1%, 1 cm) at one such spot is more intense than the spot in the
ASSAY
solution containing 0.25% w/v of 4-chlorophenol (internal
uté.20 mL of the filtrate to 100 mL standard) in methanol (solution A).
with methanol and mé Ye, absorbance of the resulting (1) Dilute a volume of the eye drops containing 20 mg of
solution at the maximu: m, Appendix II B. Cyclopentolate Hydrochloride to 10 mL with the mobile
Calculate the content o O,S, taking 585 as the phase.
value of A(1%, 1 cm) at the giaxi it 273 nm. (2) Add 4 mL of solution A to a volume of the eye drops
bye ad
containing 20 mg of Cyclopentolate Hydrochloride and
dilute to 10 mL with the mobile phase.
(3) Add 4 mL of solution A to 4 mL of a 0.5% w/v solution
of cyclopentolate hydrochloride BPCRS in water and dilute to
Cyclopentolate Eye Drops 10 mL with the mobile phase.
Action and use CHROMATOGRAPHIC CONDITIONS
Anticholinergic. (a) Use a stainless steel column (20 cm x 4.6 mm) packed
DEFINITION
m) (Nucleosil C18 is suitable).
Cyclopentolate Eye Drops area sterile solution of
e isocratic elution and the mobile phase described
Cyclopentolate Hydrochloride in Purified Water.
Content of cyclopentolate hydrochloride,
C,7H,;NO3,HC1
Add 2M ammonia to a volume of the eye drops containing 45 volumes of 0.2M sodium dihydrogen orthophosphate and
25 mg of Cyclopentolate Hydrochloride until alkaline and 55 volumes of methanel, fixture adjusted to pH 3.0 with
extract immediately with 50 mL of ether. Wash the extract orthophosphoric acid.
with 5 mL of water, filter through anhydrous sodium sulfate SYSTEM SUITABILITY
and evaporate the filtrate to dryness. The infrared absorption
The test is not valid unless, in t *Omatogram obtained
spectrum of the oily residue, Appendix II A, is concordant
with solution (3), the resolution fact setween the peaks due
with the reference spectrum of cyclopentolate (RS 078).
to cyclopentolate hydrochloride and raal standard is
TESTS greater than 4.0.
Acidity DETERMINATION OF CONTENT
Calculate the content of C)7H»;NO3,HCI in thé eye drops
Related substances using the declared content of C;7H2;NO3,HCI in
Carry out the method for thin-layer chromatography, cyclopentolate hydrochloride BPCRS.
Sees
(1) Use the eye drops diluted, if necessary, to contain

0.5% w/v of Cyclopentolate Hydrochloride.
(2) Dilute 1 volume of solution (1) to 50 volumes with water. Cyclophosphamide Injection
(3) Dilute 1 volume of solution (1) to 200 volumes with Action and use
water. Cytotoxic alkylating agent.
(a) Use as the coating silica gel G. DEFINITION

Cyclophosphamide Injection is a sterile, isotonic solution of
Cyclophosphamide in Water for Injections. It is prepared by
(c) Apply 20 uL of each solution. dissolving Cyclophosphamide for Injection in the requisite
(d) Develop the plate to 15 cm. amount of Water for Injections immediately before use.
IWI-424 Cyclophosphamide Preparations 2016
The injection complies with the requirements stated under blue colour with potassium iodide and starch solution; avoid
Parenteral Preparations. prolonged exposure to cold air. Spray the plate with
STORAGE potassium todide and starch solution and allow to stand for
ewe
5 minutes.
Cyclophosphamide Injection deteriorates on storage and
should be used immediately after preparation. MOBILE PHASE
2 volumes of anhydrous formic acid, 4 volumes of acetone,
12 volumes of water and 80 volumes of butan-2-one.
CYCLOPHOSPHAMIDE FOR INJECTION
LIMITS
DEFINITION
Cyclophosphamide for Injection is a sterile material Any secondary spot in the chromatogram obtained with
consisting of Cyclophosphamide with or without excipients. solution (1) is not more intense than the spot in the
It is supplied..in a sealed container. chromatogram obtained with solution (2) (1%). Disregard
any spot remaining on the line of application.
ASSAY
ene
ms or Infusions stated under Parenteral

‘the following requirements. Dissolve the contents of a sealed container containing the
equivalent of 0.1 g of anhydrous cyclophosphamide in 30 mL
92.5 to 107.5% of th of chloroform, shake vigorously for 15 minutes, filter
cyclophosphamide. (Whatman GF/F is suitable) and wash the filter with 15 mL
of chloroform. Evaporate the combined filtrate and washings
IDENTIFICATION to dryness and dissolve the residue in 50 mL of a 0.1% w/v
solution of sodium hydroxide in ethane-1,2-diol. Boil the
anhydrous cyclophosphamide w solution under a reflux condenser for 30 minutes and allow
filter. The :nfrared absorption spect? to cool. Rinse the condenser with 25 mL of water, add
75 mL of propan-2-ol, 15 mL of 2m mitric acid, 10 mL of
0.1m silver nitrate VS and 2 mL of ammonium iron(m) sulfate
solution R2 and titrate with 0.1M ammonium thiocyanate VS.
Each mL of 0.1M silver nitrate VS is equivalent to 13.05 mg
of C7H,5Cl,N,O.P. Calculate the content of
and add 5 mL of silver nitrate solution; no precipitate
‘is C7H,5Cl,N20O>P in the sealed container.
produced. Boil; a white precipitate is produced which is Repeat the procedure with a further nine sealed containers.
insoluble in mitric acid but soluble in 5M ammonia from whit alculate the content of C7H,5Cl,N.O.P per container from
it is reprecipitated on the addition of mitric acid. age of the 10 individual results thus obtained.
TESTS
Acidity
pH of a freshly prepared 2% w/v solution, 4.0 to 6.0,
Appendix V L.
Sealed containers containing the equivalent of 1 g or less of
anhydrous cyclophosphamide comply with the requirements
stated under Parenteral Preparations, Powders for Injections
or Infusions. Use the individual results obtained in the Assay.
the United Kingdom.
Related substances
tee Carry out the method for thin-layer chromatography, Action and use
hed
Appendix III A, using the following solutions. Cytotoxic alkylating agent. «
containing the equivalent of 0.2 g of anhydrous DEFINITION
cyclophosphamide in sufficient ethanol (96%) to produce Cyclophosphamide Oral Solution is a sol ining
10 mL. Cyclophosphamide in a suitable flavoured vehigle.
(2) Dilute 1 volume of solution (1) to 100 volumes with The oral solution complies with the requirements st.
ethanol (96%).
(a) Use as the coating silica gel G. Content of anhydrous cyclophosphamide,
C,H,;CLN,O,P
IDENTIFICATION
(e) After removal of the plate, dry in air and heat at 100° for
10 minutes. Place the plate while hot in a chromatography
eA
tank in which is placed an evaporating dish containing equal
volumes of a 5% w/v solution of potassium permanganate and B. In the Assay, the retention time of the principal peak in
a
hydrochloric acid, close the tank and allow to stand for

2 minutes. Remove the plate and place it in a current of cold that of the peak due to cyclophosphamide in the
air until excess chlorine is removed and an area of coating chromatogram obtained with solution (2).
below the line of application gives not more than a very faint
AA
anaes
\-
:
“y
Pry
“ey
2016
oy
Cyclophosphamide Preparations III-425
TESTS (e) Use a detection wavelength of 200 nm.

Acidity (f) Inject 5 uwL of each solution.
vee we
od ~
MOBILE PHASE
Related substances
»
Le as “4
3 volumes of acetomtrile R1 and 7 volumes of 0.01M potassium

te
ey

dihydrogen orthophosphate, adjusted to pH 6.0 using 1m sodium
2
Appendix III A, using the following solutions in ethanol

et
hydroxide.
(96%).
SYSTEM SUITABILITY
ee
(1) Dilute a volume of the oral solution, if necessary, to

yh
produce a solution containing the equivalent of 1% w/v of The Assay is not valid unless, in the chromatogram obtained
anhydrous cyclophosphamide. with solution (3), the resolution factor between the peaks due
to cyclophosphamide and methyl-4-hydroxybenzoate is at
(2) 1% wWv of cyclophosphamide BPCRS.
least 2.0.
C7H,5Cl,N,O2P, weight in volume, using the declared
content of C7H,5Cl,N2O>P in cyclophosphamide BPCRS.
STORAGE
Cyclophosphamide Oral Solution should be stored at a
(e) After removal of the pi: temperature of 2° to 8°.
and heat at 100° for 10 m1
LABELLING
in a chromatography tankin.
aA ‘4
equivalent amount of anhydrous cyclophosphamide.
and allow to stand for 2 minutes. Rend
place it in a current of cold air until exce
Cyclophosphamide Tablets
air. Spray the plate with potassium todide and starch soba
and allow to stand for 5 minutes.
MOBILE PHASE
2 volumes of anhydrous formic acid, 4 volumes of acetone,

12 volumes of water and 80 volumes of butan-2-one.
LIMITS

Disregard any spot remaining on the line of application.
Chlorides A. Shake a quantity oft
Dilute a quantity of the oral solution containing the of Cyclophosphamide wi
equivalent of 15 mg of anhydrous cyclophosphamide to infrared absorption spectrum
‘
15 mL with water. The resulting solution complies with the concordant with the reference sfectrasm
limit test for chlorides, Appendix VII (0.33%). (RS 079).
ASSAY B. Extract a quantity of the powdere
Carry out the method for liquid chromatography, 0.1 g of Cyclophosphamide with ether #
Appendix III D, using the following solutions prepared extract to dryness. Dissolve the residuein ]
immediately before use. and add 5 mL of silver nitrate solunion; no precipita
the equivalent of 10 mg of anhydrous cyclophosphamide to insoluble iin nitric acid but dissolvesin 5M ammonia from
10 mL with water. which it is reprecipitated on the addition of nitric acid.
(2) 0.1% w/v of cyclophosphamide BPCRS in water. TESTS

(3) 0.1% wWv of methyl-4-hydroxybenzoate in solution (2). Acidity
Shake a quantity of the powdered tablets containing 0.25 g
of Cyclophosphamide with 20 mL of carbon dioxide-free water,
(a) Use a stainless steel column (15 cm x 4.6 mm) packed filter and titrate the filtrate with 0.1m sodium hydroxide VS
with octadecylsilyl silica gel for chromatography (5 um) (Waters using phenolphthalein solution R1 as indicator. Not more than
Symmetry C18 is suitable). 0.2 mL of 0.1M sodium hydroxide VS is required to change
(b) Use isocratic elution and the mobile phase described the colour of the solution.
(c) Use a flow rate of 1.5 mL per minute. Carry out the method for thin-layer chromatography,
(d) Use a column temperature of 30°. Appendix III A, using the following solutions.
IW-426 Cyproheptadine Preparations 2016
(1) Shake vigorously a quantity of the powdered tablets IDENTIFICATION |

containing 0.2 g of Cyclophosphamide with 50 mL of A. To a quantity of the powdered tablets containing the
chloroform for 15 minutes, filter, evaporate the filtrate to equivalent of 20 mg of anhydrous cyproheptadine
dryness and dissolve the residue in 10 mL of ethanol (96%). hydrochloride add 10 mL of water and 2.5 mL of
(2) Dilute 1 volume of solution (1) to 100 volumes with 0.1M sodium hydroxide, extract with 10 mL of dichloromethane,
ethanol (96%). filter through anhydrous sodium sulfate moistened with
dichloromethane on absorbent cotton and evaporate the filtrate
to dryness. The infrared absorption spectrum of the residue,
(a) Use as the coating silica gel G. AppendixII A, is concordant with the reference spectrum of
(b) Use the mobile phase as described below. cyproheptadine (RS 080).
(c) Apply 10 pL of each solution. B. In the test for Related substances, the principal spot in the
(d) Develop.the plate to 15 cm. chromatogram obtained with solution (3) corresponds to that
7 10 minutes. Place the plate while hotin C. Extract a quantity of the powdered tablets containing the
in which is placed an evaporating - equivalent of 20 mg of anhydrous cyproheptadine
umes of a 5% w/v solution of hydrochloride with 7 mL of water, filter, add 0.3 mL of
5M ammonia to the filtrate and filter again. The filtrate yields
and allow to stand f6 Remove the plate and reaction A characteristic of chlorides, Appendix VI.
place it in a current ofc until excess chlorine is TESTS _
removed and an area of C6: w the line of application
Related substances
gives not more than a very
todide and starch solution; avoi
Appendix III A, using a silica gel precoated plate (Merck
air. Spray the plate with potassz:
silica gel 60 plates are suitable) and as the mobile phase a
and allow to stand for 5 minutes.
mixture of 10 volumes of methanol and 90 volumes of
MOBILE PHASE dichloromethane. Apply separately to the plate 10 wL of each
2 volumes of anhydrous formic acid, 4 volumes of the following solutions. For solution (1) add a quantity of
12 volumes of water and 80 volumes of butan-2-¢ the powdered tablets containing the equivalent of 50 mg of
anhydrous cyproheptadine hydrochloride to 5 mL of the
LIMITS
mobile phase, shake mechanically for 10 minutes and filter
In the chromatogram obtained with solution ( 1): (Whatman GF/C filter paper is suitable). Solution (2)
any secondary spot is not more intense than the spot in th contains 0.002% w/v of dibenzocycloheptene EPCRSin the
chromatogram obtained with solution (2) (1%). ase. For solution (3) dilute 1 volume of solution
Disregard any spot remaining on the line of application. olumes with the mobile phase. For solution (4)
lume of solution (1) to 100 volumes with the
ASSAY
e and dilute 1 volume to 10 volumes with the
powdered tablets containing 0.1 g of Cyclophosphamide in
30 mL of chloroform, shake vigorously for 15 minutes, filter
(Whatman GF/F is suitable) and wash the filter with 15 mL
for 30 minutes and examine under
of chloroform. Evaporate the combined filtrate and washings
In the chromatogram obtained with
to dryness and dissolve the residue in 50 mL of a 0.1% w/v
solution of sodium hydroxide in ethane-1,2-diol. Boil under a
reflux condenser for 30 minutes and allow to cool. Rinse the
condenser with 25 mL of water, add 75 mL of propan-2-ol,
spot is not more intense than
15 mL of 2M nitric acid, 10 mL of 0.1m silver nitrate VS and
2 mL of ammonium iron(m) sulfate solution R2 and titrate with
0.1M ammonium thiocyanate VS. Each mL of 0.1m silver ASSAY
nitrate VS is equivalent to 13.94 mg of Weigh and powder 20 tablets. To a qu
C7H,5Cl,N2,02P,H.0. containing the equivalent of 1.5 mg of ari
cyproheptadine hydrochloride add sufficient« é
produce 100 mL and filter if necessary. Measure
286 nm, Appendix II B. Calculate the content of
Cyproheptadine Tablets C,,H2;N;,HCI taking 355 as the value of A(1%, 1 cm) at the
maximum at 286 nm.
Action and use
<a wad
Histamine H, receptor antagonist; antihistamine. LABELLING

DEFINITION equivalent amount of anhydrous cyproheptadine
Cyproheptadine Tablets contain Cyproheptadine hydrochloride.
Hydrochloride.
Content of anhydrous cyproheptadine hydrochloride,
C,,H,,N,HC1
ee Ne ol
“tate ny
mA A
2016 Cyproterone Preparations IIJ-427
Cyproterone Tablets acetate BPCRS in a 4:1 mixture of acetonitrile and water to

vase!
wee es
waves Action and use (4) Dilute 1 volume of solution (2) to 10 volumes with the
mobile phase.
ewe
ANAS
awe eo Antiandrogen.
DEFINITION
Cyproterone Tablets contain Cyproterone Acetate.
The tablets comply with the requirements stated under Tablets and (Spherisorb ODS 2 is suitable).
Content of cyproterone acetate, C,,H,,C1O, below.
ARRAN
ATION (d) Use an ambient column temperature.
Lee ete a
riatetas
wwewees
ity of the powdered tablets containing 0.1 g (e) Use a detection wavelength of 254 nm.
of Cyproterofie cetate with 20 mL of dichloromethane, filter
through a gla
MOBILE PHASE

the residue, Appe concordant with the reference When the chromatograms are recorded under the prescribed
spectrum of cyproterori S 395). conditions the retention time of cyproterone acetate is about
wee eel
n..obtained with solution 22 minutes.
we eed
wees
SYSTEM SUITABILITY
wwe
Stead
wee solution (2). The test is not valid unless, in the chromatogram obtained
with solution (3), the resolution between the two principal
weed
TESTS peaks is at least 3.0.
Dissolution
LIMITS
Comply with the requirements for Monogr
Pharmacopoeia in the dissolution test for tablets an In the chromatogram obtained with solution (1):
Appendix XII B1. the area of any secondary peak is not greater than half the area
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 75 revolutio
per minute. uum of the areas of all the secondary peaks is not greater
5 times the area of the principal peak in the
(b) Use 900 mL of 0.1m hydrochloric acid containing
ogram obtained with solution (2) (1.5%).
0.25% wiv sodium dodecyl sulfate, at a temperature of 37°, as
the medium.
PROCEDURE
filter. Measure the absorbance of the filtered medium, suitably
Weigh and pow
diluted with the dissolution medium, if necessary, to produce
liquid chromatograpy
sey 1

solutions.
peeey
cyproterone acetate, at the maximum at 285 nm,
sd Appendix II B using dissolution medium in the reference (1) Shake a quantity
arenes
cell. 50 mg of Cyproterone A
of acetonitrile and water for dilute to 100 mL with
(2) 0.0011% w/v of cyproterone acetate BPCRS in dissolution
the same solvent mixture and filte ugh a glass-fibre filter
medium.
(Whatman GF/C is suitable); dilu time of the filtrate
DETERMINATION OF CONTENT to 10 volumes with the mobile phase.
Calculate the total content of cyproterone acetate, (2) Dilute 1 volume of a 0.05% w/v sol Hof cyproterone
C34H29Cl1O,4, in the medium from the absorbances obtained acetate BPCRS in a 4:1 mixture of acetoni uter to
and using the declared content of C2,H9Cl1Ox4, in cyproterone 10 volumes with the mobile phase.
acetate BPCRS.
(3) Dilute 1 volume of a solution containing 0.01% w/v each
Related substances of cyproterone acetate BPCRS and medroxyprogesterone
AANA Carry out the method for liquid chromatography, acetate BPCRS in a 4:1 mixture of acetonitrile and water to
Appendix III D, using the following solutions. 10 volumes with the mobile phase.
(1) Shake a quantity of the powdered tablets containing 0.1 g CHROMATOGRAPHIC CONDITIONS
of Cyproterone Acetate with 50 mL of a 4:1 mixture of
acetonitrile and water for 5 minutes, dilute to 100 mL with
water and filter througha glass-fibre filter (Whatman GF/C is
WM
suitable). SYSTEM SUITABILITY
(2) Dilute 1 volume of solution (1) to 100 volumes with the The test is not valid unless, in the chromatogram obtained
mobile phase. with solution (3), the resolution between the two principal
peaks is at least 3.0.
(3) Dilute 1 volume of a solution containing 0.01% w/v each
of cyproterone acetate BPCRS and medroxyprogesterone
~
“
va.
fon
at.
tat. tr”
yee
o re nt
IWI-428 Cytarabine Preparations 2016
Calculate the content of C,H. ClO, in the tablets, using the
Cytarabine Injection
declared content of C,H29Cl1O, in cyproterone Action and use
acetate BPCRS.
Nead
Pyrimidine analogue; cytotoxic.

IMPURITIES
DEFINITION
monograph include those listed in the monograph for Cytarabine Injection is a sterile solution of Cytarabine in
Water for Injections. It is supplied as a ready-to-use injection
Cyproterone Acetate and the following:
or it is prepared immediately before use by dissolving
Cytarabine for Injection in the requisite amount of the liquid
stated on the label.
7S ae
yee When supplied as a ready-to-use injection, the injection
complies with the following requirements.
Content of cytarabine, C.H,3N30,;
IDENTIFICATION
1. 6B-Chloro-7«, 17a-dihyd Evaporate a volume of the injection containing 0.1 g of
ene-3,20-dione (chlorohydn Cytarabine to dryness at 60° at a pressure of 0.7 kPa, mix
the residue with a minimum amount of hot ethanol (96%),
filter, allow the filtrate to cool and induce crystallisation if
necessary. Filter, wash the crystals with 2 mL of ethanol
(96%) and dry at 60° at a pressure of 0.7 kPa. The infrared
absorption spectrum of the dried crystals, Appendix II A, is
concordant with the reference spectrum of cytarabine (RS 081).
TESTS
elated substances
the method for thin-layer chromatography,
2. 17a-Hydroxy-6-chloro-1a«-chloromethylpregna-4,6-diene-
III A, using the following solutions in water.
3,20-dione (1-chloromethyl derivative)
if necessary, a volume of the injection to produce
ontaining 2% w/v of Cytarabine.
CHROMATOGRAP
(a) Use as the coa
suitable).
erra (c) Apply 10 pL of each solution

(d) Develop the plate to 15 cm. :
(e) After removal of the plate, dry 1 amine under
tN eo

MOBILE PHASE
15 volumes of water, 20 volumes of acetone and

of butan-2-one.
SYSTEM SUITABILITY
twrnae
vw ene
rae ee
,
LIMITS
4. 17a-Hydroxy-6-chloro-1a,2«-methylenepregna-4,6-diene- In the chromatogram obtained with solution (1):
3,20-dione (cyproterone)
any spot corresponding to uracil arabinoside is not more
solution (3) (2%);
the chromatogram obtained with solution (2) (0.5%).
wwe a,
AM eal
wata
amas
rae
ee
Pome eR
aus
2016 Dacarbazine Preparations III-429
ASSAY (d) Develop the plate to 15 cm.

Carry out the method for liquid chromatography, (e) After removal of the plate, dry in air and examine under
AN AY
Appendix III D, using the following solutions. ultraviolet ght (254 nm).
vend (1) Dissolve 20 mg of cytarabine BPCRS in water and dilute MOBILE PHASE
to 100 mL with the same solvent. Dilute 10 mL to 100 mL
15 volumes of water, 20 volumes of acetone and 65 volumes
with water.
of butan-2-one.
(2) Dilute a volume of the injection to produce a solution
SYSTEM SUITABILITY
containing 0.002% w/v of Cytarabine.
LIMITS
(Spherisé#h ODS 2 is suitable). In the chromatogram obtained with solution (1):
‘elution and the mobile phase described any spot corresponding to uracil arabinoside is not more
solution (3) (1%); :
Water
(f) Inject 20 uL of ea
MOBILE PHASE
ASSAY
ee yl
Appendix XII C1, Powders for Parenteral Use. Carry out the
Calculate the content of Cp)H,3N305 Assay described for the ready-to-use injection but using the
the declared content of C>H,3N30s5 in following solution as solution (2). Dissolve sufficient of the
mixed contents of the 10 containers in water to produce a
solution containing 0.002% w/v of Cytarabine.
CYTARABINE FOR INJECTION
Calculate the content of Co)H,3N3Q0s5 in a container of
DEFINITION average content weight using the declared content of
Cytarabine for Injection is a sterile material consisting CyH,3N305 in cytarabine BPCRS.
Cytarabine with or without excipients. It is supplied in a
sealed container.
azine Injection
Content of cytarabine, C.H,3N30;
IDENTIFICATION
ae Fe we!
Mix a quantity of the contents of the sealed container sterile solution of Dacarbazine in
containing 0.1 g of Cytarabine with 10 mL of hot ethanol Water for Injections: fe ared by dissolving Dacarbazine
(96%), filter, allow the filtrate to cool and induce
eG a
for Injection in the requisite ar unt of Water for Injections.

crystallisation if necessary. Filter, wash the crystals with 2 mL
eeen
The injection complies with the*requir

ceter ra EFeeeNa
of ethanol (96%) and dry at 60° at a pressure of 0.7 kPa. The

Parenteral Preparations. e
infrared absorption spectrum of the crystals, Appendix II A, is
concordant with the reference spectrum of cytarabine. STORAGE
7 Tye
Pu jee
Acidity Dacarbazine Injection should be use

pH of a solution containing 2% w/v of Cytarabine in the preparation but, in any case, within th :
re Te
liquid stated on the label, 4.0 to 6.0, Appendix V L. by the manufacturer when prepared and stored
a?Ot to.:
accordance with the manufacturer’s instruction

Related substances
Ce
647, Ff
Appendix III A, using the following solutions in water. DACARBAZINE FOR INJECTION
TUS Ce eye
(1) Dissolve the contents of the sealed container in a DEFINITION

Se NRC
sufficient volume to produce a solution containing 2% w/v of Dacarbazine for Injection is a sterile material consisting of
Cytarabine. Dacarbazine with or without excipients. It is supplied in a
(2) Dilute 1 volume of solution (1) to 200 volumes. sealed container.
, ah olae

a
(3) 0.020% w/v of uracil arabinoside EPCRS.

Tet

ete gett
(4) 0.020% w/v each of uridine and uracil arabinoside EPCRS.

-
Content of dacarbazine, C;H,)N-O

(a) Use as the coating silca gel GF 254.
1
reewetan lS eet
Gb

CHARACTERISTICS
My ON"
A white or very pale yellow powder.

IlI-430 Dalteparin Sodium Preparations 2016

A. Dissolve a quantity of the contents of the sealed container 0.005m dioctyl sodium sulfosuccinate in a mixture of
containing 0.1 g of Dacarbazine in 200 mL of 0.1M mixed 1.5 volumes of glacial acetic acid and 98.5 volumes of water.
phosphate buffer pH 7.0, dilute with the buffer solution to
am ee
Ve Awe
LIMITS
250 mL and dilute 3 mL to 200 mL with the same buffer
solution. The light absorption of the resulting solution,
Appendix II B, in the range 230 to 350 nm exhibits two the area of any secondary peak is not greater than the area of
maxima, at 237 nm and 330 nm. the principal peak in the chromatogram obtained with
solution (2) (1%);
B. In the test for 5-aminoimidazole-4-carboxamide
hydrochloride, the principal peak in the chromatogram not more than one such peak has an area greater than half
obtained with solution (2) corresponds to that in the the area of the peak in the chromatogram obtained with
chromatogram obtained with solution (3). solution (2) (0.5%);
the sum of the areas of all such peaks is not greater than
three times the area of the peak in the chromatogram
‘4-carboxamide hydrochloride
wee
6 aes
raw AN
AS tee

Carry out th i for liquid chromatography,
Appendix III D.prote from light, using the following Uniformity of content
solutions in low-act: Sealed containers containing 200 mg or less of Dacarbazine
comply with the requirements stated under Parenteral
Preparations, Powders for Injections or Infusions. Use the
individual results obtained in the Assay.
(2) Dilute 1 volume of solu ASSAY

0.1M acetic acid. & Carry out the following procedure protected from light.
Dissolve the contents of one container in 0.1m hydrochloric
(3) 0.004% wy of dacarbazine I
acid and dilute with sufficient 0.1m hydrochloric acid to
(4) 0.0024% w/v of 5-aminoimidazole-4-cai
: producea final solution containing 0.0008% w/v of
hydrochloride in 0.1M acetic acid.
Dacarbazine. Measure the absorbance of the resulting solution
CHROMATOGRAPHIC CONDITIONS at the maximum at 323 nm, Appendix II B. Calculate the
The chromatographic conditions described under’ Relate content of C,H,)N,O in the sealed container taking 1090 as
substances may be used using the mobile phase des¢ribe the value of A(1%, 1 cm) at the maximum at 323 nm.
below. Inject each sample within 1 hour of preparation: Repeat the procedure with a further nine sealed containers
MOBILE PHASE ind calculate the average content of CgH, )N,O per
0.005m dioctyl sodium sulfosuccinate in a mixture of 3 volumes fitairier from the 10 individual results thus obtained.
of glacial acetic acid, 87 volumes of water and 110 volumes of
methanol. ontainer should be protected from light and
LIMITS mperature of 2° to 8°.
The area of any peak corresponding to 5-aminoimidazole-4-
carboxamide hydrochloride in the chromatogram obtained
with solution (1) is not greater than the area of the peak in
Related substances
Carry out the method for liquid chromatography, Action and use
Appendix III D protected from light, using the following Low molecular weight hep
ete te solutions.
DEFINITION
Dalteparin Sodium Injectionis a stefile so
containing 0.20 g of Dacarbazine in 40 mL of 0.25M acetic
Dalteparin Sodiumin a suitable diluent? <
acid and add sufficient 0.25m acetic acid to produce 50 mL.
(2) 0.0040% w/v of 2-azahypoxanthine BPCRS in 0.25M acetic PRODUCTION
acid. The final productis produced by methods o ’
designed to ensure that substances loweringblog
are not introduced and to ensure freedom from
(a) Use a stainless steel column (20 cm x 4 mm) packed contamination by over-sulfated glycosaminoglycans.
Activity
below.
The estimated activity for anti-factor Xa is not less than 90%
(c) Use a flow rate of 1.5 mL per minute. and not more than 110% of the stated activity.
(d) Use an ambient column temperature. The ratio of anti-factor Xa to anti-factor Ia is not less than
(e) Use a detection wavelength of 254 nm. 1.9 and not more than 3.2.
(f) Inject 20 wL of each solution within 1 hour of IDENTIFICATION
preparation. A. Carry out the method for size-exclusion chromatography,
(g) After use the column should be thoroughly flushed with Appendix ITI C, using the following solutions in the mobile
methanol to remove dacarbazine which does not elute with phase.
ve ww a
the mobile phase.
rane
a
2016 Dalteparin Sodium Preparations III-431
(1) Dilute the injection to contain 1600 units of anti-factor Inject 25 wL of the test solution and record the
Xa per mL. chromatogram for a period of time, ensuring complete
(2) 1% w/v of heparin low-molecular-mass for elution of sample and solvent peaks.
calibration EPCRS. The mass-average relative molecular mass is defined by the
CHROMATOGRAPHIC CONDITIONS following expression:
(a) Use a column (30 cm x 7.5 mm) packed with
appropriate porous silica beads (5 um) with a fractionation
> (RLM)
RI
range for proteins of approximately 15 000 to 100 000
(Waters Protein-Pak and Toso Hass TSK G2000SW are
suitable).
where:
RI; = mass of substance eluting in the fraction 2;
M; = relative molecular mass corresponding to fraction 2.
MOBILE PHASE
2.84% w/v solution of anhydrous sodium sulfate adjusted to

spectrophotometer pH 5.0 with dilute sulfuric acid.
monitor is connecte SYSTEM SUITABILITY
et. It is necessary to measure
the time lapse between theé:2 tors accurately so that
with solution (2), the column efficiency is not less than
their chromatograms can b
20 000 per metre.
times used in the calibration mi
detector. CONFIRMATION
(f) Inject 25 wL of each solution. The mass-average relative molecular mass ranges between
5600 and 6400. The mass percentage of chains lower than
3000 is not more than 13.0%. The mass percentage of chains
higher than 8000 ranges between 15.0% and 25.0%.
RI (ZRI) curves by numerical integration over the rgatige B. The ratio of anti-factor Xa activity to anti-factor Ila
interest (i.e. excluding salt and solvent peaks at the eng activity, determined as described under Assay, is not less
the chromatogram). Calculate the ratio r using the follow than 1.9 and not more than 3.2.
expression: Ids reaction A characteristic of sodium salts,
> RI
> UV.
Calculate the factor f using the following expression:
Bacterial endotoxits:
M,. Carry out the test for bac
r
where:
Mra = assigned number-average relative molecular mass of
the heparin low-molecular-mass for calibration EPCRS
found in the leaflet supplied with the EPCRS. to accelerate the inhibition of factor Xa (anti ca
thrombin, factor IIa (anti-IIa assay), by antithrorg
Provided the UV234 and the RI responses are aligned, the
relative molecular mass M at any point is calculated using the The International Units for anti-Xa and anti-Ia activity are
following expression: the activities contained in a stated amount of the
International Standard for low-molecular-mass heparin.
Heparin low-molecular-mass for assay EPBRP, calibrated in
RI International Units by comparison with the International
Standard using the two assays given below, is used as the
! UNs, reference preparation.
For anti-factor Xa activity
The resulting table of retention times and relative molecular Test solutions (1) to (4) Prepare a series of 4 independent
masses may be used to derive a calibration curve for the dilutions of the injection being examined in tris-chloride buffer
chromatographic system by fitting a suitable mathematical pH 7.4; the concentration range of the solutions should be
relationship to the data. A polynomial of the 3°° degree is within 0.025 IU to 0.2 IU of anti-factor Xa activity per mL
recommended. It must be stressed that the extrapolation of this and the dilutions chosen should give a linear response when
fitted calibration curve to higher molecular masses 1s not valid. results are plotted as absorbance against log concentration.
Iil-432 Dantrolene Preparations 2016
Reference solutions (1) to (4) Prepare a series of 4 dilutions of significantly. Calculate the regression of the absorbance on
the reference preparation of low-molecular-mass heparin in log concentrations of the solutions of the substance to be
Nw aA tris-chlonide buffer pH 7.4; the concentration range of the examined and of the reference preparation of low-molecular-
Lua
solutions should be within 0.025 IU to 0.2 IU of anti-factor mass heparins, and calculate the potency of the substance
Xa activity per mL and the dilutions chosen should give a being examined in International Units of anti-factor Ila
linear response when results are plotted as absorbance against activity per mL using the usual statistical methods for
log concentration. parallel-line assays.
Label 16 tubes in duplicate: T1, T2, 13, T4 for the dilutions LABELLING
of the injection being examined and R1, R2, R3, R4 for the The label states the number of IU (Units) of anti-factor Xa
dilutions of the reference preparation. To each tube add per unit volume.
50 uL of anuthrombin I solution R1 and 50 uwL of the
order R1, Dantrolene Oral Suspension

T4, Rl, R2, NOTE: Dantrolene Oral Suspension is not currently licensed in the
United Kingdom.
1 minute and add 250 yl Action and use

the reaction after exactly Skeletal muscle relaxant.
acetic acid. Transfer the mixtt
measure the absorbance at 405 DEFINITION
suitable reading device. Determir Dantrolene Oral Suspensionis a suspension of Dantrolene
L rocedure in a Sodiumin a suitable flavoured vehicle.
p
similar manner, using cris-chloride buffer instead of the The oral suspension complies with the requirements stated under
reference and test solutions; the 2 blank v Oral Liquids, the requirements stated under Unlicensed Medicines
Content of dantrolene sodium, C,,Ho»N,NaO,,3'2H,O
examined and of the reference preparation of low-molec
mass heparins and calculate the potency of the substang
being examinedin International Units of anti-factor Xa hake the oral suspension vigorously before carrying out the
activity per mL using the usual statistical methods for llowing tests.
parallel-line assays.
For anti-factor Ila activity quantity of the oral suspension containing 0.1 ¢g
Test solutions (1) to (4) Prepare a series of 4 independent ne Sodium with sufficient 0.01mM sodium hydroxide
dilutions of the injection being examined in tris-chloride buffer
pH 7.4; the concentration range should be within 0.015 IU
to 0.075 IU of anti-factor IIa activity per mL and the
dilutions chosen should give a linear response when results a maximum at 314 nm.
are plotted as absorbance against log concentration. B. In the Assay, th atogram obtained with solution
Reference solutions (1) to (4) Prepare a series of 4 independent (1) shows a peak with Saime retention time as the
dilutions of the reference preparation of low molecular-mass principal peak in the cht matogram obtained with
heparin in tris-chloride buffer pH 7.4; the concentration range solution (2).
should be within 0.015 IU to 0.075 IU of anti-factor Ila TESTS
Tet on et
activity per mL and the dilutions chosen should give a linear Acidity
response when results are plotted as absorbance against log pH, 4.5 to 5.5, Appendix V L.
concentration.
Dissolution
Label 16 tubes in duplicate: T1, T2, T3, T4 for the dilutions
Complies with the requirements stated under lreensed
of the injection being examined and R1, R2, R3, R4 for the
Medicines, Oral Suspensions. Use a volume of
dilutions of the reference preparation. To each tube add suspension containing one dose.
50 wL of antithrombin II solution R2 and 50 uL of the
appropriate dilution of the injection being examined or the Related substances
reference preparation. After each addition, mix but do not Carry out the method for liquid chromatography,
allow bubbles to form. Treating the tubes in the Appendix III D, using the following solutions.
order R1, R2, R3, R4, T1, T2, T3, T4, T1, T2, T3, (1) Dissolve a quantity of the oral suspension containing
T4, R1, R2, R3, R4, allow to equilibrate at 37° (in a water- 50 mg of Dantrolene Sodium in 20 mL of tetrahydrofuran
bath or heating block) for 1 minute and add to each tube and 2 mL of glacial acetic acid and dilute with sufficient
100 pL of human thrombin solution. Incubate for exactly absolute ethanol to produce 100 mL.
1 mimute and add 250 uL of chromophore substrate R2. Stop (2) Dilute 1 mL of solution (1) to 100 mL with absolute
the reaction after exactly 4 minutes by adding 375 wL of ethanol.
acetic acid. ‘Transfer the mixtures to semi-micro cuvettes and (3) Dissolve 5 mg of dantrolene sodium BPCRS and 0.1 g of
measure the absorbance at 405 nm, Appendix II B, using a theophylline BPCRS in 20 mL of tetrahydrofuran and 2 mL of
suitable reading device. Determine the blank amidolytic glacial acetic acid and dilute with sufficient absolute ethanol to
activity at the beginning and at the end of the procedure in a produce 100 mL. Dilute 10 mL of the resulting solution to
similar manner, using tris-chlonide buffer pH 7.4 instead of the 100 mL with absolute ethanol.
reference and test solutions; the 2 blank values do not differ
2016 Dapsone Preparations III-433
CHROMATOGRAPHIC CONDITIONS STORAGE

(a) Use a stainless steel column (15 cm x 4.6 mm) packed Dantrolene Oral Suspension should be protected from light.
with silica gel for chromatography (5 um) (Zorbax Sil is
suitable).
below. | Dapsone Tablets
(c) Adjust the flow rate of the mobile phase so that the
retention time of the peak corresponding to Dantrolene Action and use
Sodium is about 8 minutes. Folic acid synthesis inhibitor; treatment of leprosy.
DEFINITION
(e) Use a detection wavelength of 300 nm. Dapsone Tablets contain Dapsone.
‘l) allow the chromatography to proceed for with the following requirements.
fetention time of the principal peak.
Content of dapsone, C,,H;,N,0,2S
IDENTIFICATION
SYSTEM SUITABILITY of Dapsone with 20 mL of acetone, filter and evaporate the
The test is not valid unles filtrate to dryness. The infrared absorption spectrum of the
with solution (3), the resolut residue, Appendix II A, is concordant with the reference
corresponding to theophylline’a spectrum of dapsone (RS 084).
LIMITS
B. In the test for Related substances, the principal spot in the
chromatogram obtained with solution (2) is similar in
In the chromatogram obtained with s
position, colour and size to that in the chromatogram
the total area of all the secondary peaks is rik obtained with solution (5).
area of the principal peak in the chromatogranit «
solution (2) (1%). TESTS
Dissolution
ASSAY Comply with the requirements for Monographs of the British
Carry out the method for liquid chromatography, Pharmacopoeia ii n the dissolution test for tablets and capsules,
(1) Add 50 mL of dimethylformamide to a weighed quantity o
the oral suspension containing 60 mg of Dantrolene Sodium
and dilute 1 volume of this solution to 100 volumes with the
mobile phase.
(2) Dilute 1 volume of a 0.12% w/v solution of dantrolene
sodium BPCRS in dimethylformamide to 100 volumes with the
mobile phase.
with spherical particles of silica, 5 um in diameter, the
surface of which has been modified with chemically-bonded
nitrile groups (Spherisorb CN is suitable).
below.
(d) Use an ambient column temperature. procedure at the same time andinthe sammie
(e) Use a detection wavelength of 262 nm. volume of 0.1m hydrochloric acid equal to that
sample and beginning at the words ‘add 1 mL éef'a freshly
prepared 0.5% w/v solution of sodium nitrite...’ (solution B).
MOBILE PHASE Allow solutions A and B to stand for at least 2 minutes and
15 volumes of acetonitrile and 85 volumes of a phosphate measure the absorbance of solution A at the maximum at
buffer pH 6.8 prepared by dissolving 11.88 g of disodium 538 nm, Appendix IT B, using solution B in the reference
hydrogen orthophosphate and 9.08 g of potassium dihydrogen cell.
orthophosphate in 1000 mL of water. (2) Repeat the operation using a solution containing 0.1 mg
DETERMINATION OF CONTENT of dapsone BPCRS in a volume of 0.1m hydrochloric acid equal
Determine the weight per mL of the oral suspension, to that of the filtered sample and beginning at the words ‘add
Appendix V G, and calculate the content of 1 mL of a freshly prepared 0.5% w/v solution of sodium nitrite
C,4H»N4NaO5,3’2H.0, weight in volume, using the . and using solution B 1in the reference cell.
declared content of C;4HoN4NaQOs in dantrolene DETERMINATION OF CONTENT
sodium BPCRS. Each mg of C,;4HoN4NaOs is equivalent to Calculate the total content of dapsone, C,,H,,N,0_S, in the
1.1873 mg of C)4HoN4NaO;5,3'2H,0. medium from the absorbances obtained and using the
declared content of C;2H)2N2O02S in dapsone BPCRS.
IiI-434 Demeclocycline Preparations 2016
Related substances (2) 0.05% wiv of demeclocycline hydrochloride BPCRS in

Carry out the method for thin-layer chromatography, methanol.
Appendix III A, using the following solutions. (3) 0.05% w/v of each of demeclocycline hydrochloride BPCRS,
(1) Shake a quantity of the powdered tablets containing 0.1 g oxytetracycline hydrochloride BPCRS and metacycline
of Dapsone with 10 mL of methanol and filter. hydrochloride EPCRS in methanol.
(2) Dilute 1 volume of solution (1) to 10 volumes with CHROMATOGRAPHIC CONDITIONS
methanol. (a) Use as the coating silica gel H. Adjust the pH of a
(3) Dilute 1 volume of solution (2) to 10 volumes with 10% w/v solution of disodium edetate to 7.0 with 10m sodium
methanol. hydroxide and spray the solution evenly onto the plate (about
(4) Dilute 1 volume of solution (3) to 5 volumes with 10 mL for a plate 100 mm x 200 mm). Allow the plate to
methanol. dry in a horizontal position for at least 1 hour. At the time of
tana (5) 0.1% f dapsone BPCRS in methanol. use, dry the plate in an oven at 110° for 1 hour.
CHROMATOG {IG CONDITIONS
oat, 4
ie
(c) Apply 1 ul of each solution.

(a) Usea T
s described below.
(e) After removal of the plate, allow it to dry in a stream of
solutions (1), (3) and (4) and
air and examine under ultraviolet light (365 nm).
1 pL of each of solutio
(d) Develop the plate t MOBILE PHASE
6 volumes of water, 35 volumes of methanol and 59 volumes

of dichloromethane.
Tes!
ReteoN
Se
mixture of 1 volume of hydroch SYSTEM SUITABILITY
ethanol (96%) and examine in daylight, The test is not valid unless the chromatogram obtained with
MOBILE PHASE solution (3) shows three clearly separated spots.
1 volume of 13.5mM ammonia, 6 volumes of nie CONFIRMATION
20 volumes of ethyl acetate and 20 volumes of fi neptan The principal spot in the chromatogram obtained with
LIMITS solution (1) corresponds to that in the chromatogram
Any secondary spot in the chromatogram obtained with obtained with solution (2).
solution (1) is not more intense that the spot in the B. Add 20 mL of warm methanol to a quantity of the
chromatogram obtained with solution (3) (1%) and not mor of the capsules containing 10 mg of Demeclocycline
than two such spots are more intense than the spot in the ride, allow to stand for 20 minutes, filter and
e add 2 mL of sulfuric acid; a purple colour is
ASSAY
dd 1 mL of water; the colour changes to yellow.
powder containing 0.25 g of Dapsone in a mixture of 15 mL
of water and 15 mL of 2m hydrochloric acid, add 3 g of water and 7 4
potassium bromide, cool in ice and titrate slowly with 30 seconds. Ni
0.1m sodium nitrite VS, stirring constantly and determining TESTS

the end point electrometrically. Each mL of 0.1m sodium Dissolution
nitrite VS is equivalent to 12.42 mg of C,2H 2N20.2S. Comply with the requirems
Pharmacopoeia in the disso
Appendix XII B1.
TEST CONDITIONS
Demeclocycline Capsules
per minute.
Action and use (b) Use 900 ml of 0.1m hydrochloric acid, at
Tetracycline antibacterial. 37°, as the medium. "
DEFINITION PROCEDURE
Demeclocycline Capsules contain Demeclocycline Carry out the method for liquid chromatography,
Hydrochloride. Appendix III D, using the following solutions.
aN ua
enw
The capsules comply with the requirements stated under Capsules (1) After 45 minutes, withdraw a 10 ml sample of the
and with the following requirements. medium and filter. Dilute the filtered solution, if necessary,
Content of demeclocycline hydrochloride, with sufficient 0.1m hydrochloric acid to give a solution
ee
C,,H,,CIN,O;,HCl
expected to contain about 0.015% w/v of Demeclocycline
90.0 to 107.0% of the stated amount. Hydrochloride.
(2) 0.015% w/v. of demeclocycline hydrochloride BPCRS in
IDENTIFICATION
0.1m hydrochloric acid.
Appendix III A, using the following solutions. CHROMATOGRAPHIC CONDITIONS
(1) Extract a quantity of the contents of the capsules (a) Use a stainless steel column (25 cm x 4.6 mm) packed
“ON ee
ane
awe nw
akan, containing 10 mg of Demeclocycline Hydrochloride with with octadecylsilyl silica gel for chromatography (5 wm)
‘eee!
aAyoad
~ .
20 mL of methanol and centrifuge. (Lichrosorb RP18 is suitable).
so tw as
Fite ee SAE ee tee
2016 Desferrioxamine Preparations III-435

tN
(b) Use isocratic elution and the mobile phase described (3) 0.015% w/v of each of demeclocycline
below. hydrochloride BPCRS and 4-epidemeclocycline
awn
wt eter t (c) Use a flow rate of 2 ml per minute. hydrochloride EPCRS in 0.01m hydrochloric acid.
(d) Use a column temperature of 40°. CHROMATOGRAPHIC CONDITIONS
(e) Use a detection wavelength of 355 nm. The chromatographic conditions described under Dissolution
(f) Inject 20 ul of each solution. may be used.
20 volumes of dimethylformamide and 80 volumes of The Assay is not valid unless, in the chromatogram obtained
0.1m oxalic acid the pH of which has been adjusted to 2.2 with solution (3), the resolution factor between the two
with triethylamine. principal peaks is at least 3.0.
DETERM ATION OF CONTENT DETERMINATION OF CONTENT

Calculate the content of C2;H2;CIN.Og,HCI in the capsules
using the declared content of C,,;H»,;CIN.Os,HCl in
demeclocycline hydrochloride BPCRS.
Appendix III D, usin Desferrioxamine Injection

(1) Mix a quantity of th
0.5 g of Demeclocycline H wath 50 mL of Action and use
0.01mM hydrochloric acid, add siittici M hydrochloric acid Chelating agent (iron).
to produce 100 mL, filter anddilu ime of the filtrate
DEFINITION
to 5 volumes with 0.01m hydrochloric a
Desferrioxamine Injection is a sterile solution of
(2) 0.010% w/v of demeclocycline hydrochk S in
Desferrioxamine Mesilate in Water for Injections. It is
prepared by dissolving Desferrioxamine Mesilate for Injection
(3) 0.015% w/v of each of demeclocycline in the requisite amount of Water for Injections immediately
hydrochloride BPCRS and 4-epidemeclocycline before use.
hydrochloride EPCRS in 0.01m hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS teral Preparations.
The chromatographic conditions described under Dissolutio GE
may be used.
SYSTEM SUITABILITY

LIMITS

solution (2) (10%);
than 1.5 times the area of the principal peak in the for Powders for Injections or Infusio
chromatogram obtained with solution (2) (15%). Preparations and with the following
Loss on drying
When dried at 60° at a pressure not exceeding 0.7 kPa for
C,5H4gsN-O3,CH,SO3
3 hours, the contents of the capsules lose not more than 94.0 to 110.0% of the stated amount.
5.0% of their weight. Use 1 g.
IDENTIFICATION
ASSAY A. Dissolve 40 mg of the contents of the sealed container in
Carry out the method for liguid chromatography, 2 mL of absolute ethanol by heating on a water bath at 60°,
Appendix III D, using the following solutions. cool in ice until the substance begins to crystallise and
(1) Mix a quantity of the mixed contents of 20 capsules evaporate to dryness at room temperature under a gentle
containing 0.5 g of Demeclocycline Hydrochloride with current of nitrogen. The infrared absorption spectrum of the
50 mL of 0.01m hydrochloric acid, add sufficient residue, Appendix II A, is concordant with the reference
0.01m hydrochloric acid to produce 100 mL, filter and dilute spectrum of desferrioxamine mesilate (RS 086).
1 volume of the filtrate to 5 volumes with 0.01m hydrochloric B. In the test for Related substances the chromatogram
acid. obtained with solution (1) shows a peak with the same
(2) 0.10% w/v of demeclocycline hydrochloride BPCRS in retention time as the principal peak in the chromatogram
0.01m hydrochlone acid. obtained with solution (3).
anu ad
Sten eH
a Ne NG
IlIl-436 Desmopressin Preparations 2016
TESTS
Related substances
Desmopressin Injection
Carry out the method for liguid chromatography, Action and use
Appendix III D, using the following solutions. Prepare the
sae ay
Vasopressin analogue; treatment of diabetes insipidus;

solutions immediately before use and protect from light. nocturnal enuresis; haemophillia; von Willebrand’s disease.
(1) Dissolve a quantity of the contents of the sealed
containers containing 75 mg of Desferrioxamine Mesilate in DEFINITION
sufficient of the mobile phase to produce 50 mL. Desmopressin Injection is a sterile solution of Desmopressin
(2) Dilute 1 volume of solution (1) to 25 volumes with the in Water for Injections.
mobile phase. The injection complies with the requirements stated under
(3) 0.15% w/v of desferrioxamine mesilate EPCRSin the Parenteral Preparations and with the following requirements.
Content of desmopressin, C4¢;H¢4N,401,S,
90.0 to 110.0% of the stated amount of the peptide.
ke
(C CONDITIONS
eNews
yee ae
teel column (25 cm x 4.6 mm) packed CHARACTERISTICS

IDENTIFICATION
(b) Use isocratic elt In the Assay, the principal peak in the chromatogram
below. obtained with solution (1) corresponds to that in the
(c) Use a flow rate of 2 chromatogram obtained with solution (2).
TESTS
(e) Use a detection wavelength Acidity
wen ea
(f) Inject 20 pL of each solution. pH, 3.5 to 6.0, Appendix V L.

(g) For solutions (1) and (2) allow the ch Related substances
proceed for three times the retention time Carry out the method for liquid chromatography,
peak. Appendix III D, using the following solutions and the
MOBILE PHASE
normalisation procedure.
55 volumes of tetrahydrofuran and 950 volumes of a solaitio (1) Dilute the injection, if necessary, with water to give a final
containing 0.039% w/v of disodium edetate and 0.139% w/e of concentration of 0.0004% w/v of the peptide.
ammonium phosphate adjusted to pH 2.8 with orthophosp (2)Dissolve the contents of a vial of ororocindesmopressin
acid in water.
SYSTEM SUITABILITY
with solution (3), the resolution factor between the peak with
relative retention time of about 0.8 and the principal peak is
at least 1.0.
LIMITS

the principal peak in the chromatogram obtained with (f) Inject 200 pL of e
worse
AYN
solution (2) (4%);
MOBILE PHASE
a eae Mobile phase A 0.067m mixed
pH 7.0.
we we
Mobile phase B’ A mixture of acetonit
pala
and mobile phase A in equal volumes.
solution (2) (0.08%).
Time Mobile phase A% Mobile phase B% |
ASSAY (Minutes)
Determine the weight of the contents of 10 containers as 0-4 76 24 isocratic
4-18 76 > 58 24 — 42 linear gradient
wen
Pe ae
4
wwe ad
18-35 58 > 48 42> 52 linear gradient
eee en Dissolve a quantity of the mixed contents of the 10
containers containing 0.3 g of Desferrioxamine Mesilate in 35 - 40 48 > 76 52 > 24 linear gradient
15 mL of water and add 2 mL of 0.05m sulfuric acid. Titrate 40 - 50 76 0 re-equilibration

slowly with 0.1m ammonium iron(m) sulfate VS determining
the end point potentiometrically and using a platinum
electrode and a calomel reference electrode. Each mL of The retention time of desmopressin is about 16 minutes and
0.1M ammonium tron(m) sulfate VS is equivalent to 65.68 mg the retention time for oxytocin is about 17 minutes.
of Cz5HigN60Og,CH,SO3. Calculate the content of SYSTEM SUITABILITY
Cyr5H1igN.0g,CH,4SO3 in a container of average content
weight.
wT
yee ed
2016 Desmopressin Preparations TII-437
LIMITS The intranasal solution complies with the requirements stated

In the chromatogram obtained with solution (1): under Nasal Preparations and with the following requirements.
wanes
the area of any secondary peak is not more than 4.0%; Content of desmopressin, C4¢H,¢4N140;28;
owe Nd
the total area of any such peaks is not more than 5.0%. 90.0 to 110.0% of the stated amount of the peptide.
Disregard any peak due to the solvent or with an area less CHARACTERISTICS
than 2.0%. A colourless solution.
Bacterial endotoxins IDENTIFICATION
Carry out the test for bacterial endotoxins, Appendix XIV C. In the Assay, the principal peak in the chromatogram
The endotoxin limit concentration is less than 10 IU per ug obtained with solution (1) corresponds to that in the
peptide. chromatogram obtained with solution (2).
TESTS
aw ae 4 method for liquid chromatography, Acidity
. 2a us
eawad ID, using the following solutions. pH, 3.5 to 5.5, Appendix V L.
Related substances
Appendix III D, using the following solutions and the
(1) Dilute a volume of the intranasal solution in water to give
a final concentration of 0.0025% w/v of the peptide.
(2) Dissolve the contents of a vial of oxytocin/desmopressin
with octadecylsilyl silica gel for é& validation mixture EPCRS in 10 mL of water.
te aN
(Nucleosil C18 is suitable). CHROMATOGRAPHIC CONDITIONS

below. with octadecylsilyl sihca gel for chromatography (5 um).
(c) Use a flow rate of 2 mL per minute. (Nucleosil C18 is suitable).
(d) Use an ambient column temperature. (b) Use gradient elution and the mobile phase described
(e) Use a detection wavelength of 220 nm. below.
(f) Inject 200 wL of each solution. (c) Use a flow rate of 1.5 mL per minute.
se an ambient column temperature.
MOBILE PHASE
20 volumes of acetonitrile for chromatography and 80 volumes —
of 0.067 M mixed phosphate buffer solution, pH 7.0.
SYSTEM SUITABILITY

principal peaks at least 1.5.
The retention time of desmopressin is about 5 minutes;
if necessary adjust the concentration of acetonitrile in the
mobile phase to obtain a retention time of about 5 minutes. Time Comment
DETERMINATION OF CONTENT (Minutes)
rane a Calculate the content of C4gH64Nj40}2S> in the injection 0-4 76 isocratic

from the chromatograms obtained and from the declared 4-18 76 > 58 linear gradient
content of CygH,_4N)4012S. in desmopressin EPCRS.
18 - 35 58 — 48 linear gradient
STORAGE 35 - 40 48 > 76 ear gradient
Desmopressin Injection should be protected from light and
40 - 50 76 0
Using the prescribed conditions the retention time of

desmopressin is about 16 minutes and the retention time of
a even
Desmopressin Intranasal Solution oxytocin is about 17 minutes.
Action and use |
wanes
SYSTEM SUITABILITY
Vasopressin analogue; treatment of diabetes insipidus; The test is not valid unless, in the chromatogram obtained
haemophillia; von Willebrand’s disease. with solution (2), the resolution factor between the two
principal peaks is at least 1.5;
DEFINITION
the peak due to desmopressin is clearly separated from the
Desmopressin Intranasal Solution is a solution of
peak due to the antimicrobial preservative stated on the label.
Desmopressin containing suitable buffering agents and
preservatives. LIMITS

the area of any secondary peak is not more than 4.0%.
Aw ee
aw el
I-438 Desmopressin Preparations 2016
the total area of any such peaks is not more than 5.0%. IDENTIFICATION
Disregard any peak due to the solvent, any antimicrobial In the test for Uniformity of content, the principal peak in
preservative stated on the label and any peak with an area the chromatogram obtained with solution (1) corresponds to
wens
less than 0.3%. that in the chromatogram obtained with solution (2).
ASSAY TESTS
Carry out the method for liguid chromatography, Dissolution
Appendix II D, using the following solutions. Comply with the dissolution test for tablets and capsules,
(1) Dilute a volume of the intranasal solution in water to give Appendix XII B 1.
a final concentration of 0.0025% w/v of the peptide. TEST CONDITIONS
(2) 0.0025% w/v of desmopressin EPCRS in water. (a) Use Apparatus 2, rotating the paddle at 75 revolutions
(3)Diss lve the contents of a vial of oxytocin/desmopressin per minute.
wet Ae ieture EPCRSin 1 mL of water. (b) Use 500 mL of water as the medium.
tute weet
PROCEDURE
Nw ANY
ian
(a) Use a sté : (c) After 45 minutes, withdraw a 20 mL sample of the

with octadecyls medium and filter.
(Nucleosil C18 (d) Carry out the method for liquid chromatography,
(b) Use isocratic elu Appendix III D, using the following solutions.
below. (1) Use the filtered dissolution medium.
(2) Prepare a solution of desmopressin EPCRS in water with a
(d) Use an ambient column té final concentration equal to that expected for solution (1).
Sw rn ei
(e) Use a detection wavelength: CHROMATOGRAPHIC CONDITIONS
(f) Inject 200 pL of each solution. The chromatographic procedure described under Uniformity
MOBILE PHASE
Calculate the total content of desmopressin

SYSTEM SUITABILITY
C46H64N 1401282, in the medium using the declared content
of C4gH64N 1401282 in desmopressin EPCRS.
» Related substances
in the chromatogram obtained with solution (3), the re
out the method for liquid chromatography,
factor between the two principal peaks is at least 1.5.
III D, using the following solutions and the
the peak due to desmopressin is clearly separated from the on procedure:
peak due to the antimicrobial preservative stated on the label.
a quantity of powdered tablets containing 0.5 mg
The retention time of desmopressin is about 5 minutes.
If necessary adjust the concentration of acetonitrile in the
mobile phase to obtain the correct retention time and
resolution factor.
Calculate the content of C4g6H64N ,40;2S> in the intranasal
solution from the chromatograms obtained and from the
7A AS
declared content of CygH64N14012S. in desmopressin EPCRS.
STORAGE
Desmopressin Intranasal Solution should be protected from
ere
light and stored at a temperature of 2° to 8°, unless otherwise
(e) Use a detection wavelength of 220 n
Mobile phase A 0.067M mixed phosphate buff
pH 7.0.
Desmopressin Tablets
Mobile phase B10 volumes of acetonitrile for chromatography
ete
Action and use and 10 volumes of mobile phase A.
teh ag
wie ve
Vasopressin analogue; treatment of diabetes insipidus;
Set Ae, A
TNR AN
nocturnal enuresis; haemophillia; von Willebrand’s disease.
(Minutes)
DEFINITION
Desmopressin Tablets contain Desmopressin. 0-4 76 24 isocratic
The tablets comply with the requirements stated under Tablets and 4-18 76 > 58 24 — 42 linear gradient
with the following requirements. 18 - 35 58 > 48 42 > 52 linear gradient
Content of desmopressin, C4g,H.¢4N140;282 35 - 40 48 > 76 52 —> 24 linear gradient

90.0 to 110.0% of the stated amount of the peptide. 40 - 50 76 0 re-equilibration
a a)
Say on
vo 2016 Desogestrel Preparations II-439
The retention time of desmopressin is about 16 minutes and IDENTIFICATION

the retention time for oxytocin is about 17 minutes. A. In the Assay, the principal peak in the chromatogram
SYSTEM SUITABILITY obtained with solution (1) has the same retention time as the
solution (2).
principal peaks is at least 1.5. B. Carry out the method for thin-layer chromatography,
LIMITS
dichloromethane.
(1) Disperse a quantity of powdered tablets containing
the area of any secondary peak is not more than 2.0%. 0.75 mg of Desogestrel in 8 mL of dichloromethane, mix with
the total area of any such peaks is not more than 4.0%. the aid of ultrasound and dilute to 10 mL with
y peak due to the solvent or with a relative dichloromethane and filter.
swe ad
(2) 0.0075% w/v of desogestrel BPCRS.
(3) 0.0075% w/v each of desogestrel BPCRS and
lynestrenol BPCRS.
(a) Use asilica gel 60 precoated plate for high performance

method for liguid
thin-layer chromatography (Merck silica gel 60
following solutions:
HPTLC plates are suitable)..
containing 0.01% w/v of Des?
(2) 0.01% w/v of desmopressin.
than
(d) After removal of the plate, dry in. air, sprayit with
CHROMATOGRAPHIC CONDITIONS « ethanolic sulfuric acid (2%), heat at 110° for 10 minutes and
(a) Use a stainless steel column (12 cm: examine under ultraviolet light (365 nm).
with octadecylsilyl silica gel for chromatograph
MOBILE PHASE
(b) Use isocratic elution and the mobile phase ¢ A mixture of 20 volumes of ethyl acetate and 80 volumes of
below.
toluene.
(c) Use a flow rate of 2 ml per minute.
SYSTEM SUITABILITY
(e) Use a detection wavelength of 220 nm. (3) shows two clearly separated spots.
ATION
MOBILE PHASE
al spot in the chromatogram obtained with
2 volumes of acetonitrile for chromatography and 8 volumes of is similar in colour, position and size to the
0.067m mixed phosphate buffer solution pH 7.0. the chromatogram obtained with
The retention time of desmopressin is about 5 minutes. solution
DETERMINATION OF CONTENT TESTS
Calculate the content of C4gH64N1402S. in each tablet Dissolution
from the chromatograms obtained and from the declared Comply with the réquyirements for Monographs of the British
content of C4sH64N14012S>2 in desmopressin EPCRS. Pharmacopoeia in the dissilus
Appendix XII B1.
ASSAY
Use the average of the 10 individual results obtained in the TEST CONDITIONS
ng th
test for Uniformity of content. (a) Use Apparatus 2, rotati
STORAGE per minute.
Desmopressin Tablets should be protected from moisture.
sulfate, at a temperature of 37°, as the
PROCEDURE
Carry out the method for liquid chromatography, -

Desogestrel Tablets
Action and use filter. Use the filtered medium, diluted with a 0.3% w/v
Progestogen. solution of sodium lauryl sulfate if necessary, expected to
contain 0.000015% w/vof Desogestrel.
DEFINITION (2) 0.000015% w/v of desogestrel BPCRS in a mixture of
Desogestrel Tablets contain Desogestrel. 1 volume of propan-2-ol and 99 volumes of a 0.3% w/v
The tablets comply with the requirements stated under Tablets and solution of sodium lauryl sulfate.
with the following requirements. CHROMATOGRAPHIC CONDITIONS
Content of desogestrel, C,,H3,O0 (a) A stainless steel column (15 cm x 4.6 mm) packed with
90.0 to 105.0% of the stated amount. octadecylsilyl silica gel for chromatography R (5 wm) (Zorbax
ODS is suitable).
II-440 Desogestrel Preparations 2016
(b) Use isocratic elution and the mobile phase described LIMITS
Ree
below. In the chromatogram obtained with solution (1) at 210 nm:
Pee
the area of any peak due to desogestrel impurity E is not

AN SNA!
Pree
sASA Ry
(d) Use a column temperature of 40°. greater than the area of the corresponding peak in the
(e) Use a detection wavelength of 205 nm. chromatogram obtained with solution (3) (1%);
(f) Inject 200 uL of each solution. the area of any other peak other than the principal peak is
not greater than the area of the principal peak in the
MOBILE PHASE
In the chromatogram obtained with solution (1) at 230 nm:
DETERMINATION OF CONTENT the area of any peak due to desogestrel impurity D is not
Calculate the content of C..H3.0 in the medium from the greater than the area of the corresponding peak in the
chrom s obtained and using the declared content of chromatogram obtained with solution (3) (2%).
trel BPCRS.
Pa ae
AANA C22H5 Uniformity of content

of Desogestrel comply with the requirements stated under
Tablets using the following method of analysis. Carry out the
method for liguid chromatography, Appendix III D, using the
Related substanc
following solutions in 20 volumes of water and 80 volumes of
Carry out the method }
acetomtrile (Solution A).
Appendix III D, using
(1) To one tablet add 5 mL of solution A, mix with the aid
of ultrasound and add sufficient solution A to produce a
solution expected to contain 0.00075% w/v of Desogestrel.
produce 20 mL, mix and filter. (3) 0.00075% w/v of desogestrel BPCRS, 0.000015% w/v of
(2) Dilute 1 volume of solution (1) to 100°% desogestrel impurity D BPCRS and 0.0000075% w/v of
solution A and further dilute 2 mL of this sol desogestrel impurity E BPCRS.
with solution A. CHROMATOGRAPHIC CONDITIONS
(3) 0.00375% w/v of desogestrel BPCRS, 0.000075% ¥ The chromatographic procedure described under Related
desogestrel impurity D BPCRS and 0.0000375% w/v of substances may be used with the following amendments:
desogestrel impurity E BPCRS. se a detection wavelength of 210 nm.
with octadecylsilyl sihca gel for chromatography R (5 um)
(Zorbax ODS 1s suitable).
(b) Use a gradient elution and the mobile phase described
below. retention
(c) Use a flow rate of 2 mL per minute. 6 minutes.
(f) Inject 25 wL of each solution. declared content of C,H,
PANY
MOBILE PHASE ASSAY
Mobile phase _A acetonitrile. For tablets containing less tha ig and/or less than
Mobile phase B 50 volumes of acetonitrile and 50 volumes of 2% w/w of Desogestrel
water. Use the average of the 10 individual regults ¢ tained in the
For tablets containing 2 mg or more atid
Desogestrel
(Minutes)
0-4.5 0 100 isocratic Appendix II D, using the following solutions in 20 volumes
were d
4.5-4.6 0100 100-0 linear gradient of water and 80 volumes of acetonitrile (Solution A).
Nos ana
4.6-10.7 100 0 isocratic (1) To a quantity of powdered tablets containing 0.75 mg of
Desogestrel add 10 mL of solution A, mix with the aid of
aS ays ed
10.7-10.8 100-0 0-100 linear gradient

ultrasound and add sufficient solution A to produce 20 mL.
10.8-14 0 100 re-equilibration
(3) 0.00375% w/v of desogestrel BPCRS, 0.000075% w/v of
desogestrel impurity D BPCRS and 0.0000375% w/v of
SYSTEM SUITABILITY
desogestrel impunty E BPCRS.
with solution (3), at 210 nm the resolution between the peaks
due to desogestrel impurity E and desogestrel impurity D is The chromatographic procedure described under Related
at least 1.5 and the retention time of desogestrel impurity D substances may be used with a detection wavelength of
is not greater than 6 minutes. 210 nm.
2016 Dexamethasone Preparations III-441
SYSTEM SUITABILITY (4) Dilute 1 volume of solution (1) to 100 volumes with the
The test is not valid unless, in the chromatogram obtained mobile phase, dilute 1 mL of this solution to 10 volumes
|
with solution (3), the resolution between the peaks due to with mobile phase.
desogestrel impurity D and desogestrel is at least 1.5 and the CHROMATOGRAPHIC CONDITIONS
retention time of desogestrel impurity D is not greater than
6 minutes.
with octadecylsilyl silica gel for chromatography R (5 wm)
DETERMINATION OF CONTENT (Waters Symmetry C18 is suitable).
Calculate the content of C2.H3,0 in the tablets using the (b) Use isocratic elution and the mobile phase described
declared content of C,.H3 90 in desogestrel BPCRS. below.
IMPURITIES (c) Use a flow rate of 1.5 mL per minute.
The impurities limited by the requirements of this (d) Use an ambient column temperature.
include impurities D andE listed under (e) Use a detection wavelength of 254 nm.
six times the retention time of dexamethasone.
Dexamethason
MOBILE PHASE
Drops, Suspension 27 volumes of acetonitrile and 73 volumes of a 0.3% wiv
Action and use
solution of orthophosphoric acid that has been previously
adjusted to pH 3.0 with dilute sodium hydroxide.
Glucocorticoid.
SYSTEM SUITABILITY
DEFINITION The test is not valid unless, the chromatogram obtained with
Dexamethasone Eye Drops, Suspensiin are solution (3):
suspension of Dexamethasone in a suitals
the resolution factor between the peaks due to impurity 3 and
The eye drops comply with the requirementssta dexamethasone is at least 1.5;
Preparations and with the following requiremen
closely resembles the chromatogram supplied with
Content of dexamethasone, C,,H>,FO; dexamethasone impurity standard BPCRS.
LIMITS
The eye drops should be shaken vigorously before carrying o
following tests.
4m of the areas of any peaks, apart from the principal
IDENTIFICATION ; not greater than the area of the peak in the
Mix a quantity of the Eye drops containing 20 mg of am obtained with solution (2) (3%).
Dexamethasone with 5 mL of 0.1M sodium hydroxide, add
ny peak with an area less than the area of the
50 mL of dichloromethane and mix with the aid of ultrasound
et hromatogram obtained with solution (4) (0.1%).
for 20 minutes, filter the dichloromethane layer and
evaporate to dryness using a rotary evaporator. Dry the
residue at 105° for 2 hours. The infrared absorption spectrum
of the dried residue, Appendix II A, is concordant with the
reference spectrum of dexamethasone (RS 089).
TESTS
Dexamethasone in 7 0 m
Particle size
of ultrasound for 10 minu
The eye drops are a suspension and comply with the
following test:
Examine using an automated light obscuration instrument
such as that described in Appendix XIII A. Not more than
20 particles greater than 25 um, not more than 2 particles
greater than 50 um and no particles greater than 90 um.
Acidity substances may be used.
SYSTEM SUITABILITY
Related substances The test is not valid unless the chromatogram obtained with
Carry out the method for liguid chromatography, solution (3):
phase.
dexamethasone is at least 1.5;
(1) Disperse a quantity of the eye drops containing 20 mg of
closely resembles the chromatogram supplied with
Dexamethasone in 70 mL of mobile phase, mix with the aid
dexamethasone impurity standard BPCRS.
of ultrasound for 10 minutes, dilute with sufficient mobile
phase to produce 100 mL and filter. DETERMINATION OF CONTENT
(2) Dilute 3 volume of solution (1) to 100 volumes with the Calculate the content of C,H 2 .FOs in the eye drops using
mobile phase. the declared content of C2,H». 9.FOs in dexamethasone BPCRS.
(3) 0.02% w/v of dexamethasone impurity standard BPCRS. STORAGE
Dexamethasone Eye Drops, Suspension should be stored in
IiI-442 Dexamethasone Preparations 2016
IMPURITIES Carry out all of the following procedures protected from light.
IDENTIFICATION
Mix a quantity of the powdered tablets containing 20 mg of
Dexamethasone with 5 mL of 0.1m sodium hydroxide, add
iene m
50 mL of dichloromethane and mix with the aid of ultrasound

for 20 minutes, filter and evaporate to dryness using a rotary
evaporator. Dry the residue at 105° for 2 hours. The infrared
absorption spectrum of the dried residue, Appendix II A, is
concordant with the reference spectrum of dexamethasone
(RS 089).
TESTS
Related substances
(1) To a quantity of the powdered tablets containing 2.5 mg
of Dexamethasone add 10 mL of acetonitrile, mix with the aid
of ultrasound and filter through a 0.45-um filter. Dilute
4 mL of the filtrate to 10 mL with water.
(2) Dilute 1 volume of solution (1) to 100 volume with
mobile phase A.
(3) 0.002% w/v each of dexamethasone BPCRS and
methylprednisolone BPCRS in mobile phase A.
awe ad
mobile phase A.

ODS is suitable).
b) Use gradient elution and the mobile phases described
flow rate of 2.5 mL per minute.

olumn temperature of 45°.
€'a detection wavelength of 254 nm.
2.0% of each solution.
u are: methylprednisolone about
MOBILE PHASE
Mobile phase A 15°

Mobile phase B_ aceto
Ane
Time Mobile Mobile, Comments

(min) phase A phase B
(% viv) (% viv)
) 100 0
15 100-0 0-100
40 0 100
5. Dexamethasone-17(20)-enol-2 1-aldehyde.
4} 100 0 begin equilibration ©
with A
46 =0 100 0 end equilibration,
begin next ©
Dexamethasone Tablets
eR mene oN
awe wo
chromatogram
Action and use
Glucocorticoid.
SYSTEM SUITABILITY
DEFINITION The test is not valid unless, in the chromatogram obtained

Dexamethasone Tablets contain Dexamethasone. with solution (3), the resolution factor between
The tablets comply with the requirements stated under Tablets and methylprednisolone and dexamethasone is at least 2.8.
with the following requirements. LIMITS
Content of dexamethasone, C,,H,,.FO,; In the chromatogram obtained with solution (1):

Male tee Ue a - -. of Ye Ne De a a ek tena eter a eee
the area of any secondary peak is not greater than 0.5 times
Dexamethasone and Neomycin Ear
a als
with solution (2) (0.5%); Spray
Action and use
than the area of the principal peak in the chromatogram
Glucocorticoid.
Disregard any peak due to mobile phase A and any peak with DEFINITION
an area less than the area of the principal peak in the Dexamethasone and Neomycin Ear Spray is an emulsion
chromatogram obtained with reference solution (4) (0.05%). containing Dexamethasone in microfine powder and Neomycin
Uniformity of content Sulfate in a suitable vehicle in a suitable metered-dose
Tablets containing less than 2 mg and or less than 2% w/w container. It may contain acetic acid.
thasone¢ comply with the requirements stated The ear spray complies with the requirements stated under Ear
hwnd
AN ua Preparations and with the following requirements.

Content of dexamethasone, C,,H>,FO;
80.0 to 120.0% of the amount stated to be delivered by
(1) To one tables, actuation of the valve.
a solution containi
Shake the ear spray vigorously before carrying out the following
tests.
IDENTIFICATION
A. In the Assay for dexamethasone, the chromatogram
(a) Use a stainless steel column (20 obtained with solution (2).
with octadecylsilyl silica gel for chromatogté
(b) Use isocratic elution and the mobile phase
: (1) Discharge the container a sufficient number of times to
below.
obtain a suitable quantity and dilute with methanol, if
(c) Use a flow rate of 1.4 mL per minute. necessary, to produce a solution containing 0.1% w/v of
(d) Use an ambient column temperature. Dexamethasone.
(e) Use a detection wavelength of 238 nm. 1% w/v of dexamethasone BPCRS in methanol.
(f) Inject 20 pL of each solution. % wiv of each of dexamethasone BPCRS and
MOBILE PHASE
asone BPCRS in methanol.
Calculate the content of C2.H».FOs in each tablet using the
declared content of C..H. 9FOs in dexamethasone BPCRS.
ASSAY
For tablets containing less than 2 mg and/or less than
2% v/w of Dexamethasone
Use the average of the 10 individual results obtained in the (254 nm) (detection method
test for Uniformity of content. n of sulfuric acid. Heat at 120°
" Allow to cool.
For tablets containing 2 mg or more and 2% w/w of
igh d under ultraviolet
Dexamethasone
Weigh and powder 20 tablets. Carry out the method for light (365 nm) (detection method B
liquid chromatography, Appendix III D, using the following MOBILE PHASE
solutions. 5 volumes of butan-2-ol saturated with water,
(1) To a quantity of the powdered tablets containing 2.5 mg toluene and 85 volumes of ether.
of Dexamethasone add 20 mL of methanol (50%), shake for SYSTEM SUITABILITY
20 minutes and filter through glass-fibre filter (Whatman
GF/C is suitable).
solution (3) shows two spots which may, however, not be
(2) 0.0125% w/v of dexamethasone BPCRS in methanol completely separated.
(50%).
CONFIRMATION
Method A The principal spot in the chromatogram obtained
The chromatographic conditions described under Uniformity with solution (1) is similar in position and size to the
of content may be used. principal spot in the chromatogram obtained with
DETERMINATION OF CONTENT solution (2).
Calculate the content of C,,H. FO; in the tablets using the Method B The principal spot in the chromatogram obtained
declared content of C22H2. 9FOs5 in dexamethasone BPCRS. with solution (1) is similar in position, colour in daylight,
fluorescence in ultraviolet light at 365 nm and size to the
STORAGE
Dexamethasone Tablets should be protected from light.
solution (2).
et
rosy
4
y
:
-
-
.
_
ao .
‘
te
.
IlI-444 Dexamethasone Preparations 2016

Oy
ee
wy
wae
wy
.
ae
C. In the test for Neomycin C, the principal spot in the MOBILE PHASE
chromatogram obtained with solution (1) is similar in 20 volumes of methanol and 80 volumes of a 20% w/v
position, colour and size to the principal spot in the solution of sodium chloride.
SYSTEM SUITABILITY
Dexamethasone and Neomycin Ear Spray containing acetic acid
complies with the following additional test.
with solution (4), a spot appears with anRfvalue slightly less
D. Discharge the container a sufficient number of times to than that of the principal spot.
produce 0.2 g. The solution yields reaction A characteristic
LIMITS
of acetates, Appendix VI.
TESTS
with an Rf value slightly less than that of the principal spot
Acidity (neomycin C) is not more intense than the spot in the
pH, 2.0 Q, Appendix V L. chromatogram obtained with solution (2) (15%) but is more
Neamine |= intense than the spot in the chromatogram obtained with
Carry out the gt od for thin-layer chromatography, solution (3) (3%).
Appendix III"A the following solutions. Related substances
(1) Discharge the ¢ tairier a sufficient number of times to
Dexamethasone
obtain a suitable quar 2% w/w of neomycin sulfate is
suitable).
(2) 0.01% w/v of neami
(1) After priming the pump, discharge the container a
sufficient number of times to obtain 2.5 mg of
solution (2). Dexamethasone, add 1.5 mL of acetonitrile R and 5 mL of
CHROMATOGRAPHIC CONDITI
ton ete F
mobile phase A. Mix with the aid of ultrasound, add

(a) Use a TLC silica gel plate. . sufficient mobile phase A to produce 10 mL and filter
through a 0.45-1m filter.
(2) Dilute 1 mL of solution (1) to 100 mL with mobile
(c) Apply 5 uL of each solution, as 5-mm b
phase A.
(3) 0.002% w/v of each of methylprednisolone BPCRS and
(e) After removal of the plate, dry it at 100° to 105° dexamethasone BPCRS in mobile phase A.
10 minutes, spray with ninhydrin and stannous chloride reag
{4) Dilute 1 mL of solution (2) to 20 mL with mobile phase
heat at 110° for 15 minutes, spray with the same reagent ari
heat at 110° for 15 minutes.
FOGRAPHIC CONDITIONS
MOBILE PHASE
10 volumes of dichloromethane, 20 volumes of 13.5mM ammonia
and 30 volumes of methanol.
SYSTEM SUITABILITY

solution (3) shows two clearly separated principal spots. (c) Use a flowrat
LIMITS (d) Use a column teff
In the chromatogram obtained with solution (1) any spot (ec) Use a detection wavele: !
corresponding to neamine is not more intense than the spot
te Nw
(f) Inject 20 pL of each solu 0
in the chromatogram obtained with solution (2) (2%).
MOBILE PHASE :
Neomycin C
Carry out the method for thin-layer chromatography, Mobile phase A 25% vv acetonitrile
ct
wbw ee
Appendix III A, using the following solutions. Mobile phase B acetonitrile.

ve nee
(1) Discharge the container a sufficient number of times to

obtain a suitable quantity (0.5% w/w of neomycin sulfate is
suitable).
(min) (per cent V/V) (per cent V/V)
(2) 0.075% wiv of framycetin sulfate EPCRS in water.
(3) Dilute 1 volume of solution (2) to 5 volumes with water. 0 100 0 isocratic
aanwad (4) 0.5% w/v of neomycin sulfate EPCRS in water.
woe te
15 100-0 0-100 begin linear gradient
we No
40 0 100 end chromatogram,
(a) Use a TLC silica gel plate. return to LOO A
4] 100 0 begin equilibration
(c) Apply 5 uL of each solution, as 5-mm bands. with A
46 =0 100 0 end equilibration, begin
(e) After removal of the plate, dry it at 100° to 105° for next chromatogram
10 minutes, spray with ninhydrin solution R1 and heat at 100°
to 105° for 10 minutes.
2016 Dexamethasone Preparations TI-445
When the chromatograms are recorded under the prescribed error are not less than 95% and not more than 105% of the
conditions, the retention times are: methylprednisolone, estimated potency. The upper fiducial limit of error is not
,ew ew
about 12 minutes; dexamethasone, about 14 minutes. less than 90.0% and the lower fiducial limit of error is not
swany
SYSTEM SUITABILITY
more than 115.0% of the stated number of IU per mL.
The test is not valid unless: STORAGE
(a) in the chromatogram obtained with solution (3), the Dexamethasone and Neomycin Ear Spray should not be
resolution factor between the peaks corresponding to allowed to freeze.
methylprednisolone and dexamethasone is at least 1.5 (af LABELLING
necessary, adjust the concentration of acetonitrile in mobile The strength with respect to Neomycin Sulfate is stated as
phase A); the number of IU (Units) per mL.
(b) ii n the chromatogram obtained with solution (4), the
ratio of the peak due to dexamethasoneis at
‘mene
SN
Dexamethasone Sodium Phosphate Eye

Drops, Solution
Action and use
Glucocorticoid.
than the area of the principal, DEFINITION

obtained with solution (2) (1 Dexamethasone Sodium Phosphate Eye Drops, Solution are
Disregard any peak due to m a sterile Solution of Dexamethasone Sodium Phosphate in a
an area less than the area of the princip suitable vehicle.
chromatogram obtained with reference ‘ The eye drops comply with the requirements stated under Eye
ASSAY Preparations and with the following requirements.
For dexamethasone Content of dexamethasone sodium phosphate,
Carry out the method for liquid chromatography, C,,H23sFNa,03P
Appendix III D, using the following solutions protectéd frém.. 95.0 to 105.0% of the stated amount.
light. IDENTIFICATION
(1) After priming the pump, discharge the container a uantity of the eye drops containing 20 mg of
sufficient number of times to obtain 1 mg of hasone Sodium Phosphate with 5 mL of
Dexamethasone, add 10 mL of methanol, place in an um hydroxide, add 50 mL of dichloromethane and mix
ultrasonic bath for 10 minutes, cool, dilute to 25 mL with d of ultrasound for 20 minutes, filter the
water, mix and filter through a 0.45-um PTFE filter. ane layer and evaporate to dryness using a
(2) Dilute 10 volumes of a 0.010% w/v solution of . Dry the residue at 105° for 2 hours.
dexamethasone BPCRS in methanol to 25 volumes with water. : #1 spectrum of the dried residue,
Appendix Ir ordant with the reference spectrum of
dexamethasone"(RS 89
with octadecylsilyl sihca gel for chromatography (5 um) TESTS
(Spherisorb ODS2 1s suitable). Alkalinity
(b) Use isocratic elution and the mobile phase described pH, 7.0 to 7.5, Appendix
(c) Use a flow rate of 2 mL per minute. Carry out the method for kiguid chyomatography,
Appendix III D, using the following:soliti6ns in the mobile
phase. :
(1) Disperse a quantity of the eye drops c 20 mg of
(f) Inject 20 wL of each solution. Dexamethasone Sodium Phosphatein 70 mL,,an1x with the
MOBILE PHASE aid of ultrasound for 10 minutes, dilute to 100 mi and filter.
Mix 10 volumes of glacial acetic acid, 350 volumes of (2) Dilute 3 volumes of solution (1) to 100 volumes.
acetonitrile and 640 volumes of water and filter (Whatman (3) 0.02% wiv of dexamethasone impurity standard BPCRS.
GFF is suitable).
DETERMINATION OF CONTENT dilute 1 volume of this solution to 10 volumes
Calculate the content of C,H..FOs in the ear spray using CHROMATOGRAPHIC CONDITIONS
the declared content of C,H 9FOs in dexamethasone BPCRS
For neomycin sulfate with octadecylsilyl sthca gel for chromatography R (5 wm)
Prime the pump and discharge the container a sufficient (Waters Symmetry C18 is suitable).
number of times to obtain a quantity of the emulsion (b) Use isocratic elution and the mobile phase described
containing 3250 IU; dilute to 50 mL with sterile phosphate below.
buffer pH 8.0. Dilute 10 mL of the resulting solution to
100 mL with the same solvent and carry out the
microbiological assay of antibiotics, Appendix XIV A. (d) Use an ambient column temperature.
The precision of the assay is such that the fiducial limits of (e) Use a detection wavelength of 254 nm.
IWI-446 Dexamethasone Preparations 2016

for six times the retention time of dexamethasone sodium
phosphate.
MOBILE PHASE

solution of orthophosphoric acid that has been previously
adjusted to pH 3.0 with 2m sodium hydroxide.
SYSTEM SUITABILITY

(3):
actor.between the peaks due to impurity 3 and
least 1.5;
losely resembles the chromatogram
peaks is not greater than

am obtained with
solution (2) (3%). &
Disregard any peak with an aréd le area of the
peak in the chromatogram obtained ition (4) (0.1%).
ASSAY
Carry out the method for liquid chromatograpt
Appendix III D, using the following solutions in;
phase.
(1) Disperse a quantity of the eye drops containing 20m
Dexamethasone Sodium Phosphate in 70 mL, mix with £
aid of ultrasound for 10 minutes, dilute to 100 mL and filte
(2) 0.015% w/v of dexamethasone BPCRS.
(3) 0.02% wiv of dexamethasone impurity standard BPCRS.

SYSTEM SUITABILITY
5. dexamethaso
with solution (3):
dexamethasone is at least 1.5;
the chromatogram closely resembles the chromatogram Dexamethasone So jm Phosphate
supplied with dexamethasone impurity standard BPCRS.
Injection ‘
Calculate the content of Cz.H»3FNa2OgP in the eye drops Action and use
using the declared content of C,H» .FOs in . Glucocorticoid.
dexamethasone BPCRS. Each mg of C.,H29FOs is equivalent

DEFINITION 2
to 1.3157 mg of Cz,H»3sFNa,OgP.
Dexamethasone Sodium Phosphate Injection is a-terile
STORAGE solution of Dexamethasone Sodium Phosphate in Water for
Dexamethasone Sodium Phosphate Eye Drops should be Injections.
aN
“ioe
wie ~ ~
‘ae PN
NT
stored in accordance with the manufacturer’s instructions. The injection complies with the requirements stated under
‘~

ete ot
aw aN
er rea
IMPURITIES
Content of dexamethasone, C,H,.FO;
CHARACTERISTICS
IDENTIFICATION
Appendix ITI A, using the following solutions in methanol.
(1) Dilute, if necessary, a volume of the injection to contain
1. dexamethasone-17B-carboxylic acid, the equivalent of 0.08% w/v of dexamethasone.
ata ata
(2) 0.1% w/v of dexamethasone phosphate BPCRS. Mobile phase B_ 300 volumes of 0.09M ammonium acetate,
(3) 0.1% w/v each of dexamethasone phosphate BPCRS and adjusted to pH 4.0 with acetic acid, and 700 volumes of
prednisolone sodium phosphate BPCRS. methanol.
raw ny
*
Bet eMe S

(a) Use as the coating silica gel F254 (Merck plates are
suitable).
0-3.5 90 10 isocratic
(b) Use the mobile phase as described below. 3.50-23.5 90-60 1040 linear gradient
(c) Apply 5 uL of each solution. 23.5-34.5 60-5 40-95 linear gradient
(d) Develop the plate to 15 cm. 34.5-50 5 95 isocratic
(e) After removal of the plate, dry in air, heat at 110° for 50-55 590 95-10 linear gradient
tes, spray the plate, whilst hot, with ethanolic sulfuric 55-65 90 10 re-equilibration
we and
rae ey

conditions the retention times relative to dexamethasone
20 volumes of phosphate (retention time about 22 minutes) are
60 volumes of impurity 1, about 0.1; impurity C, about 0.5;
impurity D, about 0.6; impurity E, about 0.8;
impurity F, about 0.92; impurity B, about 0.95;
impurity A, about 1.37 and impurity G, about 1.41.
completely separated. SYSTEM SUITABILITY
CONFIRMATION The test is not valid unless, in the chromatogram obtained

betamethasone sodium phosphate and dexamethasone
phosphate is at least 2.0.
fluorescence in ultraviolet light at 365 nm* o that in
the chromatogram obtained with solution (2)« < LIMITS
B. In the Assay, the chromatogram obtained with’so Identify any peak corresponding to impurity A in the
(1) shows a peak with the same retention time as th chromatogram obtained with solution (1) using the
principal peak in the chromatogram obtained with chromatogram obtained with solution (4) and multiply the
solution (2). | by a correction factor of 0.75.
TESTS «chromatogram obtained with solution (1):
Alkalinity s of any peak corresponding to impurity A,
pH, 7.0 to 8.5, Appendix V L. »B, impurity C, impurity D, impurity E, impurity F
Related substances
phase A. the area of any.¢ t.secondary peaks is not greater than
0.4 times the ir : rincipal peak in the chromatogram
(1) Dilute a volume of the injection to produce a solution
obtained with so (0.2%).
containing the equivalent of 0.08% w/v of dexamethasone.
ndary peaks is not greater than
(3) 0.01% w/v each of dexamethasone phosphate BPCRS and
betamethasone sodium phosphate BPCRS.
the area of the
(4) 0.1% w/w of dexamethasone sodium phosphate for peak principal peak in the chromatogr ned with
identification EPCRS. solution (5) (0.1%).
ASSAY
CHROMATOGRAPHIC CONDITIONS Carry out the method for liquid chromatograp
(a) Use a stainless steel column (12.5 cm x 4.6 mm) packed Appendix III D, using the following solutions 1 the mobile
with end-capped octylsilyl silica gel for chromatography R (5 um) phase.
(Kromasil C8 is suitable). (1) Dilute a volume of the injection to produce a solution
(b) Use gradient elution and the mobile phase described containing the equivalent of 0.0066% w/v of dexamethasone.
below. (2) 0.008% w/v of dexamethasone phosphate BPCRS.
(c) Use a flow rate of 1 mL per minute. (3) 0.002% w/v each of dexamethasone phosphate BPCRS and
(d) Use a column temperature of 30°. betamethasone sodium phosphate BPCRS.
(e) Use a detection wavelength of 254 nm. CHROMATOGRAPHIC CONDITIONS
(f) Inject 20 pL of each solution. (a) Use a stainless steel column (25 cm x 4.6 mm) packed
MOBILE PHASE with octadecylsilyl silica gel for chromatography R (5 wm)
Mobile phase A 300 volumes of 0.09M ammonium acetate (Hypersil ODS is suitable).
and 350 volumes of water, adjusted to pH 3.8 with acetic (b) Use isocratic elution and the mobile phase described
acid, then add 350 volumes of methanol. below.
IWI-448 Dexamethasone Preparations 2016
(d) Use an ambient column temperature. CHROMATOGRAPHIC CONDITIONS
(e) Use a detection wavelength of 254 nm. (a) Use as the coating silica gel Fz54.
sana
(f) Inject 20 uL of each solution. (b) Use the mobile phase as described below.
SYSTEM SUITABILITY (c) Apply 5 uL of each solution.
The test is not valid unless, in the chromatogram obtained (d) Develop the plate to 15 cm.
with solution (3), the resolution between the peaks due to (e) After removal of the plate, dry in air and examine under
betamethasone sodium phosphate and dexamethasone ultraviolet light (254 nm).
phosphate is at least 2.2. MOBILE PHASE
DETERMINATION OF CONTENT 20 volumes of glacial acetic acid, 20 volumes of water and
Calculate the content of C2,H. .FOs in the injection from the 60 volumes of butanol.
peak areas ined and from the declared content of CONFIRMATION

LABELLING peak in the chromatogram obtained with solution (2).
The content of active ingré ted as the equivalent TESTS
amount of dexamethasone i dose-volume. Related substances
IMPURITIES Carry out the method for liguid chromatography,
The impurities limited by the req Appendix III D, using the following solutions in methanol
monograph those listed under Dexametha (40%).
Phosphate and: - (1) To a quantity of the oral solution containing 10 mg of
1. disodium 9-fluoro-11{,17-dihydroxy-1 60-nt o-1C- Dexamethasone Sodium Phosphate add sufficient methanol
sulfopregn-4-ene-2 1-yl phosphate. (40%) to produce 100 mL and filter.
(2) 0.0001% w/v of dexamethasone sodium phosphate BPCRS.
(3) 0.0001% w/v of betamethasone sodium phosphate BPCRS.
4) 0.0025% w/v of each of dexamethasone BPCRS and
suitable
r
(b) Use gradic
below.
Dexamethasone Sodium Phosphate Oral

Solution
NN tS
(f) Inject 25 wL of each solutis

Action and use MOBILE PHASE
Glucocorticoid Mobile phase A 39 volumes of meth
0.68% w/v solution of potassium dihydrog f
DEFINITION
adjust the pH to 3.5 with dilute orthophospho
Dexamethasone Sodium Phosphate Oral Solution contains
sodium hydroxide. :
Dexamethasone Sodium Phosphate in a suitable vehicle.
Mobile phase B41 volumes of methanol and 59 vaoliimes of a
0.68% w/v solution of potassium dihydrogen orthophosphate;
adjust the pH to 3.5 with dilute orthophosphonic acid or dilute
one al
Content of dexamethasone sodium phosphate, sodium hydroxide.
awn
C,2H>3;FNa,03P
Carry out all of the following procedures protected from light.
(min) (% viv) (% viv)
IDENTIFICATION 0 100 0 isocratic
3040 1000 0-100 linear gradient
4075 0 100 isocratic
(1) To a quantity of the oral solution containing 25 mg of
Dexamethasone Sodium Phosphate add sufficient methanol to 7580 0-100 1000 linear gradient
Tete wel
produce 100 mL, centrifuge and use the supernatant liquid. 80-90 100 0 re-equilibration
yen yal
(2) 0.025% wiv of dexamethasone sodium phosphate BPCRS in

Fate ns
ea re
aN WA
aN a methanol.
ae Ne
2016 Dextran Preparations III-449
SYSTEM SUITABILITY
Dexamfetamine Tablets
teeny
naa ad with solution (4), the resolution factor between the peaks due Action and use
to dexamethasone and betamethasone is at least 1.5. Amfetamine.
LIMITS
DEFINITION
Dexamfetamine Tablets contain Dexamfetamine Sulfate.
the area of any peak due to betamethasone sodium
phosphate is not greater than half the area of the principal The tablets comply with the requirements stated under Tablets and
peak in the chromatogram obtained with solution (3) (0.5%); with the following requirements.
the area of any secondary peak is not greater than 0.2 times Content of dexamfetamine sulfate, (C.H,3N)2,H,SO,
IDENTIFICATION
A. Dissolve a quantity of the powdered tablets containing
0.1 g of dexamfetamine sulfate as completely as possible in
20 mL of water, filter, add 2 mL of 5M sodium hydroxide and
extract with three 25 mL quantities of ether, washing the
combined extracts with 5 mL of water. To the ether solution
add 10 mL of 0.05m sulfuric acid and shake well. The acid
layer, after warming to dispel residual ether and cooling to
20°, is dextrorotatory.
obtained with solution (2) (3 B. Extract a quantity of the powdered tablets containing
50 mg of dexamfetamine sulfate with 10 mL of water, filter,
ASSAY :
cool to about 15°, add 3 mL of 1M sodium hydroxide and
Carry out the method for liguid chrom
Pat
shake for 2 minutes with 1 mL of a mixture of 1 volume of

Appendix III D, using the following s
benzoyl chloride and 2 volumes of ether. Filter, wash the
methanol (45%).
residue with 15 mL of water and recrystallise twice from
(1) To a quantity of the oral solution containi : ethanol (50%). The melting point of the crystals, after drying
equivalent of 8 mg of Dexamethasone Sodium Pkos at 105° for 1 hour, is about 156°, Appendix V A.
add sufficient methanol (45%) to produce 100 mL a;
through a 0.45-um nylon filter. ASSAY
Weigh and powder 20 tablets, or more if necessary. Dissolve
(2) 0.008% w/v of dexamethasone sodium phosphate BPCR
lantity of the powder containing 0.1 g of Dexamfetamine
and 0.0027% w/w of dexamethasone BPCRS.
é.as completely as possible in 20 mL of water, add 8 g
chloride and 2 mL of 5M sodium hydroxide and
(a) Use a stainless steel column (15 cm x 4.6 mm) packed vith successive quantities of 50, 20, 20 and 20 mL of
with octadecylsilyl sihca gel for chromatography (5 um) teaét the combined ether extracts with four 10 mL
(b) Use isocratic elution and the mobile phase described ?with 5M sodium hydroxide. Dilute to
below. nd distil into 20 mL of
(d) Use a column temperature of 30°. in the distillation ‘Hag
Bail, cool and titrate the excess of
(e) Use a detection wavelength of 240 nm. acid with 0.05M sod ivdrexyde VS using methyl red solution
as indicator. Each mL o .05x hydrochloric acid VS is
equivalent to 9.212 mgo 61113N)2,H2SO,.
MOBILE PHASE
solution of potassium dihydrogen orthophosphate, adjust the pH
to 3.5 with dilute orthophosphonic acid or dilute sodium
hydroxide. Dextran 40 Infusion
SYSTEM SUITABILITY Dextran 40 Injection, Dextran 40 Intraven
Action and use
Plasma substitute.
to dexamethasone sodium phosphate and dexamethasone is
at least 10.0. DEFINITION
DETERMINATION OF CONTENT Dextran 40 Infusion is a sterile solution containing Dextran
Calculate the content of C,,H2.3FNa,OgP using the declared 40 for Injection in Glucose Infusion or in Sodium Chloride
content of C..H»sFNa.OgP in dexamethasone sodium Infusion. It is supplied as a ready-to-use solution.
phosphate BPCRS and the declared content of C,H».FOs in The infusion complies with the requirements stated under
dexamethasone BPCRS. Each mg of Cz2H29FOs is equivalent Parenteral Preparations and with the following requirements.
to 1.3158 mg of C,,H»gFNa,OsP.
Content of dextrans
Calculate the total content of C,H ,3,FNa,Og¢P in the oral 9.0 to 11.0% w/v.
solution from the equivalent amount of dexamethasone
sodium phosphate due to Free dexamethasone and CHARACTERISTICS
a
ae
aw ee
we combining this with the content of dexamethasone sodium An almost colourless, slightly viscous solution.
ays “m
2Ose
ere
phosphate.
woe
II-450 Dextran 70 Preparations 2016
TESTS Content of glucose

Acidity For solutions in Glucose Infusion, 4.5 to 5.5% w/v, when
Titrate 25 mL with 0.01M sodium hydroxide VS using phenol determined by the following method. Dilute 15 mL to
red solution as indicator. Not more than 2.0 mL of 50 mL with water. To 5 mL in a stoppered flask add 25 mL
0.01M sodium hydroxide VS is required to neutralise the of a buffer solution containing 14.3% w/w of sodium carbonate
solution. and 4.0% w/v of potassium todide and 25 mL of 0.05M todine
Molecular size VS. Stopper the flask, allow to stand for exactly 30 minutes
For solutions in Glucose Infusion, before proceeding with at 20°, add 35 mL of 2m hydrochloric acid and titrate
tests A, B and C add 4 volumes of ethanol (96%), centrifuge immediately with 0.1M sodium thiosulfate VS. Repeat the
and dissolve the residue in sufficient Sodium Chloride operation using 5 mL of water beginning at the words ‘add
Infusion to restore the original volume. 25 mL...’. The difference between the titrations represents
the amount of iodine required to oxidise the glucose. Each
ifié.the viscosities, Appendix V H, Method I, at
mL, of 0.05m todine VS is equivalent to 9.01 mg of glucose.
AN ela
37°, usi a ‘ viscometer (size C) of solutions in saline
solution coritainig Bacterial endotoxins
Dextrans, acer The endotoxin limit concentration is 1.25 ITU per mL,
1 for the meniscus to fall from E to Appendix XIV C.
xamined by the time taken using ASSAY
Gn plot (viscosity ratio —
‘
For solutions in Glucose Infusion

ts
1.00)/concentration against co céntration. The intercept on

‘
Add 0.05 mL of 5m ammonia to the required volume and

oo
the viscosity ratio axis of a s ine through the points measure the optical rotation, Appendix V F. Calculate the
ait
an
represents the intrinsic visco content of dextrans from the expression

0.16 to 0.20. 0.5076(a — 0.528D)
state fete
where « is the observed angular rotation and D is the content

contain 6% w/v of Dextrans. Place 100 mly of glucose as a percentage w/v determined in the test for
stoppered flasks and adjust the temperatui £02 Content of glucose.
Maintaining this temperature, add slowly with..¢
For solutions in Sodium Chloride Infusion
(about 45 mL). To the separate flasks add 0.5, 1.0 Measure the optical rotation, Appendix V F, and multiply the
and 2.5 mL of absolute ethanol, stopper the flasks and value obtained by 0.5076.
immerse in a water bath at about 35°, shaking occasionall, STORAGE
until clear solutions are obtained. Transfer the flasks toa 40 Infusion should not be exposed to undue
water bath maintained at 24.9° to 25.1° and allow to stand ns of temperature.
overnight or until two clear liquid phases are formed. Discard —
the supernatant liquids, dissolve separately the syrupy
h is stated as the percentage w/v of dextrans.
residues in sufficient saline solution to produce 25.0 mL,
remove the ethanol by evaporation at a pressure of 2 kPa,
states (1) the name of the solvent; (2) that the
infusign. sk ot be used if it is cloudy or if a deposit is
dilute to 25.0 mL with water and determine the optical
rotation, Appendix V F. From the optical rotations calculate
present. : |
the amounts of dextrans precipitated as described in the
Assay. Choose that fraction containing as nearly as possible
but not more than 10% of the dextrans present in the
infusion and determine its intrinsic viscosity by the method Dextran 70 Infusioi
described under test A using a U-tube viscometer (size A).
Dextran 70 Injection, Dextran 79 Intravenous Infusion
The intrinsic viscosity is not more than 0.27.
C. Place in each of four stoppered flasks 100 mL of the Action and use
diluted infusion in saline solution containing 6% w/v of Plasma substitute.
aie Dextrans and add slowly, with continuous stirring, 80, 90,
100 and 110 mL respectively of absolute ethanol. Stopper the DEFINITION
flasks, transfer to a water bath maintained at 24.9° to 25.1° Dextran 70 Infusion is a sterile solution contin xtran
and allow to stand overnight or until two clear liquid phases 70 for Injection, in Glucose Infusion or in Soditg
are formed. Separate the supernatant solutions from the Infusion. It is supplied as a ready-to-use solution.
syrupy residues. Remove the ethanol from each supernatant The infusion complies with the requirements stated under
solution separately by evaporation at a pressure of 2 kPa, Parenteral Preparations and with the following requirements.
eS dialyse in cellophane tubing against water to remove sodium
Content of dextrans
enw a
chloride, adjust the volume to 25.0 mL with water, add

5.5 to 6.5% w/v.
Awe wa
sufficient sodium chloride to produce solutions containing

0.9% w/v and determine the optical rotation, Appendix V F. CHARACTERISTICS
From the optical rotations calculate the amounts of dextrans An almost colourless, slightly viscous solution.
present as described in the Assay. Choose that fraction
TESTS
containing as nearly as possible but not more than 10% of
Acidity
the dextrans present in the infusion and determine the
Titrate 25 mL with 0.01m sodium hydroxide VS using phenol
intrinsic viscosity by the method in test A above.
red solution as indicator. Not more than 1.25 mL of
The intrinsic viscosity is not less than 0.08.
0.01m sodium hydroxide VS is required to neutralise the
solution.
we end
2016 Dextromoramide Preparations III-451
Molecular size ‘add 25 mL...’. The difference between the titrations

For solutions in Glucose Infusion, before proceeding with represents the amount of iodine required to oxidise the
pats
tests A, B and C add 4 volumes of ethanol (96%), centrifuge glucose. Each mL of 0.05m 1todine VS is equivalent to
and dissolve the residue in sufficient Sodium Chloride 9.01 mg of glucose.
NN as
Infusion to restore the original volume. Bacterial endotoxins

A. Determine the viscosities, Appendix V H, Method I, at The endotoxin limit concentration is 1.21 IU per mL,
37°, using a U-tube viscometer (size C) of solutions in saline Appendix XIV C.
solution containing about 3.5, 2.5, 1.5 and 0.75% w/v of
ASSAY
Dextrans, accurately determined. Calculate the viscosity ratio
For solutions in Glucose Infusion
by dividing the time taken for the meniscus to fall from E to
Add 0.05 mL of 5m ammonia to the required volume and
F using the liquid being examined by the time taken using
measure the optical rotation, Appendix V F. Calculate the
salinesolugjon.For each solution plot (viscosity ratio —
content of dextrans from the expression
Cm Ne
encer n against concentration. The intercept on
a
vivte wid
0.5076(a — 0.528D)
where « is the observed angular rotation andD is the content
of glucose as a percentage w/v determined in the test for
Content of glucose.
For solutions in Sodium Chloride Infusion
Measure the optical rotation, Appendix V F, and multiply the
absolute ethanol to produce ‘loudiness (about 45 mL). value obtained by 0.5076.
To the separate flasks add 5 2.0 and 2.5 mL of
STORAGE
Dextran 70 Infusion should not be exposed to undue
fluctuations in temperature.
LABELLING |
The strength is stated as the percentage w/v of dextrans.
The label states (1) the name of the solvent; (2) that the
saline solution to produce 25.0 mL, remove the*ethanol'b infusion should not be used if it 1s cloudy or if a deposit is
evaporation at a pressure of 2 kPa, dilute to 25.0 mL present.
water and determine the optical rotation, Appendix V‘F. F
the optical rotations calculate the amounts of dextrans
precipitated as described in the Assay. Choose that fracti
containing as nearly as possible but not more than 10% of i ‘omoramide Tablets
the dextrans present in the infusion and determine its
intrinsic viscosity by the method described under test A using
a U-tube viscometer (size A). The intrinsic viscosity is not
more than 0.36.
C. Dilute the solution being examined with saline solution to
contain 6% w/v of Dextrans. Place 100 mL in each of four
stoppered flasks and add slowly, with continuous stirring, 80,
90, 100 and 110 mL respectively of absolute ethanol. Stopper
the flasks, transfer to a water bath maintained at 24.9° to
25.1° and allow to stand overnight or until two clear liquid
phases are formed. Separate the supernatant solutions from IDENTIFICATION
the syrupy residues. Remove the ethanol from each
A. Shake a quantity of the powdde
supernatant solution separately by evaporation at a pressure
equivalent of 30 mg of dextromor
of 2 kPa, dialyse in cellophane tubing against water to remove
sodium chloride, adjust the volume to 25.0 mL with water,
add sufficient sodium chloride to produce solutions containing
0.9% w/v and determine the optical rotation, Appendix V F.
From the optical rotations calculate the amounts of dextrans
present as described in the Assay. Choose that fraction
the reference spectrum of dextromoramide (RS con
containing as nearly as possible but not more than 10% of
the dextrans present in the infusion and determine the B. Shake a quantity of the powdered tablets containing the
intrinsic viscosity by the method in test A. The intrinsic equivalent of 25 mg of dextromoramide with 25 mL of
aay
viscosity is not less than 0.13. 1m hydrochloric acid and filter. The light absorption of the
resulting solution, Appendix IT B, in the range 230 to
Content of glucose 350 nm exhibits maxima at 254, 259 and 264 nm.
For solutions in Glucose Infusion, 4.5 to 5.5% w/v, when
determined by the following method. Dilute 15 mL to TEST
50 mL with water. To 5 mL in a stoppered flask add 25 mL Related substances
of a buffer solution containing 14.3% w/v of sodium carbonate Carry out the method for thin-layer chromatography,
and 4.0% w/v of potassium iodide and 25 mL of 0.05m todine Appendix III A, using the following solutions.
VS. Stopper the flask, allow to stand for exactly 30 minutes (1) Shake a quantity of the powdered tablets containing the
at 20°, add 35 mL of 2M hydrochloric acid and titrate equivalent of 20 mg of dextromoramide with 1 mL of
we ee
aN
era immediately with 0.1m sodium thiosulfate VS. Repeat the methanol for 5 minutes, centrifuge and use the supernatant
operation using 5 mL of water and beginning at the words liquid.
Por le ne
IWI-452 Dextropropoxyphene Preparations 2016
(2) Dilute 1 volume of solution (1) to 100 volumes with C. Evaporate 0.4 mL ona piece of filter paper and burn the
methanol. residue by the method for oxygen-flask combustion,
Appendix VIII C, using 5 mL of 1.25m sodium hydroxide as
vee inte
the absorbing liquid. When the process is complete, dilute
the liquid to 25 mL with water. To 5 mL of the solution so
(b) Use the mobile phase as described below. obtained add 1 mL of hydrogen peroxide solution (100 vol) and
(c) Apply 10 wL of each solution. 1 mL of 1m hydrochloric acid, mix and add 0.05 mL of barium
(d) Develop the plate to 15 cm. chloride solution. The solution becomes turbid.
(e) After removal of the plate, dry in air, spray with dilute ASSAY
potassium iodobismuthate solution. Stir a quantity of the mixed contents of 20 capsules
MOBILE PHASE containing the equivalent of 0.5 g of dextropropoxyphene
with 25 mL of chloroform and filter through absorbent cotton,
washing the flask and filter with small quantities of chloroform.
Add to the combined filtrates a mixture of 50 mL of water
and 5 mL of 5M sodium hydroxide, shake, allow the layers to
»intense than the spot in the separate and wash the chloroform extract with 25 mL of
chromatogram ob ith solution (2). water. Extract the aqueous layer with five 25 mL quantities of
ASSAY chloroform, washing each extract with the 25 mL of water and
adding it to the original extract. Dry the combined extracts
with anhydrous sodium sulfate, evaporate to about 3 mL ona
water bath in a current of air, remove from the water bath
and allow to evaporate to dryness at room temperature.
Appendix VIII A, on the residue using crystal violet solution as
the combined chloroform extracts with quantities
indicator. Each mL of 0.1M perchloric acid VS is equivalent to
of water and extract the combined wash 10 mL of
33.95 mg of Co2H.9NOrz.
dbrough
absorbent cotton moistened with chloroform and.awash th LABELLING
filter with a small quantity of chloroform. Heat on a.aWat The quantity of active ingredient is stated in terms of the
bath until the volume is reduced to about 25 mL, c equivalent amount of dextropropoxyphene.
50 mL of anhydrous acetic acid, previously neutralised to
crystal violet solution, and titrate with 0.02m perchloric acid
using crystal violet solution as indicator. Each mL of
0.02m perchloric acid VS is equivalent to 7.851 mg of
C25H32N20>.
LABELLING
equivalent amount of dextromoramide.
Diamorphine Injécti
Hydrochloride in Wé
Dextropropoxyphene Capsules dissolving Diamorphiri
requisite amount of W
Action and use use.
seas 4
Opioid receptor agonist; analgesic. The injection complies with the

DEFINITION
STORAGE
Dextropropoxyphene Capsules contain Dextropropoxyphene
Diamorphine Injection deteriorates on
Napsilate.
used immediately after preparation.
Content of dextropropoxyphene, C,,H, .9NO,
DIAMORPHINE HYDROCHLORIDE FOR
92.5 to 107.5% of the stated amount. INJECTION
ye Ne
IDENTIFICATION DEFINITION
Shake a quantity of the contents of the capsules containing Diamorphine Hydrochloride for Injection is a sterile material
the equivalent of 0.15 g of dextropropoxyphene with 5 mL of prepared from Diamorphine Hydrochloride with or without
chloroform and filter. The filtrate complies with the following excipients. It is supplied in a sealed container.
tests. The contents of the sealed container comply with the requirements
A. Evaporate 3 mL to dryness and dry the residue at 105° for Powders for Injections or Infusions stated under Parenteral
se ee
for 1 hour. The infrared absorption spectrum of the residue,

Appendix IT A, is concordant with the reference spectrum of Content of diamorphine hydrochloride,
dextropropoxyphene napsilate (RS 092). C,,H,3NO;,HCI1,H,O
B. Evaporate 0.05 mL in a porcelain dish and streak the spot 95.0 to 105.0% of the stated amount.
Sty
Oe ae
rae nd
with sulfuric acid containing 0.05 mL of formaldehyde solution
em
per mL. A purple colour is produced.
Rae Co a a a SL Te ET ee a es aS at en ate at . Seth doa dts
Pelee
2016 Diamorphine Preparations III-453
IDENTIFICATION Appendix IT B, and calculate the content of

Dissolve a sufficient quantity of the contents of the sealed C2;H23NO5,HCI,H2O in each container by comparing the
container in the minimum volume of dichloromethane and absorbances with that obtained by treating a mixture of 5 mL
275
+ AN A
evaporate to dryness. The infrared absorption spectrum of the of a 0.015% w/v solution of anhydrous morphine in
Nw NY
residue, Appendix II A, is concordant with the reference Im hydrochloric acid and 5 mL of water in the same manner,
spectrum of diamorphine hydrochloride (RS 093). beginning at the words ‘add 5 mL of a freshly prepared...’.
Each g of anhydrous morphine is equivalent to 1.486 g of
TESTS
C,,H23NO;5,HCI,H,O. Calculate the average content of
6-O-Acetylmorphine
C3,;H23NOs5,HCI,H.O per container from the 10 individual
results thus obtained.
(1)Dissolve a quantity of the contents of the sealed container STORAGE
2 g of Diamorphine Hydrochloridein 10 mL of The sealed container should be protected from light.
ANA N IMPURITIES
a are
The impurity limited by the requirements of this monograph

is:
(a) Usea stainless steel co x

with octylsilyl silica gel for ch
RP-select B is suitable).
(b) Use isocratic elution and the mobi
below.
A. 6-O-Acetylmorphine.
MOBILE PHASE
morphine Tablets
0.11% w/v of sodium octanesulfonate in a mixture of
10 volumes of glacial acetic acid, 10 volumes of methanol, and use
115 volumes of acetonitrile and 365 volumes of water. eptor agonist analgesic.
SYSTEM SUITABILITY
The chromatogram obtained with solution (3) exhibits two
secondary peaks with retention times relative to the principal
peak of about 0.23 (morphine) and 0.43 (6-O-acetyl-
morphine). The test is not valid unless the resolution factor é
between the peaks due to morphine and 6-O-acetyl-morphine Content of dian
.
,;,HCI,
is at least 2. C,,H,3NO
95.0 to 105.0% of the
LIMITS
IDENTIFICATION
the area of any peak corresponding to 6-O-acetylmorphine is
not greater than the area of the peak in the chromatogram
dichloromethane, filter and evaporate t
absorption Spectrum of the residue, Ap
The content of C2;H23NO;5,HCI,H2O in each of 10 hydrochloride (RS 093).
individual containers as determined in the Assay is not less
TESTS
than 90.0% and not more than 110.0% of the average except
Dissolution
that in one container the content may be not less than 80.0%
and not more than 120.0% of the average. Comply with the requirements in the dissolution test for tablets
ASSAY
TEST CONDITIONS
Dissolve the contents of a sealed container in a suitable
volume of water and dilute with sufficient water to produce a (a) Use Apparatus 2, rotating the paddle at 50 revolutions
solution containing 0.025% w/v of Diamorphine per minute.
Hydrochloride. To 5 mL add 5 mL of 1m hydrochloric acid (b) Use 900 mL of 0.1m hydrochloric acid, at a temperature of
and boil vigorously under a reflux condenser for 15 minutes. 37°, as the medium.
Cool, add 5 mL ofa freshly prepared 0.5% w/v solution of PROCEDURE
sodium nitrite, mix and add 2.5 mL of 5M ammonia and
sufficient water to produce 25 mL. Repeat the operation with
a further nine sealed containers. Measure the absorbance of
each of the resulting solutions at the maximum at 435 nm,
filter. Use the filtered medium, diluted with water if
IlIJ-454 Diazepam Preparations
necessary, to produce a solution expected to contain SYSTEM SUITABILITY

0.0011% w/v of Diamorphine Hydrochloride. The chromatogram obtained with solution (3) exhibits two
(2) 0.0011% w/v of diamorphine hydrochloride BPCRS in the secondary peaks with retention times relative to the principal
dissolution medium. peak of about 0.23 (morphine) and 0.43 (6-O-acetyl-
morphine). The test is not valid unless the resolution between
the peaks due to morphine and 6-O-acetyl-morphine is at
(a) Use a stainless steel column (25 cm x 4.6 mm) packed least 2.0.
LIMITS
(b) Use isocratic elution and the mobile phase described In the chromatogram obtained with solution (1):
below. the area of any peak corresponding to 6-O-acetylmorphine is
1 mL per minute.
(c) Use a flow rate of
not greater than twice the area of the principal peak in the
n temperature of 30°.
the area of any other secondary peaks is not greater than twice
(e) Use a tection vavelength of 260 nm.
greater than half the area of the principal peak in the
ASSAY
hydrochloride BPCRS. liquid chromatography, Appendix III D, using the following
LIMITS solutions.
The amount of diamorphine hydrochloride releaée (1) Disperse a quantity of the powdered tablets containing
less than 75% (Q) of the stated amount. 30 mg of Diamorphine Hydrochloride in water, dilute to
100 mL with water.
Related substances
Carry out the method for liquid chromatography, (2) 0.03% wiv of diamorphine hydrochloride BPCRS in water.
Appendix III D, using the following solutions. VLATOGRAPHIC CONDITIONS
(1) Disperse a quantity powdered tablets containing 80 mg of | atographic conditions described under Dissolution
Diamorphine Hydrochloridein 10 mL of water. d with an injection volume of 10 uL.
water.
(3) Disperse a quantity of the powdered tablets to give a
solution containing 0.1% w/v of Diamorphine Hydrochloride
in 0.01m sodium hydroxide; the solution should be freshly
prepared.
(4) Dilute 1 volume of solution (2) to 10 volumes with water.
of this
RP-select B is suitable).
monograph those listed under Diamoarp.
below.
Diazepam Injection
(f) Inject 50 wL of each solution. Action and use
aaa
(g) For solution (1), allow the chromatography to proceed Benzodiazepine.
wey te
PA, eS
for twice the retention time of the peak due to diamorphine.
DEFINITION
i ae
MOBILE PHASE
Diazepam Injection is a sterile solution of Diazepam in Water
0.11% w/v of sodium octanesulfonate in a mixture of for Injections or other suitable solvent.
10 volumes of glacial acetic acid, 10 volumes of methanol, The injection complies with the requirements stated under
115 volumes of acetomtrile and 365 volumes of water. Parenteral Preparations and with the following requirements.
Content of diazepam, C,¢H,;CIN,O
conditions the retention time of diamorphine is about
20 minutes.
IDENTIFICATION
A. The light absorption, Appendix II B, of the solution
obtained in the Assay exhibits a maximum at 368 nm.
rom ow asl
2016 Diazepam Preparations III-455
B. Complies with test B for Identification described under solvent front to ascend 12 cm above the line of application.
Diazepam Tablets applying separately to the plate 10 pL of Apply separately to the plate 25 yL of each of the following
each of the following solutions. For solution (1) dilute a solutions. For solution (1) add 40 mL of water to a volume
suitable volume of the injection with sufficient methanol to of the oral solution containing 8 mg of Diazepam and extract
produce a solution containing 0.10% w/v of Diazepam. with three 50-mL quantities of ether. Wash the combined
Solution (2) contains 0.10% w/v of diazepam BPCRS in ether extracts with 30 mL of 1m sodium hydroxide followed by
methanol. two 40 mL quantities of water. Shake the extract with
anhydrous sodium sulfate, filter, evaporate to dryness and
TESTS
dissolve the residue in 2 mL of ethanol (96%). Solution (2)
contains 0.0080% w/v of 5-chloro-2-
methylaminobenzophenone BPCRS in ethanol (96%). Solution
(3) contains 0.0040% w/v of 3-amino-6-chloro-1-methyl-4-
phenylquinolin-2-ol BPCRS in ethanol (96%). For solution (4)
er DH 7.0 and extract with four 20 mL dilute 2 mL of solution (1) to 100 mL with ethanol (96%)
quantities « ‘form, passing each extract through the and dilute 1 mL of the resulting solution to 10 mL with the
same 5 g of same solvent. After removal of the plate, allow it to dry in air
and examine under ultraviolet light (254 nm). In the
dissolve the residue i corresponding to 5-chloro-2-methylaminobenzophenone is
acid, mix and measure ‘th: not more intense than the spot in the chromatogram
at the maximum at 368 n obtained with solution (2) and any spot corresponding to
content of C,;,H)3CIN.O takiz 3-amino-6-chloro-1-methyl-4-phenylquinolin-2-ol is not more
A(1%, 1 cm) at the maximum intense than the spot in the chromatogram obtained with
STORAGE é solution (3). Any other secondary spot in the chromatogram
obtained with solution (1) is not more intense than the spot
Diazepam Injection should be protected
in the chromatogram obtained with solution (A).
ASSAY
To a weighed quantity containing 1 mg of Diazepam add
25 mL of a mixture of equal volumes of 1M sodium hydroxide
Diazepam Oral Solution and methanol and shake for 2 minutes. Extract with five
25 mL quantities of chloroform, shaking for 2 minutes each
Action and use
Combine the chloroform extracts, shake with 5 g of
Benzodiazepine.
sodium sulfate and filter. Evaporate to dryness,
DEFINITION e residue in 25 mL of 0.1m methanolic sulfuric acid
‘Measure the absorbance of the filtrate,
Diazepam Oral Solution is a solution of Diazepam in a
kpependix [LeB, at the maximum at 368 nm. Calculate the
con CiéH3CIN2O taking 151 as the value of
AU%, 1 ¢ 1 aximum at 368 nm. Determine the
weight per m al solution, Appendix V G, and
Content of diazepam, C,,H,;CIN,O calculate the c Ci6H13CIN2O, weight in volume.
STORAGE
IDENTIFICATION Diazepam Oral Solu | be protected from light.
400 nm of the final solution obtained in the Assay exhibits a
maximum at 368 nm. The light absorption in the range 230 to
330 nm of a solution prepared by diluting 1 volume of the
final solution obtained in the Assay to 5 volumes with Diazepam Rectal Solut
0.1m methanolic sulfunc acid exhibits two maxima, at 243 nm
and 286 nm. Action and use
Benzodiazepine.
B. Carry out the method described under Related substances
applying separately to the plate 10 wL of each of solution (1) DEFINITION :
and solution (2) and using as solution (2) a 0.4% w/v Diazepam Rectal Solution is a solution of Diazepam in a
solution of diazepam BPCRS in ethanol (96%). After removal suitable vehicle.
of the plate, allow the solvent to evaporate and examine
The rectal solution complies with the requirements stated under
under ultraviolet hght (254 nm). The principal spot in the
Rectal Preparations and with the following requirements.
in the chromatogram obtained with solution (2). Content of diazepam, C,,H,3;CIN,O
TESTS
Acidity IDENTIFICATION
pH, 4.0 to 6.6, Appendix V L. A. The light absorption, Appendix II B, of the solution
obtained in the Assay exhibits a maximum at 368 nm.
Related substances
Carry out in subdued light the method for thin-layer B. Carry out the method for thin-layer chromatography,
chromatography, Appendix III A, using silica gel GF254 as the Appendix III A, using szica gel G as the coating substance
©an iw ~.
Me
sa
w 4 coating substance and a mixture of equal volumes of ethyl and a mixture of 10 volumes of methanol and 100 volumes of
acetate and hexane as the mobile phase but allowing the chloroform as the mobile phase. Apply separately to the plate
II-456 Diazepam Preparations 2016
10 pL of each of the following solutions. For solution (1) CONFIRMATION
NN
dilute a suitable volume of the rectal solution with sufficient The principal spot in the chromatogram obtained with
re me,
wewwed methanol to produce a solution containing 0.10% w/v of solution (1) corresponds to that in the chromatogram
waa
| Diazepam. Solution (2) contains 0.10% w/v of | obtained with solution (2).
diazepam BPCRS in methanol. After removal of the plate,
TESTS
spray it with a 10% v/v solution of sulfuric acid in absolute
Related substances and decomposition products
ethanol, heat at 105° for 10 minutes and examine under
ultraviolet ight (365 nm). The principal spot in the Carry out the procedure in subdued light. Carry out the
method for thin-layer chromatography, Appendix III A, using
the following solutions in ethanol (96%).
50 mg of Diazepam with 5 mL of solvent, filter and use
AAAS immediately.
rete
(2) Dilute 1 volume of solution (1) to 50 volumes and use

seen nl
AAA,
weeee
immediately.
10 mg of Diazepam add 20 mL of
7.0 and extract with four 20 mL
(a) Use as the coating silica gel Fz54.
dium ulfate. Combine the (b) Use the mobile phase as described below.
3 0@.mL with chloroform and (c) Apply 20 uL of solution (1) and 5 uL of solution (2).
yee
mix. Evaporate 10 mL to ‘ (d) Develop the plate to 12 cm.
dissolve the residue in 25 m
(e) After removal of the plate, allow the solvent to evaporate
and examine under witraviolet light (254 nm).
peewee
g 151 ds MOBILE PHASE

content of Ci¢6H,3CIN,O takin
nni Equal volumes of ethyl acetate and hexane.
A(1%, 1 cm) at the maximum at 368
STORAGE : LIMITS
Diazepam Rectal Solution should be protected from i Any secondary spot in the chromatogram obtained with
ys Ney
Diazepam Tablets
Action and use
weed Benzodiazepine.
DEFINITION
Diazepam Tablets contain Diazepam.
The tablets comply with the requirements stated under Tablets and 37°, as the medi
vv yee
PROCEDURE
Content of diazepam, C,;H,3;CIN,O
92.5 to 107.5% of the stated amount. (1) After 45 minutes withd
measure the absorbance of
wees
IDENTIFICATION
ween

ween
350 nm of the final solution obtained in the Assay exhibits
two maxima, at 242 nm and 284 nm.
VATS
ae
Calculate the total content of diazepam,
the medium taking 488 as the value of A(1%, 1 ¢
(1) Shake a quantity of the powdered tablets with sufficient maximum at 286 nm. ‘
--3t-
solvent to produce a solution containing 0.50% w/v of
Diazepam, allow to settle and decant the supernatant liquid.
(2) 0.5% wy of diazepam BPCRS. of Diazepam comply with the requirement stated under
CHROMATOGRAPHIC CONDITIONS Tablets using the following method of analysis. To one tablet
(a) Use as the coating silica gel G. add 1 mL of water, allow the tablet to disintegrate and stand
(b) Use the mobile phase as described below. for 15 minutes. Add 80 mL of a 0.5% w/v solution of sulfuric
Navas
acid in methanol, shake for 15 minutes, add sufficient of the

PRA
rina
methanolic sulfuric acid to produce 100 mL and filter.
weet es
(d) Develop the plate to 15 cm. Measure the absorbance of the filtrate at the maximum at
(e) After removal of the plate, spray it with a 10% v/v 284 nm, Appendix II B. Calculate the content of
Ve
mA
solution of sulfuric acid in absolute ethanol, heat at 105° for C16H,3CIN2O taking 450 as the value of A(1%, 1 cm) at the
10 minutes and examine under ultraviolet light (365 nm). maximum at 284 nm.
aver ed
aA
were
MOBILE PHASE
vtetete ete
10 volumes of methanol and 100 volumes of chloroform.
wey eee
ce NAN
Aree
au .
2016 Diazoxide Preparations II-457
ASSAY CONFIRMATION
Weigh and powder 20 tablets. To a quantity of the powder The principal spot in the chromatogram obtained with
containing 10 mg of Diazepam add 5 mL of water, mix and solution (1) corresponds in position and colour to that in the
allow to stand for 15 minutes. Add 70 mL of a 0.5% wiv chromatogram obtained with solution (2).
solution of sulfuric acid in methanol, shake for 15 minutes, add
TESTS
sufficient of the methanolic sulfuric acid to produce 100 mL
Alkalinity
and filter. Dilute 10 mL of the filtrate to 50 mL with the
same solvent and measure the absorbance of the resulting
solution at the maximum at 284 nm, Appendix II B. Related substances
Calculate the content of C,,H,3CIN.2O taking 450 as the Carry out the method for thin-layer chromatography,
value of A(1%, 1 cm) at the maximum at 284 nm. Appendix III A, using the following solutions.
STORAGE (1) Use the injection diluted, if necessary, with 0.1m sodium
hydroxide to contain 1.5% w/v of Diazoxide.
Dia “ ablets should be protected from light.
0.1M sodium hydroxide.

Diazoxide it
Action and use * (c) Apply 5 pL of each solution.
Vasodilator; treatment (d) Develop the plate to 15 cm.
DEFINITION | & (e) After removal of the plate, allow it to dry in air and
Diazoxide Injection is a steri Diazoxide in Water examine under ultraviolet light (254 nm).
for Injections, prepared with the ai Hydroxide. MOBILE PHASE
The injection complies with the requirements site 7 volumes of 18m ammonia, 25 volumes of methanol and
Parenteral Preparations and with the followtrigs 68 volumes of chloroform.
Content of diazoxide, C;H,CIN,O,S LIMITS
95.0 to 105.0% of the stated amount. Any secondary spot in the chromatogram obtained with
CHARACTERISTICS solution (1) is not more intense than the spot in the
A colourless solution. chromatogram obtained with solution (2) (0.5%).
IDENTIFICATION
To a volume containing 0.3 g of Diazoxide add 2 mL of olume containing 75 mg of Diazoxide add sufficient
2M hydrochloric acid, stir, filter the precipitate and wash the a um hydroxide to produce 500 mL. Dilute 5 mL to
filter thoroughly with water until the filtrate is free from acid.
The precipitate, after drying at 105°, complies with the
following tests.
concordant with the reference spectrum of diazoxide (RS 094).
B. The light absorption, Appendix II B, in the range 230 to STORAGE
350 nm of a 0.001% w/v solution in 0.1m sodium hydroxide Diazoxide Injection protected from light.
C. Carry out the method for thin-layer chromatography,
(1) Use the injection, diluted if necessary, with methanol to Diazoxide Tablets
contain 0.02% w/v of Diazoxide.
(2) 0.02% w/v of diazoxide EPCRS in methanol. Action and use
Vasodilator; treatment of hypertension.
(a) Use as the coating silica gel GF 54. DEFINITION

(b) Use the mobile phase as described below. Diazoxide Tablets contain Diazoxide.
(c) Apply 5 wL of each solution. The tablets comply with the requirements stated under Tablets and
(d) Develop the plate to 15 cm. with the following requirements.
(e) After removal of the plate, allow it to dry in air until the Content of diazoxide, CgH,CIN,O,S
solvent has evaporated, examine under ultraviolet hght 92.5 to 107.5% of the stated amount.
(254 nm) and then treat the plate by Method I and examine IDENTIFICATION
again. Shake a quantity of the powdered tablets containing 0.2 g of
MOBILE PHASE Diazoxide with 50 mL of absolute ethanol, filter and evaporate
20 volumes of acetone, 30 volumes of ether and 50 volumes of the filtrate to dryness at a pressure of 2 kPa. The residue
toluene. complies with the following tests.
350 nm of a 0.001% w/v solution in 0.1m sodium hydroxide
I-458 Dichlorophen Preparations 2016

Dichlorophen Tablets
(1) 0.02% w/v of the residue in methanol. Action and use
(2) 0.02% w/v of diazoxide EPCRS in methanol. Antihelminthic.
DEFINITION
(a) Use silica gel GF254 as the coating. Dichlorophen tablets contain Dichlorophen.
(b) Use the mobile phase as described below. The tablets comply with the requirements stated under Tablets and
(c) Apply 20 uwL of each solution. with the following requirements.
(d) Develop the plate to 15 cm. Content of dichlorophen, C,3;H; )ClLO,
(e) After removal of the plate, dry in air until the solvent has 95.0 to 105.0% of the stated amount.
Meter NS
IDENTIFICATION
of dichlorophen with 50 mL of 0.1M sodium hydroxide for
20 volumes of aé 15 minutes, add sufficient 0.1m sodium hydroxide to produce
of toluene. 100 mL, centrifuge and dilute a suitable volume of the
supernatant liquid with 0.1m sodium hydroxide to produce a
CONFIRMATION
solution containing 0.002%w/v of dichlorophen. The light
The principal spot in the’¢h ategram obtained with absorption of the resulting solution, Appendix II B, in the
solution (1) corresponds in intensity to that in the range 220 to 350 nm exhibits two maxima, at 245 nm and
chromatogram obtained with so} 304 nm. The absorbances at the maxima are about 1.3 and
sete NG TEST about 0.54, respectively.
Related substances é B. Shake a quantity of the powdered tablets containing 0.2 g
Carry out the method for thin-layer chroma of dichlorophen with a mixture of 5 mL of water and 5 mL
Appendix III A, using the following solutions of 5m sodium hydroxide, filter, cool in ice and add a solution
(1) Shake a quantity of the powdered tablets cox prepared by mixing 1 mL of sodium nitrite solution with a cold
0.75 g of Diazoxide with 40 mL of 0.1M sodium hydr solution containing 0.15 mL of amine in a mixture of 4 mL
30 minutes, filter and dilute the filtrate to 50 mL wit of water and 1 mL of hydrochloric acid. A reddish brown
0.1M sodium hydroxide. precipitate is produced.
(2) Dilute 1 volume of solution (1) to 200 volumes with Fuse a quantity of the powdered tablets containing 0.5 g
0.1M sodium hydroxide. erophen with 2 g of anhydrous sodium carbonate, cool,
residue with water and filter. The filtrate yields
characteristic of chlorides, Appendix VI.
(a) Use a TLC sihca gel GF 254 plate.
(e) After removal of the plate, dry in air and examine under th 20 mL of methanol for
ultraviolet light (254 nm). : f water and dilute to 50 mL
MOBILE PHASE
7 volumes of 18M ammonia, 25 volumes of methanol and Solution (3) contains 0.001
68 volumes of chloroform. mobile phase.
LIMITS The chromatographic procedure maybe ied out using
Any secondary spot in the chromatogram obtained with (a) a stainless steel column (20 cm packed with
solution (1) is not more intense than the spot in the octadecylsilyl silica gel for chromatograp
of 1.5 mL per minute a mixture of 1 volume gf glagjal..acetic
ASSAY
acid and 25 volumes of water and sufficient methe :
produce a chromatogram with solution (2) closely résembling
containing 50 mg of Diazoxide add 70 mL of methanol, shake
the reference chromatogram supplied with the
for 1 hour, add sufficient methanol to produce 100 mL, mix
impurity standard (75 volumes of methanol is usually suitable)
and filter. Dilute 5 mL of the filtrate to 250 mL with
and (c) a detection wavelength of 280 nm. Record the
|
0.1M sodium hydroxide and measure the absorbance of the
chromatograms until all of the peaks named on the reference
sea

chromatogram have emerged.
Appendix II B. Calculate the content of CgH7CIN,O.S
taking 585 as the value of A(1%, 1 cm) at the maximum at In the chromatogram obtained with solution (1) the area of
280 nm. any peak corresponding to 4-chlorophenol is not greater than
with solution (3) (0.1%). Calculate the content of
4,4'-dichloro-2,2'-(2-hydroxy-4-chloro-m-xylene-o,0’-
diyl)diphenol and the sum of the nominal contents of any
other impurities, excluding 4-chlorophenol, with reference to
Daw AA
aes fete]
dichlorophen using the declared content of 4,4’-dichloro-
Sit
owe
hey
sg
hw ol 2,2'-(2-hydroxy-4-chloro-m-xylene-a,«'-diyl)diphenol in
i~!
oe
2016 Diclofenac Preparations IJI-459
dichlorophen impurity standard BPCRS. The content of (2) Dilute 1 volume of solution (1) to 100 volumes with
4,4'-dichloro-2,2'-(2-hydroxy-4-chloro-m-xylene-0,0'~ solvent A and dilute 1 volume of this solution to 5 volumes
diyl)diphenol does not exceed 8.0% w/w and the sum of the with solvent A.
nominal contents of any other impurities does not exceed 2% (3) 0.0005% w/v of diclofenac sodium BPCRS and
w/w. 0.0005% w/v of diclofenac impurity A BPCRS in solvent A.
ASSAY CHROMATOGRAPHIC CONDITIONS
Weigh and powder 20 tablets. Shake a quantity of the (a) Use a stainless steel column (25 cm x 4 mm) packed
powder containing 0.1 g of dichlorophen with 50 mL of with octadecylsilyl silica gel for chromatography (5 um)
0.1m sodium hydroxide for 15 minutes and add sufficient (Lichrospher RP Select B or equivalent is suitable).
0.1m sodium hydroxide to produce 100 mL. Centrifuge, dilute
10 mL of the clear supernatant liquid to 100 mL with
below.
hydroxide, dilute 20 mL of this solution to
vane
O.km sodium hydroxide and measure the (c) Use a flow rate of 1.5 mL per minute.
-esulting solution at the maximum at (d) Use ambient column temperature.
II B. Calculate the content of (e) Use a detection wavelength of 230 nm.
C13H)9Cl,O% takie 75 as the value of A(1%, 1 cm) at the (f) Inject 20 wL of each solution.
maximum at 30% n
MOBILE PHASE
A mixture of 5 volumes of tetrahydrofuran, 30 volumes of
acetonitrile and 65 volumes of 0.05m ammonium dihydrogen
orthophosphate, previously adjusted to pH 5.0 using
Prolonged-release ‘fenac Capsules 18M ammonia.
awoAS
Prolonged-release Diclofenac C When the chromatograms are recorded under the prescribed
manufacturers, whilst complying with t conditions, the retention times are about 18 minutes for
monograph, are not interchangeable unless tse justified and diclofenac and about 26 minutes for diclofenac impurity A.
authonised. Continue the chromatography for 5 times the retention time
DEFINITION . | of diclofenac.
Prolonged-release Diclofenac Capsules contain D. SYSTEM SUITABILITY
Sodium. They are formulated so that the medicamexit i The test is not valid unless, in the chromatogram obtained
released over a period of several hours. with solution (3), the resolution factor between the peaks
PRODUCTION . sponding to diclofenac and diclofenac impurity A is at
appropriate release of Diclofenac Sodium. The dissolution
profile reflects the 1m vivo performance which in turn is Hromatogram obtained with solution (1):
compatible with the dosage schedule recommended by the
manufacturer. k in the chromatogram obtained with
and with the following requirements. f all the secondary peaks is not greater
Content of diclofenac sodium, C,,H;>CLNNaO, the principal peak in the
95.0 to 105.0% of the stated amount. ith solution (2) (0.5%).
IDENTIFICATION Disregard any peak wi less than 0.25 times the area
Add 0.5 mL of glacial acetic acid and 15 mL of methanol to a of the principal peak in yomatogram obtained with
quantity of the powdered capsule contents containing 0.15 g solution (2) (0.05%).
of Diclofenac Sodium and mix with the aid of ultrasound for ASSAY
40 minutes. Shake gently for 1 minute, filter and collect the Dissolve 6.8 g of potasstum dihydro; osphate in
filtrate in 15 mL of water. Filter the precipitate (Whatman 1000 mL of water and adjust the pH > with 1M sodium
GF/C is suitable) under reduced pressure, wash with four hydroxide (solution A). To a quantity o
5-mL quantities of water and dry at 105° for 2 to 3 hours. of 20 capsules containing 100 mg of Diclofengs
The infrared absorption spectrum of the dried precipitate, 10 mL of ethanol (96%) and mix with the aid
Appendix II A, is concordant with the reference spectrum of for 20 minutes or until completely dispersed. Add 150 mL of
diclofenac (RS 096). solution A and mix with the aid of ultrasound for a further
TESTS 20 minutes or until completely dispersed. Cool to room
RELATED SUBSTANCES temperature, dilute to 250 mL with solution A and shake
Carry out the method for liquid chromatography, thoroughly. Filter the resulting solution and dilute 5 mL to
Appendix III D, using the following solutions. 100 mL with solution A. Prepare a reference standard in the
following manner. Dissolve 50 mg of diclofenac
To 30 volumes of acetonitnile for chromatography add
sodium BPCRS in 10 mL of ethanol (96%) with the aid of
70 volumes of water (solvent A).
ultrasound for 5 minutes. Add 150 mL of solution A and
(1) Add 30 mL of solvent A to a quantity of the powdered mix with the aid of ultrasound for a further 5 minutes. Cool
contents of the capsules containing 0.1 g of Diclofenac to room temperature, dilute to 250 mL with solution A and
Sodium and mix with the aid of ultrasound for 10 minutes shake thoroughly. Dilute 5 mL of the resulting solution to
with occasional shaking. Cool, add sufficient solvent A to 50 mL with solution A. Measure the absorbance,
produce 50 mL and filter (Whatman GF/C is suitable). Appendix II B, of the solutions at 275 nm using in the
Il-460 Diclofenac Preparations 2016
reference cell a 0.4% v/v solution of ethanol (96%) in solution (1) Shake a quantity of the gel containing 50 mg of
A. Diclofenac Diethylamine with 50 mL of acetone for
Calculate the content of C,4H;9Cl,NNaO, in the capsules 10 minutes, filter and evaporate the filtrate to dryness under
van ~~
ehgtgt ens
weSeal using the absorbances at the maximum at 275 nm and the reduced pressure. Dissolve the residue in 10 mL of a mixture
declared content of C,4H;)9Cl,ANNaOz in diclofenac of 40 volumes of water and 60 volumes of methanol, dilute
sodium BPCRS. 1 volume of this solution to 5 volumes with the mobile phase
and filter througha glass fibre filter (Whatman GF/C is
STORAGE
suitable).
Prolonged-release Diclofenac Capsules should be protected
from moisture.
methanol.
IMPURITIES (3) 0.01% w/v of diclofenac sodium BPCRS and 0.01% w/v of
limited by the requirements of this diclofenac impurity A BPCRS in methanol.
de those listed in the monograph for

(end-capped Zorbax C8 is suitable).
Diclofenac Ge below.
Action and use
Cyclo-oxygenase inhibitor; (d) Use an ambient column temperature.
DEFINITION
Diclofenac Gel contains Diclofenac Die ina
suitable basis.
1.5 times the retention time of diclofenac.
The gel complies with the requirements stated und
MOBILE PHASE
solid Preparations and with the following requirement
34 volumes of a mixture of equal volumes of a 0.1% w/v
Content of diclofenac diethylamine, C,3H,,Cl,)
solution of orthophosphoric acid and a 0.16% w/v solution of
sodium dihydrogen orthophosphate, adjusted to pH 2.5, and
IDENTIFICATION 66 volumes of methanol.
Carry out the method for thin-layer chromatography, he chromatograms are recorded under the prescribed
Appendix III A, using the following solutions. the retention times are about 25 minutes for
(1) Add to a quantity of the gel containing 50 mg of and about 12 minutes for diclofenac impurity A.
Diclofenac Diethylamine 12.5 mL of 0.5m lithium chloride
and shake until a homogeneous suspension is obtained.
Add 12.5 mL of chloroform, shake briefly and mix with the
aid of ultrasound for 5 minutes. Allow to separate, filter the
chloroform layer through a glass fibre filter (Whatman GF/C corresponding®
is suitable) and use the filtrate. least 6.5.
(2) 0.2% w/v of diclofenac diethylamine BPCRS in a mixture LIMITS
of equal volumes of 0.5m lithium chloride and dichloromethane. In the chromatogram obtaii
CHROMATOGRAPHIC CONDITIONS the area of any secondary peak
of the principal peak in the cl
yee no
ew en
mA
eee
ald
(a) Use as the coating silica gel 60 (Merck silica gel 60 plates
are suitable). solution (2) (0.5%);
wee sy

Disregard any peak with an area less than 0.05 tis
(e) After removal of the plate, dry it in a stream of warm air of the principal peak in the chromatogram obtai
for 10 minutes. Spray with ninhydrin solution and heat at 110° solution (2) (0.05%). |
for 15 minutes.
ASSAY
MOBILE PHASE
wae
te ted
ae
roe
1 volume of hydrochloric acid, 1 volume of water, 6 volumes of Appendix III D, using the following solutions.
glacial acetic acid and 11 volumes of ethyl acetate.
(1) Shake a quantity of the gel containing 50 mg of
CONFIRMATION Diclofenac Diethylamine with 50 mL of acetone for
The two principal spots in the chromatogram obtained with 10 minutes, filter and evaporate the filtrate to dryness under
solution (1) correspond in position and colour to those in the reduced pressure. Dissolve the residue in 100 mL ofa
chromatogram obtained with solution (2). mixture of 40 volumes of water and 60 volumes of methanol,
dilute 1 volume of this solution to 10 volumes with the
TESTS
mobile phase and filter through a glass fibre filter (Whatman
Related substances
GF/C is suitable).
ee Nw al
roe
(2) 0.005% w/v of diclofenac sodium BPCRS in methanol.
a Ay
en ed
wien Se
2016 Diclofenac Preparations III-461
(3) 0.01% w/v of diclofenac sodium BPCRS and 0.01% w/v of TESTS
diclofenac impurity A BPCRS in methanol. Related substances
CHROMATOGRAPHIC CONDITIONS Carry out the method for liquid chromatography,
with end-capped octylsilyl silica gel for chromatography (5 wm) (1) Shake a quantity of the powdered tablets containing
(end-capped Zorbax C8 is suitable). 50 mg of Diclofenac Sodium with 70 mL of the mobile
phase for 30 minutes, add sufficient of the mobile phase to
produce 100 mL, mix, centrifuge an aliquot and filter the
below.
supernatant liquid through a 0.45-um filter.
(d) Use an ambient column temperature. mobile phase and dilute 1 volume of this solution to
etection wavelength of 254 nm. 5 volumes with the mobile phase.
(3) 0.0005% w/v of diclofenac sodium BPCRS and
0.0005% w/v of diclofenac impurity A BPCRS in the mobile
phase.
When the chromatogra (end-capped Zorbax C8 is suitable).
conditions, the retentio (b) Use isocratic elution and the mobile phase described
diclofenac and about 4 m below.
SYSTEM SUITABILITY (c) Use a flow rate of 1 mL per minute.
with solution (3), the resolution factor bet (e) Use a detection wavelength of 254 nm.
corresponding to diclofenac and diclofenas (f) Inject 20 uwL of each solution.
least 2.0.
(g) Allow the chromatography to proceed for 1.5 times the
DETERMINATION OF CONTENT € retention time of diclofenac.
Calculate the content of C;gH..Cl,N.O, in the ge
MOBILE PHASE
declared content of C,4H)9ClaNNaOz in diclofenac
34 volumes of a mixture of equal volumes of a 0.1% w/v
sodium BPCRS. Each mg of C,4H;pCl,NNaO, is equ
ion of orthophosphoric acid and a 0.16% w/v solution of
to 1.1609 mg of CisH22.ClNO>.
dihydrogen orthophosphate, adjusted to pH 2.5, and
es of methanol.
e chromatograms are recorded in the prescribed
Gastro-resistant Diclofenac Tablets

Diclofenac Tablets
Action and use

corresponding to di
DEFINITION least 2.0.
Gastro-resistant Diclofenac Tablets contain Diclofenac LIMITS
Sodium. They are made gastro-resistant by enteric-coating or
by other means.
than the area of
The tablets comply with the requirements stated under Tablets and ined with
Content of diclofenac sodium, C,,H;9CLNNaQ,
95.0 to 105.0% of the stated amount. 2.5 times the area of the principal peak in the ck
IDENTIFICATION obtained with solution (2) (0.5%). |
Remove the coating from 10 tablets and powder the cores. Disregard any peak with an area less than 0.25 times the area
Add 0.5 mL of glacial acetic acid and 15 mL of methanol to a of the principal peak in the chromatogram obtained with
quantity of the powdered tablet cores containing 0.15 g of solution (2) (0.05%) and any peaks with retention times
Diclofenac Sodium and mix with the aid of ultrasound. relative to the principal peak of 0.67 and 0.1.
Shake gently for 1 minute, filter and collect the filtrate in ASSAY
15 mL of water. Filter the precipitate under reduced pressure Carry out the method for liguid chromatography,
(A Whatman GF/C filter paper is suitable), wash with four Appendix II D, using the following solutions.
5-mL quantities of water and dry at 105° for 2 to 3 hours.
(1) Shake 10 tablets with 700 mL of methanol (50%) for
The infrared absorption spectrum of the dried precipitate,
30 minutes with the aid of ultrasound, add sufficient mobile
phase to produce 1000 mL, centrifuge an aliquot and filter
diclofenac (RS 096).
the supernatant liquid through a 0.45-um filter. Dilute the
filtrate with the mobile phase to produce a solution
containing 0.005% w/v of Diclofenac Sodium.
Ill-462 Diclofenac Preparations 2016
(2) 0.005% w/v of diclofenac sodium BPCRS in the mobile The tablets comply with the requirements stated under Tablets and
phase. with the following requirements.
(3) 0.0005% w/v of diclofenac sodium BPCRS and Content of diclofenac sodium, C,,H,)CL.NNaO,
0.0005% w/v of diclofenac impurity A BPCRS in the mobile 95.0 to 105.0% of the stated amount.
phase.
IDENTIFICATION
CHROMATOGRAPHIC CONDITIONS Remove the coating from 10 tablets and powder the cores.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed To a quantity of the powdered tablet cores containing 0.15 g
with end-capped octylsilyl silica gel for chromatography (5 um) of Diclofenac Sodium, add 0.5 mL of glacial acetic acid and
(end-capped Zorbax C8 1s suitable). 15 mL of methanol and mix with the aid of ultrasound. Shake
(b) Use isocratic elution and the mobile phase described gently for 1 minute, filter and collect the filtrate in 15 mL of
below. water. Filter the precipitate under reduced pressure (A
1 mL per minute. Whatman GF/C filter paper is suitable), wash with four
5-mL quantities of water and dry at 105° for 2 to 3 hours.
The infrared absorption spectrum of the dried precipitate,
diclofenac (RS 096).
TESTS
Related substances
sodium dthydrogen orthophospha Appendix III D, using the following solutions.
80 volumes of methanol. (1) Shake a quantity of the powdered tablets containing
50 mg of Diclofenac Sodium with 70 mL of the mobile
conditions, the retention times are about phase for 30 minutes, add sufficient of the mobile phase to
diclofenac and about 4 minutes for diclofey produce 100 mL, mix, centrifuge an aliquot and filter the
SYSTEM SUITABILITY
supernatant liquid through a 0.45-um filter.
mobile phase and dilute 1 volume of this solution to
enac impurity a . 5 volumes with the mobile phase.
corresponding to diclofenac and diclof
least 2.0. 3) 0.0005% w/v of diclofenac sodium BPCRS and
005% w/v of diclofenac impurity A BPCRS in the mobile
Calculate the content of C,,H)9Cl,NNaO, in the tablets

GRAPHIC CONDITIONS
using the declared content of C,4H; 9Cl,NNaO, in diclofenac
sodium BPCRS. inless steel column (25 cm x 4.6 mm) packed
pped octylsilyl silica gel for chromatography (5 \m)
STORAGE
Gastro-resistant Diclofenac Tablets should be protected from
moisture.
IMPURITIES
monograph include those listed in the monograph for
Diclofenac Sodium. |
(f) Inject 20 wL of each solution
(g) Allow the chromatography to.pr for 1.5 times the
retention time of Diclofenac. .
Prolonged-release Diclofenac Tablets MOBILE PHASE
Prolonged-release Diclofenac Tablets from different manufacturers, 34 volumes of a mixture of equal volume
whilst complying with the requirements of the monograph, are not solution of orthophosphonic acid and a 0.16% we¥ sol
interchangeable unless otherwise justified and authorised. sodium dihydrogen orthophosphate, adjusted to pH..2.
66 volumes of methanol. |
Action and use When the chromatograms are recorded in the prescribed
Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory. conditions, the retention times are about 25 minutes for
diclofenac and about 12 minutes for diclofenac impurity A.
DEFINITION
SYSTEM SUITABILITY
Prolonged-release Diclofenac Tablets contain Diclofenac
Sodium. They are formulated so that the medicament is The test is not valid unless, in the chromatogram obtained
released over a period of several hours. with solution (3), the resolution factor between the peaks
corresponding to diclofenac and diclofenac impurity A is at
PRODUCTION least 6.5.
LIMITS
appropriate release of diclofenac sodium. The dissolution
profile reflects the 77 vivo performance which in turn is In the chromatogram obtained with solution (1):
compatible with the dosage schedule recommended by the the area of any secondary peak is not greater than the area of
manufacturer. the principal peak in the chromatogram obtained with
FET ee
2016 Dicycloverine Preparations III-463
the sum of the areas of all the secondary peaks 1s not greater
Dicycloverine Oral Solution
chromatogram obtained with solution (2) (0.5%). Action and use
Disregard any peak with an area less than 0.25 times the area Anticholinergic.
solution (2) (0.05%). DEFINITION
ASSAY Dicycloverine Oral Solution is a solution of Dicycloverine
Hydrochloride in a suitable flavoured vehicle.
liquid chromatography, Appendix III D, using the following The oral solution comphes with the requirements stated under Oral
solutions. Liquids and with the following requirements.
(1) Toa quantity of the powdered tablets containing 0.5 g of Content of dicycloverine hydrochloride,
add 800 mL of methanol and mix with C,9H3;NO,,HCI
ind. Dilute the resulting solution with the 90.0 to 110.0% of the stated amount.
roduce a solution containing 0.005% w/v of IDENTIFICATION
A. To a volume containing 0.1 g of dicycloverine
(2) 0.005% wiv hydrochloride add 10 mL of water and 1 mL of hydrochloric
phase. acid, shake with 30 mL of ether and allow to separate. Extract
(3) 0.0005% w/v of di the aqueous layer with 30 mL of chloroform, wash the extract
0.0005% w/v ofdiclofenié with two 10 mL quantities of water and filter the chloroform
phase. solution through anhydrous sodium sulfate. Evaporate the
filtrate to dryness, recrystallise the residue from hot acetone
and dry the precipitate at 105° for 30 minutes. The infrared
4.6 mm) packed
absorption spectrum of the residue, Appendix II A, is
graphy (5 wm) concordant with the reference spectrum of dicycloverine
(Zorbax C8is suitable). hydrochloride (RS 098).
(b) Use isocratic elution and the mobile pit ibed B. Acidify the oral solution with 2m nitric acid and add silver
below. nitrate solution. A white precipitate is produced.
TESTS
Related substances
(e) Use a detection wavelength of 254 nm. Carry out the method for thin-layer chromatography,
(f) Inject 20 wL of each solution. ix III A, using the following solutions.
MOBILE PHASE 10 mL of water and 1 mL of hydrochloric acid to a
20 volumes of a mixture of equal volumes of a 0.1% w/v ntaining 0.1 g of dicycloverine hydrochloride,
solution of phosphonic acid and a 0.16% w/v solution of sodium 30 mL of ether and allow to separate. Extract the
dihydrogen orthophosphate, adjusted to pH 2.5, and
suitable), evapo rat e filtrate to dryness and dissolve the
conditions, the retention times are about 5 minutes for
residuein 4 mL megmethane.
diclofenac and about 4 minutes for diclofenac impurity A.
(2) Dilute 1 volume ion (1) to 500 volumes with
SYSTEM SUITABILITY
dichloromethane.
The test is not valid unless, in the chromatogram obtained (3) 0.1% w/v of each of dé sverine hydrochloride BPCRS
with solution (3), the resolution factor between the peaks and tropicamide BPCRS in m
corresponding to diclofenac and diclofenac impurity A is at
least 2.0. CHROMATOGRAPHIC CONDITIO S
(a) Use as the coating silica gel. G
(b) Use the mobile phase as described”
Calculate the content of C;4H,)9CIl,NNaO, in the tablets
using the declared content of C,;4H)9Cl,NNaO, in diclofenac (c) Apply 10 uL of each solution.
sodium BPCRS. (d) Develop the plate to 15 cm. |
STORAGE (e) After removal of the plate, dry it in a current of warm air
Prolonged-release Diclofenac Tablets should be protected and spray with dilute potassium todobismuthate solution.
from moisture. MOBILE PHASE
IMPURITIES 5 volumes of 13.5m ammonia, 10 volumes of ethyl acetate,

The impurities limited by the requirements of this 10 volumes of water and 75 volumes of propan-1-ol.
monograph include those listed in the monograph for SYSTEM SUITABILITY
Diclofenac Sodium. The test is not valid unless the chromatogram obtained with
LIMITS

Disregard any spot remaining on the line of application.
IlI-464 Dicycloverine Preparations 2016
ASSAY | MOBILE PHASE

To a weighed quantity containing 5 mg of dicycloverine 5 volumes of 13.5M ammonia, 10 volumes of ethyl acetate,
hydrochloride add 5 mL of sulfuric acid (10%) and 2 mL of 10 volumes of water and 75 volumes of propan-1-ol.
0.02M potassium permanganate, mix, allow to stand, add
SYSTEM SUITABILITY
20 mL of water and 20 mL of chloroform to the decolourised
solution and titrate with 0.001m sodium dodecyl sulfate VS The test is not valid unless the chromatogram obtained with
using 1 mL of dimethyl yellow solution as indicator. Each mL solution (3) shows two clearly separated spots.
of 0.001m sodium dodecyl sulfate VS is equivalent to LIMITS
0.3460 mg of C;>.H3;NO,,HCI. Determine the weight per mL In the chromatogram obtained with solution (1), any
of the oral solution, Appendix V G, and calculate the content secondary spot 1s not more intense than the spot in the
of C;9H35;NO2,HCI, weight in volume. chromatogram obtained with solution (2) (0.2%).
ASSAY
wea
containing 30 mg of Dicycloverine Hydrochloride add 20 mL
of water and shake. Add 10 mL of 1M sulfuric acid, 1 mL of
dimethyl yellow solution and 40 mL of chloroform, shake and
titrate with 0.004m sodium dodecyl sulfate VS, shaking
vigorously and allowing the layers to separate after each
addition, until a permanent orange—pink colour is produced
Action and use
in the chloroform layer. Each mL of 0.004m sodium dodecyl
Anticholinergic.
sulfate VS 1s equivalent to 1.384 mg of C;>)H3;NO2,HCL.
DEFINITION |
Dicycloverine ‘Tablets contain
The tablets comply with the requirements stat nd Tablets and
with the following requirements. Diethylamine Salicylate Cream
Content of dicycloverine hydrochloride, DEFINITION
C,90H3;NO,,HC1
Diethylamine Salicylate Cream is a dispersion of
Diethylamine Salicylate in a suitable basis.
IDENTIFICATION The cream complies with the requirements stated under Topical
A. Extract a quantity of the powdered tablets containing -solid Preparations and with the following requirements.
0.2 g of Dicycloverine Hydrochloride with 20 mL of
f diethylamine salicylate, C,,;,H,,NO;3
chloroform, filter, evaporate the filtrate to dryness, recrystallise
the residue from acetone and dry at 105° for 4 hours. The
concordant with the reference spectrum of dicycloverine
hydrochloride (RS 098).
B. Shake a quantity of the powdered tablets containing
10 mg of Dicycloverine Hydrochloride with 5 mL of water . after recrystallisation from water and
and 0.2 mL of 2m nitric acid, filter and add 0.5 mL of silver JJ A, is concordant with the
nitrate solution to the filtrate. A white precipitate is produced.
TESTS
B. To 5 mL of the filtrat
water and 0.05 mL of iron(
|
Related substances
violet colour is produced.
vem

of Dicycloverine Hydrochloride with 8 mL of water and
evolved, which turns moistred litmus papé
2 mL of 13.5mM ammonia, extract with two 20-mL quantities
of dichloromethane, shake with anhydrous sodium sulfate, filter ASSAY
(Whatman 1PS paper is suitable), evaporate the filtrate to To a quantity containing 50 mg of diethylami J
dryness and dissolve the residue in 4 mL of dichloromethane. add 30 mL of 0.5m sodium hydroxide and 15 mL of ethanol
(2) Dilute 1 volume of solution (1) to 500 volumes with (96%), mix, heat under a reflux condenser for 30 minutes
dichloromethane. and cool. To the resulting mixture add 20 mL of
1m hydrochloric acid, mix, dilute to 250 mL with water and
(3) 0.1% w/v of each of dicycloverine hydrochloride BPCRS
filter. Shake 15 mL of the filtrate with 25 mL of chloroform
and tropicamide BPCRS in methanol.
for 2 minutes. To 5 mL of the chloroform layer add 10 mL
CHROMATOGRAPHIC CONDITIONS of zvon(i) nitrate solution and shake for 5 minutes. Centrifuge
(a) Use a TLC silica gel G plate. the aqueous layer and measure the absorbance at the
(b) Use the mobile phase as described below. maximum at 530 nm, Appendix II B, using iron(im) nitrate
solution in the reference cell. Calculate the content of
salicylate as salicylic acid, C7H,O3, from the absorbance
obtained by repeating the operation using 15 mL ofa
(e) After removal of the plate, dry in a current of warm air 0.013% w/v solution of salicylic acid in 0.02m hydrochloric
and spray with dilute potassium iodobismuthate solution. acid, beginning at the words ‘Shake 15 mL...’. Each g of
salicylic acid is equivalent to 1.530 g of C,,;H,7NO3.
2016 Diethylstilbestrol Preparations TII-465
Diethylcarbamazine Tablets dimethylpiperazine in methanol and dilute to 200 mL with the

same solvent. Dry the plate at 105° and expose to iodine
ywerad
Action and use vapour for 30 minutes. Any spots corresponding to

methylpiperazine and dimethylpiperazine in the
se aad
cate 4
Antihelminthic.
chromatogram obtained with solution (1) are not more
DEFINITION intense than the spots in the chromatogram obtained with
Diethylcarbamazine Tablets contain Diethylcarbamazine solutions (3) and (4) respectively (0.2% of each).
Citrate. Related substances
The tablets comply with the requirements stated under Tablets and Weigh and finely powder 20 tablets. Dissolve 31.24 g of
with the following requirements. potassium dihydrogen orthophosphate in water, add sufficient
water to produce 1000 mL and mix (solution A). Carry out
Content of diethylcarbamazine citrate, C,;>H2,N30,
the following solutions. For solution (1) shake a quantity of
the powdered tablets containing 0.3 g of Diethylcarbamazine
Citrate in 100 mL of solution A, centrifuge and use the clear
powdered tablets containing 0.15 g supernatant liquid. For solution (2) dilute 1 volume of
itrate add 15 mL of ethanol (96%), solution (1) to 100 volumes with solution A and further
d evaporate the filtrate to dilute 1 volume of the resulting solution to 10 volumes with
solution A to produce a solution containing 0.0003% w/v
Diethylcarbamazine Citrate. Solution (3) contains 0.2% w/v
tracts over anhydrous of citric acid in solution A.
nfrared absorption The chromatographic procedure described under Assay may
is concordant be used.
zine (RS 411).
The area of any secondary peak in the chromatogram obtained
with solution (1) is not greater than the area of the principal
obtained with solution (1) shows a peak w peak in the chromatogram obtained with solution (2) (0.1%).
retention time as the peak due to citric aci Disregard any peak with the same retention time as citric
chromatogram obtained with solution (3). acid in the chromatogram obtained with solution (1).
TESTS ASSAY |
Dissolution Weigh and finely powder 20 tablets. Dissolve 31.24 g of
Comply with the requirements for Monographs of the Brit
Pharmacopoeia in the dissolution test for tablets and capsules, produce 1000 mL and mix (solution A). Carry out
Appendix XII B1, using Apparatus 2. Use as the medium od for liquid chromatography, Appendix II D, using
900 mL of water and rotate the paddle at 50 revolutions per Hoyang solutions. For solution (1) dissolve a quantity of
minute. Carry out the method for liquid chromatography, dered tablets containing 25 mg of
Appendix III D. Dissolve 31.24 g of potassium dihydrogen ( ine Citrate in 100 mL of solution A, shake
orthophosphate in water, add sufficient water to produce 0.40lumes to 50 volumes with solution A.
1000 mL and mix (solution A). Solution (1) contains
0.0025% w/v of diethylcarbamazine citrate BPCRS in solution
A. For solution (2) dilute 10 mL of the filtered dissolution
The chromatographic@ procedure may be carried out using
medium with an equal volume of a 6.248% w/v solution of
(a) a stainless steel cé | cm x 3.9 mm) packed with
potassium dihydrogen orthophosphate, filter and dilute with
solution A to produce a solution expected to contain about
4e mobile phase with a flow
0.0025% w/v of Diethylcarbamazine Citrate.
100 mL of methanol
The chromatographic procedure described under Assay may and 900 mL ofa solution containing 1¢ of potassium
be used. dihydrogen orthophosphate in 1000 mik*ot ater and (c) a
Calculate the total content of diethylcarbamazine citrate, detection wavelength of 220 nm.
Ci9H21N30,C.6HsO-7, in the medium using the declared Calculate the content of CjoH21N30,Ce6Hs@7 ir tablets
content of C,;9H.;N30,CgHsO7 in diethylcarbamazine using the declared content of CjoH21N30,CeHg
citrate BPCRS. diethylcarbamazine citrate BPCRS. ,
Dimethylpiperazine and methylpiperazine
and a mixture of 5 volumes of 13.5mM ammonia, 30 volumes
of butan-2-one and 65 volumes of methanol as the mobile Diethylstilbestrol Tablets
phase. Allow the solvent front to ascend 12 cm above the
Action and use
line of application. Apply separately to the plate 20 uL of
Estrogen.
each of the following solutions. For solution (1) shake a
quantity of the powdered tablets containing 0.50 g of
DEFINITION
Diethylcarbamazine Citrate with 20 mL of methanol and
Diethylstilbestrol Tablets contain Diethylstilbestrol.
filter. For solution (2) dissolve 0.05 g of diethylcarbamazine
citrate BPCRS in methanol and dilute to 2.0 mL with the The tablets comply with the requirements stated under Tablets and
same solvent. For solution (3) dissolve 10 mg of with the following requirements.
methylpiperazine in methanol and dilute to 200 mL with the Content of diethylstilbestrol, C,;3;H> ,O,
same solvent. For solution (4) dissolve 10 mg of 90.0 to 110.0% of the stated amount.
III-466 Diflucortolone Preparations 2016
IDENTIFICATION ultraviolet light (254 nm). The principal spot in the

Extract a quantity of the powdered tablets containing 3 mg chromatogram obtained with solution (1) corresponds to that
of Diethylstilbestrol with ether, filter and evaporate the filtrate in the chromatogram obtained with solution (2).
to dryness. The residue complies with the following tests. The principal spot in the chromatogram obtained with
A. The light absorption, Appendix II B, in the range 230 to solution (3) appears as a single compact spot.
350 nm of a 0.002% w/v solution in absolute ethanol exhibits B. In the Assay, the chromatogram obtained with solution
a maximum only at 241 nm. (2) shows a peak with the same retention time as the peak
B. The light absorption, Appendix II B, in the range 230 to due to diflucortolone valerate in the chromatogram obtained
450 nm of the irradiated solution prepared as directed in the with solution (1).
Assay exhibits two maxima, at 292 nm and 418 nm. ASSAY
C. Dissolve 0.5 mg in 0.2 mL of glacial acetic acid, add 1 mL Carry out the method for lguid chromatography,
ric acid and heatin a water bath for 3 minutes. Appendix III D, injecting 20 wL of each of the following
A deep’ Our is produced which almost disappears solutions. For solution (1) dissolve 20 mg of diflucortolone
Sw AY
L of glacial acetic acid (distinction from valerate BPCRS in a 0.02% w/v solution of clocortolone
hexanoate BPCRS (internal standard) in methanol and dilute
to 200 mL with the internal standard solution. Add 30 mL
of methanol to 10 mL of the resulting solution and dilute to
50 mL with water. For solution (2) add 40 mL of methanol to
a quantity of the cream containing 1 mg of Diflucortolone
Valerate, disperse by heating on a water bath at 60° for
to produce 100 mL and ceri
5 minutes and shake for 30 seconds. Add 10 mL of water,
clear supernatant liquid to 5
cool in ice for 10 minutes and filter. Prepare solution (3) in
the same manner as solution (2) but adding 10 mL of a
0.02% w/v solution of clocortolone hexanoate BPCRS in
methanol and 30 mL of methanol.
mixture to a 1 cm, closed quartz cell, place
from a 15-watt, short-wave, ultraviolet lam The chromatographic procedure may be carried out using
at the maximum at 418 nm, Appendix II B, and caleule end-capped octadecylsilyl silica gel for chromatography (10 um)
content of C,;3H» 90. from the absorbance obtained by (uBondapak C18 is suitable), (b) as the mobile phase with a
repeating the operation using diethylstilbestrol BPCRS in pi flow rate of 2 mL per minute a mixture of 250 volumes of
of the powdered tablets. and 750 volumes of methanol and (c) a detection
STORAGE
the content of C,7H3.F,O5 in the cream using the
Diethylstilbestrol Tablets should be protected from light.
tent of C.7H36F20s5 in diflucortolone
Diflucortolone Cream
Action and use
Glucocorticoid.
Action and use
DEFINITION Glucocorticoid.
Diflucortolone Cream contains Diflucortolone Valerate in a
suitable non-oily basis. DEFINITION
Diflucortolone Oily Cream contéin
aP 1

Semi-solid Preparations and with the following requirements. in a suitable oily basis.
wet Nee
Content of diflucortolone valerate, C,7H3,F,0; The cream complies with the requirements
90.0 to 110.0% of the stated amount. Semi-solid Preparations and with the followt
Content of diflucortolone valerate, Co7H3cE O;
IDENTIFICATION
Appendix III A, usinga silica gel 60 F554 precoated plate IDENTIFICATION
(Merck silica gel 60 plates are suitable) and a mixture of A. Carry out the method for thin-layer chromatography,
2 volumes of diethylamine, 50 volumes of cyclohexane and Appendix III A, usinga silica gel 60 F54 precoated plate
50 volumes of ethyl acetate as the mobile phase. Apply (Merck silica gel 60 plates are suitable) and a mixture of
Nw ew
oN
a
separately to the plate 10 wL of each of the following 2 volumes of diethylamine, 50 volumes of cyclohexane and
tet we
solutions. For solution (1) disperse a quantity of the cream 50 volumes of ethyl acetate as the mobile phase. Apply
containing 1 mg of Diflucortolone Valerate in 5 mL of separately to the plate 20 uL of each of the following
dichloromethane by heating on a water bath, shake vigorously solutions. For solution (1) disperse a quantity of the cream
for 15 seconds, cool in ice, filter the dispersion and use the containing 1 mg of Diflucortolone Valerate in 10 mL of
filtrate. Solution (2) contains 0.02% w/v of diflucortolone dichloromethane by heating on a water bath, shake vigorously
valerate BPCRS in dichloromethane. Solution (3) contains a for 1 minute, cool in ice, filter the dispersion and use the
mixture of equal volumes of solutions (1) and (2). Develop filtrate. Solution (2) contains 0.01% w/v of diflucortolone
the chromatogram twice drying the plate in air for valerate BPCRS in dichloromethane. Solution (3) contains a
~e awd
a
tet
’
Rete!
N 2s Ud
15 minutes between developments. After removal of the mixture of equal volumes of solutions (1) and (2). Develop
plate, allow it to dry in air for 15 minutes and examine under the chromatogram twice drying the plate in air for
2016 Digitoxin Preparations TII-467
15 minutes between developments. After removal of the (f) Place the plate in the same tank using the mobile phase as
plate, allow it to dry in air for 15 minutes and examine under described below.
raewe!
ultraviolet light (254 nm). The principal spot in the (g) After removal of the plate, dry in air for 15 minutes and
au al
chromatogram obtained with solution (1) corresponds to that examine under ultraviolet light (254 nm).
MOBILE PHASE
solution (3) appears as a single compact spot. 2 volumes of diethylamine, 50 volumes of cyclohexane and
(2) shows a peak with the same retention time as the peak CONFIRMATION
due to diflucortolone valerate in the chromatogram obtained The principal spot in the chromatogram obtained with
with solution (1). solution (1) corresponds in position and colour to that in the
chromatogram obtained with solution (2). The principal spot
in the chromatogram obtained with solution (3) appears as a
aN eA
injecting 20 wL of each of the following single compact spot.
ion (1) dissolve 20 mg of diflucortolone B. In the Assay, the chromatogram obtained with solution
.02% w/v solution of clocortolone (2) shows a peak with the same retention time as the peak
due to diflucortolone valerate in the chromatogram obtained
‘thal standard solution. Add 30 mL with solution (1).
ASSAY ,
Valerate, disperse by heati
(1) Dissolve 20 mg of diflucortolone valerate BPCRS in a
5 minutes and shake for 30.
nw al 0.02% w/v solution of clocortolone hexanoate BPCRS (internal
standard) in methanol and dilute to 200 mL with the internal
the same manner as solution (2) but a
standard solution. Add 30 mL of methanol to 10 mL of the
0.02% w/v solution of clocortolone hexano
resulting solution and dilute to 50 mL with water.
methanol and 30 mL of methanol.
(2) Shake a quantity of the ointment containing 1 mg of
The chromatographic procedure describedurfder ?
Diflucortolone Valerate with 10 mL of a 0.02% w/v solution
Diflucortolone Cream may be used. :
of clocortolone hexanoate BPCRS in methanol and add 30 mL
Calculate the content of C,7H3.F2Os5 in the cream U of methanol. Disperse by heating on a water bath at 60° for
declared content of C.7H3,F,05 in diflucortolone 5 minutes and shake for 30 seconds. Add 10 mL of water,
valerate BPCRS. ice for 10 minutes and filter.
ATOGRAPHIC CONDITIONS
stainless steel column (30 cm x 3.9 mm) packed
Diflucortolone Ointment pped octadecylsilyl silica gel for chromatography
Action and use

Glucocorticoid.
DEFINITION (c) Use a flow r L per minute.

Diflucortolone Ointment contains Diflucortolone Valerate in (d) Use an amb in temperature.
a suitable basis.
(e) Use a detection
MOBILE PHASE if
Content of diflucortolone valerate, C,,H3,F,O;
90.0 to 110.0% of the stated amount. 250 volumes of water and 750 vélum methanol.
A. Carry out the method for thin-layer chromatography, Calculate the content of C7H3.6F.205 in
Appendix III A, using the following solutions. the declared content of C27H35F2Os in difluceriol
(1) Disperse a quantity of the ointment containing 1 mg of valerate BPCRS. .
Diflucortolone Valerate in 5 mL of dichloromethane by heating
on a water bath, shake vigorously for 15 seconds, cool in ice,
filter the dispersion and use the filtrate.
we nw
(2) 0.02% w/v of diflucortolone valerate BPCRS in Digitoxin Tablets
dichloromethane.
(3) A mixture of equal volumes of solutions (1) and (2). Action and use
Na /K-ATPase inhibitor; cardiac glycoside.
(a) Use as the coating silica gel 60 GF254 (Merck silica gel DEFINITION
60 plates are suitable). Digitoxin Tablets contain Digitoxin.
(b) Use the mobile phase as described below. The tablets comply with the requirements stated under Tablets and
(c) Apply 10 uL of each solution. with the following requirements.
AS
wi ee
(d) Develop the plate to 15 cm. Content of digitoxin, C4,;H,¢,0;3
Fa
(e) After removal of the plate, dry in air for 15 minutes. 90.0 to 110.0% of the stated amount.
IWI-468 Digoxin Preparations 2016
IDENTIFICATION Extemporaneous preparation

To a quantity of the powdered tablets containing 0.25 mg of The following directions apply.
eA e A
Digitoxin add 1 mL of glacial acetic acid containing Dissolve the digoxin in the ethanol (80 per cent) and add the
wieee
0.01% w/v of tron(im) chloride, shake for a few minutes, filter propylene glycol, a solution of the citric acid monohydrate
through sintered glass and cautiously add 1 mL of sulfuric and the disodium hydrogen phosphate dodecahydrate in
acid to the filtrate without mixing. A brown ring free from Water for Injections and sufficient Water for Injections to
red colour is produced at the interface and, after a short produce 100 mL. Sterilise by heating in an autoclave.
time, an indigo colour is produced in the upper layer. The injection complies with the requirements stated under
TEST Parenteral Preparations and with the following requirements.
Uniformity of content Content of digoxin, C4,;,H¢4O044
Tablets containing less than 2 mg and/or less than 2% w/w 0.0225 to 0.0275% w/v.
of Digitoxin comply with the requirements stated under
IDENTIFICATION
LANs
following method of analysis. Shake one
Evaporate 2 mL to dryness, dissolve the residue in 1 mL of
raALR es
oA
vite we ofmethanol (50%) for 30 minutes and
glacial acetic acid containing 0.01% w/v of tron(im) chloride and
the same solvent. Filter through a
cautiously add 1 mL of sulfuric acid without mixing. A brown
ring, free from red colour, is produced at the interface and,
.8 um, discarding the first few mL
of the filtrate, and tix kemL to a 10 mL graduated flask. after a short time, an indigo colour is produced in the upper
layer.
Add 3 mL of a 0.1% w
methanol and 0.2 mL of a3 TEST
peroxide prepared by accurati Acidity or alkalinity
sete we ASSAY
Leen
Transfer 20 mL to a separating funnel containing 10 mL of
fluorescence of the solution, Appendix II E.
water. Make alkaline with 5M ammonia and extract with four
wavelength of 400 nm and an emission wav:
25 mL quantities of chloroform. Wash each extract with the
same 10 mL of water. Evaporate the combined chloroform
Calculate the content of digitoxin, C,,;H,40;3, fr
extracts to dryness on a water bath, dry the residue at 105°
fluorescence obtained by carrying out the operation at
for 15 minutes, cool, dissolve the residue in 5 mL of a
same time using a 0.0004% w/v solution of digitoxin BPER
mixture of 65 volumes of chloroform and 35 volumes of
in methanol (50%) and beginning at the words ‘transfer 1 gil
methanol and add 20 mL of glacial acetic acid (solution A).
é aL of a 0.2% w/v solution of digoxin EPCRS in glacial
ASSAY
Weigh and finely powder 20 tablets. To a quantity of the
powder containing 1.25 mg of Digitoxin add 3 mL of water, produce 50 mL (solution B). Dilute 5 mL of
swirl to disperse the powder and allow to stand for mL with digoxin reagent, mix, allow to stand
10 minutes, swirling occasionally. Add 25 mL of glacial acetic sure the absorbance of the resulting
acid, shake for 1 hour and filter (Whatman No. | paper is spendix II B, using water in the
suitable), discarding the first few mL of filtrate. To 4 mL of the content of C4jHo2014 from the
the filtrate add 1 mL of dimethyl sulfoxide, dilute to 25 mL
with xanthydrol reagent, mix well and allow to stand in the
dark for 4.5 hours (solution A). At the same time prepare
STORAGE
two further solutions in the same manner but using for
Digoxin Injection should be protected from light.
solution B 4 mL of digitoxin standard solution and for solution
C 4 mL of a muxture of 25 volumes of glacial acetic acid and
ye aS
ve Ae
3 volumes of water and beginning at the words ‘add 1 mL of

dimethyl sulfoxide ...’. Measure the absorbances of solutions A
and B at the maximum at 550 nm, Appendix II B, using Paediatric Digoxin Injection
solution C in the reference cell.
Action and use
Na /K-ATPase inhibitor; cardiac glycoside.
Digoxin Injection DEFINITION

Digoxin 10 mg
ANN
waned
Met Petes vd
Ven od Action and use Ethanol (80 per cent) 12.5 mL
a8 as
wien wal
Na /K-ATPase inhibitor; cardiac glycoside. Propylene Glycol 40 mL

Citric Acid Monohydrate 75 mg
DEFINITION Disodium Hydrogen 0.45 g
Digoxin 25 mg Phosphate Dodecahydrate
Ethanol (80 per cent) 12.5 mL Water for Injections Sufficient to produce 100 mL
Propylene Glycol 40 mL Extemporaneous preparation
Citric Acid Monohydrate 75 mg The following directions apply.
Disodium Hydrogen 0.45 g
Dissolve the digoxin in the ethanol (80 per cent) and add the
eat
Phosphate Dodecahydrate
propylene glycol, a solution of the citric acid monohydrate
Tee
SS
fe ge!
Water for Injections Sufficient to produce 100 mL
and the disodium hydrogen phosphate dodecahydrate in
Ve bts.
re
2.
2016 Digoxin Preparations II-469
Water for Injections and sufficient Water for Injections to solution of digoxin EPCRS in glacial acetic acid with 10 mL of
Siwie ow
produce 100 mL. Sterilise by heating in an autoclave. a mixture of 65 volumes chloroform and 35 volumes of
methanol and adding sufficient glacial acetic acid to produce
es
os The injection complies with the requirements stated under

0 Parenteral Preparations and with the following requirements. 50 mL, beginning at the words ‘Dilute 5 mL of the filtrate
... and using water in the reference cell.
Content of digoxin, C4,;H,4014
0.0090 to 0.0110% w/v. STORAGE
Paediatric Digoxin Oral Solution should be protected from
IDENTIFICATION
light.
Evaporate 5 mL to dryness, dissolve the residue in 1 mL of
glacial acetic acid containing 0.01% w/v of iron(im) chloride and
cautiously add 1 mL of sulfuric acid without mixing. A brown
Digoxin Tablets
Action and use
Na/K-ATPase inhibitor; cardiac glycoside.
DEFINITION
Digoxin tablets contain digoxin.
Content of digoxin, C4,H64014
IDENTIFICATION
To a quantity of the powdered tablets containing 0.25 mg of
Paediatric Digoxin Oral So Digoxin, add 1 mL of glacial acetic acid containing 0.01% w/v
of tron(m) chloride hexahydrate, shake for a few minutes, filter
Action and use through sintered glass and cautiously add 1 mL of sulfuric
Na /K-ATPase inhibitor; cardiac glycoside. acid without mixing. A brown ring, free from red colour, is
produced at the interface and, after a short time, an indigo
DEFINITION colour is produced in the upper layer.
Paediatric Digoxin Oral Solution is a solution containing
0.005% w/v of Digoxin in a suitable flavoured vehicle.
‘ation
Paediatric Digoxin Oral Solution should not be diluted.
The oral solution complies with the requirements stated under Ora epoeia in the dissolution test for tablets and capsules,
XH B1, placing six tablets in the basket, using as
Content of digoxin, Cy4,;H64O 14 60Q mL of water freshly prepared by distillation
0.0045 to 0.0055% w/v.
IDENTIFICATION
Extract 5 mL with four 20 mL quantities of chloroform,
ater than 0.8 jm, discarding the
washing each extract with the same 10 mL of water,
d.transfer 1 mL to a 10 mL
evaporate the combined extracts to dryness and dissolve the
residue in 1 mL of glacial acetic acid containing 0.01% w/v of
tronat) chloride hexahydrate. Cautiously add 1 mL of sulfuric
acid without mixing. A brown ring, free from red colour, is
produced at the interface and, after a short time, an indigo
titration with 0.02M potassium permixtize
colour is produced in the upper layer.
dilute to volume with hydrochloric acid
ASSAY
Extract 100 mL with four 25 mL quantities of chloroform, with water and to 100 with a solution prepared at the same
washing each extract with the same 5 mL of water, and time as the test solution in the following manner. Dilute
evaporate the combined extracts to dryness. To the residue 2.5 mL of a 0.100% w/v solution of digoxin EPCRS in ethanol
add 3 mL of absolute ethanol and carefully evaporate to (80%) to 100 mL with water, dilute the resulting solution
dryness on a water bath with the aid of a gentle current of further with water to produce a solution containing in 1 mL
air. Repeat the evaporation using a further 3 mL of absolute an amount of Digoxin equal to one-hundredth of the
ethanol and cool. Dissolve the residue in 5 mL of a mixture strength of the tablets being examined, transfer 1 mL of the
of 65 volumes of chloroform and 35 volumes of methanol, add solution to a 10 mL graduated flask and carry out the
20 mL of glacial acetic acid and filter if necessary. Dilute operation described above, beginning at the words ‘Add
5 mL of the filtrate to 25 mL with digoxin reagent, allow to 3mL... ‘. The amount of digoxin, C4;H¢4O,4, per tablet in
stand for 2 hours and measure the absorbance of the resulting solution is not less than 75% of the stated amount.
solution at the maximum at 590 nm, Appendix II B. Uniformity of content
Calculate the content of C4,;H,¢4,O 4 from the absorbance Tablets containing less than 2 mg and/or less than 2% w/w
obtained by carrying out the operation at the same time but of Digoxin comply with the requirements stated under
using a solution prepared by mixing 5 mL of a 0.2% w/v Tablets using the following method of analysis. For tablets
aye e rnd
IW-470 Dihydrocodeine Preparations
containing 0.125 mg of digoxin, place one tablet in 5 mL of solution RI and warm gently. A brownish yellow colour is
water at 37°, agitate to disintegrate, add 28 mL of ethanol produced which does not become red on the addition of
oe
(96%), shake for 1 hour and add sufficient ethanol (80%) to 0.05 mL of 2m mitnc acid (distinction from codeine and
we At
produce 50 mL. For tablets containing more or less than morphine).
0.125 mg of Digoxin carry out the same procedure but using D. Yields reaction B characteristic of tartrates, Appendix VI.
correspondingly greater or smaller quantities of water, ethanol
(96%) and ethanol (80%). Filter the resulting solution TESTS
through a suitable membrane filter disc with a nominal pore Acidity
size not greater than 0.8 um, discarding the first few mL of pH, 3.0 to 4.5, Appendix V L.
the filtrate, and transfer 1.0 mL to a 10 mL graduated flask. ASSAY
Add 3 mL of a 0.1% w/v solution of L-ascorbic acid in Dilute a volume containing 50 mg of Dihydrocodeine
methanol, 0.2 mL of a 0.009M solution of hydrogen peroxide Tartrate to 500 mL with water and measure the absorbance of
urately diluting hydrogen peroxide solution the resulting solution at the maximum at 284 nm,
ee
we ae been standardised by titration with Appendix II B. Calculate the content of
anganate VS, mix and dilute to volume C,gH23NO3,C,H,O¢ taking 35.7 as the value of
Appendix II E, using an excitation
STORAGE
an emission wavelength of
Dihydrocodeine Injection should be protected from light.
H640 14; from the
the operation at the
‘transfer 1.0 mL ...’.

Dihydrocodeine Oral Solution
seem ee

Opioid receptor agonist; analgesic.
swirl to disperse the powder and allow to stand for DEFINITION

10 minutes swirling occasionally. Add 25 mL of glacial, Dihydrocodeine Oral Solution is a solution of
acid, shake for 1 hour and filter (Whatman No. 1 pap Dihydrocodeine Tartrate in a suitable flavoured vehicle.
suitable), discarding the first few mL. To 4 mL of the filt The oral solution complies with the requirements stated under Oral
add 1 mL of dimethyl sulfoxide, dilute to 25 mL with . and with the following requirements.
xanthydrol reagent, mix well and allow to stand in the dark for of dihydrocodeine tartrate, C,3;H,;NO3,C,H,O,
4 hours (solution A). At the same time prepare two further 5.0% of the stated amount.
solutions in the same manner but using for solution B 4 mL
of digoxin standard solution and for solution C 4 mL of a
mixture of 25 volumes of glacial acetic acid and 3 volumes of
water and beginning at the words ‘add 1 mL of dimethyl
sulfoxide ...’. Measure the absorbances of solutions A and B at
the maximum at 545 nm, Appendix II B, using solution C in chloroform |ex acts,5 3 mL of 5m sodium hydroxide to the
the reference cell. aqueous layer, mix ract with 25 mL of chloro orm.
Dihydrocodeine Injection
Action and use prepared using 0.3 g of potassium 6
Opioid receptor agonist; analgesic. solvent to evaporate between applic
DEFINITION
Appendix IT A, is concordant with the referer
Dihydrocodeine Injection is a sterile solution of
dihydrocodeine (RS 102).
Dihydrocodeine Tartrate in Water for Injections.
TESTS
Parenteral Preparanons and with the following requirements. Related substances
aN uae
wen em Content of dihydrocodeine tartrate, C,;3;H,3;3NO3,C,H,O, Appendix III A, using the following solutions.
(1) Add 10 mL of water and 3 mL of 5m sodium hydroxide to
IDENTIFICATION a quantity of the oral solution containing 20 mg of
ead
A. Add 0.05 mL to a mixture of 5 mL of sulfuric acid and Dihydrocodeine Tartrate, mix, extract with two 30 mL
0.05 mL of formaldehyde solution. A purple colour is produced quantities of chloroform and wash each extract successively
(distinction from pholcodine). with the same 10 mL of water. Filter each extract in turn
B. To a volume containing 10 mg of Dihydrocodeine through anhydrous sodium sulfate on a plug of absorbent
Tartrate add 0.05 mL of mitnc acid. A yellow but no red cotton moistened with chloroform, wash the filter with
colour is produced (distinction from morphine). chloroform, evaporate the combined filtrate and washings to
“SoM C. Evaporate a volume containing 0.1 g of Dihydrocodeine dryness and dissolve the residue in 2 mL of methanol.
awe
A,
eetne
aAywend
wie Fete
Tartrate to dryness on a water bath. Dissolve the residue in (2) Dilute 1 volume of solution (1) to 100 volumes with
1 mL of sulfuric acid, add 0.05 mL of iron(im) chloride methanol.
Aas
2016 Diloxanide Preparations III-471
(3) Dilute 1 volume of solution (2) to 2 volumes with STORAGE

methanol. Dihydrocodeine Oral Solution should be protected from
(4) 0.0050% w/v of codeine phosphate BPCRS in methanol. light.
(5) A mixture containing 1 volume of solution (1) and
1 volume of solution (4).
(a) Use as the coating silica gel GF 254. Dihydrocodeine Tablets

Action and use
(c) Apply 20 uL of each solution. Opioid receptor agonist; analgesic.
moval of theplate, allow it to cry in air and spray DEFINITION
Dihydrocodeine Tablets contain Dihydrocodeine Tartrate.
Content of dihydrocodeine tartrate, C,;H,,NO3,C,H,O,
The test is not va
solution (5) shows twé.
IDENTIFICATION
Shake a quantity of the powdered tablets containing 0.15 g
LIMITS
of Dihydrocodeine Tartrate with 50 mL of water, filter and
In the chromatogram obta evaporate the filtrate to dryness on a water bath. The residue
any spot due to codeine is nét mi complies with the following tests.
corresponding spot in the chromatog A. Add 10 mg, in powder, to 1 mL of a mixture of sulfuric
solution (4) (0.5%); acid and 0.05 mL offormaldehyde solution. A purple colour is
produced (distinction from pholcodine).
B. Dissolve 10 mg in 0.05 mL of nitric acid. A yellow but no
red colour is produced (distinction from morphine).
the chromatogram obtained with solution (3) ag Yo C. Dissolve 0.1 gin 1 mL of sulfuric acid, add 0.05 mL of
ASSAY iron(m) chloride solution R1 and warm gently. A brownish
Carry out the method for liquid chromatography, llow colour is produced which does not become red on the
Appendix III D, using the following solutions. of 0.05 mL of 2m nitric acid (distinction from
and morphine).
(1) Disperse a weighed quantity of the oral solution
containing 10 mg of Dihydrocodeine Tartrate in water, dilute
to 25 mL with water. powder 20 tablets. Dissolve a quantity of the
(2) 0.04% wiv of dthydrocodeine tartrate BPCRS in water. } ng 0.15 g of Dihydrocodeine Tartrate as
; sibple1in 30 mL of water, make alkaline with
5M ammonia act with five 20 mL quantities of
(a) Use a stainless steel column (10 cm x 4.6 mm) packed chloroform, washing each extract with the same 10 mL of
with end-capped octadecylsilyl silica gel for chromatography water. Filter the cém xtracts through absorbent cotton
(5 um) (Nucleosil C18 is suitable). moistened with chlor: wash the filter with a small
(b) Use isocratic elution and the mobile phase described quantity of chloroform on a water bath until the
below. volume is reduced to abowut5@mL and titrate with
(c) Use a flow rate of 2 mL per minute. 0.02m perchloric acid VS using crystalwiolet solution as
indicator. Each mL of 0.02 pereiloric:acid VS is equivalent
to 9.030 mg of C1gH23NO3,C,Heé fe
STORAGE
Dihydrocodeine Tablets should be protects
MOBILE PHASE
0.01M sodium acetate and 0.005m dioctyl sodium sulfosuccinate
in a mixture of 40 volumes of water and 60 volumes of
methanol, the pH of the mixture being adjusted to 5.5 with
glacial acetic acid. Diloxanide Tablets
SYSTEM SUITABILITY
Action and use
The test is not valid unless, in the chromatogram obtained Antiprotozoal.
with solution (2) the symmetry factor of the peak
corresponding to dihydrocodeine is less than 1.5. DEFINITION
DETERMINATION OF CONTENT Diloxanide Tablets contain Diloxanide Furoate.
Determine the weight per mL of the oral solution, The tablets comply with the requirements stated under Tablets and
Appendix V G, and calculate the content of with the following requirements.
"
Te
fee
CisH23NO3,C4,H.O¢, weight in volume, using the declared

af
Content of diloxanide furoate, C,,H,,;CILNO,

a ae
Peete et Oc
content of C;gH.3NO3,C,H,.O, in dihydrocodeine 95.0 to 105.0% of the stated amount.

yt
ee
tartrate BPCRS.
Teybtds
4
IW-472 Diltiazem Preparations 2016
IDENTIFICATION The tablets comply with the requirements stated under Tablets and
Extract a quantity of the powdered tablets containing 0.2 g of with the following requirements.
Diloxanide Furoate with 20 mL of chloroform, filter and Content of diltiazem hydrochloride, C,,H,,;N,0,S,HCI
evaporate the filtrate to dryness. The dried residue complies 95.0 to 105.0% of the stated amount.
with the following tests.
IDENTIFICATION
concordant with the reference spectrum of diloxanide furoate
(RS 103).
B. Burn 20 mg by the method for oxygen-flask combustion,
powdered tablets containing 50 mg of Diltiazem
Appendix VIII C, using 10 mL of 1m sodium hydroxide as the
Hydrochloride with 25 mL of methanol for 15 minutes and
absorbing liquid. When the process is complete acidify the
filter through a 0.45-m PTFE filter.
uric acid and add silver nitrate solution. A white
roduced. (2) 0.2% wv of diltiazem hydrochloride BPCRS in methanol.
ra 4s
(a) Use a silica gel F254 precoated plate (Merck silica gel 60
Appendix III A, using s (c) Apply 10 uL of each solution.
substance and a mixture (d) Develop the plate to 10 cm.
solutions. For solution (1) shake
tablets containing 0.5 g of Diloxanide Fuiroaté with 5 mL of MOBILE PHASE
chloroform, centrifuge and use the supernataiit liqui 1 volume of 5M acetic acid, 3 volumes of water, 10 volumes of
For solution (2) dilute 1 volume of solutio dichloromethane and 12 volumes of absolute ethanol.
400 volumes with chloroform. After removal o CONFIRMATION
it to dry in air and examine under ultraviolet light®(z
Any secondary spot in the chromatogram obtained wifl
btained with solution (2).
. In the Assay, the chromatogram obtained with solution
ASSAY nilar to that of the principal peak in the
Weigh and powder 20 tablets. Shake a quantity of the ram obtained with solution (2).
powder containing 40 mg of Diloxanide Furoate with
150 mL of ethanol (96%) for 30 minutes, add sufficient
ethanol (96%) to produce 200 mL, mix and filter. Dilute
10 mL of the filtrate to 250 mL with ethanol (96%) and
measure the absorbance of the resulting solution at the e following solutions prepared
maximum at 258 nm, Appendix II B. Calculate the content immediately {
of C,4H,,Cl,NO, taking 705 as the value of A (1%, 1 cm) (1) Mix with the @id rasound a quantity of the
at the maximum at 258 nm. powdered tablets cor g°0.12 g of Diltiazem
Hydrochloride with 70°mL ethanol (50%), filter through
STORAGE
a 0.45-um PTFE filter and tlute to 100 mL with methanol
Diloxanide Tablets should be protected from light.
(50%).
(2) Dilute 1 volume of solution 5 0 volumes with
methanol (50%).
(3) 0.12% w/v of diltiazem impurity standérd BPCRS in
mA ag
Prolonged-release Diltiazem Tablets methanol (50%).

Prolonged-release Diltnazem Tablets from different manufacturers (4) 0.00036% w/v of diltiazem impurity F EPGR ethanol
containing more than 60 mg of Diltiazem Hydrochloride, whilst (50%). ;
complying with the requirements of the monograph, are not
interchangeable unless otherwise justified and authorised. CHROMATOGRAPHIC CONDITIONS
Action and use with octadecylsilyl sihca gel for chromatography (3 um) (Hypersil
Nahe ata
tae ad
re aw
Calcium channel blocker. BDS is suitable).
mee
DEFINITION
below.
Prolonged-release Diltiazem Tablets contain Diltiazem
Hydrochloride. They are formulated so that the medicament
is released over a period of several hours. (d) Use an ambient column temperature.
PRODUCTION
A suitable dissolution test is carried out to demonstrate the (f) Inject 20 wL of each solution.
appropriate release of Diltiazem Hydrochloride. (g) Allow the chromatography to proceed for 5 times the
ay ane
The dissolution profile reflects the in vivo performance which retention time of diltiazem.
in turn 1s compatible with the dosage schedule recommended
by the manufacturer.
2016 Dimenhydrinate Preparations III-473

5 volumes of absolute ethanol, 25 volumes of acetonitrile and The impurities limited by the requirements of this
70 volumes of a phosphate buffer prepared by dissolving monograph include those impurities listed under Diltiazem
6.8 g of potassium dihydrogen orthophosphate in 250 mL of Hydrochloride.
water, adding 0.1 mL of N,N-dimethyloctylamine and
sufficient water to produce 1000 mL and adjusting the pH to
4.5 with 2m orthophosphoric acid.
SYSTEM SUITABILITY Dimenhydrinate Tablets
Action and use
with solution (3):
theresolution factor between the peaks due to diltiazem
: d diltiazemis at least 4.0; DEFINITION
Dimenhydrinate ‘Tablets contain Dimenhydrinate.
Content of dimenhydrinate, C,,H,;NO,C,H,CIN,O,;
IDENTIFICATION
Shake a quantity of the powdered tablets containing 0.1 g of
chromatogram obtained with. Dimenhydrinate with 10 mL of a mixture of equal volumes
the area of any other secondary ‘greater than the of chloroform and ether for 5 minutes, filter and evaporate the
area of the principal peakin the sram obtained with filtrate to an oily residue on a water bath. Add 3 mL of ether
solution (2) (0.2%); to the residue and scratch the interface between the residue
and the ether gently with a glass rod until crystals appear in
than 5 times the area of the principal peak’ the liquid. Transfer the suspension of crystalline material in
chromatogram obtained with solution (2) (1.0! ether to a watch glass, allow the solvent to evaporate in a
current of air and dry the residue at 60°. The infrared
Disregard any peak with an area less than 0.5 ti
of the principal peak in the chromatogram obtained*
concordant with the reference spectrum of dimenhydrinate
(RS 104).
ASSAY
ylline and substances related to
solutions prepared immediately before use.
powdered tablets containing 50 mg of Diltiazem
ityeof the powdered tablets containing 0.1 ¢g
Hydrochloride with 70 mL of methanol (50%) for
ath three 10-mL quantities of chloroform,
20 minutes, cool to room temperature, dilute to 100 mL
filter, evaporate’t
:t
with methanol (50%) and filter through a 0.45-um PTFE
dissolve the residué
filter. Dilute 1 volume of the resulting filtrate to 5 volumes
(2) Dilute 1 volume ‘
with methanol (50%).
chloroform.
(2) 0.01% w/v of diltiazem hydrochloride BPCRS in methanol
(3) 0.010% w/v of theophyilwe
(50%).
(3) 0.01% w/v of diltiazem impurity standard BPCRS in CHROMATOGRAPHIC CONDITIONS
methanol (50%). (a) Use as the coating silica gel GF,
CHROMATOGRAPHIC CONDITIONS (b) Use the mobile phase as describe
The chromatographic conditions described under Related (c) Apply 10 pL of each solution.
substances may be used. (d) Develop the plate to 15 cm.
SYSTEM SUITABILITY (e) After removal of the plate, dry in a current ef’cold air and
The test is not valid unless, in the chromatogram obtained examine under ultraviolet light (254 nm) (first examination).
with solution (3): Spray the plate with potassium todobismuthate solution, allow it
to dry in air and spray with hydrogen peroxide solution (10 vol)
the resolution factor between the peaks due to diltiazem
and examine in daylight (second examination).
impurity A and diltiazem is at least 4.0;
MOBILE PHASE
the symmetry factor of each peak is not more than 2.0.
1 volume of 13.5m ammonia, 9 volumes of methanol and
If necessary, adjust the concentration of
N,N-dimethyloctylamine in the mobile phase. 90 volumes of dichloromethane.
LIMITS
In the first examination:
Calculate the content of C,.H»,N.0O,S,HCI in the tablets
using the declared content of C2,H»~N2O,S,HCI in diltiazem any spot corresponding to theophylline in the chromatogram
hydrochloride BPCRS. obtained with solution (1) is not more intense than the spot
In the second examination:
IWI-474 Dimercaprol Preparations 2016
any secondary spot in the chromatogram obtained with LABELLING

solution (1) is not more intense than the spot in the The label states (1) the nature of the solvent; (2) that the
ween
chromatogram obtained with solution (2) (1%). preparation is intended for intramuscular injection only.
reas
Disregard any spot extending from the line of application to
anRf value of about 0.1.
ASSAY Dinoprostone Oral Solution
Weigh and powder 20 tablets. Dissolve a quantity of the NOTE: Dinoprostone Oral Solution 1s not currently licensed in the
powder containing 0.1 g of Dimenhydrinate as completely as Umited Kingdom.
possible in 20 mL of water, add 10 mL of 5M ammonia, mix,
extract with successive quantities of 15, 15, 15, 10 and DEFINITION
10 mL of ether and wash the combined extracts with 10 mL Dinoprostone Oral Solution is a solution of Dinoprostone in
orate the ether, warm the residue with 10 mL a suitable aqueous vehicle. It is intended to be diluted before
weaned use. :
id VS and titrate the excess of acid with The oral solution complies with the requirements stated under Oral
ae|
de VS using methyl red mixed solution as Liquids, the requirements stated under Unlicensed Medicines and
01m hydrochloric acid VS is with the following requirements.
Content of dinoprostone, C,,H;3,0,
TESTS
Dimercaprol Injectic IDENTIFICATION
A. Evaporate about 20 mL of the oral solution to 15 mL
Action and use , under a stream of nitrogen, extract the remaining solution
Chelating agent for use in heavy metal, with two 5-mL quantities of chloroform, combine the
chloroform extracts and evaporate almost to dryness using a
DEFINITION rotary evaporator. The infrared absorption spectrum of the
Dimercaprol resulting solution, Appendix II A, is concordant with the
Benzyl Benzoate reference spectrum of dinoprostone (RS 448).
Arachis Oil Sufficient to produc : B. In the Assay, the chromatogram obtained with solution
Extemporaneous preparation (1) shows a peak with the same retention time as the
Dissolve the dimercaprol in the benzyl benzoate and add
sufficient arachis oil to produce 100 mL. Add sufficient of a
35% v/v solution of strong ammonia solution in ethanol
(96 per cent) until the acidity, when determined by the D, using the following solutions. The solutions
method described below, corresponds to a pH of 6.8 to 7.0. jected immediately after preparation.
Add about 0.2 g of activated charcoal, stir, allow to stand for
not less than 1 hour and filter. Distribute the solution in methano (60
ampoules, the air in which is replaced by nitrogen or other of Dinoprostone
suitable gas and seal immediately. Sterilise by dry heat at a (2) Dilute 1 volume of
minimum of 150° for not less than 1 hour. methanol (60%) and*tuy
The injection complies with the requirements stated under with methanol (60%).
wiete ee 4]
aera
Content of dimercaprol, C;H;,OS,
4.75 to 5.25% wiv. allow to stand for 4 minutes andtheri
1M acetic acid (a yellowish-white op
CHARACTERISTICS
produced). Dilute the resulting solu
A bright, pale yellow solution.
TESTS 10 mL with methanol (60%). The solution cg ]
Acidity of prostaglandin A, (Ph Eur impurity D) and pg
Shake with an equal volume of water for 2 minutes and allow B, (Ph Eur impurity E).
to separate. The pH of the aqueous layer, after filtration CHROMATOGRAPHIC CONDITIONS
through neutral filter paper, is 4.5 to 6.5, Appendix V L. (a) Use a stainless steel column (25 cm x 4.6 mm) packed
PP erat: Refractive index with end-capped octadecylsilyl silica gel for chromatography
1.482 to 1.486, Appendix V E. (5 um) (Kromasil C18 is suitable).
Weight per mL (b) Use isocratic elution and the mobile phase described
0.940 to 0.955 g, Appendix V G. below.
ASSAY (c) Use a flow rate of 1 mL per minute.
To 1 g add 20 mL of 0.1m hydrochloric acid and titrate with (d) Use a column temperature of 30°.
0.05M todine VS. Each mL of 0.05 todine VS is equivalent (e) Use a detection wavelength of 210 nm.
to 6.21 mg of Cz3HgOS3. Use the weight per mL of the (f) Inject 200 wL of each solution.
injection to calculate the percentage w/v of Cz3HgOS;. MOBILE PHASE
Maen STORAGE 40 volumes of a 1% v/v solution of triethylamine, adjusted to
Dimercaprol Injection should be protected from light. pH 2.3 with orthophosphoric acid, and 60 volumes of methanol.
aCe aS
Vtete etd
2016 Diphenhydramine Preparations III-475
When the chromatograms are recorded under the prescribed IDENTIFICATION

conditions the retention time of Dinoprostone is about A. Carry out the method for thin-layer chromatography,
22 minutes. The retention times relative to Dinoprostone are: Appendix III A, using silica gel G as the coating substance
impurity D, about 1.7; impurity E, about 1.8. and a mixture of 50 volumes of ethanol (96%), 30 volumes of
SYSTEM SUITABILITY glacial acetic acid and 20 volumes of water as the mobile
following freshly prepared solutions. For solution (1) acidify
a quantity of the oral solution containing 50 mg of
to impurity D and impurity E is at least 1.5.
diphenhydramine hydrochloride with 2m hydrochloric acid,
LIMITS shake with three 20 mL quantities of ether, discard the ether,
In the chromatogram obtained with solution (1): extract with two 20 mL quantities of chloroform, dry the
peak corresponding to prostaglandin A, using combined extracts over anhydrous sodium sulfate, filter,
nd multiply the area of this peak by the evaporate the chloroform and dissolve the cooled residue in
5 mL of chloroform. Solution (2) contains 1% w/v of
corresponding to prostaglandin A, is not diphenhydramine hydrochloride BPCRS in chloroform. After
removal of the plate, allow it to dry in air and spray with a
greater than< aunties the area of the principal peak in the
chromatogram solution containing 0.25% w/v of chloroplatinic(1v) acid and
5% wiv of potassium iodide. The principal spot in the
ASSAY chromatogram obtained with solution (1) corresponds in
colour and position to that in the chromatogram obtained
Appendix III D, using tl ato with solution (2).
should be injected immediat B. Evaporate to dryness 1 mL of solution (1) obtained in test
(1) Dilute a quantity of the « A, dissolve the residue in 0.15 mL of water and add 2 mL of
methanol (60%) to produce a solut sulfuric acid; a yellow colour is produced which, on the
of Dinoprostone. a addition of 0.5 mL of mtric acid, changes to red. Add 15 mL
(2) Dissolve 10 mg of dinoprostone BPCRS iranet. of water, cool, add 5 mL of chloroform, shake and allow to
with the aid of ultrasound for 5 minutes dil separate; the chloroform layer is violet.
100 mL with methanol (60%). Related substances
CHROMATOGRAPHIC CONDITIONS Carry out the method for thin-layer chromatography,
The chromatographic conditions described under the te Appendix III A, using silica gel H as the coating substance
Prostaglandin A, may be used, but injecting 20 pL ofe and a mixture of 80 volumes of chloroform and 20 volumes of
solution. anol as the mobile phase. Apply separately to the plate
each of the following solutions. For solution (1) use
(1) described under test A for Identification.
Determine the weight per mL of the oral solution, tion (2) dilute 1 volume of solution (1) to
Appendix V G, and calculate the content of C,9H320s, s with chloroform. After removal of the plate, allow
weight in volume, using the declared content of C.)9H3,05 in nd spray with dilute potassium iodobismuthate
dinoprostone BPCRS. indary spot in the chromatogram obtained
STORAGE with solutié' isot more intense than the spot in the
The oral solution should be protected from light and stored
at a temperature of 2° to 8°.
LABELLING
The label states (1) that the preparation is to be diluted hydrochloride with 2m hydroch!
before use; (2) that any oral solution not used within 7 days 20 mL quantities of ether, discard the ether, make the
of the date of preparation should be discarded.
Diphenhydramine Oral Solution

Action and use 0.1m sodium hydroxide VS using methyl red solution as
Histamine H, receptor antagonist; antihistamine. indicator. Each mL of 0.05m sulfuric acid VS is equivalent to
29.18 mg of C,7H2;NO,HCI.
DEFINITION
STORAGE
Diphenhydramine Oral Solution is a solution of
Diphenhydramine Hydrochloride in a suitable flavoured Diphenhydramine Oral Solution should be protected from
vehicle. light.
Liguids and with the following requirements.
Content of diphenhydramine hydrochloride,
C,7H,,NO,HCl
IWI-476 Diphenhydramine Preparations 2016
10 mL with the mobile phase. To 4 volumes of this solution

Diphenhydramine Tablets add 3 volumes of solution (1) and dilute to 20 volumes with
Action and use the mobile phase.
Histamine H, receptor antagonist; antihistamine. (4) Dilute 1 volume of solution (2) to 5 volumes with the
mobile phase.
Diphenhydramine Tablets contain Diphenhydramine
Hydrochloride.
with base-deactivated octylsilyl silica gel for chromatography
The tablets comply with the requirements stated under Tablets and (5um) (Lichrospher RP Select B is suitable).
Content of diphenhydramine hydrochloride, below.
Shake a quantity o
Diphenhydramine i
retention time of the peak due to diphenhydramine.
centrifuge and filter th
filtrate to dryness under a" MOBILE PHASE
residue at 105° for 1 hour. T 35 volumes of acetonitrile and 65 volumes of a 0.54% w/v
the residue, Appendix II A, 1 with the reference solution of potassium dihydrogen orthophosphate adjusted to
spectrum of diphenhydramine hydro: pH 3.0 using orthophosphonic acid.
TESTS When the chromatograms are recorded under the prescribed
Dissolution conditions, the relative retentions with reference to
Comply with the dissolution test for tablets an diphenhydramine (retention time = about 6 minutes) are:
Appendix XII Bl. impurity A = about 0.9; impurity B = about 1.5; impurity C
= about 1.8; impurity D = about 2.6; impurity E = about
TEST CONDITIONS
5.1.
(a) Use Apparatus 1, and rotate the basket at 100 rev
SYSTEM SUITABILITY
per minute.
(b) Use 500 mL of mixed phosphate buffer pH 6.8, at a is not valid unless, in the chromatogram obtained
on (3), the resolution factor between the peaks due
temperature of 37°, as the medium.
ydramine and impurity A is at least 2.0.
PROCEDURE
medium and measure the absorbance of the filtered sample (a
0.45um filter is suitable), suitably diluted with the dissolution
medium, if necessary, to produce a solution expected to
contain 0.005% w/v of Diphenhydramine Hydrochloride, at
the maximum at 254 nm, Appendix IT B, using mixed
phosphate buffer pH 6.8 in the reference cell.
(2) Measure the absorbance of a 0.005% w/v solution of chromatogram obtained wit
diphenhydramine hydrochlonde BPCRS using mixed phosphate the area of any peak corres
buffer pH 6.8 in the reference cell.
Calculate the total content of diphenhydramine the area of any other secondary peak ‘ise
hydrochloride, C;7H,;NO,HCI, in the medium from the 0.4 times the area of the principal peak
absorbances obtained and using the declared content of obtained with solution (2) (0.2%);
Cy7H2;NO,HCI in diphenhydramine hydrochlonde BPCRS. the sum of the areas of the secondary peaks is not :
twice the area of the principal peak in the chromategram
LIMITS
obtained with solution (2) (1.0%). |
The amount of diphenhydramine hydrochloride released is
not less than 75% (Q) of the stated amount.
Related substances (4) (0.1%).
Appendix III D, using the following solutions. ASSAY
70 mg of Diphenhydramine Hydrochloride in 20 mL of the
solutions.
mobile phase. Dilute 1 volume to 5 volumes with the mobile
phase. (1) Mix for 10 minutes, with the aid of ultrasound, a
quantity of the powdered tablets containing 50 mg of
Diphenhydramine Hydrochloride with 50 mL of water, add
mobile phase.
sufficient water to produce 100 mL, mix and filter, use the
(3) Dissolve 5 mg of diphenhydramine impurity A EPCRS and filtrate.
5 mg of diphenylmethanol in the mobile phase and dilute to
(2) 0.05% wiv diphenhydramine hydrochloride BPCRS.
f eon, - ate “or Vt ee
Fm em a ee a a ei AE de ale
al ee eee
ee ey tts wkete
ea
2016 Dipipanone Preparations III-477
(3) Dissolve 5 mg of benzophenone in 5 mL of acetonitrile; add C. Evaporate the filtrate reserved in test B to dryness.
SS
sufficient water to produce 100 mL. To 1 mL of this The residue yields reaction A characteristic of chlorides,
NANA
Bese,
solution add 5 mg of diphenhydramine hydrochloride BPCRS Appendix VI.
NS A8ae
and add sufficient water to produce 10 mL.
TEST
CHROMATOGRAPHIC CONDITIONS Related substances
(a) Use a stainless steel column (25 cm x 4.6 mm) packed Carry out the method for thin-layer chromatography,
with muitrile silica gel for chromatography (5um). Appendix III A, using silica gel G as the coating substance
(b) Use isocratic elution and the mobile phase described and as the mobile phase the lower layer obtained after
below. shaking together a mixture of 2 volumes of 13.5M ammonia,
8 volumes of methanol and 90 volumes of dichloromethane and
allowing the layers to separate. Apply separately to the plate
(d) Use an ambient column temperature. 20 uL of each of the following freshly prepared solutions.
end
sae
fer te
ion wavelength of 254 nm. For solution (1) shake a quantity of the powdered tablets
‘each solution. containing 30 mg of Cyclizine Hydrochloride with 50 mL of
Nwaaand
a mixture of equal volumes of methanol and dichloromethane,

filter, evaporate the filtrate to dryness and dissolve the
residue in 3 mL of the same solvent mixture. For solution
(2) dilute 1 volume of solution (1) to 200 volumes with
methanol. Solution (3) contains 0.0050% w/v of
N-methylpiperazine in methanol. Solution (4) contains
0.10% w/v of each of cychzine hydrochloride BPCRS and
hydroxyzine hydrochloride BPCRS in methanol. After removal
cones
of the plate, allow it to dry in air and expose to iodine vapour
et
for 10 minutes. Any spot corresponding to N-methylpiperazine
in the chromatogram obtained with solution (1) is not more
Calculate thecontent of C,;;H2;NO,HCI. intense than the spot in the chromatogram obtained with
the declared content of C;7H2,;NO,HC1 i solution (3) (0.5%). Any other secondary spot in the
hydrochloride BPCRS. chromatogram obtained with solution (1) is not more intense
STORAGE w 4 than the spot in the chromatogram obtained with solution (2)
Diphenhydramine Tablets should be protected from‘li (0.5%). The test is not valid unless the chromatogram
obtained with solution (4) shows two clearly separated spots.
IMPURITIES
monograph include those listed under Diphenhydramine
Hydrochloride.
ichloromethane to produce 100 mL (solution A).
cena
tHe method for gas chromatography,
Dipipanone and Cyclizine Tablets d 50 mg of dipipanone

d..dilute to 50 mL with
Action and use (2) add 40 mL of
Opioid receptor agonist. the powdered tablets
DEFINITION
Dipipanone and Cyclizine Tablets contain, in each, 10 mg of
Dipipanone Hydrochloride and 30 mg of Cyclizine
Hydrochloride.
15 mL of dichloromethane in place
The tablets comply with the requirements stated under Tablets and dichloromethane.
Content of dipipanone hydrochloride,
C,4,H3;NO,HCI,H,O
9.0 to 11.0 mg. 3% wiw of silicone grease (ApiezonL is suitable) and
Content of cyclizine hydrochloride, C;sH>.N>,,HCl 5% wiw of potassium hydroxide and maintained at 250°.
27.75 to 32.25 mg. In the chromatogram obtained with solution (2) the peaks, in
order of emergence, are due to cyclizine, chlorcyclizine and
IDENTIFICATION
dipipanone.
Calculate the content of C3,H3,NO,HCI1,H,O using the
(3) exhibits two peaks having the same retention times as
declared content of C24H3,;NO,HCI,H,O in dipipanone
those due to dipipanone and cyclizine in the chromatogram
hydrochloride BPCRS and the content of CygH»2N2,HCl using
the declared content of C;gH.2.N2,HCl in cychzine
60 mg of Cyclizine Hydrochloride with 10 mL of acetone and
filter, reserving the filtrate for test C. Add 10 mL of
chloroform to the residue, mix with the aid of ultrasound for
2 to 3 minutes, filter and evaporate to dryness. The residue
yields reaction A characteristic of chlorides, Appendix VI.
IlJ-478 Dipivefrine Preparations 2016

Dipivefrine Eye Drops any peak corresponding to dipivalyladrenalone hydrochloride
+ aN ee
Action and use is not greater than the area of the peak corresponding to
Adrenaline prodrug; treatment of glaucoma. dipivalyladrenalone hydrochloride in the chromatogram
obtained with solution (3) (1%) and the area of any other
DEFINITION secondary peak is not greater than the area of the peak in the
Dipivefrine Eye Drops area sterile solution of Dipivefrine chromatogram obtained with solution (2) (0.4%).
Hydrochloride in purified water. ASSAY
The eye drops comply with the requirements stated under Eye Carry out the method for liquid chromatography,
Preparations and with the following requirements. Appendix III D, using the following solutions. For solution
Content of dipivefrine hydrochloride, C,;,)H,.NO;,HCl (1) use the eye drops diluted, if necessary, with water to
90.0 to 1 % of the stated amount. contain 0.1% w/v of dipivefrine hydrochloride. Solution (2)
contains 0.1% w/v of dipivefrine hydrochloride BPCRS in water.
IDE For solution (3) use solution (3) prepared for the Related
substances.
and a mixture of 1 volume of
anethanol and 30 volumes of
10 uL of each of the folles solution (3) resembles the appropriate chromatogram
the eye drops diluted with i provided with the impurity standard.
solution containing 0.1% w/ Calculate the content of Cj9Hz)NO5,HCI in the eye drops
Solution (2) is a 0.1% w/v solt from the chromatograms obtained and using the declared
content of CjgH2.NOs5,HCl in dipivefrine
allow it to dryin air and spray with a mt hydrochloride BPCRS.
of cunyienedianine, 45 volumes of ethanol
100° for 10 minutes and examine inndaylight. The prin

spot in the chromatogram obtained with solution (1) < Dipotassium Hydrogen Phosphate
corresponds to thatin the chromatogram obtained with Injection
solution (2).
solution (2).
TESTS
Clarity of solution
The eye drops are clear, Appendix IV A.
Content of dipetas m hydrogen phosphate, K,HPO,
Acidity amount.
95.0 to 105.0% of #
Related substances
IDENTIFICATION.
Yields the reactions characteris f potassium salts and
twand
reaction B characteristic of p hates, Appendix VI.
se any
(1) use the eye drops diluted, if necessary, to contain TESTS

0.1% w/v of dipivefrine hydrochloride. For solution (2) dilute Alkalinity
4 volumes of solution (1) to 10 volumes with water and pH, 9.0 to 10.0, Appendix V L.
further dilute 1 volume of this solution to 100 volumes with
ASSAY
water. For solution (3) dissolve the contents of one vial of
Dilute, if necessary, a volume of the injection Ww:
dipivefrine impurity standard BPCRS (the impurity standard
carbon dioxide-free water to produce a solution contgining
contains 99 mg of dipivefrine hydrochloride and 1 mg of
8.71% w/v (1 millimole of potassium ion per mL) of
dipivalyladrenalone hydrochloride) in 0.0015m hydrochloric
dipotassium hydrogen phosphate. Titrate 20 mL with
acid, wash the container with the same solvent and dilute the
0.5m hydrochloric acid VS using a mixture of 4 volumes of
nwt en etd
solution and washings to 100 mL with the same solvent.
nw aA bromocresol green solution and 1 volume of methyl red solution as
xe
indicator. Each mL of 0.5m hydrochloric acid VS is equivalent

(a) a stainless steel column (30 cm x 3.9 mm) packed with to 87.1 mg of K,HPOx,.
(uBondapak C18 is suitable), (b) as the mobile phase with a LABELLING
flow rate of 1 mL per minute a mixture of 1 volume of glacial The label states (1) the percentage w/v of Dipotasstum
acetic acid, 15 volumes of 0.014m sodium dodecyl sulfate and Phosphate; (2) the concentration of the potassium ion in
24 volumes of acetonitrile, (c) a detection wavelength of millimoles.
254 nm and (d) an electronic integrator.
solution (3) resembles the appropriate chromatogram
provided with the impurity standard.
2016 Dipyridamole Preparations ITI-479
MOBILE PHASE
Prolonged-release Dipyridamole
Mobile phase A Dissolve 1.0 g of potassium dihydrogen
Capsules orthophosphate in 900 mL of water, adjust to pH 7.0 with
Prolonged-release Dipyridamole Capsules from different 0.5M sodium hydroxide and dilute to 1000 mL with water,
manufacturers, whilst complying with the requirements of the Mobile phase B- methanol.
monograph, are not interchangeable unless otherwise justified and
authonised.
Action and use
0-5 40 60 isocratic
Adenosine reuptake inhibitor; inhibitor of platelet
aggregation.
SYSTEM SUITABILITY

resembles the chromatogram supplied with dipyridamole
resembles the chromatogram supplied with dipyridamole for
and with the following requirem peak identification EPCRS;
Content of dipyridamole, C,,H49! in the chromatogram obtained with solution (4) the resolution
95.0 to 105.0% of the stated amount. * between impurity D and dipyridamole is at least 2.0.
LIMITS
IDENTIFICATION :
Shake a quantity of the powdered capsule cont In the chromatogram obtained with solution (1):
containing 50 mg of Dipyridamole with 20 mL o: identify any peak corresponding to impurity B using the
dichloromethane, filter and evaporate to dryness. The chromatogram obtained with solution (4) and the
absorption spectrum of the residue, Appendix II A, is chromatogram supplied with dipyridamole for peak
concordant with the reference spectrum of dipyridamole ification EPCRS and multiply the area of this peak by a
(RS 108). n factor of 1.7;
TESTS of any peak corresponding to impurity 1 is not
Related substances # thran 4 times the area of the principal peak in the
Carry out the method for liquid chromatography, cogram obtained with solution (2) (4.0%);
Appendix III D, using the following solutions in amber
glassware and protected from light.
(1) Shake, with the aid of ultrasound for 5 minutes, a
quantity of the powdered capsule contents containing 0.2 g
of Dipyridamole with 10 mL of methanol (60%), dilute to E is not greater than:0.5 times the area of the principal peak
100 mL with methanol (60%), filter through a 0.45-um filter in the chromatogram ebt
and use the clear solution. each);
(2) Dilute 1 volume of solution (1) to 100 volumes with the area of any other seco
methanol (60%). 0.2 times the area of the principakpe
(3) 0.05% w/v of dipyridamole impurity standard BPCRS in obtained with solution (2) (0.2%
methanol (60%).
(4) Dissolve the contents of a vial of dipyridamole for peak
identification EPCRS in 1 mL of methanol (60%).
methanol (60%). principal peak in the chromatogram obtained wi
solution (5) (0.05%).
(a) Use a stainless steel column (10 cm x 4.0 mm) packed ASSAY
with end-capped octadecylsilyl silica gel for chromatography Carry out the method for liquid chromatography,
(5 wm) (Inertsil ODS2 is suitable). Appendix III D, using the following solutions in amber
below. (1) Shake with the aid of ultrasound for 5 minutes, a
quantity of the mixed contents of 20 capsules containing
50 mg of Dipyridamole with 10 mL of methanol (60%),
(d) Use a column temperature of 45°. dilute to 100 mL with methanol (60%) and filter through a
(e) Use a detection wavelength of 290 nm. 0.45-um filter. Dilute 10 mL of the filtrate to 100 mL with
(f) Inject 5 uL of each solution. the mobile phase.
(2) 0.005% w/v of dipyridamole BPCRS in methanol (60%).
IWI-480 Dipyridamole Preparations 2016
(3) Dissolve the contents of a vial of dipyridamole for peak 0.05% w/v of Dipyridamole and further dilute 1 volume of
identification EPCRS in 1 mL of methanol (60%). the resulting solution to 10 volumes with methanol. The light
range 220 to 450 nm exhibits three maxima, at 231, 284 and
The chromatographic conditions procedure described under
405 nm.
Related substances test may be used.
SYSTEM SUITABILITY
The Assay is not valid unless the chromatogram obtained principal peak due to dipyridamole in the chromatogram
with solution (3) closely resembles the chromatogram obtained with solution (2).
supplied with dipyridamole for peak identification EPCRS;
TESTS
the resolution between the peaks due to impurity D and
Acidity
DETER} Related substances
Calculate it of Cy4H49NgQO, in the capsules using Carry out the method for liquid chromatography,
fief CosHagNgOx in dipyridamole
BPCRS. Appendix III D, using the following solutions in amber
the requirements of this (1) Dilute the infusion with methanol (60%) to produce a
d under Dipyridamole and the solution containing 0.01% w/v of Dipyridamole.
following: (2) Dilute 1 volume of solution (1) to 100 volumes with
methanol (60%).
methanol (60%).
N7 S Ns
(5) 0.01% w/v of dipyridamole impurity standard BPCRS in
HOLA yA ZN methanol (60%).
6

with octadecylsilyl silica gel for chromatography (5 um) (Inertsil
1. Dipyridamole tartaric acid monoester,
low rate of 1.2 mL per minute.

gltimn temperature of 45°.
- O
OH NO Sv N. OS~) ON SO CcP
HO. Jk OH
PANO NZ ZN OH
O
OH O 7 N g of potassium dihydrogen
OD 0.5m sodium hydroxide and
9 adjust to pH 7.0 with
2. Dipyridamole ditartaric acid ester. Mobile phase B- methanol.

0-5 40 60
Dipyridamole Infusion 5-19 405 60-95
19-24 540 95-60 linear gradiéi

Action and use
Adenosine reuptake inhibitor; inhibitor of platelet
aggregation.
DEFINITION SYSTEM SUITABILITY
Dipyridamole Infusion is a sterile solution containing The test is not valid unless;
Dipyridamole. It is supplied as a ready-to-use solution. the chromatogram obtained with solution (4) closely
The infusion complies with the requirements stated under resembles the chromatogram supplied with dipyridamole for
Parenteral Preparations and with the following requirements. peak identification EPCRS;
Content of dipyridamole, C,,H4)NsO4 the chromatogram obtained with solution (5) closely
93.0 to 105.0% of the stated amount. resembles the chromatogram supplied with dipyridamole
IDENTIFICATION
A. Dilute a volume of the infusion with a mixture of in the chromatogram obtained with solution (4) the resolution
1 volume of 0.1M hydrochloric acid, 4 volumes of water and between impurity D and dipyridamole is at least 2.0.
5 volumes of methanol to produce a solution containing
2016 Dipyridamole Preparations III-481
CJ} OF
LIMITS

identify any peak corresponding to impurity B using the
and Nw NAO AL
Tr “OH
N7oS
chromatogram supplied with dipyridamole for peak |
identification EPCRS and multiply the area of this peak by a
6
correction factor of 1.7;
the area of any peak corresponding to impurity 1 is not
greater than 4 times the area of the principal peak in the
the areaaot any peak corresponding to impurity 2 is not
1. Dipyridamole tartaric acid monoester;
a of the principal peakin the
ned with solution (2) (1.0%);
not greater O
the chromatogr O
the area of any 0 ] OH Nu NS NN Ag NN. OH
the sum ofthe areas of any

greater than the area of the
the sum of the areas of all secondary

pe 2. Dipyridamole ditartaric acid ester
5 times the area of the principal peak 1
Disregard any peak with an area less than 0.54
the principal peak in the chromatogram obtained Dipyridamole Oral Suspension
Carry out the method for liquid chromatography, ‘“denosine reuptake inhibitor; inhibitor of platelet
Appendix III D, using the following solutions in amber
(1) Dilute the infusion with methanol (60%) to produce a
solution containing 0.005% w/v of Dipyridamole.
(3) Dissolve the contents of a vial of dipyridamole for peak e following requirements.
Content of dip Yi le, Cz4H 4 oNsO4
CHROMATOGRAPHIC CONDITIONS 95.0 to 105.0% o stated amount.
The chromatographic conditions described under the Related IDENTIFICATION
substances test may be used. A. To 10 mL of solution pared in the Assay add
SYSTEM SUITABILITY

solution (3) closely resembles the chromatogram supplied solutionin the range 220 to 450 ;
with dipyridamole for peak identification EPCRS; at 230, 285 and 405 nm.
the resolution between impurity D and dipyridamole is at least
2.0.
Calculate the content of C2,4H4 9NegO, in the infusion using
the declared content of Co,H49NgOq in dipyndamole BPCRS. solution (2).
STORAGE TESTS
Dipyridamole Infusion should be protected from light. Acidity
IMPURITIES
Related substances
monograph include those listed under Dipyridamole and the
Appendix III D, using the following solutions prepared
following:
immediately before use in amber glassware and protected
from light.
(1) To a volume of the oral suspension containing 50 mg of
Dipyridamole add 1.0 g of sodium chloride and 20 mL of
water, shake, add 90 mL of methanol, shake vigorously, cool
Be and add sufficient methanol to produce 100 mL. Filter
aes
em
through a 0.45-um nylon filter and dilute 10 mL of the
filtrate to 20 mL with water.
Ill-482 Dipyridamole Preparations 2016
(2) Dilute 1 volume of solution (1) to 100 volumes with (1) To a weighed quantity of the oral suspension containing
methanol (50%) and further dilute 1 volume of the resulting 50 mg of Dipyridamole add 1.0 g of sodium chloride and
solution to 5 volumes with methanol (50%). 20 mL of water, shake, add 90 mL of methanol, shake
(eK we
(3) Dissolve the contents of a vial of dipyridamole for peak vigorously, cool and add sufficient methanol to produce
identification EPCRS in 1 mL of methanol (50%). 100 mL. Filter through a 0.45-um nylon filter and dilute
10 mL of the filtrate to 100 mL with methanol (50%).
with end-capped octadecylsilyl silica gel for chromatography (3) Dissolve the contents of a vial of dipyridamole for peak
(5 um) (Inertsil ODS2 is suitable). identification EPCRS in 1 mL of methanol (50%).
(b) Use gradient elution and the mobile phase described CHROMATOGRAPHIC CONDITIONS |
below. The chromatographic conditions described under the Related

anwnad (c) Use. eof 1.2 mL per minute. substances test may be carried out.
(d) Use mperature of 45°. SYSTEM SUITABILITY

(f) Inject 5 uL of solution (3) closely resembles the chromatogram supplied
with dipyridamole for peak identification EPCRS;
MOBILE PHASE
the resolution factor between impurity D and dipyridamole is
at least 2.0.
0.5m sodium hydroxide and DETERMINATION OF CONTENT
Mobile phase B- methanol. Determine the weight per mL of the oral suspension,
Appendix V G, and calculate the content of C,,HiyNgO.,
weight in volume, using the declared content of C2,H4)>)NgOz
in dipyridamole BPCRS.
0-5 40 60 c IMPURITIES
5-19 40-5 60-95 linear gradie The impurities limited by the requirements of this
19-24 540 95-60 linear gradient = monograph include those listed under Dipyridamole.
SYSTEM SUITABILITY amole Tablets

solution (3) closely resembles the chromatogram supplied
with dipyridamole for peak identification EPCRS;
at least 2.0.
LIMITS
In the chromatogram obtained with solution (1): coated.

multiply the area of any peak corresponding to impurity B by The tablets comply with’ ments stated under Tablets and
ees
a correction factor of 1.7; with the following requir
ee AN
the area of any peaks corresponding to impurity A, Content of dipyridamole

impurity B or impurity C is not greater than 2.5 times the 95.0 to 105.0% of the stated anyount
IDENTIFICATION
the area of any peaks corresponding to impurity D or
impurity E is not greater than the area of the principal peak
the area of any other secondary peak is not greater than the spectrum of dipyridamole (RS 108).
TESTS
Related substances |
the sum of the areas of any such peaks is not greater than Carry out the method for liguid chromatography,
5 times the area of the peak in the chromatogram obtained Appendix III D, using the following solutions in amber
with solution (2) (1%). glassware and protected from light.
Disregard any peak with an area less than 0.5 times that of (1) Shake a quantity of the powdered tablets containing
the peak in the chromatogram obtained with solution (2) 50 mg of Dipyridamole with 100 mL of methanol (60%) for
(0.1%). 15 minutes, filter (Whatman GF/C filter is suitable) and use
ASSAY the filtrate.
Carry out the method for liquid chromatography, (2) Dilute 1 mL of solution (1) to 200 mL with methanol
Appendix III D, using the following solutions prepared (60%).
immediately before use in amber glassware and protected (3) Dissolve the contents of a vial of dipyridamole for peak
from light. identification EPCRS (dipyridamole and impurities A to F) in
1 mL of methanol (60%).
::
Oa Thee
a ee
ett
re
2016 Disodium Edetate Preparations III-483

oo:
ee,
na
>
,
:
’
(4) Dilute 1 mL of solution (2) to 10 mL with methanol CHROMATOGRAPHIC CONDITIONS

po
(60%). The chromatographic conditions described under the Related

SIN
Se .
substances test may be used.

Sy
Ce
2

»
ate ee
SYSTEM SUITABILITY
LENS
CO
Fy
with end-capped octadecylsilyl silica gel for chromatography The test is not valid unless the chromatogram obtained with
ie
er
tee
(5 um) (Inertsil ODS2 is suitable). solution (3) closely resembles the chromatogram supplied
we
POT
(b) Use gradient elution and the mobile phase described with dipyridamole for peak identification EPCRS;
‘
below.
_
4 ey

.
‘
ee
4
(c) Use a flow rate of 1.2 mL per minute. at least 2.0.

\
\
:
.

vs
:
;
:
.
(e) Use a detection wavelength of 290 nm. Calculate the content of C2,H49NegQOy, in the tablets using the
:
..
1
vo
te te
heptals
declared content of C2,H49NgOx in dipyridamole BPCRS.

ef
,
ag Bente
tate hah hs
1. feeb
.
fast
IMPURITIES
yee
Oe

tn
1
Ly
monograph include those listed under Dipyridamole.

1
tee
,
Mt
atay
’
Mobile phase B- me
noe
‘
:
Oy et
et
a
ett tt en fa et
Disodium Edetate Eye Drops

tp
ar
ta
Time Mobile phase A

ba
(Minutes) (% viv)
NOTE: Disodium Edetate Eye Drops are not currently licensed in
Db
nr
0-5 40
Ce
the United Kingdom.

.
ee yet
5-19 4035
2 eh
eve
Ce
eae ad
19-24 540 Action and use

a
.
an
24-29 40 60 Chelating agent.

ce
,
So
.
DEFINITION
oe
ee
aanyo
.
SYSTEM SUITABILITY Disodium Edetate Eye Drops area sterile solution of

SY .
Disodium Edetate in Purified Water.

:
The test is not valid unless the chromatogram obtairied

:
.
.
solution (3) closely resembles the chromatogram supplié

:
.
with dipyridamole for peak identification EPCRS; ations, the requirements stated under Unlicensed Medicines
;
ne
woeso
the following requirements.

:

:
ot
:SO
at least 2.0. of disodium edetate, C19H,4N2,Na,03 2H,O

4
:
. .

. Bag
LIMITS
:
o
:

ae
identify any peak corresponding to impurity B and multiply

sy
drop
the area of this peak by a correction factor of 1.7;
.
st
produced. Make alkaline to red litmus

.
the area of any peak corresponding to impurity A, B, C, D or a-42 and add 3 mL of ammonium
.
us
E is not greater than the area of the principal peak in the

.
,,
.

Oe
,
the area of any other secondary peak not greater than

tie eee
ons ey Se
eye drops, make alkaline

ete vet
0.4 times the area of the principal peak in the chromatogram ammonia R2 and add 3 m
a ANE
obtained with solution (2) (0.2%); no precipitate 1s produced.

oe
C. Yield the reactions characteristie..of s

re

Ea
Appendix VI.
Dead

>
TESTS
:
‘
in the chromatogram obtained with solution (4) (0.05%). Acidity or alkalinity

.
oa

.
oat
ASSAY
: a
ASSAY
.
wth

:
liquid chromatography, Appendix III D, using the following Carry out the method for liquid chromatography,
TS
aie ete Gs
wee
solutions in amber glassware and protected from light. Appendix III D, using the following solutions.
8 ee
ee
(1) Shake a quantity of the powdered tablets containing (1) Dilute a volume of the eye drops containing 20 mg of
Loans
50 mg of Dipyridamole with 100 mL of methanol (60%) for Disodium Edetate with sufficient water to produce 100 mL.
es
.
15 minutes and filter (Whatman GF/C is suitable). Dilute (2) 0.02% w/v of disodium edetate BPCRS in water.
aoe yy
a atea
wate
1 mL of the filtrate to 10 mL with methanol (60%). Before injection, mix solutions (1) and (2) with an equal
st
we
(2) 0.005% w/v of dipyridamole BPCRS 1n methanol (60%). volume of a 0.04% w/v solution of copper(1) nitrate.
.
:
ale
rn
SO

.
ey
Coote
Ts
Set te
identification EPCRS (dipyridamole and impurities A to F) in

a
oy

1 mL of methanol (60%). with end-capped octadecylsilyl silica gel for chromatography
we
e ceeh tty
Me.
er
(10 um) (uBondapak or Bondclone C18 are suitable).

Men
eS
ree
*vo Fo
aon
ee
oN
te
i
ae
ey
IfI-484 Disopyramide Preparations

‘
2016
a
on
to
eye
ve
(b) Use isocratic elution and the mobile phase described LIMITS
below. Any secondary spot in the chromatogram obtained with
(c) Use a flow rate of 2 mL per minute. solution (1) is not more intense than the spot in the
(d) Use an ambient column temperature. chromatogram obtained with solution (2) (0.25%).
(e) Use a detection wavelength of 254 nm. ASSAY
(f) Inject 20 wL of each solution. To a quantity of the mixed contents of 20 capsules
containing 40 mg of Disopyramide, add 40 mL of
MOBILE PHASE
0.05m methanolic sulfuric acid, shake for 15 minutes, dilute to
Add 6 volumes of tetrabutylammonium hydroxide solution to 100 mL with the same solvent and filter. Dilute 5 mL of the
195 volumes of water; adjust the pH to 6.5 with filtrate to 100 mL with 0.05m methanolic sulfuric acid and
orthophosphoric acid, add 200 volumes of acetonitrile and measure the absorbance of the resulting solution at the
sufficient water to produce 1000 volumes. maximum at 269 nm, Appendix II B. Calculate the content
awe nd
N F CONTENT of C,,;H2 N30 taking 198.5 as the value of A(1%, 1 cm) at
vanes
nt of CygH,4N.Na,0g,2H.O in the eye the maximum at 269 nm.
ed content of CoH 4N2Na20g,2H,O
S.
STORAGE
Disodium Edetate Ey Drop should be protected from light. Disopyramide Phosphate Capsules
Action and use
Class I antiarrhythmic.
Disopyramide Capsu g
DEFINITION
ee Ne Action and use Disopyramide Phosphate Capsules contain Disopyramide
Class I antiarrhythmic. Phosphate.
DEFINITION : and with the following requirements.
Disopyramide Capsules contain Disopyramide. *
Content of disopyramide, C,;Hj.>N3;O
The capsules comply with the requirements stated under ap: 92.5 to 107.5% of the stated amount.
DENT IFICATION
Content of disopyramide, C,,;H,.N;O
the equivalent of 0.2 g of disopyramidein 50 mL
IDENTIFICATION rm, add 2 mL of 13.5M ammonia, shake and filter
A. Shake a quantity of the contents of the capsules a mahydrous sodium sulfate. Evaporate the filtrate to
containing 0.2 g of Disopyramide with 50 mL of chloroform rotary evaporator and dissolve the residuein
for 15 minutes, filter, evaporate the filtrate to dryness using a . The infrared absorption spectrum,
rotary evaporator and dissolve the residue in 2 mL of ngordant with the reference spectrum of
chloroform. The infrared absorption spectrum, Appendix II A, is disopyramide®
concordant with the reference spectrum of disopyramide B. The light absorption; ppendix IJ B, in the range 230 to
(RS 110). 350 nm of the solutior inediin the Assay exhibits a
B. The light absorption, Appendix II B, in the range 230 to maximum only at 269 shoulder at 263 nm.
350 nm of the solution obtained in the Assay exhibits a C. Shake a quantity of the gontents of the capsules
ene ed
ee ne
containing the equivalent of 0:42 of disopyramide with
20 mL of water and filter. The faltrate’Vields the reactions
My we
TEST
ee ete
Related substances characteristic of phosphates, Appen

Carry out the method for thin-layer chromatography, TESTS
Appendix III A, using the following solutions. Dissolution
(1) Shake a quantity of the contents of the capsules Comply with the requirements for Monograj
containing 0.20 g of Disopyramide with 20 mL of methanol
for 30 minutes and filter. Appendix XII B1.
(2) Dilute 1 volume of solution (1) to 400 volumes with TEST CONDITIONS
methanol.
wees (a) Use Apparatus 2, rotating the paddle at 50 revolutions
CHROMATOGRAPHIC CONDITIONS per minute.
Met ae
wanes
Niet ed
(a) Use a TLC silica gel GF 254 plate.

VAN 2
(b) Use 900 mL of water at a temperature of 37°, as the

award
(b) Use the mobile phase as described below. medium.

(c) Apply 10 pL of each solution. PROCEDURE
(d) Develop the plate to 15 cm. After 45 minutes withdraw a 10 mL sample of the medium
(e) After removal of the plate, dry in a current of air and and measure the absorbance of the filtered sample, suitably
examine under ultraviolet light (254 nm). diluted with the dissolution medium if necessary, at the
maximum at 262 nm, Appendix II B, using water in the
MOBILE PHASE
wi
reference cell.
weve a
Se We te
take tee
1 volume of 18m ammonia, 30 volumes of acetone and
wa od
BF
7 1
=
nanaad
~s|
2016 Disulfiram Preparations III-485
DETERMINATION OF CONTENT B. In the test for Related substances, the principal spot in the
AAAS
we wwe J
were
ave
Calculate the total content of disopyramide, C2;H29N30, in chromatogram obtained with solution (2) corresponds to that
wees
seventy
RAN S
wae ee
the medium taking 125 as the value of A(1%, 1 cm) at the in the chromatogram obtained with solution (3).
maximum at 262 nm. C. Extract a quantity of the powdered tablets containing
Related substances 0.3 g of disulfiram with ethanol (96%), filter and evaporate
Carry out the method for thin-layer chromatography, the filtrate to dryness. Dissolve 50 mg of the residue in 5 mL
Appendix III A, using the following solutions. of ethanol (96%) and add 1 mL of potassium cyanide solution.
A yellow colour is produced which becomes green and then
darkens to bluish green.
containing the equivalent of 0.20 g of disopyramide with
20 mL of methanol for 30 minutes and filter. TESTS
1 volume of solution (1) to 200 volumes with Diethyldithiocarbamate
weweee|
Disulfiram with 10 mL of chloroform and filter. Add 10 mL
of 0.1m sodium hydroxide to the filtrate, shake, discard the
chloroform layer and wash the aqueous layer with three
10 mL quantities of chloroform. To the aqueous layer add
teed 0.25 mL of a 0.4% w/v solution of copper() sulfate and 2 mL
of dichloromethane, shake and allow to separate. The lower
fed
layer is not more intensely coloured than a standard prepared
aneeteeEe
at the same time and in the same manner by adding 10 mL
we OLY
of 0.1M sodium hydroxide to 0.2 mL of a freshly prepared
MOBILE PHASE 0.0075% w/v solution of sodium diethyldithiocarbamate and
1 volume of 18M ammonia, 30 volupies of beginning at the words ‘add 0.25 mL of a 0.4% w/v solution
ween
30 volumes of cyclohexane. of copper(ID sulfate ...? (0.01%, calculated as the acid).

Any secondary spot in the chromatogram obtaix tb Carry out the method for thin-layer chromatography,
solution (1) is not more intense than the spot in the Appendix III A, using silica gel GF254 as the coating
chromatogram obtained with solution (2) (0.5%). substance and a mixture of 30 volumes of butyl acetate and
70 volumes of n-hexane as the mobile phase. Apply separately
ASSAY to the plate 10 uwL of each of the following solutions.
To a quantity of the mixed contents of 20 capsules solution (1) extract a quantity of the powdered tablets
containing the equivalent of 40 mg of disopyramide, add edntaining 0.50 g of Disulfiram with 20 mL of ethyl acetate
40 mL of 0.05m methanolic sulfuric acid, shake for 15 minute filter. For solution (2) dilute 1 volume of solution (1) to
dilute to 100 mL with the same solvent and filter. Dilute ames with ethyl acetate. Solution (3) contains
5 mL of the filtrate to 100 mL with 0.05m methanolic sulfuric ly.of disulfiram BPCRS in ethyl acetate. Solution (4)
acid and measure the absorbance of the resulting solution at 0: w/v of monosulfiram BPCRS in ethyl acetate.
the maximum at 269 nm, Appendix II B. Calculate the ‘the*plate, allow it to dry in air and examine
content of C,;H» N30 taking 125 as the value of ight. (254 nm). In the chromatogram
A(1%, 1 cm) at the maximum at 269 nm. obtained with $olutign (1) any spot corresponding to
say
LABELLING monosulfiram is ri oréintense than the spot in the

The quantity of active ingredient is stated in terms of the chromatogram obtained with.solution (4) (2%) and any other
equivalent amount of disopyramide. secondary spot is not moresinterige than the spot in the
aN
te kad
chromatogram obtained olution (2) (1%).
MENS
es
ASSAY a
Weigh and powder 20 tablets. Ta. a tity of the powder
containing 0.4 g of Disulfiram add°73 mL i methanol and
wee AN
Disulfiram Tablets shake for 30 minutes. Add sufficient

Action and use 100 mL, filter and dilute 5 mL of the filtrg
Aldehyde dehyrogenase inhibitor; treatment of alcoholism. methanol. To 5 mL of this solution add suffiggent QF
0.1% w/v solution of copper(m) chloride in methaypi to produce
DEFINITION 25 mL, mix and allow to stand for 1 hour. Measure the
Disulfiram Tablets contain Disulfiram. absorbance of the resulting solution at the maximum at
400 nm, Appendix II B, using in the reference cell a solution
prepared by diluting 5 mL of methanol to 25 mL with the
copper(II) chloride solution. Repeat the operation using
Content of disulfiram, C,)H,).N>S, 5 mL of a 0.020% w/v solution of disulfiram BPCRS in
95.0 to 105.0% of the stated amount. methanol, beginning at the words ‘add sufficient of a
IDENTIFICATION 0.1% w/v solution of copper(m) chloride ...’. Calculate the
A. Extract a quantity of the powdered tablets containing content of C;j>H2oN2S, from the absorbances obtained and
0.2 g of Disulfiram by shaking with 5 mL of dichloromethane using the declared content of CygH29N2S,4 in
and filter. Evaporate the filtrate to dryness and dry the disulfiram BPCRS.
residue at 40° at a pressure not exceeding 0.7 kPa. The STORAGE
infrared absorption spectrum of the residue, Appendix II A, is Disulfiram Tablets should be protected from light.
concordant with the reference spectrum of disulfiram (RS 111).
Reaves
Vy
wes
OEPa
IWI-486 Dithranol Preparations 2016
and filter (Whatman GF/C paper is suitable). Evaporate the

Dithranol Cream filtrate to dryness under reduced pressure and dissolve the
Action and use residue in 10 mL of a mixture of 5 volumes of glacial acetic
Coal tar extract; treatment of psoriasis. acid and 95 volumes of acetomitrile; filter if necessary.
(2) Dissolve 25 mg of 1-hydroxy-9-anthrone BPCRS in
DEFINITION 0.5 mL of glacial acetic acid and add sufficient acetonitrile to
Dithranol Cream contains Dithranol in a suitable oil-in-water produce 50 mL (solution A); dilute 1 mL of solution A to
emulsified basis. 20 mL with acetonitrile.
The cream complies with the requirements stated under Topical (3) Dilute 1 volume of solution (1) to 40 mL with a mixture
Semi-solid Preparations and with the following requirements. of 5 volumes of glacial acetic acid and 95 volumes of
ithranol, Ci4H1903
acetonitrile.
(4) Dissolve 50 mg of dithranol BPCRS in 0.5 mL of glacial
acetic acid, add 2 mL of solution A and sufficient acetonitrile
to produce 50 mL.
5 mL of 1m sodium hydroxeg (5 um) (Nucleosil C18 and Spherisorb ODS 2 are suitable).
1 minute while stirring. A pif (b) Use isocratic elution and the mobile phase described
TESTS & below.
sean Dihydroxyanthraquinone and di imer (c) Use a flow rate of 1.5 mL per minute.
Carry out the method for quid chromag (d) Use an ambient column temperature.
Appendix III D, using the following soluts (e) Use a detection wavelength of 254 nm.
(1) For creams containing more than 0.5% | (f) Inject 20 wL of each solution.
use as solution (1) solution A obtainedin the Assay.
MOBILE PHASE
For creams containing 0.5% w/v or less ofDithrano! :
solution (1) solution B obtainedin the Assay. . 2.5 volumes of glacial acetic acid, 40 volumes of
tetrahydrofuran and 60 volumes of water.
(2) For creams containing more than 0.5% w/v of Dithr
add 4 mL of glacial acetic acid to 20 mL of a solution SYSTEM SUITABILITY
containing 0.005% w/v of 1,8-dihydro-xyanthraquinone and is not valid unless the chromatogram obtained with
0.005% w/v of dithranol dimer BPCRS in dichloromethane and ) closely resembles the chromatogram supplied
add sufficient n-hexane to produce 100 mL. For creams
containing 0.5% w/v or less of Dithranol, add 20 mL of
glacial acetic acid to 10 mL of a solution containing
0.005% w/v of 1,8-dihydroxyanthraquinone and 0.005% w/v of
dithranol dimer BPCRS in dichloromethane and add sufficient
dichloromethane to produce 100 mL.
be used but using a detection wavelength of 380 nm.
In the chromatogram obtained with solution (2), the the method for liquid chromate
substances elute in the following order: the following solutions.
dihydroxyanthraquinone and dithranol dimer.
LIMIT
Not more than 10.0% of the stated amount of dithranol,
calculated as the sum of the amounts of dichloromethane, filter through a glass microfi 1
dihydroxyanthraquinone and dithranol dimer. Calculate the (Whatman GF/Cis suitable) into a 100 mL grac
amounts of dihydroxyanthraquinone and dithranol dimer in wash the filter with dichloromethane and add suffici
the cream with reference to the corresponding peaks in the dichloromethane to produce 100 mL. Shake the flask
chromatogram obtained with solution (2). vigorously and allow to stand until two layers are obtained,
add dichloromethane until the dichloromethane and water
1-Hydroxy-9-anthrone
fa”
ia a wd
ie ne 7
Carry out the method for liguid chromatography, interface is level with the calibration mark, shake vigorously
and again allow to stand until two layers are obtained. Dilute
Appendix III D, in subdued light using the following freshly
prepared solutions. 20 volumes of the lower layer to 50 volumes with n-hexane
(solution A). Dilute a suitable volume of solution A with
(1) Disperse a quantity of the cream containing 10 mg of
n-hexane to contain 0.002% w/v of Dithranol. For creams
Dithranol in 30 mL of water at about 50°, add 30 mL ofa
containing 0.5% w/w or less of Dithranol, disperse, by
warm, saturated solution of sodium chloride, cool and extract
shaking, a quantity of the cream containing 5 mg of
with three 40-mL quantities of chloroform. Filter the extract
Dithranol in 10 mL of glacial acetic acid and 20 mL of
successively through anhydrous sodium sulfate on a suitable
dichloromethane, filter through a glass microfibre filter paper
filter (Whatman GF/C is suitable). Evaporate the filtrate
(Whatman GF/C is suitable) into a 50 mL graduated flask,
mA ee 4
ete tet under reduced pressure to a volume of about 2 mL, add
aw wash the filter with dichloromethane and add sufficient
ae ee 4
hele
25 mL of warm methanol, shake, cool in ice for 15 minutes
wens dichloromethane to produce 50 mL. Shake the flask vigorously
te te +t
Se ee te ae
EN cattailscorsd
15 By olsSin tn eed
a ered
2016 Dithranol Preparations III-487
and allow to stand until two layers are obtained, add (1) Disperse a quantity of the ointment containing 20 mg of
dichloromethane until the dichloromethane and water interface Dithranol in 20 mL of dichloromethane, add 1 mL of glacial
is level with the calibration mark, shake vigorously and again acetic acid, dilute to 100 mL with hexane and filter through a
allow to stand until two layers are obtained (solution B). fine glass microfibre filter paper (Whatman GF/C is suitable).
Dilute a suitable volume of solution B with n-hexane to (2) Add 1 mL of glacial acetic acid to 20 mL of a solution
contain 0.002% w/v of Dithranol. containing 0.0050% w/v of 1,8-dihydroxyanthraquinone and
(2) Add 1 mL of glacial acetic acid to 10 mL of a 0.02% wiv 0.0050% w/v of dithranol dimer BPCRS in dichloromethane and
solution of dithranol BPCRS in dichloromethane and add add sufficient hexane to produce 100 mL.
sufficient of the mobile phase to produce 100 mL. CHROMATOGRAPHIC CONDITIONS
CHROMATOGRAPHIC CONDITIONS (a) Use a stainless steel column (25 cm x 4.6 mm) packed
(a) Use a stainless steel column (25 cm x 4.6 mm) packed with silica gel for chromatography (5 um) (Lichrosorb Si 60 is
with salt for chromatography (5 um) (Lichrosorb Si 60 is suitable).
enw:
tion and the mobile phase described below.
L per minute. (d) Use an ambient column temperature.
temperature. (e) Use a detection wavelength of 380 nm.
(e) Use a detection ways (f) Inject 20 wL of each solution.
(f) Inject 20 uwL of each selution In the chromatogram obtained with solution (2), the
MOBILE PHASE de substances elute in the following order:
1 volume of glacial acetic acu f dichloromethane dihydroxyanthraquinone and dithranol dimer.
and 82 volumes of n-hexane. MOBILE PHASE
DETERMINATION OF CONTENT : 1 volume of glacial acetic acid, 5 volumes of dichloromethane

Calculate the content of C,4H 903 in the tr and 82 volumes of hexane.
declared content of C,4H 903 in dithranol B. LIMIT
STORAGE Not more than 10.0% of the stated amount of dithranol,

Dithranol Cream should be protected from light. calculated as the sum of the amounts of
dihydroxyanthraquinone and dithranol dimer. Calculate the
ts of dihydroxyanthraquinone and dithranol dimer in
tment with reference to the corresponding peaks in
matogram obtained with solution (2).
Dithranol Ointment lydroxy-9-anthrone
xe method for liquid chromatography,
Action and use
in subdued light using the following freshly
Coal tar extract; treatment of psoriasis.
prepared §
DEFINITION (1) Disperse.a g of the ointment containing 10 mg of
Dithranol Ointment contains Dithranol, in fine powder, in a Dithranol in 25 hloroform, evaporate under reduced
suitable hydrophobic basis.
methanol, shake, coo 4
(Whatman GF/C paper
dryness under reduced pré
Triturate dithranol, in fine powder, with Yellow Soft Paraffin, 10 mL of a mixture of 5 volurr
add sufficient Yellow Soft Paraffin to produce an ointment of 95 volumes of acetonitrile; filter 1
the required strength and mix thoroughly. Part of the Yellow
(2) Dissolve 25 mg of 1-hydroxy-
Soft Paraffin may be replaced by Hard Paraffin to produce
0.5 mL of glacial acetic acid and add sts
an ointment of stiffer consistency.
produce 50 mL (solution A); dilute 1 mL
The ointment complies with the requirements stated under Topical 20 mL with acetonitrile.
(3) Dilute 1 volume of solution (1) to 40 mL with a mixture
Content of dithranol, C,,H; 9O3 of 5 volumes of glacial acetic acid and 95 volumes of
85.0 to 110.0% of the stated amount. acetonitrile. |
IDENTIFICATION (4) Dissolve 50 mg of dithranol BPCRS in 0.5 mL of glacial
A. In the Assay, the principal peak in the chromatogram acetic acid, add 2 mL of solution A and sufficient acetonitrile
obtained with solution (1) corresponds to the principal peak to produce 50 mL.
in the chromatogram obtained with solution (2). CHROMATOGRAPHIC CONDITIONS
B. Heat a quantity containing 0.5 mg of dithranol with 5 mL (a) Use a stainless steel column (20 cm x 4.6 mm) packed
of 1m sodium hydroxide on a water bath with constant stirring. with end-capped octadecylsilyl silica gel for chromatography
A pink colour is produced in the aqueous layer. (5 um) (Nucleosil C18 and Spherisorb ODS 2 are suitable).
TESTS (b) Use isocratic elution and the mobile phase described
Dihydroxyanthraquinone and dithranol dimer below.
Carry out the method for liquid chromatography, (c) Use a flow rate of 1.5 mL per minute.
Appendix III D, using the following solutions. (d) Use an ambient column temperature.
IlI-488 Dithranol Preparations 2016

(f) Inject 20 pL of each solution. A. In the Assay for dithranol, the principal peak in the
chromatogram obtained with solution (1) corresponds to the
MOBILE PHASE
2.5 volumes of glacial acetic acid, 40 volumes of solution (2).
tetrahydrofuran and 60 volumes of water.
B. Suspend a quantity containing 0.5 mg of Dithranol in
SYSTEM SUITABILITY 5 mL of 1m sodium hydroxide and heat on a water bath for
The test is not valid unless the chromatogram obtained with 1 minute while stirring. A pink colour is produced.
solution (4) closely resembles the reference chromatogram C. Disperse 0.5 g in 10 mL of chloroform, filter, extract the
supplied with dithranol BPCRS. filtrate with 10 mL of a 1% w/v solution of sodium hydrogen
LIMITS carbonate and wash the extract with 5 mL of chloroform.
obtained with solution (1): To 5 mL add 3 mL of zron(im) chlonde solution R1. A violet
colour is produced which persists after the addition of
orresponding to the principal peak in
0.5 mL of 5M acetic acid.
btained with solution (2) (1-hydroxy-9-
TESTS
Dihydroxyanthraquinone and dithranol dimer
(1) Disperse a quantity of the paste containing 20 mg of
Dithranol in 20 mL of dichloromethane with warming and
stirring, centrifuge and decant the supernatant layer into a
100 mL flask. Disperse the residue in 20 mL of hexane,
centrifuge, decant the supernatant layer into the 100 mL
acetic acid, dilute to 100 mL with hexane
flask and repeat the procedure with a further two 20-mL
fine glass microfibre filter paper (Whatman GF
quantities of hexane. Add 1 mL of glacial acetic acid to the
(2) Add 1 mL of glacial acetic acid to 20 mL'é a 0s / combined extracts, dilute to 100 mL with hexane and filter
solution of dithranol BPCRS in dichloromethane arid add through a fine glass microfibre filter paper (Whatman GF/C
sufficient hexane to produce 100 mL. paper is suitable).
CHROMATOGRAPHIC CONDITIONS 2) Add 1 mL of glacial acetic acid to 20 mL of a solution
The chromatographic conditions described under ontaining 0.0050% w/v of 1,8-dihydroxyanthraquinone and
Dihydroxyanthraquinone and dithranol dimer may be used % wiv of dithranol dimer BPCRS in dichloromethane and
but using a detection wavelength of 354 nm. sient hexane to produce 100 mL.
MOBILE PHASE RAPHIC CONDITIONS
1 volume of glacial acetic acid, 5 volumes of dichloromethane inless steel column (25 cm x 4.6 mm) packed
and 82 volumes of hexane. F for.chromatography (5 um) (Lichrosorb Si 60 is
(b) Use isocr
Calculate the content of C,;,H,)03 in the oitment using the
below.
declared content of C,4H1 903 in dithranol BPCRS.
STORAGE
Dithranol Ointment should be protected from light.
MOBILE PHASE
Dithranol Paste 1 volume of glacial acetic acid, 5 volu

and 82 volumes of hexane.
NOTE: Dithranol Paste is not currently licensed in the United
Kingdom.
Action and use to: dihydroxyanthraquinone and dithranol dimer.

Treatment of psoriasis. LIMITS .
Calculate the amounts of dihydroxyanthraquinone and

DEFINITION
dithranol dimer in the paste using the chromatograms
Dithranol Paste contains Dithranol in a suitable hydrophobic
obtained with solutions (1) and (2).
basis containing Zinc Oxide and Salicylic Acid.
The sum of the amounts of dihydroxyanthraquinone and
The paste complies with the requirements stated under Topical
dithranol dimer is not more than 10.0% of the stated amount
Semi-solid Preparations, the requirements stated under Unlicensed
of dithranol.
Medicines and with the following requirements.
Content of dithranol, C,,H,,O3 ASSAY
85.0 to 110.0% of the stated amount. For dithranol
Content of salicylic acid, C;,H;O3
(1) Disperse a quantity of the paste containing 5 mg of
Content of zinc oxide, ZnO Dithranol in 20 mL of dichloromethane with warming and
tte at th ee =. . ee
NN net Oe ee a oe et el LL ba cof cyte core Rm yee Qf Af se BE Re the ete
COU g ether tet at “6 ere ow
Be ACU Dk a aN nhae ads a ba tn Tage
2016 Dithranol Preparations IJJ-489
stirring, centrifuge and decant the supernatant layer into a Content of salicylic acid, C;,H;O;3
100 mL flask. Disperse the residue in 20 mL of hexane, 90.0 to 110.0% of the stated amount.
centrifuge, decant the supernatant layer into the 100 mL
IDENTIFICATION
flask and repeat the procedure with a further two 20-mL
A. In the Assay for Dithranol, the principal peak in the
quantities of hexane. Add 1 mL of glacial acetic acid to the
chromatogram obtained with solution (1) corresponds to the
combined extracts, dilute to 100 mL with hexane and filter
through a fine glass microfibre filter paper (Whatman GF/C
solution (2).
is suitable).
B. Heat a quantity of the ointment containing 0.5 mg of
(2) Add 1 mL of glacial acetic acid to 20 mL of a 0.025% wiv
Dithranol with 5 mL of 1M sodium hydroxide on a water bath
solution of dithranol BPCRS in dichloromethane and add
with constant stirring. A pink colour is produced in the
sufficient hexane to produce 100 mL.
aqueous layer.
cow and
C. Shake 1 g with 10 mL of water, filter and add to the
enw ad
filtrate zronam chloride solution R1; an intense reddish violet
colour is produced which persists on the addition of 6M acetic
acid. Add 2m hydrochloric acid; the colour disappears and a
white, crystalline precipitate is produced.
Calculate the coi } TESTS
declared content of ¢ Dihydroxyanthraquinone and dithranol dimer
For salicylic acid Carry out the method for liquid chromatography,
Shake 0.5 g with 10 mL Appendix III D, using the following solutions.
ether until fully dispersed. (1) Disperse a quantity of the ointment containing 20 mg of
layer. Extract the ether layer w y TUE Dithranol in 20 mL of dichloromethane, add 1 mL of glacial
quantities of 1m hydrochloric acid, combixi€ 1 acetic acid, dilute to 100 mL with hexane and filter through a
extracts with the reserved aqueous la fine glass microfibre filter paper (Whatman GF/C is suitable).
ether and reserve for the Assay for zinc (2) Add 1 mL of glacial acetic acid to 20 mL of a solution
containing 0.0050% w/v of 1,8-dihydroxyanthraquinone and
0.0050% w/v of dithranol dimer BPCRS in dichloromethane and
quantities of 20 mL, 10 mL and 10 mL of borate buffe add sufficient hexane to produce 100 mL.
pH 9.0. Dilute the combined extracts to 100 mL with
2M hydrochloric acid, dilute 15 mL of the resulting solu
50 mL with the same solvent and measure the absorbance Dse a stainless steel column (25 cm x 4.6 mm) packed
the final solution at the maximum at 302 nm, Appendix II Silica gel for chromatography (5 ym) (Lichrosorb Si 60 is
Calculate the content of C7H,O3 taking 260 as the value of
A(1%, 1 cm) at the maximum at 302 nm. ocratic elution and the mobile phase described
For zinc oxide
To the combined aqueous extracts obtained in the Assay for
salicylic acid add 20 mL of 1M sodium hydroxide and 50 mg
of xylenol orange triturate. To the resulting solution add
(e) Use a deteg tion wavelength of 380 nm.
sufficient hexamine to change the colour of the solution to 20uL é
(f) Inject
red, and then a further 3 g of hexamine, and titrate with
0.1m disodium edetate VS. Each mL of 0.1m disodium edetate
VS is equivalent to 8.137 mg of ZnO.
STORAGE
Dithranol Paste should be protected from light.
to: dihydroxyanthraquinone and di

ve nee
LIMITS
Dithranol and Salicylic Acid Ointment Calculate the amounts of dihydroxyanthra

dithranol dimer in the ointment using the chrog
NOTE: Dithranol and Salicylic Acid Ointment is not currently obtained with solutions (1) and (2).
licensed in the United Kingdom.
The sum of the amounts of dihydroxyanthraquinone and
Action and use dithranol dimer is not more than 10.0% of the stated amount
rae
aN AA
Treatment of psoriasis. of dithranol.
ASSAY
DEFINITION For dithranol
Dithranol and Salicylic Acid Ointment contains Dithranol Carry out the method for liquid chromatography,
and Salicylic Acid in a suitable emulsifying basis. Appendix III D, using the following solutions.
The ointment complies with the requirements stated under Topical (1) Disperse a quantity of the ointment containing 5 mg of
Semi-solid Preparations, the requirements stated under Unlicensed Dithranol in 20 mL of dichloromethane, add 1 mL of glacial
Medicines and with the following requirements. acetic acid, dilute to 100 mL with hexane and filter through a
Content of dithranol, C,,H,,O3 fine glass microfibre filter paper (Whatman GF/C is suitable).
ana! ee a
LA ee
III-490 Dobutamine Preparations 2016
(2) Add 1 mL of glacial acetic acid to 20 mL of a 0.025% wiv IDENTIFICATION

solution of dithranol BPCRS in dichloromethane and add A. In the Assay, the chromatogram obtained with solution
sufficient hexane to produce 100 mL. (1) shows a peak with the same retention time as that of the
CHROMATOGRAPHIC CONDITIONS principal peak in the chromatogram obtained with
The chromatographic conditions described under solution (2).
Dihydroxyanthraquinone and dithranol dimer may be used B. Carry out the method for thin-layer chromatography,
but using a detection wavelength of 354 nm. Appendix III A, using the following solutions.
DETERMINATION OF CONTENT (1) Use the infusion being examined diluted, if necessary, in
a mixture of 1 volume of water and 4 volumes of methanol to
Calculate the content of C,,4H; 903 in the ointment using the
produce a solution containing the equivalent of 0.05% w/v of
declared content of C,4H, 903 in dithranol BPCRS.
dobutamine.
(2) 0.05% wiv of dobutamine hydrochlonde BPCRS in a
the omtment containing 10 mg of
mixture of 1 volume of water and 4 volumes of methanol.
mL of 1m hydrochloric acid and 10 mL
persed. Decant the aqueous layer and CHROMATOGRAPHIC CONDITIONS
th two further 10-mL quantities of (a) Usea silica gel precoated plate.
1m hydrochloric acid ether layer add 15 mL of (b) Use the mobile phase as described below.
petroleum spirit (boiling ¥a: 40° to 60°) and extract with (c) Apply 10 uL of each solution.
successive quantities of 2) m 10 mL and 10 mL of borate
buffer pH 9.0. Dilute the corm xtracts to 100 mL with
2m hydrochloric acid, dilute 15 the resulting solution to (e) After removal of the plate, allow it to dry in air and spray
50 mL with the same solvent a asute the absorbance of with a 0.5% w/v solution of potassium permanganate in
the final solution at the maximuit im, Appendix II B. 1M sodium hydroxide.
Calculate the content of C7H,O; taking'26 the value of MOBILE PHASE
A(1%, 1 cm) at the maximum at 302 nm 2 volumes of water, 6 volumes of glacial acetic acid,
STORAGE 12 volumes of ether and 18 volumes of butan-1-ol.
Dithranol and Salicylic Acid Ointment should b CONFIRMATION
from light.
omatogram obtained with solution (2).
Dobutamine Infusion substances

Dobutamine Intravenous Infusion ith the test described in the requirements for
Action and use

Beta,-adrenoceptor agonist.
DEFINITION
Dobutamine Infusion is a sterile solution containing
Dobutamine Hydrochloride. It is supplied as a ready-to-use
solution or it is prepared by diluting either Sterile
Dobutamine Concentrate or Dobutamine Hydrochloride for
Injection with a suitable diluent in accordance with the
manufacturer’s instructions.
Parenteral Preparations and with the following requirements. (3) Dilute 1 volume of solution (1) 1t
mixture of equal volumes of mobile pha
TEST phase B.
Carry out the test for bacterial endotoxins, Appendix XIV C, ASSAY
Method D. Dilute the infusion, if necessary, with water BET Carry out the Assay described under the requirements for
to give a solution containing the equivalent of 10 mg of Sterile Dobutamine Concentrate but for solution (1) use the
dobutamine per mL (solution A). The endotoxin limit infusion being examined diluted, if necessary, with the
concentration of solution A is 10 IU per mL. mobile phase to contain the equivalent of 0.05% w/v of
dobutamine.
STORAGE
Dobutamine Infusion prepared from Sterile Dobutamine LABELLING
Concentrate or from Dobutamine Hydrochloride for The quantity of active ingredient is stated in terms of the
Injection should be used immediately after preparation but, equivalent amount of dobutamine.
in any case, within the period recommended by the
manufacturer when prepared and stored strictly in STERILE DOBUTAMINE CONCENTRATE
DEFINITION
When supplied as a ready-to-use solution, the infusion complies
Sterile Dobutamine Concentrate is a sterile solution of
Dobutamine Hydrochloride in Water for Injections.
Content of dobutamine, C,3H.3NO3
wen SO I
Se at ar A Pee oe nd apd
as.
So ee eed ota alee leis,
Dobutamine Preparations III-491
The concentrate comphes with the requirements for Concentrates (3) Dilute 1 volume of solution (1) to 100 volumes with a
for Injections or Infusions stated under Parenteral Preparations mixture of equal volumes of mobile phase A and mobile
and with the following requirements. phase B.
Content of dobutamine, C,;H,3;NO; CHROMATOGRAPHIC CONDITIONS
95.0 to 105.0% of the stated amount. (a) Use a stainless steel column (15 cm x 4.6 mm) packed
CHARACTERISTICS with end-capped octadecylsilyl silica gel for chromatography
A colourless or pale yellow solution. (5 um) (Supelcosil LC-18-DB is suitable).
IDENTIFICATION
below.
(1) shows a peak with the same retention time as that of the (c) Use a flow rate of 1 mL per minute.
zak in the chromatogram obtained with (d) Use an ambient column temperature.
thod for thin-layer chromatography, (f) Inject 20 pL of each solution.
the following solutions.
MOBILE PHASE
(1) Use the concentgate being examined diluted, if necessary,
Mobile phase A Dissolve 2.60 g of sodium octanesulfonate in
with water to produ ution containing the equivalent of
1000 mL of water and add 3 mL of triethylamine; adjust to
1.25% wiv of dobutam
(2) 1.25% wv of dobutamitx hloride BPCRS in
Mobile phase B18 volumes of acetonitrile and 82 volumes of
methanol.
methanol.
CHROMATOGRAPHIC CONDIT bs
(a) Use a silica gel 60 F454 prec Time Mobile phase A Mobile phase B
(b) Use the mobile phase as described* (min) (percent P/V) (Goer cent PIP}
(c) Apply 10 pL of each solution. 0-5 65 35
(d) Develop the plate to 15 cm. 5-20) 65— 20 35980
(e) After removal of the plate, allow it to dry in dir a 20-25 20 80
examine under ultraviolet light (254 nm). Spray the plate 5
a 6.0% w/v solution of iron(im) chloride hexahydrate and*th
with a 2% w/v solution of potassium hexacyanoferrate
(11).
SYSTEM SUITABILITY
MOBILE PHASE
5 volumes of glacial acetic acid, 15 volumes of water, n (2), the resolution factor between the peaks
40 volumes of propan-1-ol and 100 volumes of ethyl acetate. ing to dobutamine hydrochloride and anisaldehyde
CONFIRMATION
By each method of visualisation the principal spot in the
TESTS
Acidity
pH of the concentrate diluted, if necessary, to contain the
equivalent of 1.25% w/v of dobutamine, 2.5 to 4.0,
Appendix V L.
Clarity of solution
Dilute the concentrate, if necessary, to contain the equivalent of the principal peak in the chromat gram, ained with
of 1.25% w/v of dobutamine. The solution is not more solution (3) (0.05%).
opalescent than reference suspension I, Appendix IV A.
ASSAY
Light absorption Carry out the method for liguid chromatography, .
The light absorption, Appendix II B, at 400 nm of the Appendix III D, using the following solutions. |
concentrate diluted, if necessary, to contain the equivalent of
(1) Dilute the concentrate with the mobile phase to produce
1.25% w/v of dobutamine is not more than 0.20.
Related substances dobutamine.
Carry out the method for liquid chromatography, (2) 0.06% w/v of dobutamine hydrochloride BPCRS in the
Appendix III D, using the following solutions. mobile phase.
(1) Dilute the concentrate with a mixture of equal volumes (3) 0.06% w/v of dobutamine hydrochloride BPCRS and
of mobile phase A and mobile phase B to produce a solution 0.03% wv of 4-(4-hydroxyphenyl) butan-2-one in the mobile
containing the equivalent of 0.5% w/v of dobutamine. phase.
0.005% w/v solution of anisaldehyde in a mixture of equal
volumes of mobile phase A and mobile phase B and dilute (a) Use a stainless steel column (25 cm x 4.6 mm) packed
1 volume of the solution to 10 volumes with the same with end-capped octadecylsilyl silica gel for chromatography
mixture of mobile phases. (5 um) (Supelcosil LC-18-DB 1s suitable).
below.
II-492 Dobutamine Preparations 2016
“4
o
‘

(d) Use an ambient column temperature. The principal spot in the chromatogram obtained with
‘
Nw aye
(e) Use a detection wavelength of 280 nm. solution (1) corresponds in position and colour to that in the
nwa
TESTS
MOBILE PHASE
Acidity
58 volumes of a solution prepared by dissolving 3.38 g of
dobutamine, 2.5 to 4.5, Appendix V L.
sodium octanesulfonate in 1000 mL of water, adding 3 mL of
triethylamine and adjusting the pH to 2.5 with orthophosphoric Clarity of solution
acid. A solution containing the equivalent of 2.5% w/v of
dobutamine is not more opalescent than reference suspension
II, Appendix IV A.
nless, in the chromatogram obtained
Light absorption
resolution factor between the peaks due
‘ye Ae
awene
The absorbance, Appendix IT B, at 480 nm of a solution

rate
echloride and 4-(4-hydroxyphenyl)butan-

containing the equivalent of 2.5% w/v of dobutamine is not
more than 0.065.
Related substances
Comply with the test described in the requirements for
Sterile Dobutamine Concentrate but preparing solution (1)
in the following manner. Dissolve the contents of the sealed
LABELLING container in a mixture of equal volumes of mobile phase A
The quantity of active ingrediext't erms of the and mobile phase B to produce a solution containing the
equivalent of 0.5% w/v of dobutamine.
i~feae
equivalent amount of dobutamine.

Water
DOBUTAMINE HYDROCHLORIDE FOR Not more than 2.0%, Appendix IX C. Use the contents of a
single container and add 7 g of salicylic acid and 20 mL of
INJECTION 4 formamide before the determination.
DEFINITION
ASSAY
Dobutamine Hydrochloride for Injection is a sterile miteri
consisting of Dobutamine Hydrochloride with or without
excipients. It is supplied in a sealed container.
ssqlve the contents of one container in the mobile
oduce a solution containing the equivalent of
f dobutamine.
vof dobutamine hydrochlonde BPCRS in the
Content of dobutamine, C,;H,,NO;3
obygamuine hydrochloride BPCRS and
IDENTIFICATION ydxoxyphenyl) butan-2-one in the mobile
(1) shows a peak with the same retention time as that of the CHROMATOGRAPH NDETIONS
The chromatographic ¢ ier described under Assay in
solution (2).
vent
the requirements for Sterile obytamine Concentrate may be
B. Carry out the method for thin-layer chromatography, used.
AAwaAd Appendix III A, using the following solutions.
SYSTEM SUITABILITY
(1) Dissolve the contents of the sealed container in sufficient
of a mixture of 1 volume of water and 4 volumes of methanol The test is not valid unless, in the chs ram
: obtained
to produce a solution containing the equivalent of 1.0% w/v with solution (3), the resolution factor between; e, peaks due
of dobutamine. to dobutamine hydrochloride and 4-(4-hytit
2-one is at least 1.5.
(2) 1% wWv of dobutamine hydrochloride BPCRS in a mixture
of 1 volume of water and 4 volumes of methanol. DETERMINATION OF CONTENT
Calculate the content of C;gH.3NO; in the container using
the declared content of C,;gH.3,NO3 in dobutamine
(a) Usea silica gel precoated plate.
ene 4 hydrochloride BPCRS.
wet
cae
ae NW
ae 7 Repeat the procedure on the contents of a further two
vwave
containers. Determine the content of C;gH23NO3 using the

(d) Develop the plate to 15 cm. average of the three individual results obtained.
(e) After removal of the plate, allow it to dry in air and spray LABELLING
with a 0.5% w/v solution of potassium.permanganate in The quantity of active ingredient is stated in terms of the
1m sodium hydroxide. equivalent amount of dobutamine.
MOBILE PHASE
2 volumes of water, 6 volumes of glacial acetic acid,
Awe sy
12 volumes of ether and 18 volumes of butan-1-ol.
AN ae
nee ot
2016 Docusate Preparations III-493
Docusate Capsules Compound Docusate Enema

aN

Ee AN
Stimulant laxative; faecal softener. Stimulant laxative; faecal softener.

SAAN
sees!
Docusate Capsules contain a solution of Docusate Sodium in Compound Docusate Enema is a rectal solution containing
a suitable water miscible vehicle. Docusate Sodium and Glycerol in a suitable water-miscible
The capsules comply with the requirements stated under Capsules vehicle.
and with the following requirements. The enema complies with the requirements stated under Rectal
Content of docusate sodium, C,,)H3,Na0O,S Preparations and with the following requirements.
*h10.0% of the stated amount. Content of docusate sodium, C,,H3,Na0,S
|
wie wee

IDENTIFICATION
Appendix III A, usinga silica gel precoated plate (Merck
silica gel 60 plates are suitable) and a mixture of 2 volumes
- ethyl acetate as the mobile phase. of 13.5mM ammonia, 20 volumes of ethanol (96%), 40 volumes
“20 uL of each of the following of water and 50 volumes of ethyl acetate as the mobile phase.
ve, by heating on a water Apply separately to the plate 20 wL of each of the following
¥tSsproduce a solution solutions. For solution (1) dissolve, by heating on a water
-ass 1 mL of this bath, a quantity of the enema containing 50 mg of Docusate
one ed
a solid-phase Sodium in 5 mL of water. Pass 1 mL of this solution with
extraction column of 1 mL capacity ining 0.1 g of
veined
the aid of vacuum through a solid-phase extraction column

an octadecyl-bonded silica sorbent (a of 1 mL capacity and containing 0.1 g of an octadecyl-
bonded silica sorbent (a Sep-pak C18 column is suitable)
previously washed with 2 mL of methanol, followed by 5 mL
of water. Wash the column with 2 mL of water, discarding
sodium with 4 mL of methanol, retaining the methagiol the aqueous eluate and then elute the Docusate Sodium with
solution. Solution (2) contains 0.25% w/v of docusate 4 mL of methanol, retaining the methanol solution. Solution
sodium BPCRS in methanol. After removal of the plate, ).contains 0.25% w/v of docusate sodium BPCRS in
it to dry in air and expose to iodine vapour. The principa ethanol. After removal of the plate, allow it to dry in air and
spot in the chromatogram obtained with solution (1) s to 1odine vapour. The principal spot in the
corresponds to that in the chromatogram obtained with togram obtained with solution (1) corresponds to that
solution (2).
solution (2).
ASSAY f nitric acid and superimpose
Carry out the method for liguid chromatography, mate solution. A blue ring develops
(1) add 200 mL of water to a number of whole capsules lower layer within 10 m
containing 1 g of docusate sodium and warm on a water bath
until the capsules have dissolved. Add 200 mL of acetonitrile, TESTS «
shake the mixture thoroughly and cool. Add sufficient of a Acidity or alkalinity
mixture of equal volumes of acetonitrile and water to produce pH, 5.0 to 8.0, Appendix V L.
1000 mL, mix well and filter to obtain a clear solution ASSAY
(Whatman No. 1 paper followed by a 0.4-um filter is Carry out the method for liquid chromatograph
suitable). Solution (2) contains 0.1% w/v of docusate Appendix III D, using the following solutioris. E solution
sodium BPCRS in a mixture of equal volumes of acetonitrile
and water. 50 mg of Docusate Sodium, shake thoroughly and allow to
The chromatographic procedure may be carried out using stand for 16 hours. Filter the ether extract through anhydrous
(a) a stainless steel column (15 cm x 4.6 mm) packed with sodium sulfate using a glass-fibre filter (Whatman GF/C is
end-capped octadecylsilyl silica gel for chromatography (5 um) suitable). Extract the aqueous layer with a further 50 mL
(Ultracarb ODS is suitable), (b) as the mobile phase with a quantity of ether and filter through anhydrous sodium sulfate.
flow rate of 1.5 mL per minute a mixture of 30 volumes of Evaporate the combined ether extracts to dryness and
0.005 tetrabutylammonium dihydrogen orthophosphate and dissolve the residue obtained in 100 mL of a mixture of
70 volumes of acetonitrile and (c) a detection wavelength of 70 volumes of acetonitrile and.30 volumes of water. Solution
214 nm. (2) contains 0.05% w/v of docusate sodium BPCRS in a
Calculate the content of C,,>H37NaQO-7S in the capsules using mixture of 70 volumes of acetonitrile and 30 volumes of water.
the declared content of C.)H37NaO-S in docusate The chromatographic procedure may be carried out using
sodium BPCRS. (a) a stainless steel column (25 cm x 4.6 mm) packed with
ra
ley
STORAGE silica gel with a chemically bonded, strongly basic quaternary
Docusate Capsules should be kept in an airtight container. ammonium anion-exchange coating (10 um) (Spherisorb
II-494 Docusate Preparations 2016
SAX is suitable), (b) as the mobile phase with a flow rate of 2 mL of methanol, followed by 5 mL of water. Wash the
2 mL per minute a mixture of 1.6 volumes of orthophosphoric column with 2 mL of water, discarding the aqueous eluate.
acid, 350 volumes of water and 650 volumes of acetonitrile Elute the docusate sodium with 4 mL of methanol and dilute
and (c) a detection wavelength of 214 nm. to 20 mL with a mixture of 70 volumes of acetonitrile and
Calculate the content of C29H37NaQO-S in the enema using 30 volumes of water.
the declared content of C29H37NaO7S in docusate (2) 0.05% w/v of docusate sodium BPCRS in a mixture of
sodium BPCRS. 70 volumes of acetonitrile and 30 volumes of water.

with silica gel with a chemically bonded, strongly basic
Docusate Oral Solution quaternary ammonium anion-exchange coating (10 pm)
(Spherisorb SAX is suitable).
Action and:
Stimulant laxative: softener.
below.
DEFINITION ‘ (c) Use a flow rate of 2 mL per minute.
Docusate Oral Solution: co 1.0% w/v of Docusate (d) Use an ambient column temperature.
icle. (e) Use a detection wavelength of 214 nm.
The oral solution complies wit. uixements stated under Oral (f) Inject 20 wL of each solution.
Liquids and with the following req
MOBILE PHASE
Content of docusate sodium,
1.6 volumes of orthophosphoric acid, 350 volumes of water and
0.95 to 1.05% w/v.
IDENTIFICATION
SYSTEM SUITABILITY
Appendix III A, using the following solutions. The test is not valid unless, in the chromatogram obtained
with solution (2) the symmetry factor of the peak
(1) Pass a volume of the oral solution containing 10
corresponding to docusate sodium is less than 1.5.
docusate sodium, with the aid of vacuum, througha solids
phase extraction column of 1 mL capacity and containiri DETERMINATION OF CONTENT
0.1 g of an octadecyl-bonded silica sorbent (a Sep-pak C18 * Determine the weight per mL of the oral solution,
column is suitable) which has been previously washed with endix V G, and calculate the content of Cz>)H37NaO-S,
2 mL of methanol, followed by 5 mL of water. Wash the ume, using the declared content of
column with 2 mL of water, discarding the aqueous eluate in docusate sodium BPCRS.
and then elute the docusate sodium with 4 mL of methanol,
retaining the methanol solution.
(2) 0.25% w/v of docusate sodium BPCRS in methanol.
(a) Use as the coating silica gel G (Merck silica gel 60 plates
are suitable). Action and use :
Stimulant laxative; faec
(c) Apply 20 uL of each solution. DEFINITION
(e) After removal of the plate, allow it to dry in air, expose to Docusate Sodium in a suitable fla
iodine vapour and examine in daylight. The oral solution complies with the require
MOBILE PHASE
2 volumes of 13.5mM ammonia, 20 volumes of ethanol (96%),
40 volumes of water and 50 volumes of ethyl acetate. 0.238 to 0.263% w/v.
CONFIRMATION IDENTIFICATION
The principal spot in the chromatogram obtained with Complies with the tests described under Docusate
solution (1) corresponds in position and colour to that in the Solution.
chromatogram obtained with solution (2). ASSAY
B. In the Assay, the chromatogram obtained with solution Carry out the Assay described under Docusate Oral Solution
(1) shows a peak with the same retention time as the but preparing solution (1) in the following manner.
principal peak in the chromatogram obtained with For solution (1) pass a weighed quantity of the oral solution
solution (2). containing 5 mg of docusate sodium, with the aid of vacuum,
ASSAY through a solid-phase extraction column of 1 mL capacity
and containing 0.1 g of an octadecyl-bonded silica sorbent (a
Sep-pak C18 column is suitable) previously washed with
2 mL of methanol, followed by 5 mL of water. Wash the
(1) Pass a weighed quantity of the oral solution containing column with 2 mL of water, discarding the aqueous eluate.
10 mg of docusate sodium, with the aid of vacuum, through Elute the docusate sodium with 4 mL of methanol and dilute
a solid-phase extraction column of 1 mL capacity and to 10 mL with a mixture of equal volumes of acetonitrile and
containing 0.1 g of an octadecyl-bonded silica sorbent (a water.
Sep-pak C18 column is suitable) previously washed with
2016 Domperidone Preparations III-495

Domperidone Tablets dompendone maleate BPCRS in the dissolution medium using
Action and use dissolution medium in the reference cell.
Peripheral dopamine receptor antagonist; antiemetic. DETERMINATION OF CONTENT
Calculate the total content of domperidone, C22H2,CIN50,,
DEFINITION
in the medium from the absorbances obtained and using the
Domperidone Tablets contain Domperidone Maleate. declared content of C2,H»,CIN5O., in domperidone
The tablets comply with the requirements stated under Tablets and maleate BPCRS.
Related substances
Content of domperidone, C,,H,,CIN;O, Carry out the method for liguid chromatography,
95.0 to 105.0% of the stated amount. Appendix III D, using the following solutions prepared
ION immediately before use.
BNA
method for thin-layer chromatography, (1) To a quantity of the powdered tablets containing the
ising the following solutions in a mixture of equivalent of 50 mg of domperidone add 10 mL of a mixture
of equal volumes of 0.01m hydrochloric acid and methanol, mix
powdered tablets containing the with the aid of ultrasound for 20 minutes and filter through a
equivalent of 10 mg « aperidone with 10 mL of solvent glass microfibre filter (Whatman GF/C is suitable).
and filter through a ¢ refibre filter (Whatman GF/C is (2) Dilute 1 volume of solution (1) to 200 volumes with a
suitable). mixture of equal volumes of 0.01m hydrochloric acid and
methanol. Dilute 1 volume of the resulting solution to
(2) 0.127% w/v of dompenda
2 volumes with the same solvent.
CHROMATOGRAPHIC CONDE
(3) Dilute 1 volume of solution (2) to 5 volumes of a mixture
of equal volumes of 0.01m hydrochloric acid and methanol.
(4) 0.01% w/v of domperidone maleate BPCRS and
(b) Use the mobile phase as described 0.015% w/v of droperidol EPCRS in a mixture of equal
(c) Apply 10 pL of each solution. volumes of 0.01M hydrochloric acid and methanol.
(d) Develop the plate to 15 cm. CHROMATOGRAPHIC CONDITIONS
(e) After removal of the plate, dry in air and examifie u (a) Use a stainless steel column (10 cm x 4.6 mm) packed
ultraviolet ight (254 nm). Spray the plate with potassium with base-deactivated, end-capped octadecylsilyl silica gel for
todobismuthate solution and examine again. matography (3 um) (Hypersil BDS is suitable).
MOBILE PHASE Use gradient elution and the mobile phase described
5 volumes of a solution prepared by dissolving 1.36 g of
sodium acetate in 50 mL of water, adjusting the pH to 4.7 flow rate of 1.5 mL per minute. Equilibrate the
with dilute acetic acid and adding sufficient water to produce ferat least 30 minutes with methanol and equilibrate
100 mL, 18 volumes of methanol, 23 volumes of withthe
dichloromethane and 54 volumes of ethyl acetate. (d) Use an
CONFIRMATION (e) Use a deteétio
Using each method of visualisation, the principal spot in the (f) Inject 10 pL of
chromatogram obtained with solution (1) corresponds to that volumes of 0.01m hy
in the chromatogram obtained with solution (2). prior to the solutions.
B. In the Assay, the principal peak in the chromatogram MOBILE PHASE
Mobile phase A methanol. *—
solution (2). Mobile phase B- 0.5% wiv soluti
TESTS
Dissolution Time MAohbile phase A
Comply with the requirements for Monographs of the British imin} (per cent P/F}
iL 30 70
Appendix XII Bl.
1a 100 0
TEST CONDITIONS
12 100) 0
per minute.
37°, as the medium. SYSTEM SUITABILITY
PROCEDURE The test is not valid unless, in the chromatogram obtained
(1) After 45 minutes withdraw a 20 mL sample of the with solution (4), the resolution between the two principal
medium and measure the absorbance of the filtered sample, peaks is at least 2.
suitably diluted with the dissolution medium if necessary, at LIMITS
the maximum at 286 nm, Appendix II B using dissolution
IlIl-496 Dopamine Preparations 2016
the area of any secondary peak is not greater than the area of IDENTIFICATION
the principal peak in the chromatogram obtained with A. Saturate a volume containing 0.1 g of Dopamine
solution (2) (0.25%); Hydrochloride with sodium chloride and extract with three
the sum of the areas of any secondary peaks is not greater than 20-mL quantities of butan-I-ol. Filter the combined extracts
twice the area of the principal peak in the chromatogram through anhydrous sodium sulfate and evaporate the filtrate to
obtained with solution (2) (0.5%). dryness. The infrared absorption spectrum of the residue,
Disregard any peak in the chromatogram obtained with the Appendix II A, is concordant with the reference spectrum of
blank solution, any peak due to maleic acid near the start of dopamine hydrochloride (RS 113).
the chromatogram and any peak with an area less than the B. To a volume containing 10 mg of Dopamine
area of the peak in the chromatogram obtained with solution Hydrochloride add 0.1 mL of iron(am) chloride solution R1.
(3) (0.05%). An intense green colour is produced.
TESTS
ad for liquid chromatography, Acidity
ig the following solutions. pH, 3.0 to 4.5, Appendix V L.
5-Hydroxymethylfurfural
ites and filter throug
h a glass Appendix III D, using the following solutions.
iC.is suitable). To 50 mL of (1) Use the intravenous infusion.
the filtrate add 1 mL of 0: (2) 0.0025% w/v of 5-hydroxymethylfurfural in water.
(2) 0.0127% wiv of dompendon
of equal volumes of 0.002m hyd och (a) Use a stainless steel column (10 cm x 4.6 mm) packed
eA ee
The chromatographic procedure describe (b) Use isocratic elution and the mobile phase described
substances may be used. below.
DETERMINATION OF CONTENT (c) Use a flow rate of 2 mL per minute.
Calculate the content of C2,H»,CIN;5O, in the tabl (d) Use an ambient column temperature.
the declared content of C22H24CIN50> in domperidone
) Use a detection wavelength of 284 nm.
maleate BPCRS.
iect 20 uL of each solution.
STORAGE
Domperidone Tablets should be stored in an airtight
container. um hydrogen orthophosphate adjusted to pH 7.0
sOphosphoric acid.
LABELLING
The quantity of the active ingredient is stated in terms of the
equivalent amount of domperidone.
Dopamine Infusion
Dopamine Intravenous Infusion
Action and use

Dopamine receptor antagonist; beta,-adrenoceptor agonist;
produce a solution expected to conta
alpha-adrenoceptor agonist.
Dopamine Hydrochloride.
DEFINITION
Dopamine Infusion is a sterile solution containing Dopamine mobile phase.
Hydrochloride. It is supplied as a ready-to-use solution or it (3) Dilute 1 volume of solution (1) and 1 volume ara
is prepared by diluting either Sterile Dopamine Concentrate solution containing 0.030% w/v each of 4-ethylcatechol and
or Dopamine Hydrochloride for Injection with a suitable 3,4-dimethoxyphenethylamine to 50 volumes with the mobile
diluent in accordance with the manufacturer’s instructions. phase.
The infusion complies with the requirements stated under CHROMATOGRAPHIC CONDITIONS
Parenteral Preparations and with the following requirements. The chromatographic conditions described under Assay may
When supplied as a ready-to-use solution, the intravenous infusion be used.
complies with the following requirements. Under the prescribed conditions, the retention time of
Content of dopamine hydrochloride, CgsH,,;,NO,,HCl dopamine is about 5 minutes, of 4-ethylcatechol about
95.0 to 105.0% of the stated amount. 3 minutes and of 3,4-dimethoxyphenethylamine, about
Content of glucose, C;H,,0, 12 minutes.
4.75 to 5.25% wiv. LIMITS
CHARACTERISTICS In the chromatogram obtained with solution (1):

te ae
we oh y
A colourless liquid.
2016 Dopamine Preparations TI-497
the area of any secondary peak is not greater than 1.25 times TESTS
the area of the principal peak in the chromatogram obtained Acidity
with solution (2) (2.5%); pH, 2.5 to 5.5, Appendix V L.
not more than one such peak has an area greater than the Related substances
area of the principal peak in the chromatogram obtained with Carry out the method for thin-layer chromatography,
solution (2) (2%). Appendix III A, using the following solutions.
Bacterial endotoxins (1) Dilute a volume of the concentrate containing 0.15 g of
Carry out the test for bacterial endotoxins, Appendix XIV C. Dopamine Hydrochloride to 5 mL with methanol.
Dilute the intravenous infusion, if necessary, with water BET (2) 0.0075% w/v of 4-O-methyldopamine hydrochloride in
to give a solution containing 1.6 mg of Dopamine methanol.
Hydrochloride per mL (solution A). The endotoxin limit
(3) 0.0075% w/v each of 3-O-methyldopamine hydrochloride
ion of solution A is 26.67 IU per mL.
and 4-O-methyldopamine hydrochloride in methanol.

(1) Dilute a suitgb’ ume of the infusion with mobile
phase to produ tion expected to contain (c) Apply 10 uL of each solution.
0.0032% w/v of Dopamin Hydrochloride. (d) Develop the plate to 15 cm.
(2) 0.0032% w/v of dopatnine hydrochloride BPCRS in the (e) After removal of the plate, allow it to dry in air for
mobile phase. 15 minutes and spray evenly and abundantly with a mixture,
CHROMATOGRAPHIC CON bs prepared immediately before use, of equal volumes of iron(im)
chloride solution R1 and potassium hexacyanoferrate(1) solution.
(a) Use a stainless steel colu 4.6 mm) packed
with end-capped octadecylsilyl silica g romatography MOBILE PHASE
(5 um) (Nucleosil C18 is suitable). 2 volumes of anhydrous formic acid, 7 volumes of water,
(b) Use isocratic elution and the mobile pl 36 volumes of methanol and 52 volumes of chloroform.
below. SYSTEM SUITABILITY
(c) Use a flow rate of 2 mL per minute. The test is not valid unless the chromatogram obtained with
(d) Use an ambient column temperature. solution (3) shows two clearly separated spots.
(e) Use a detection wavelength of 280 nm. LIMITS
(f) Inject 20 nL of each solution. econdary spot with an Rf value higher than that of the
MOBILE PHASE
1 spot in the chromatogram obtained with solution
2 volumes of 0.1M disodium edetate, 10 volumes of glacial
acetic acid, 300 volumes of acetonitrile and 700 volumes of
0.005M sodium dodecyl sulfate.
Ce
Dil
Calculate the content of CgH,,;NO.,HCI in the infusion solution contain: 1,6 mg of Dopamine Hydrochloride per
using the declared content of CgH,;;NO2,HC1 in dopamine mL (solution A). 'F i otoxin limit concentration of
hydrochloride BPCRS. solution A is 26.67 ;
ASSAY
STERILE DOPAMINE CONCENTRATE Carry out the method deécribé in the requirements for the
DEFINITION ready-to-use solution.
Sterile Dopamine Concentrate is a sterile solution of STORAGE
Dopamine Hydrochloride in Water for Injections. Sterile Dopamine Concentrate s tected from
The concentrate complies with the requirements for Concentrates light.
for Injections or Infusions stated under Parenteral Preparations
DOPAMINE HYDROCHLORIDE
Content of dopamine hydrochloride, CsH,,NO,,HC1
INJECTION
DEFINITION
CHARACTERISTICS
ee ee
‘
Dopamine Hydrochloride for Injection is a sterile material

A colourless or pale yellow solution. consisting of Dopamine Hydrochloride with or without
IDENTIFICATION excipients. It is supplied in a sealed container.
A. Extract a volume containing 0.1 g of Dopamine The contents of the sealed container comply with the requirements
Hydrochloride with 10 mL of butan-1-ol. Filter the extract for Powders for Injections or Infusions stated under Parenteral
through anhydrous sodium sulfate and evaporate the filtrate to Preparations and with the following requirements.
dryness. The infrared absorption spectrum of the residue, Content of dopamine hydrochloride, CgsH;,NO,,HCl
Appendix IT A, is concordant with the reference spectrum of 95.0 to 105.0% of the stated amount.
dopamine hydrochloride (RS 113).
CHARACTERISTICS
B. To a volume containing 10 mg of Dopamine
Hydrochloride add 0.05 mL of tron(im) chloride solution R1. A white or almost white, crystalline powder.
An intense green colour is produced.
Ill-498 Dorzolamide Preparations 2016

A. The infrared absorption spectrum, Appendix II A, 1s Calculate the content of CgH,;;NO,,HCI in a container of
concordant with the reference spectrum of dopamine average content weight using the declared content of
hydrochloride (RS 113). CgH,,NO,,HCI in dopamine hydrochlonde BPCRS.
B. Dissolve 10 mg of the substance being examined in 2 mL
of water and add 0.05 mL of tron(im) chloride solution R1.
An intense green colour is produced.
TESTS Dorzolamide Eye Drops
Acidity
pH of a 4% w/v solution in a 1.0% w/v solution of sodium Action and use
metabisulfite, 2.5 to 5.5, Appendix V L. Carbonic anhydrase inhibitor; treatment of glaucoma and
ocular hypertension.
ethed for thin-layer chromatography,
DEFINITION
using the following solutions in methanol.
Dorzolamide Eye Drops are a sterile solution of Dorzolamide
f the contents of the sealed container
Hydrochloride in Purified Water.
to produce a solutiogi ining 3.0% w/v of Dopamine
Hydrochloride.
(2) 0.0075% w/v of 4- thyidopamine hydrochloride.
Content of dorzolamide, C;)9H,<.N20,8;3
(3) 0.0075% w/v each o idopamine hydrochloride
and 4-O-methyldopamine hydréchlorid
IDENTIFICATION
CHROMATOGRAPHIC CONDITI
(a) Use as the coating silica gel G. Appendix III A, using the following solutions in methanol.
(b) Use the mobile phase as described bel (1) Dilute a quantity of the eye drops to produce a solution
(c) Apply 10 uwL of each solution. containing the equivalent of 0.5% w/v of dorzolamide.
(d) Develop the plate to 15 cm. (2) 0.5% w/v of dorzolamide hydrochloride BPCRS.
(e) After removal of the plate, allow it to dry in air for (3) 0.5% w/v of dorzolamide hydrochloride BPCRS and
15 minutes and spray evenly and abundantly with a‘mixg 0.15% w/v of timolol maleate BPCRS.
prepared immediately before use, of equal volumes of i7o
HROMATOGRAPHIC CONDITIONS
chloride solution R1 and potassium hexacyanoferrate(1) solutio
s the coating silica gel F254 (Merck silica gel 60 Fos54
MOBILE PHASE
uitable).
2 volumes of anhydrous formic acid, 7 volumes of water, mobile phase as described below.
36 volumes of methanol and 52 volumes of chloroform.
SYSTEM SUITABILITY
ultraviolet lightest
LIMITS
MOBILE PHASE
Any secondary spot with an Rf value higher than that of the
1 volume of concentrétec
principal spot in the chromatogram obtained with solution
and 80 volumes of dichi
(1) is not more intense than the spot in the chromatogram
obtained with solution (2) (0.25%). SYSTEM SUITABILITY
Bacterial endotoxins The test is not valid unless

give a solution containing 1.6 mg of Dopamine
Hydrochloride per mL (solution A). The endotoxin limit solution (1) corresponds in position and col
concentration of solution A is 26.67 IU per mL. chromatogram obtained with solution (2).
ASSAY
Determine the weight of the contents of 10 containers as the chromatogram obtained with solution (1) is similar to
described in the test for uniformity of weight, that of the principal peak in the chromatogram obtained with
Appendix XII C1, Powders for Parenteral Administration. solution (2).
Carry out the method for liquid chromatography, TESTS
Appendix III D, using the following solutions. Acidity
(1) Dissolve sufficient of the mixed contents of the 10 pH, 5.0 to 6.0, Appendix V L.
containers in the mobile phase to produce a solution Related substances
containing 0.0032% w/v of Dopamine Hydrochloride. Carry out the method for liguid chromatography,
(2) 0.0032% w/v of dopamine hydrochloride BPCRS in the Appendix III D, using the following solutions in the mobile
mobile phase. phase.
CHROMATOGRAPHIC CONDITIONS (1) Use the eye drops diluted to contain the equivalent of
The chromatographic procedure described under the Assay 0.01% w/v of dorzolamide.
for the ready-to-use solution may be used. (2) Dilute 1 volume of solution (1) to 100 volumes.
2016 Dorzolamide Preparations III-499
(3) Dilute 1 volume of solution (2) to 5 volumes. SYSTEM SUITABILITY
(4) 0.011% w/v of dorzolamide hydrochloride BPCRS and The test is not valid unless, in the chromatogram obtained
,N aA
0.000011% w/v each of dorzolamide impurity B BPCRS and with solution (3):
weg dorzolamide impurity D BPCRS. the resolution factor between the peaks due to dorzolamide
CHROMATOGRAPHIC CONDITIONS and impurity B is at least 3.0;
(a) Use a stainless steel column (25 cm x 4.6 mm) packed the resolution factor between the peaks due to impurity D and
with octylsilyl silica gel for chromatography (5 wm) (Zorbax dorzolamide is at least 3.0.
Rx-C8 and Zorbax SB-C8 are suitable). DETERMINATION OF CONTENT
(b) Use isocratic elution and the mobile phase described Calculate the content of C;p>H;¢N20,S3 in the eye drops
below. using the declared content of Cj9H,sN20,S3,HCI in
(c) Use flow rate of 1 mL per minute. dorzolamide hydrochloride BPCRS. Each mg of
|
@U ambient column temperature. Ci90Hi6N20,483,HCI is equivalent to 0.8990 mg of
C1o0Hi6N20,48s.
LABELLING
equivalent amount of dorzolamide.
retention time
1 volume of acetomitrile
monograph include impurities B andD listed under
solution of orthophosphori
Dorzolamide Hydrochloride.
using triethylamine.
When the chromatograms aii
conditions, the relative retentions w
dorzolamide (retention time = about F.
impurity D = about 0.9; impurity B = Dorzolamide and Timolol Eye Drops
SYSTEM SUITABILITY
Action and use
The test is not valid unless, in the chromatogra
Carbonic anhydrase inhibitor + beta-adrenoceptor antagonist;
with solution (4):
treatment of glaucoma and ocular hypertension.
the resolution factor between the peaks due to dorzolami
and impurity B is at least 3.0; FINITION
the resolution factor between the peaks due to impurity D a rzGlamide and Timolol Eye Drops are a sterile solution of
dorzolamide is at least 3.0. amide Hydrochloride and Timolol Maleate in Purified
LIMITS
»s comply with the requirements stated under Eye
id with the following requirements.
greater than 1.3 times the area of the principal peak obtained lamide, Cj9H,.N20,S;3
with solution (2) (1.3%); ot the stated amount.
the area of any peak corresponding to impurity D is not Content of tim €j3H24N,038
greater than the area of the principal peak obtained with 95.0 to 105.0% of the stated amount.
solution (3) (0.2%); IDENTIFICATION
the area of any other secondary peak is not greater than the A. Carry out the metho n-layer chromatography,
area of the principal peak obtained with solution (3) (0.2%); Appendix III A, using the folk ing*sglutions in methanol.
the sum of the areas of all the secondary peaks is not greater (1) Dilute a quantity of the eye
than 1.5 times the area of the principal peak obtained with
Disregard any peak with an area less than half the area of the
principal peak in the chromatogram obtained with solution (4) 0.5% w/v of dorzolamide hydrochloride BP
(3) (0.1%).
0.15% w/v of timolol maleate BPCRS.
ASSAY CHROMATOGRAPHIC CONDITIONS
(a) Use as the coating silica gel Fz54 (Merck silica gel 60 Fos,
phase.
(1) Use the eye drops diluted to contain the equivalent of
veal 0.01% w/v of dorzolamide. (c) Apply 20 uL of each solution.
mee
Sta
a ee
(2) 0.011% w/v of dorzolamide hydrochloride BPCRS. .
(3) 0.011% w/v of dorzolamide hydrochloride BPCRS and (e) After removal of the plate, dry in air and examine under
0.000011% w/v each of dorzolamide impunity B BPCRS and ultraviolet light (254 nm).
dorzolamide impurity D BPCRS. MOBILE PHASE
CHROMATOGRAPHIC CONDITIONS 1 volume of concentrated ammonia, 20 volumes of methanol

The chromatographic conditions described under Related and 80 volumes of dichloromethane.
wee)
IW-500 Dorzolamide Preparations 2016

The test is not valid unless the chromatogram obtained with The test is not valid unless, in the chromatogram obtained
solution (4) shows two clearly separated spots. with solution (4):
CONFIRMATION the resolution factor between the peaks due to dorzolamide
In the chromatogram obtained with solution (1) the spot and impurity B is at least 3.0;
with the lowerRf value corresponds to the principal spot in the resolution factor between the peaks due to impurity D and
the chromatogram obtained with solution (2) and the spot dorzolamide is at least 3.0.
with the higher Rf value corresponds to the principal spot in LIMITS
B. In the Assay for dorzolamide, the chromatogram obtained
with solution (1) shows a principal peak with the same
s the principal peakin the chromatogram
the area of any peak corresponding to impurity D is not
solution (1) Brincipal peak with the same retention
time as the princip eak in the chromatogram obtained
with solution (2). the area of any other secondary peak is not greater than the
TESTS solution (3) (0.2%);
Acidity : the sum of the areas of all the secondary peaks is not greater
pH, 5.0 to 6.0, Appendix V than 1.3 times the area of the principal peak in the
Related substances chromatogram obtained with solution (2) (1.3%).
For dorzolamide Disregard any peak with an area less than half the area of the
Carry out the method for liquid chromato . principal peak in the chromatogram obtained with solution
Appendix II D, using the following solutiong“in, mixture of (3) (0.1%).
1 volume of acetonitrile and 19 volumes of a ©: For timolol
solution of orthophosphoric acid. Carry out the method for liguid chromatography,
(1) Use the eye drops diluted to contain the equivaléit Appendix III D, using the following solutions in mobile
0.01% w/v of dorzolamide. phase.
(2) Dilute 1 volume of solution (1) to 100 volumes. 1) Use the eye drops diluted to contain the equivalent of
(3) Dilute 1 volume of solution (2) to 5 volumes. w/v of timolol.
(4) 0.011% w/v of dorzolamide hydrochloride BPCRS and uté.1 volume of volume (1) to 200 volumes. Dilute
0.000011% w/v each of dorzolamide impurity B BPCRS and
dorzolamide impurity D BPCRS.

with octylsilyl silica gel for chromatography (5 um) (Zorbax
Rx-C8 and Zorbax SB-C8 are suitable).
below.
(c) Use a flow rate of 1.2 mL per minute. with octadecylsilyl silica g
ODS-2 and Symmetry C18
ne |
(d) Use an ambient column temperature. |

wee

below.
(c) Use a flow rate of 1.0 mL per m
MOBILE PHASE
Mobile phase A Acetonitrile. (e) Use a detection wavelength of 295 nm.
Mobile phase B 0.2% viv orthophosphoric acid. (f) Inject 20 uL of each solution.
(g) Allow the chromatography to proceed for twice the
Time Mobile phase A Mobile phase B Comment retention time of timolol.
MOBILE PHASE
+ OS, La 0 - 15.0 5 95 isocratic
ee
Swen d 15.0 - 15.1 5 95 95 5 linear gradient
2 volumes of methanol and 3 volumes of a 1.1% w/v solution
15.1 - 20.0 95 5 isocratic of sodium dihydrogen orthophosphate monohydrate adjusted to
20.0 - 20.1 95 >5 5 > 95 linear gradient
20.1 - 30.0 5 95 re-equilibration When the chromatograms are recorded under the prescribed
conditions, the relative retentions with reference to timolol
(retention time = about 5.7 minutes) are: dorzolamide =
When the chromatograms are recorded under the prescribed about 0.5; impurity G = about 0.6, impurity B = about 0.7;
conditions, the relative retentions with reference to impurity D = about 1.5.
dorzolamide (retention time = about 12 minutes) are:
impurity D = about 0.8; impurity B = about 1.2.
2016 Dosulepin Preparations II-501
SYSTEM SUITABILITY CHROMATOGRAPHIC CONDITIONS

The test is not valid unless, in the chromatogram obtained The chromatographic conditions described under Related
AN A
with solution (3): substances for timolol may be used.
the resolution factor between the peaks due to impurity G and SYSTEM SUITABILITY
impurity B is at least 1.5. The test is not valid unless, in the chromatogram obtained
LIMITS with solution (3):
In the chromatogram obtained with solution (1): the resolution factor between the peaks due to timolol
the area of any peak corresponding to impurity B, D or G is impurity G and timolol impurity B is at least 1.5.
not greater than twice the area of the principal peak obtained DETERMINATION OF CONTENT
with solution (2) (0.4% of each); Calculate the content of C}3H24N403S, in the eye drops
ny other secondary peak is not greater than the using the declared content of C;3H24N403S,C,H,O, in
A tee
cipal peak obtained with solution (2) (0.2%); timolol maleate BPCRS. Each mg of C,3H24N403S,C4H4O, is
as of all the secondary peaks is not greater equivalent to 0.7316 mg of C,3H24N,03S.
ea of the principal peak obtained with LABELLING
solution (2) (0.5%):
The quantity of Dorzolamide Hydrochloride is stated in
Disregard any peak an area less than half the area of the terms of the equivalent amount of dorzolamide and the
principal peakin the omatogram obtained with solution quantity of Timolol Maleate is stated in terms of the
(2) (0.1%). equivalent amount of timolol.
ASSAY IMPURITIES
For dorzolamide & The impurities limited by the requirements of this
Carry out the method for liquid ¢: monograph include impurities B andD listed under
Appendix III D, using the following « Dorzolamide Hydrochloride and impurities B, D and G
1 volume of acetonitrile and 19 volumes, listed under Timolol Maleate.
of orthophosphoric acid.
(1) Use the eye drops diluted to contain the ‘equi
0.01% w/v of dorzolamide. i
(2) 0.011% w/v of dorzolamide hydrochloride BPCR .
Dosulepin Capsules
(3) 0.011% w/v of dorzolamide hydrochlonde BPCRS and
0.000011% w/v each of dorzolamide impurity B BPCRS ark and use
dorzolamide impunity D BPCRS. ine reuptake inhibitor; tricyclic antidepressant.
ION
pin Capsules contain Dosulepin Hydrochloride.
substances for dorzolamide may be used.
ly with the requirements stated under Capsules
SYSTEM SUITABILITY
requirements.
hydrochloride, C,;>H,,;NS,HCl
with solution (3):
the resolution factor between the peaks due to dorzolamide
and impurity B is at least 3.0; IDENTIFICATION
Extract a quantity ofth hts of the capsules containing
the resolution factor between the peaks due to impurity D and
0.1 g of Dosulepin Hydrochloride with 20 ml of absolute
dorzolamide is at least 3.0.
ethanol, filter and remove thé*ethanol from the filtrate by
DETERMINATION OF CONTENT evaporation. The infrared absorptiox sp m of the residue,
Calculate the content of Cyp>H)¢N2O,4S3 in the eye drops Appendix II A, is concordant wi nce spectrum of
using the declared content of Cj9H;¢.N20483,HCl in dosulepin hydrochloride (RS 114).
dorzolamide hydrochloride BPCRS. Each mg of
TESTS
Ci90H16N20483,HCI] is equivalent to 0.8990 mg of
Ci0Hi6N20483. Carry out the method for thin-layer chromatography
For timolol Appendix III A, using the following solutions.
Carry out the method for liguid chromatography, (1) Extract a quantity of the contents of the capsules
Appendix III D, using the following solutions in mobile containing 0.25 g of Dosulepin Hydrochloride by shaking for
phase. 2 minutes with 5 ml of chloroform, centrifuge and use the
(1) Use the eye drops diluted to contain the equivalent of supernatant liquid.
0.025% w/v of timolol. (2) Dilute 2 ml of solution (1) to 5 ml with chloroform.
(2) 0.0342% w/v of timolol maleate BPCRS. (3) 0.010% w/v each of 3-(dibenzo[b,e] thiepin-11(6H)-
(3) Add 8 mL of 0.1m sodium hydroxide to 90 mg of timolol ylidene)-N,N-dimethylaminopropan-1-amine S-oxide
maleate BPCRS, heat at 70° for 15 hours, cool and add hydrochloride BPCRS and dibenzo|b,e]thiepin-11(6H)-
sufficient mobile phase to produce 50 mL. Mix 1 volume of one BPCRS in chloroform.
this solution with 4 volumes of a 0.140% w/v solution of
dorzolamide hydrochlonde BPCRS.
(a) Use a TLC silica gel 60 F254 precoated plate (Merck silica
gel 60 F454 plates are suitable).
raNwd
SAN Ad

II-502 Dosulepin Preparations 2016
(c) Apply 5 ul of each solution.

Dosulepin Oral Solution
ean
NOTE: Dosulepin Oral Solution is not currently licensed in the
(e) After removal of the plate, dryin air and examine> under United Kingdom.
MOBILE PHASE Action and use
1 volume of 13.5m ammonia, 10 volumes of propan-2-ol and
90 volumes of 1,2-dichloroethane. DEFINITION
LIMITS Dosulepin Oral Solution is a solution of Dosulepin
The spot with the lower Rf value in the chromatogram Hydrochloride in a suitable flavoured vehicle.
obtained with solution (3) is more intense than any The oral solution complies with the requirements stated under Oral
spot in the chromatogram obtained with Liquids, the requirements stated under Unlicensed Medicines and
O43
ween
Content of dosulepin hydrochloride, C,;)>H2,NS,HC1
tense than the proximate spot in IDENTIFICATION
(1) Add 2 mL of 10M sodium hydroxide to a quantity of the
oral solution containing 25 mg of Dosulepin Hydrochloride
Appendix IIT B.
and extract with three 5-mL quantities of dichloromethane.
(1) Extract a quantity of the e
sew erns
Combine the dichloromethane extracts, evaporate to dryness
containing 25 mg of DosulepinHyd 2
and dissolve the residue in sufficient dichloromethane to
methanol, centrifuge and u1 se the superna
produce 5 mL.
(2) 0.5% w/v of dosulepin hydrochloride BPCRS in
CHROMATOGRAPHIC CONDITIONS dichloromethane.
washed, silanised diatomaceous support (100 to 120 mesky
(a) Use as the coating szlica gel 60 F254.
coated with 3% w/w of cyanopropylmethyl phenyl methy}
b) Use the mobile phase as described below.
silicone fluid (OV-225 is suitable).
sly 5 uwL of each solution.
(b) Use helium as the carrier gas at 1.7 ml per minute.
op the plate to 15 cm.
moval of the plate, dry in air and examine under
ht. (254 nm).
LIMITS
In the chromatogram obtained with solution (2), a peak due
to Z-dosulepin is present with a retention time of
approximately 0.83 relative to the retention time of the
principal peak which is due to E-dosulepin. solution (1) corresponds
w
In the chromatogram obtained with solution (1), the area of chromatogram obtained
Lene
twa 4
any peak corresponding to Z-dosulepin is not greater than

7.5% of the sum of the areas of the peaks due to Z-dosulepin .
and E-dosulepin. that of the principal peakin the chrom
solution (2).
ASSAY
Extract a quantity of the mixed contents of 20 capsules TESTS
containing 0.5 g of Dosulepin Hydrochloride with 20 ml Acidity
followed by four 10 ml quantities of chloroform, filtering each pH, 4.5 to 5.5, Appendix V L.
extract through the same filter. Evaporate the combined Impurity A and Z-isomer
te Nw
extracts to dryness, dissolve the residue in 100 ml of acetone, Carry out the method for liguid chromatography,
add 10 ml of mercury(m) acetate solution and carry out Appendix III D, using the following solutions.
sw ond
Method I for non-aqueous titration, Appendix VIII A, using (1) Dilute a volume of the oral solution with the mobile
3 ml of a saturated solution of methyl orange n acetone as phase, shake well and add sufficient mobile phase to produce
indicator. Each ml of 0.1m perchloric acid VS is equivalent to a solution containing 0.05% w/v of Dosulepin Hydrochloride.
33.19 mg of Cyo9H2,;NS,HC1.
(2) Dissolve 12.5 mg of [3-(dibenzo[b,e]thiepin-11(6H)-
ylidene-N,N-dimethylaminopropan-1-amine S-oxide
hydrochloride BPCRS (impurity A) in 5 mL of methanol, add
sufficient mobile phase to produce 50 mL and dilute
3 volumes of the resulting solution to 100 volumes with the
mobile phase.
crow ay
2016 Dosulepin Preparations ITI-503
(3) Dilute 1 volume of a 0.5% w/v solution of dosulepin SYSTEM SUITABILITY

hydrochloride BPCRS in methanol to 10 volumes with the The Assay is not valid unless the symmetry factor of the
mobile phase. principal peak in the chromatogram obtained with solution
CHROMATOGRAPHIC CONDITIONS (2) is not less than 2.0 and not more than 3.0.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed DETERMINATION OF CONTENT
with nitrile silica gel for chromatography (5 um) (Genesis CN, Determine the weight per mL of the oral solution,
Luna CN and Microsorb CN are suitable). Appendix V G, and calculate the content of C;>)H2,NS,HCl,
(b) Use isocratic elution and the mobile phase described weight in volume, using the declared content of
below. Cy9H2;NS,HCI in dosulepin hydrochlonde BPCRS.
(c) Use a flow rate of 1 mL per minute. IMPURITIES
(d) Use a.column temperature of 35°. The impurities limited by the requirements of the monograph
include impurities A andE listed under Dosulepin
Hydrochloride.
1 volume of 0.83% Dosulepin Tablets

30 volumes of methanot:
Action and use
When the chromatogram
DEFINITION
E-dosulepin is about 0.9. Dosulepin Tablets contain Dosulepin Hydrochloride. They
SYSTEM SUITABILITY are coated.
Content of dosulepin hydrochloride, C,)>)H,,;,NS, HCl
Z-dosulepin and H, is the height above the baseline of 95.0 to 105.0% of the stated amount.
lowest point of the curve separating this peak from th
due to E-dosulepin. IDENTIFICATION
xove the coating. Shake a quantity of the powdered tablet
LIMITS
ntaining 0.2 g of Dosulepin Hydrochloride with
In the chromatogram obtained with solution (1): f dichloromethane, centrifuge, filter the supernatant
the area of any peak corresponding to impurity A is not evaporate the filtrate to dryness. Dissolve the
the area of any peak corresponding to Z-dosulepin is not
greater than 5% of the sum of the areas of the principal peak he residue, Appendix II A, is
(E-dosulepin) and the peak due to Z-dosulepin in the erence spectrum of dosulepin
ASSAY dispersioninliquid Di
Carry out the method for liquid chromatography, TESTS
Appendix III D, using the following solutions. Related substances
(1) Dissolve a weighed quantity of the oral solution
containing 50 mg of Dosulepin Hydrochloride in the mobile
phase, add sufficient mobile phase to produce 200 mL, mix
thoroughly and filter through a 0.45-m nylon filter. n-2-ol and
(2) 0.025% w/v of dosulepin hydrochloride BPCRS in the . Apply
mobile phase.
ip
tablets containing 0.25 g of Dosulepin Hydrochloride for
2 minutes with 5 mL of dichloromethane, centrifuge and use
the supernatant liquid. For solution (2) dilute 2 mL of
(10 um) (RP-18 Spheri-10 is suitable).
solution (1) to 5 mL with dichloromethane. Solution (3)
(b) Use isocratic elution and the mobile phase described contains 0.010% w/v each of 3-(dibenzo[b,e] thiepin-11(6H)-
below. ylidene)-N,N-dimethylaminopropan-1-amine S-oxide
(c) Use a flow rate of 2 mL per minute. hydrochloride BPCRS and dibenzo|[b,e]thiepin-11(6H)-
(d) Use an ambient column temperature. one BPCRS in chloroform. After removal of the plate, allow it
(e) Use a detection wavelength of 230 nm. to dry in air and examine under ultraviolet light (254 nm).
with the lower Rf value is more intense than any
MOBILE PHASE corresponding spot in the chromatogram obtained with
15 volumes of 0.04M sodium dihydrogen orthophosphate, which solution (2) (0.5%). In the chromatogram obtained with
has been adjusted to pH 5.6 with triethylamine, 20 volumes of solution (1) any secondary spot other than any spot
acetonitrile and 65 volumes of methanol. corresponding to the spot with the lower Rf value in the
ane al
II-504 Doxapram Preparations 2016
chromatogram obtained with solution (3) is not more intense IDENTIFICATION

than the proximate spot in the chromatogram obtained with A. To a volume containing 50 mg of Doxapram
te we
solution (3) (0.2%). Hydrochloride add 10 mL of water and 2 mL of 1M sodium
Z-Isomer hydroxide and extract with two 10 mL quantities of ether.
Carry out the method for gas chromatography, Wash the combined extracts with 5 mL of water, dry over
Appendix III B, using the following solutions. Solution (1) anhydrous sodium sulfate, filter and evaporate to dryness.
contains 0.50% w/v of dosulepin hydrochlonde BPCRS in Recrystallise the residue from 10 mL of 0.01mM methanolic
methanol. For solution (2) shake a quantity of the powdered hydrochloric acid. he infrared absorption spectrum of the dried
tablets containing 25 mg of Dosulepin Hydrochloride with residue, Appendix II A, is concordant with the reference
5 mL of methanol for 15 minutes, centrifuge and use the spectrum of doxapram hydrochloride (RS 116).
supernatant liquid. B. The light absorption, Appendix II B, in the range 230 to
graphic procedure may be carried out using a 350 nm of the solution obtained in the Assay exhibits
viet we maxima at 253, 258 and 265 nm.
; support (100 to 120 mesh) coated with
ey
C. Yields the reactions characteristic of chlorides,

|
ylmethyl phenyl methyl silicone fluid Appendix VI.

<atid maintained at 200°. TEST
Acidity
pH of a solution containing 1% w/v of doxapram
hydrochloride, 3.5 to 5.0, Appendix V L.
ASSAY
Dilute a volume containing 0.2 g of Doxapram
tee of the sum of the areas of the p Hydrochloride to 250 mL with water. Measure the absorbance
E-dosulepin. of the resulting solution at the maximum at 258 nm,
Appendix IT B. Calculate the content of
ASSAY ! C34H39N202,;HCI1,H2O in the injection from the absorbance
Weigh and powder 20 tablets. Carry out th of a 0.08% w/v solution of doxapram hydrochlonde BPCRS
using the declared content of C2,H3)9N20,,HCI,H,O in
doxapram hydrochloride BPCRS.
tablets containing 50 mg of Dosulepin Hydrochloride ai
60 mL of 0.1m hydrochloric acid for 30 minutes, dilute t STORAGE
100 mL with 0.1m hydrochloric acid and filter. Discard the oxapram Injection should not be allowed to freeze.
first 25 mL of the filtrate. Dilute 25 mL of the remaining
filtrate to 100 mL with 0.1m hydrochloric acid. Solution (2)
contains 0.0125% w/w of dosulepin hydrochlonde BPCRS in
ODS 1 is suitable), (b) as the mobile phase with a flow rate
of 1.5 mL per minute a mixture of 10 volumes of DEFINITION eo
tetrahydrofuran, 40 volumes of acetonitrile and 50 volumes of a Doxepin Capsules contai pin Hydrochloride.
0.5% w/v solution of potassium dihydrogen orthophosphate, the The capsules comply wit ents stated under Capsules
ete tet
pH of the mixture being adjusted to 3.0 with orthophosphoric and with the following requirem,
acid and (c) a detection wavelength of 231 nm.
Content of doxepin, C,>5H,,NG@
Calculate the content of Cj9)H.;NS,HCI using the declared 95.0 to 105.0% of the stated amo
content of Cy9H»,;NS,HCI in dosulepin hydrochloride BPCRS.
IDENTIFICATION
Doxapram Injection air, extract the residue with three 10-mL quantiti
chloroform, evaporate the combined extracts to dryness and
Action and use dry the residue at 105°. The residue complies with the
an vwad
Respiratory stimulant. following tests.
a aa
aN A

DEFINITION
concordant with the reference spectrum of doxepin
Doxapram Injection is a sterile solution of Doxapram
Hydrochloride in Water for Injections.
B. Yields reaction A characteristic of chlorides, Appendix VI.
Parenteral Preparations and with the following requirements. TESTS
Content of doxapram hydrochloride, Z-Isomer
13.0 to 18.5%, when determined by the following method.
C,4H39N,02,HC1,H,O
90.0 to 110.0% of the stated amount. Carry out the method for gas chromatography,
wre
Appendix III B, using the following solutions.
wate tet
Mo
2016 Doxepin Preparations ITI-505
(1) Extract a quantity of the mixed contents of 20 capsules SYSTEM SUITABILITY

containing the equivalent of 25 mg of doxepin with 5 mL of The test is not valid unless, in the chromatogram obtained
methanol, centrifuge and use the supernatant liquid.
re wed
ee eed with solution (3):

(2) 0.5% w/v of doxepin hydrochloride BPCRS in methanol. the resolution between the peaks due to impurity A and
CHROMATOGRAPHIC CONDITIONS impurity C is at least 1.5;
(a) Use a fused silica capillary column (30 m x 0.53 mm) the resolution between the peaks due to impurity B and
bonded with a film (3 um) of 6% cyanopropylphenyl siloxane impurity C is at least 1.5.
and 94% polydimethylsiloxane (DB-624 is suitable). LIMITS
(b) Use helium as the carrier gas at 20 mL/min. In the chromatogram obtained with solution (1):
(c) Use an oven temperature maintained at 200°. identify any peaks corresponding to impurity A, B and C
atrinlet temperature of 240°. using the chromatogram obtained with solution (3) and the
chromatogram supplied with doxepin
(e) Use af isation detector maintained at a
temperatureso 0°. impurity standard BPCRS;
) Use a : |
the Z-isomer may appear as a shoulder on the peak due to
Doxepin;
(g) Inject 1 uLe@
immediately chromatogram obtained with solution (2) (0.2%);
precedes the principal peak due to in and the
the area of any peak corresponding to impurity C is not
resolution between the peaks due to Z-dgs im.and E-doxepin greater than 5 times the area of the principal peak in the
is at least 2.0. : chromatogram obtained with solution (2) (0.5%);
DETERMINATION OF CONTENT the area of any other peak is not greater than twice the area
Measure the areas or heights of the peaks due'to of the principal peak in the chromatogram obtained with
E-isomers in the chromatograms obtained with s¢ solution (2) (0.2%);
and (2) and calculate the content of Z-isomer in thé the sum of the areas of any other secondary peaks is not
substance being examined using the declared content 6 reater than 4 times the area of the principal peak in the
Z-isomer in doxepin hydrochloride BPCRS. atogram obtained with solution (2) (0.4%);
Related substances (other than the Z-Isomer) of the areas of all the peaks is not greater than
Carry out the method for liguid chromatography, the area of the principal peak in the chromatogram
Solvent A A mixture of 2 volumes of 2M sodium hydroxide
and 1000 volumes of mobile phase.
(1) Dissolve with the aid of ultrasound a quantity of the
contents of the capsules containing the equivalent of 100 mg
of doxepin in 100 mL of solvent A and filter.
tents of 20 capsules. Carry out the
(2) Dilute 1 volume of solution (1) to 100 volumes with method for liquid chit hy, Appendix III D, using the
solvent A and further dilute 1 volume to 10 volumes with following solutions in solvent Aj as described under Related
solvent A. substances (other than the:4
(3) Dissolve the contents of a vial of doxepin (1) Dissolve with the aid of ultra .a quantity of the
impurity standard BPCRS in 1 mL of the mobile phase. contents of the capsules containit uivalent of 100 mg
CHROMATOGRAPHIC CONDITIONS of doxepin in 100 mL of solvent A
(a) Use a stainless steel column (25 cm x 4.6 mm) packed to 10 volumes with solvent A.
with octadecylsilyl silica gel for chromatography (5 um) (2) Prepare a solution of doxepin hydrochlog
(Phenomenex Luna C18 (2) is suitable). containing the equivalent of 0.01% w/v doxey’ Solvent A.
(b) Use isocratic elution and the mobile phase described (3) Dissolve the contents of a vial of doxepin
below. impurity standard BPCRS in 1 mL of the mobile phase.
(c) Use a flow rate of 1 mL per minute. CHROMATOGRAPHIC CONDITIONS
ee
.
(d) Use a column temperature of 30°. The chromatographic conditions described under Related
aera
(e) Use a detection wavelength of 215 nm. substances (other than the Z-isomer) may be used.
(f) Inject 20 pL of each solution. SYSTEM SUITABILITY
(g) For solution (1), allow the chromatography to proceed The test is not valid unless, in the chromatogram obtained
for twice the retention time of the principal peak. with solution (3):
MOBILE PHASE the resolution between the peaks due to impurity A and
20 volumes of acetonitrile, 30 volumes of 0.01m disodium impurity C is at least 1.5;
hydrogen orthophosphate, adjusted to pH 7.7 using 0.02m the resolution between the peaks due to impurity B and
orthophosphoric acid, and 50 volumes of methanol. impurity C is at least 1.5.
II-506 Doxorubicin Preparations 2016
DETERMINATION OF CONTENT acetonitrile and 10 mL of methanol and mix [generation of

Calculate the content of C;)>9H.,;NO in the capsules using the doxorubicin aglycone (doxorubicinone)].
declared content of C;9H2;NO,HCI in doxepin (4) Dilute 5 volumes of solution (2) to 20 volumes.
See ete
hydrochloride BPCRS. Each mg of Cy9H2;NO,HCI is CHROMATOGRAPHIC CONDITIONS

equivalent to 0.884g of C;9>H2,NO.
IMPURITIES with end-capped octadecylsilyl silica gel for chromatography
The impurities limited by the requirements of this (5 um) (Hypersil C18 is suitable).
monograph include those listed under Doxepin (b) Use isocratic elution and the mobile phase described
Hydrochloride. below.
LABELLING (c) Use a flow rate of 1 mL per minute.
f active ingredient is stated in terms of the (d) Use an ambient column temperature.
awe
Doxorubicin MOBILE PHASE
Action and use . 50 volumes of acetonitrile and 50 volumes of a solution

Anthracycline antibacterial; eytst containing 0.288% w/v of sodium dodecyl sulfate and
weed 0.225% w/v of orthophosphonic acid.
DEFINITION > When the chromatograms are recorded under the prescribed
Doxorubicin Injection is a steril conditions the relative retention of doxorubicin aglycone with
Hydrochloride in Water for Injections ‘6r reference to doxorubicin (retention time, about 8 minutes) is
Injection. It is either supplied as a ready-to- about 0.4.
is prepared by dissolving Doxorubicin Hydro
SYSTEM SUITABILITY
Injection in the requisite amount of Water for Inj¢e
Sodium Chloride Injection. a The test is not valid unless:
The injection complies with the requirements stated under in the chromatogram obtained with solution (2), the resolution
Parenteral Preparations and, when supplied as a ready-to-us. between the peaks due to doxorubicin and epirubicin 1s at
solution, with the following requirements.
Content of doxorubicin hydrochloride, C,7H,)NO,,,HC1
CHARACTERISTICS
A red solution.
IDENTIFICATION
A. Dilute the injection with sufficient ethanol (96%) to doxorubicin 11’
produce a solution containing 0.001% w/v of Doxorubicin
(3%);
Hydrochloride. The light absorption of the resulting solution,
Appendix II B, in the range 220 to 550 nm exhibits two
maxima, at 234 and 252 nm, and four less clearly defined
obtained with solution (4)
maxima at 288, 475, 495 and 530 nm.
Ne ALY
B. In the Assay, the retention time of the principal peak in Bacterial endotoxins

that of the principal peak in the chromatogram obtained with Dilute the injection, if necessary, wi
solution (2). solution containing 2 mg of Doxoru
mL (solution A). The endotoxin limit cor
TESTS solution A is 4.4 IU of endotoxin per mL.
Acidity
ASSAY
Related substances Appendix III D, using the following solutions in the mobile
Carry out the method for liguid chromatography, phase. The solutions should be prepared immediately before
i oy Appendix III D, using the following solutions in the mobile use.
phase. The solutions should be prepared immediately before
ae
use.
containing 0.01% w/v of Doxorubicin Hydrochloride.
(2) 0.01% w/v of doxorubicin hydrochloride BPCRS.
containing 0.1% w/v of Doxorubicin Hydrochloride.
(2) 0.002% w/v of each of doxorubicin hydrochloride BPCRS CHROMATOGRAPHIC CONDITIONS
and epirubicin hydrochloride BPCRS. (a) Use a stainless steel column (25 cm x 4.6 mm) packed
(3) Dissolve 10 mg of doxorubicin hydrochloride BPCRS in a with end-capped octadecylsilyl silica gel for chromatography
mixture of 5 mL of water and 5 mL of orthophosphonic acid (5 um) (Hypersil C18 is suitable).
and allow to stand for 30 minutes. Adjust the pH to 2.6 with (b) Use isocratic elution and the mobile phase described
ey ee
eens
eta an 8% w/v solution of sodium hydroxide, add 15 mL of below.
aN er AW
2016 Doxycycline Preparations III-507
(d) Use an ambient column temperature. doxorubicin in the chromatogram obtained with solution (4)
(e) Use a detection wavelength of 254 nm. (1%);
(f) Inject 10 wL of each solution. the area of any other secondary peak is not greater than the
area of the peak due to doxorubicin in the chromatogram
MOBILE PHASE
Water
containing 0.288% w/v of sodium dodecyl sulfate and
0.225% w/v of orthophosphonic acid.
Calculate the content of C27H2)».NO,,,HCI in the injection Dissolve the contents of the sealed container in water BET to
using the declared content of C.7H2)9NO,,,HC1 in give a solution containing 10 mg of Doxorubicin
Hydrochloride per mL (solution A). The endotoxin limit
concentration of solution A is 22 IU of endotoxin per mL.
ve and
ven
ASSAY
id stated on the label should be Appendix XII C1, Powders for Parenteral Administration.
used immediately aftey ration but, in any case, within Carry out the method for liquid chromatography,
the period recommende¢ anufacturer when prepared Appendix III D, using the following solutions. The solutions
and stored strictly in acc should be prepared immediately before use.
instructions. o
containers in sufficient of the mobile phase to produce a
DOXORUBICIN HYDROCH solution containing 0.01% w/v of Doxorubicin
INJECTION Hydrochloride.
DEFINITION (2) 0.01% w/v of doxorubicin hydrochlonde BPCRS in the

mobile phase.
consisting of Doxorubicin Hydrochloride with or‘wi CHROMATOGRAPHIC CONDITIONS
excipients. It is supplied in a sealed container. The chromatographic conditions described under the Assay
The contents of the sealed container comply with the requi for the ready-to-use solution may be used.
for Powders for Injections or Infusions stated under Parentera INATION OF CONTENT
e the content of C,7H,>NO,,,HCI in a container of
Content of doxorubicin hydrochloride, C)7H,.NO,,,HC1 ntent weight using the declared content of
90.0 to 110.0% of the stated amount. NNO,,,HCI in doxorubicin hydrochloride BPCRS.
IDENTIFICATION
A. Shake a quantity of the powder containing 10 mg of
Doxorubicin Hydrochloride with 5 mL of 0.01M hydrochloric
acid, extract 2 mL of the resulting solution with two 5-mL Doxycycli
quantities of ether and discard the ether layer. Dilute the
aqueous solution with ethanol (96%) to contain 0.001% wiv Action and use
of Doxorubicin Hydrochloride. The light absorption of the Tetracycline antibac
resulting solution, Appendix II B, in the range 220 to
550 nm exhibits two maxima, at 234 and 252 nm, and four DEFINITION
less clearly defined maxima at 288, 475, 495 and 530 nm.
B. In the Assay, the retention time of the principal peak in The capsules comply with the requirem died under Capsules
the chromatogram obtained with solution (1) corresponds to and with the following requirements.
that of the principal peak in the chromatogram obtained with Content of anhydrous doxycycline, C
solution (2). 95.0 to 105.0% of the stated amount. :
TESTS IDENTIFICATION
Acidity A. Carry out the method for thin-layer chromatography,
pH ofa solution containing 0.2% w/v of Doxorubicin Appendix ITI A, using silica gel H as the coating substance
Hydrochloride in Water for Injections, 4.5 to 6.5, and a mixture of 6 volumes of water, 35 volumes of methanol
Appendix V L. and 59 volumes of dichloromethane as the mobile phase. Spray
Related substances the plate evenly with a 10% w/v solution of disodium edetate
Complies with the test described for the ready-to-use solution the pH of which has been adjusted to 9.0 with 10M sodium
but preparing solution (1) in the following manner. Dissolve hydroxide (about 10 mL for a 100 mm x 200 mm plate).
a quantity of the powder in sufficient of the mobile phase to Allow the plate to dry in a horizontal position for at least
produce a solution containing 0.1% w/v of Doxorubicin 1 hour. Immediately before use dry it at 110° for 1 hour.
Hydrochloride. Apply separately to the plate 1 yL of each of the following
solutions. For solution (1) shake a quantity of the contents of
LIMITS
the capsules containing the equivalent of 50 mg of anhydrous
In the chromatogram obtained with solution (1): doxycycline with 100 mL of methanol for 1 to 2 minutes,
the area of any peak corresponding to doxorubicin aglycone centrifuge and use the supernatant liquid. Solution (2)
is not greater than twice the area of the peak due to contains 0.05% w/v of doxycycline hyclate BPCRS in methanol.
IWI-508 Doxycycline Preparations 2016
Solution (3) contains 0.05% w/v each of doxycycline corresponding to 6-epidoxycycline in the chromatogram
hyclate BPCRS and tetracychne hydrochloride BPCRS in obtained with solution (5) (0.5%, with reference to
methanol. After removal of the plate, dry it in a current of air doxycycline hyclate).
and examine under ultraviolet light (365 nm). The principal
eRe aN
Loss on drying
spot in the chromatogram obtained with solution (1) is When dried at 105° for 2 hours, the contents of the capsules
similar in position, colour and size to that in the lose not more than 8.5% of their weight. Use 1 g.
chromatogram obtained with solution (2). The test is not
valid unless the chromatogram obtained with solution (3) ASSAY
shows two clearly separated spots. Carry out the method for liquid chromatography,
B. To 0.5 mg of the contents of the capsules add 2 mL of
(1) dissolve the mixed contents of 20 capsules containing the
sulfuric acid. A yellow colour is produced.
equivalent of 17.5 mg of anhydrous doxycycline in sufficient
ts of the capsules yield the reactions 0.01mM hydrochloric acid to produce 25 mL and dilute 4 mL of
we ne |
the solution to 25 mL with the same solvent. Solution (2)

et a
contains 0.0128% w/v of doxycycline hyclate BPCRS in

0.01mM hydrochloric acid.
e capsules as completely as The chromatographic conditions described under Related
> of 1 volume of substances may be used.
Calculate the content of C,.H2,N,Og using the declared
content of C,H »4,N2Ox in doxycycline hyclate BPCRS.
490 nm is not more than 0.2 LABELLING

the dried capsule contents, Ap The quantity of active ingredient is stated in terms of the
equivalent amount of anhydrous doxycycline.
Carry out the method for liguid chromatog
Appendix III D, using the following solutio
immediately before use. For solution (1) dissol
of the contents of the capsules containing the equiv an Dispersible Doxycycline Tablets
7.0 mg of anhydrous doxycyclinein 10 mL of
0.01m hydrochloric acid, filter and use the filtrate. Solu yn Action and use
(2) to (5) are solutionsin 0.01m hydrochloric acid containin Tetracycline antibacterial.
(2) 0.080% w/v of doxycycline hyclate BPCRS, (3)
ION
0.080% w/v of 6-epidoxycycline hydrochloride BPCRS, (4)
e Doxycycline Tablets contain Doxycycline
0.080% w/v of metacyclhine hydrochloride EPCRS and (5)
e in a suitable dispersible basis.
0.0016% w/v each of 6-epidoxycychine hydrochlonde BPCRS
and metacychine hydrochloride EPCRS. For solution (6) dilute a mply with the requirements stated under Tablets and
mixture of 4 volumes of solution (2), 1.5 volumes of solution
(3) and 1 volume of solution (4) to 25 volumes with
0.01m hydrochlonc acid.
(a) a column (25 cm x 4.6 mm) packed with styrene- in-layer chromatography,
divinylbenzene co-polymer (8 um) with a pore size of 10 nm Appendix III A, using siies as the coating substance
(PLRP-S from Polymer Laboratories is suitable) and and a mixture of 6 volume
maintained at 60°, (b) as the mobile phase with a flow rate of
1 mL per minute a solution prepared as described below and
We we
(c) a detection wavelength of 254 nm. For the mobile phase

a add 60 g of 2-methylpropan-2-ol to a graduated flask with the
aid of 200 mL of water, add 400 mL of phosphate buffer
pH 8.0, 50 mL of a 1% w/v solution of tetrabutylammonium
hydrogen sulfate previously adjusted to pH 8.0 with 2m sodium
hydroxide and 10 mL of a 4% w/v solution of disodium edetate solutions. For solution (1) shake a quantity ofthe owdered
previously adjusted to pH 8.0 with 2M sodium hydroxide and tablets containing the equivalent of 50 mg of anhydrous
dilute to 1000 mL with water. Inject 20 uL of each solution. doxycycline with 100 mL of methanol for 1 to 2 minutes,
Ae te.
twas
The test is not valid unless, in the chromatogram obtained centrifuge and use the supernatant liquid. Solution (2)
Lela
we AN
with solution (6), the resolution factor between the first peak contains 0.05% w/v of doxycycline hyclate BPCRS in methanol.
(metacycline) and the second peak (6-epidoxycycline) is at Solution (3) contains 0.05% w/v of each of doxycycline
least 1.25 and the resolution factor between the second peak hyclate BPCRS and tetracycline hydrochlonde BPCRS in
and the third peak (doxycycline) is at least 2.0. If necessary, methanol. After removal of the plate, dry it in a current of air
adjust the content of 2-methylpropan-2-ol in the mobile and examine under ultraviolet light (365 nm). The principal
phase. spot in the chromatogram obtained with solution (1) 1s
In the chromatogram obtained with solution (1) the area of similar in position, colour and size to that in the
any peak corresponding to metacycline or 6-epidoxycycline is chromatogram obtained with solution (2). The test is not
not greater than the area of the corresponding peak in the valid unless the chromatogram obtained with solution (3)
wena
chromatogram obtained with solution (5) (2%, with reference shows two clearly separated spots.
to doxycycline hyclate) and the area of any other secondary
nawe asd
case
an~ aed
Taom
peak is not greater than 0.25 times the area of the peak the chromatogram obtained with solution (1) is the same as
2016 Droperidol Preparations IT-509
that of the principal peak in the chromatogram obtained with and the third peak (doxycycline) is at least 2.0. If necessary,
solution (2). adjust the content of 2-methylpropan-2-ol in the mobile
phase.
TESTS
a8 aS
Disintegration In the chromatogram obtained with solution (1) the area of

Comply with the requirements for Dispersible Tablets. any peak corresponding to metacycline or 6-epidoxycycline is
not greater than the area of the corresponding peak in the
Dissolution
chromatogram obtained with solution (5) (2%) and the area
of any other secondary peak is not greater than 0.25 times the
area of the peak corresponding to 6-epidoxycycline in the
900 mL of a solution prepared by dissolving 2 g of sodium
chloride in.7 mL of hydrochloric acid and sufficient water to — Loss on drying
mL and rotate the paddle at 75 revolutions per When dried at 60° at a pressure of 2 kPa for 2 hours, the
‘a sample of 15 mL of the medium and powdered tablets lose not more than 6.0% of their weight.
easure the absorbance of the filtrate, Use 1 g.
Appendix II J with the dissolution medium if ASSAY
necessary, at 27 ng dissolution medium in the Weigh and powder 20 tablets. Carry out the method for
Re «absorbance of a suitable solution liquid chromatography, Appendix III D, using the following
of doxycycline hyclate B solutions. For solution (1) add a quantity of the powdered
calculate the total contét tablets containing the equivalent of 0.1 g of anhydrous
Co2H24N20<¢, in the medit doxycycline to 20 mL of 0.1m hydrochloric acid, mix with the
Co2H24N2O¢ in doxycycline aid of ultrasound until fully dispersed (about 10 minutes),
.e- ned
Light-absorbing impuritie add sufficient water to produce 200 mL, mix, centrifuge and
Dissolve a quantity of the powdered: use the supernatant liquid. For solution (2) dissolve 0.115 g
possible in sufficient of a mixture of 1 ¥6 of doxycycline hyclate BPCRS in 20 mL of 0.1m hydrochloric
1m hydrochloric acid and 99 volumes of mi acid and add sufficient water to produce 200 mL.
solution containing the equivalent of 1.0% w The chromatographic conditions described under Related
doxycycline and filter. The absorbance of the filtrate: substances may be used.
490 nm is not more than 0.20, calculated with ré Calculate the content of C:,H»,N2O¢ in the tablets using the
the dried powdered tablets, Appendix II B. declared content of C2xH»4N2Oxg in doxycycline
Related substances hyclate BPCRS.
LING
ntity of active ingredient is stated in terms of the
immediately before use. For solution (1) add a quantity of
amount of anhydrous doxycycline.
the powdered tablets containing the equivalent of 80 mg of
anhydrous doxycycline to 80 mL of 0.01m hydrochloric acid,
mix with the aid of ultrasound and add sufficient
0.01m hydrochloric acid to produce 100 mL. Centrifuge and
use the supernatant liquid. Solutions (2) to (5) are solutions
in 0.01m hydrochloric acid containing (2) 0.080% w/v of
doxycycline hyclate BPCRS, (3) 0.080% w/v of 6-epidoxycycline
hydrochloride BPCRS, (4) 0.080% w/v of metacycline
hydrochloride EPCRS and (5) 0.0016% w/v each of
6-epidoxycycline hydrochloride BPCRS and metacychne
hydrochloride EPCRS. For solution (6) dilute a mixture of DEFINITION g
4 volumes of solution (2), 1.5 volumes of solution (3) and Droperidol Injection is a sterile s
1 volume of solution (4) to 25 volumes with Water for Injections.
The chromatographic procedure may be carried out using Parenteral Preparations and with thefollowt
(a) a column (25 cm x 4.6 mm) packed with styrene- Content of droperidol, C,,H,.,FN3;0,
divinylbenzene co-polymer (8 um) with a pore size of 10 nm 95.0 to 105.0% of the stated amount.
(PLRP-S from Polymer Laboratories is suitable) and
maintained at 60°, (b) as the mobile phase with a flow rate of IDENTIFICATION
1 mL per minute a solution prepared as described below and A. In the Assay, the chromatogram obtained with solution
(c) a detection wavelength of 254 nm. For the mobile phase (1) shows a peak with the same retention time as the peak
add 60 g of 2-methylpropan-2-ol to a graduated flask with the due to droperidol in the chromatogram obtained with
aid of 200 mL of water, add 400 mL of phosphate buffer solution (2).
pH 8.0, 50 mL of a 1% w/v solution of tetrabutylammonium B. Carry out the method for thin-layer chromatography,
hydrogen sulfate previously adjusted to pH 8.0 with 2m sodium Appendix III A, usinga silica gel F254 precoated plate
hydroxide and 10 mL of a 4% w/v solution of disodium edetate (Merck silica gel 60 F254 plates are suitable) and a mixture of
previously adjusted to pH 8.0 with 2m sodium hydroxide and 10 volumes of acetone and 90 volumes of methanol as the
dilute to 1000 mL with water. Inject 20 wL of each solution. mobile phase. Apply separately to the plate 5 pL of each of
The test is not valid unless, in the chromatogram obtained the following solutions. For solution (1) shake a volume of
with solution (6), the resolution factor between the first peak the injection containing 10 mg of Droperidol with two
(metacycline) and the second peak (6-epidoxycycline) is at successive 10 mL quantities of dichloromethane and use the
least 1.25 and the resolution factor between the second peak combined extracts. Solution (2) contains 0.05% w/v of
IWI-510 Droperidol Preparations 2016
droperidol BPCRS in dichloromethane. After removal of the Solution (2) contains 0.010% w/v of droperidol BPCRS in
plate, allow it to dry in air and examine under ultraviolet light methanol (50%). Solution (3) contains 0.0025% w/v of each
(254 nm). The principal spot in the chromatogram obtained of droperidol BPCRS and benperidol EPCRS in methanol
with solution (1) is similar to that in the chromatogram (50%).
obtained with solution (2). The chromatographic procedure described under Related
TESTS substances may be used.
Acidity Inject 20 wL of solution (3). When the chromatogram is
pH, 2.5 to 4.5, Appendix V L. recorded under the prescribed conditions, the retention times
Related substances for benperidol and droperidol are about 6.5 minutes and
Carry out the method for liquid chromatography, about 7 minutes respectively. The assay is not valid unless in
Appendix QI D, usingthe following solutions. For solution the chromatogram obtained with solution (3) the resolution
factor between the peaks due to droperidol and benperidol is
rAM AN
net
Aed at least 2.0. If necessary, adjust the final concentration of
vi] tetrabutyla me acetonitrile in the mobile phase or adjust the time
containing 0. roperidol. For solution (2) dilute programme for the linear gradient.
o 100 volumes with a mixture of Calculate the content of C2,H22FN3Q, in the injection using
the declared content of C2.H22FN3O, in droperidol BPCRS.
aoe this solution to 20 volum

oat) Solution (3) contains 0.002'
ee and benperidol EPCRS in a mixtur Droperidol Tablets
Se dimethylformamide and a 1% why
“ey tetrabutylammonium hydrogen sulfate.
tee ee
Action and use

Dopamine receptor antagonist; beta,-adrenoceptor agonist;
alpha-adrenoceptor agonist; neuroleptic.
(3 um) (Hypersil C18 BDS 3u is suitable), (b) as DEFINITION

phase with a flow rate of 1.5 mL per minute a 1% Droperidol Tablets contain Droperidol.
solution of tetrabutylammonium hydrogen sulfate changirig b The tablets comply with the requirements stated under Tablets and
linear gradient to a mixture of 60 volumes of a 1% w/v with the following requirements.
solution of tetrabutylammonium hydrogen sulfate and i - of droperidol, C,,H,2FN30,
40 volumes of acetonitrile over 15 minutes, followed by the 105.0% of the stated amount.
final mixture for 5 minutes and (c) a detection wavelength of
275 nm. Equilibrate the column with acetonitrile for at least
30 minutes before use and then equilibrate at the initial
mobile phase composition for at least 30 minutes.
Inject 20 wL of solution (3). When the chromatogram is
recorded under the prescribed conditions, the retention times
sidue, Appendix II A, is concordant
for benperidol and droperidol are about 6.5 minutes and
about 7 minutes respectively. The test is not valid unless in
wit®£, droperidol (RS 384).
the chromatogram obtained with solution (3) the resolution B. In the Assay, the matogram obtained with solution
factor between the peaks due to droperidol and benperidol is (1) shows a peak with t ‘tention time as the peak
at least 2.0. If necessary, adjust the final concentration of due to droperidolin the ch ‘ogram obtained with
acetonitrile in the mobile phase or adjust the time solution (2).
programme for the linear gradient. TESTS
When solution (1) is prepared by diluting Droperidol Dissolution
Injection inject 20 wL of a mixture of equal volumes of Comply with the requirements for Mon f the British
dimethylformamide and a 1% w/v solution of Pharmacopoeiain the dissolution test for ta etsand sules,
tetrabutylammonium hydrogen sulfate as a blank solution. When Appendix XII B1.
solution (1) is the undiluted injection, inject 20 uL of water
TEST CONDITIONS
as a blank solution. In the chromatogram obtained with
solution (1) the area of any secondary peak is not greater than
per minute.
223 the area of the principal peak in the chromatogram obtained
er with solution (2) (0.25%) and the sum of the areas of any (b) Use 900 mL of 0.1m hydrochloric acid, at a temperature of
eee secondary peaks is not greater than twice the area of the 37°, as the medium.
principal peak in the chromatogram obtained with solution PROCEDURE
(2) (0.5%). Disregard any peak obtained with the blank (1) Withdraw a sample of 10 mL of the medium, filter
os solution and any peak with an area less than 0.2 times the through a 15-um membrane filter and immediately measure
ate area of the principal peak in the chromatogram obtained with the absorbance of the filtered solution, diluted if necessary
wo solution (2) (0.05%). with the dissolution medium, at the maximum at 247 nm,
ASSAY Appendix II B, using dissolution medium in the reference
Carry out the method for liguid chromatography, cell.
ss Appendix III D, using the following solutions. For solution (2) Measure the absorbance of a suitable solution of
ax (1) dilute the injection, if necessary, with methanol (50%) to droperidol BPCRS using 0.1m hydrochloric acid in the reference
give a solution containing 0.010% w/v of Droperidol. cell.
ae ak
pee ee
tee we
2016 Econazole Preparations TII-511
DETERMINATION OF CONTENT the area of any secondary peak is not greater than the area of
Calculate the total content of droperidol, C22H»2FN3O,, in the principal peak in the chromatogram obtained with
the medium using the declared content of C22H».»FN3O> in solution (2) (0.25%);
droperidol BPCRS. the sum of the areas of any secondary peaks is not greater than
Related substances four times the area of the principal peak in the
Carry out the method for liquid chromatography, chromatogram obtained with solution (2) (1%).
Appendix III D, using the following solutions. Disregard any peak obtained with the blank solution and any
(1) Mix with the aid of ultrasound a quantity of the peak with an area less than 0.2 times the area of the principal
powdered tablets containing 0.1 g of Droperidol with 20 mL peak in the chromatogram obtained with solution (2)
of dimethylformamide for 20 minutes, filter and dilute (0.05%).
5 volumes of the filtrate to 10 volumes with a 1% w/v ASSAY
‘yen
raya jie of solution (1) to 100 volumes with a liquid chromatography, Appendix II D, using the following
g.equal volumes of dimethylformamide and a solutions.
furtherdilute 5 20 mg of Droperidol with 75 mL of methanol for 30 minutes,
the same solvent ‘#3 dilute to 100 mL with methanol, filter and dilute 10 mL of
the resulting solution to 20 mL with water.
(2) 0.010% w/v of droperidol BPCRS in methanol (50%).
(3) 0.0025% w/v each of droperidol BPCRS and
benperidol EPCRS in methanol (50%).
(a) Use a stainless steel column (10°c
with base-deactivated octadecylsilyl silicagel
(3 um) (Hypersil C18 BDS 3u is suitable}:
SYSTEM SUITABILITY
(b) Use gradient elution and the mobile phaseé’¢
below. Inject solution (3). When the chromatogram is recorded
under the prescribed conditions, the retention times for
benperidol and droperidol are about 6.5 minutes and about
(d) Use an ambient column temperature. 7minutes respectively. he assay is not valid unless,in the
(e) Use a detection wavelength of 275 nm. mmatogram obtained with solution (3), the resolution factor
(f) Inject 20 pL of each solution. een the peaks due to droperidol and benperidolis at
(g) Inject 20 pL of a mixture of equal volumes of
dimethylformamide and a 1% w/v solution of
tetrabutylammonium hydrogen sulfate as a blank solution.
(h) Equilibrate the column with acetonitrile for at least
30 minutes before use and then equilibrate at the initial f C,,H»»FN30> in the tablets using
mobile phase composition for at least 30 minutes. the declared céftite Ca2H2.FN302 in droperidol BPCRS.
MOBILE PHASE
Mobile phase A 1% ww solution of tetrabutylammonium

hydrogen sulfate.
Mobile phase B40 volumes of acetonitrile and 60 volumes of Econazole Cream
a 1% w/v solution of tetrabutylammonium hydrogen sulfate.
Action and use
Antifungal.
-sa- 4.
(Minutes)
DEFINITION ‘
0-15 100-0 0100 linear gradient
Econazole Cream contains Econazole Nitra a suitable
basis.
20-30 100 0 re-equilibration The cream complies with the requirements stated under Topical
we
Content of econazole nitrate, C;3H,;Cl,N,O,HNO;
vwavs
SYSTEM SUITABILITY
When the chromatogram is recorded under the prescribed IDENTIFICATION
conditions, the retention times for benperidol and droperidol A. Mix a quantity of the cream containing 40 mg of
are about 6.5 minutes and about 7 minutes respectively. Econazole Nitrate with 20 mL of a mixture of 1 volume of
The test is not valid unless, in the chromatogram obtained 1m sulfuric acid and 4 volumes of methanol and shake with
with solution (3), the resolution factor between the peaks due two 50-mL quantities of carbon tetrachloride discarding the
to droperidol and benperidol is at least 2.0. If necessary, organic layers. Make the aqueous phase alkaline with
adjust the final concentration of acetonitrile in the mobile 2M ammonia and extract with two 40-mL quantities of
phase or adjust the time programme for the linear gradient. chloroform. Combine the chloroform extracts, shake with 5 g of
anhydrous sodium sulfate, filter and dilute the filtrate to
wa A
A .
LIMITS
tawny
100 mL with chloroform. Evaporate 50 mL to dryness and

re as
ros as
rw Nw

ete ay
II-512 Econazole Preparations 2016
dissolve the residue in 50 mL of a mixture of 1 volume of

0.1m hydrochloric acid and 9 volumes of propan-2-ol. The light
Econazole Pessaries
aw and
Aye Action and use

range 240 to 350 nm exhibits maxima at 265, 271 and
ane 4
Antifungal.
280 nm. The ratio of the absorbance at the maximum at
271 nm to that at the maximum at 280 nm is 1.55 to 1.77. DEFINITION
The test is not valid unless the ratio of the absorbance in the Econazole Pessaries are moulded pessaries containing
test for resolution is at least 2. Econazole Nitrate in a suitable basis.
B. In the Assay, the principal peak in the chromatogram The pessaries comply with the requirements stated under Vaginal
obtained with solution (3) has the same retention time as the Preparations and with the following requirements.
peak due to econazole in the chromatogram obtained with
Content of econazole nitrate, C,3H,;C],N,O0,HNO;
solution (4):
tNtet Ne IDENTIFICATION
A. Mix a quantity of the pessaries, cut into small pieces,
containing 40 mg of Econazole Nitrate with 20 mL of a
mixture of 1 volume of 1m sulfuric acid and 4 volumes of
methanol and shake with two 50-mL quantities of hexane,
discarding the organic layers. Make the aqueous phase
alkaline with 2M ammonia and extract with two 40-mL
quantities of dichloromethane. Combine the dichloromethane
(internal standard solution). extracts, shake with 5 g of anhydrous sodium sulfate, filter and
(2) Mixa quantity of the crea dilute the filtrate to 100 mL with dichloromethane. Evaporate
50 mL to dryness and dissolve the residue in 50 mL ofa
mixture of 1 volume of 0.1M hydrochloric acid and 9 volumes
of propan-2-ol. The light absorption of the resulting solution,
Appendix II B, in the range 240 to 350 nm exhibits maxima
15 minutes, centrifuge for 10 minutes and use the at 265, 271 and 280 nm. The ratio of the absorbance at the
supernatant liquid, filtered if necessary. maximum at 271 nm to that at the maximum at 280 nm is
1.55 to 1.77. The test is not valid unless the ratio of the
(3) Prepare in the same manner as solution (2) but using.
bsorbance in the test for resolution is at least 2.
20 mL of methanol in place of internal standard solution.
ae test for Related substances, the principal spot in the
(4) 10 mL of a 0.1% w/v solution of econazole nitrate BPCRS
seram obtained with solution (1) corresponds to that
in methanol with 20 mL of internal standard solution, 45 mL
matogram obtained with solution (3).
of methanol and 25 mL of buffer solution.

ODS is suitable).
below.
(c) Use a flow rate of 2.0 mL per minute. Allow to cool, filter (Wh 'o. 1 paper is suitable), wash
(d) Use an ambient column temperature. thefilter paper with methan evaporate the filtrate and
wo Ne
(e) Use a detection wavelength of 232 nm. er (Whatman No.

50 paper is suitable), wash the paper with:| methanol,
evaporate the filtrate and washings
°
MOBILE PHASE the residue in 2 mL of methanol.
1 volume of buffer solution and 3 volumes of methanol. (2) Dilute 0.5 mL of solution (1) to 100
DETERMINATION OF CONTENT (3) 2% wiv of econazole nitrate BPCRS in meth
Calculate the content of C)gH;5Cl,N2O,HNO; in the cream CHROMATOGRAPHIC CONDITIONS
using the declared content of C,;gH,5Cl,N,0,HNO; in
(a) Use as the coating silica gel (Merck silica gel 60 plates
econazole nitrate BPCRS.
are suitable).
wate
par aa
A
Lwin ed
STORAGE (b) Use the mobile phase as described below.
If Econazole Cream is kept in aluminium tubes, their inner
wave
., .
surfaces should be coated with a suitable lacquer.

expose to iodine vapour for 1 hour.
MOBILE PHASE
10 volumes of an 85% w/v solution offormic acid,

20 volumes of methanol and 70 volumes of dichloromethane.
LIMITS
ond
aw mS
2016 Emulsifying Wax TIT-513
chromatogram obtained with solution (2). Disregard any spot

with anRf value higher than 0.9.
Emulsifying Ointment
DEFINITION
ASSAY
Emulsifying Wax 300 g
Dissolve five pessaries in 250 mL of anhydrous acetic acid with
White Soft Paraffin 500 g
the aid of gentle heat, allow to cool and carry out Method I
Liquid Paraffin 200 g
for non-aqueous titration, Appendix VIII A, using a quantity of
the solution containing 0.3 g of Econazole Nitrate and Extemporaneous preparation
determining the end point potentiometrically. Each mL of The following directions apply.
0.1m perchloric acid VS is equivalent to 44.47 mg of Melt together and stir until cold.
CygH;5Cl,N,0,HNO3. The ointment complies with the requirements stated under Topical
Semi-solid Preparations.
ta ma
Emulsifying Wax
Cholinesterase 1 Anionic Emulsifying Wax
DEFINITION
DEFINITION Emulsifying Wax contains Cetostearyl Alcohol and either
Edrophonium Injection 1 Sodium Lauryl Sulfate or sodium salts of similar sulfated
Chloride in Water for Injec higher primary aliphatic alcohols.
The injection complies with the Extemporaneous preparation
Parenteral Preparations and with the féllowigg requirements. The following formula and directions apply.
Content of edrophonium chloride, ‘ Cetostearyl Alcohol 90 g
95.0 to 105.0% of the stated amount. Sodium Lauryl Sulfate 10g
IDENTIFICATION : Purified Water 4mL
A. Dilute a sufficient volume of the injection with Melt the Cetostearyl Alcohol and heat to about 95°. Add the
0.1m sodium hydroxide to give a solution containing Sodium Lauryl Sulfate, mix, add the Purified Water, heat to
0.001% w/v of Edrophonium Chloride. The light absorpi 115° and maintain at this temperature, stirring vigorously,
the resulting solution, Appendix II B, in the range 220 to’. i. frothing ceases and the product is translucent. Cool
350 nm exhibits two maxima, at 240 nm and 294 nm. The
absorbances at the maxima are about 1.1 and about 0.34 CTERISTICS
respectively.
white or pale yellow, waxy solid or flakes,
B. To a volume containing 20 mg of Edrophonium Chloride plastic when warmed.
add 0.05 mL of iron(am) chloride solution R1. A reddish violet
colour is produced.
C. Yields reaction A characteristic of chlorides, Appendix VI.
TESTS A. Melting point of jue obtained in the test for
Acidity Unsaponifiable matté ut 52°, Appendix V A.
B. Complies with the
Dimethylaminophenol
To a volume containing 50 mg of Edrophonium Chloride
TESTS
add 10 mL of phosphate buffer pH 8.0 and extract with two
Acidity
20 mL quantities of chloroform. Wash the extracts successively
with two 10 mL quantities of water, extract with 10 mL of
0.1m sodium hydroxide and discard the chloroform. The
absorbance of the resulting solution at 293 nm is not more
than 0.125, Appendix II B.
at least 15 seconds is obtained. Not more than 0 mL of
ASSAY 0.1m sodium hydroxide VS is required.
To a volume containing 50 mg of Edrophontum Chloride
Alkalinity
add sufficient water to produce 100 mL. Dilute 10 mL of this
Disperse 5.0 g in 25 mL of warm ethanol (96%) previously
solution to 100 mL with water and measure the absorbance of
neutralised to phenolphthalein solution R1 and cool. No colour
is produced on the addition of 0.5 mL of phenolphthalein
Appendix IT B. Calculate the content of CjpH ,.CINO taking
solution R1.
110 as the value of A (1%, 1 cm) at the maximum at
273 nm. Alcohols
To 3.5 g of the residue obtained in the test for
STORAGE Unsaponifiable matter add 12 g of stearic anhydride and
Edrophonium Injection should be protected from light. 10 mL of xylene and heat gently under a reflux condenser for
30 minutes. Cool, add a mixture of 40 mL of pyridine and
waa
4 mL of water, heat under a reflux condenser for a further
30 minutes and titrate the hot solution with 1M sodium
~
SS yan
hydroxide VS using phenolphthalein solution R1 as indicator.

van
WI-514 Enalapril Preparations 2016
Repeat the operation without the residue. The difference B. In the Assay, the retention time of the principal peak in
between the titrations is 12.8 to 14.2 mL. the chromatogram obtained with solution (1) corresponds to
Iodine value that of the principal peak in the chromatogram obtained with
Not more than 3.0 (iodine monochloride method), solution (2).
Appendix X E. TESTS
Saponification value Dissolution
Not more than 2.0, Appendix X G. Use 20 g. Comply with the requirements for Monographs of the British
Sodium alkyl sulfates
Not less than 8.7%, calculated as C;.H.50,SNa with
900 mL of water and rotate the paddle at 50 revolutions per
reference to the anhydrous substance, when determined by
minute. Withdraw a sample of 20 mL of the medium and
the following method. Dissolve 0.25 g as completely as
filter, discarding the first 10 mL of filtrate. Carry out the
method for liquid chromatography, Appendix III D, using the
and 1 mL of dimethyl yellow and oracet blue
following solutions. For solution (1) use the filtered
with 0.004m benzethonium chloride VS,
dissolution medium diluted, if necessary, to produce a
llowing the layers to separate after
solution expected to contain about 0.00028% w/v of
Enalapril Maleate. Solution (2) contains 0.00028% w/v of
Each mL of
enalapril maleate BPCRS in water.
0.004m benzethonium chioride.VS.is equivalent to 1.154 mg of
C12H250.,SNa. The chromatographic procedure described under Related
Sulfated ash
1.8 to 3.3%, Appendix IX A. S Calculate the total content of enalapril maleate,
C49H2gN205,C4,H4O,, in the medium using the declared
Unsaponifiable matter
content of C40H28N205,C4H4O, in enalapril maleate BPCRS.
Not less than 86.0%, calculated with refe
anhydrous substance, Appendix X H. Use. Related substances
titration of the residue. Carry out the method for liquid chromatography,
Water
immediately before use. Dissolve 0.136 g of potassium
Not more than 4.0% w/w, Appendix IX C. Use 0.6 ,
dihydrogen orthophosphate in 800 mL of water, adjust the pH
of the solution to 2.0 with orthophosphoric acid, add sufficient
ater to produce 1000 mL and filter through a 0.45 um filter
Enalapril Tablets tablets containing 50 mg of Enalapril Maleate with

Solution A for 15 minutes, centrifuge and use the
Action and use atant liquid (if necessary, filter through a
Angiotensin converting enzyme inhibitor. brane filter). For solution (2) dilute 1 volume
DEFINITION
Enalapril Tablets contain Enalapril Maleate.
Content of enalapril maleate, C,)>H23N,0;,C4,H404 0.01% wiv solution of
95.0 to 105.0% of the stated amount. Solution A (solution C
For solution (5) mix 1 volur
IDENTIFICATION
Appendix III A, using a TLC silica gel plate (Merck silica gel
(a) a stainless steel column (25 cm
60 HPTLC plates are suitable) and a mixture of 15 volumes
octadecylsilyl silica gel for chromatography
of glacial acetic acid, 25 volumes of water and 60 volumes of
butan-I-ol as the mobile phase. Apply separately to the plate
phase with a flow rate of 1 mL per minute a m
5 uL of each of the following solutions. For solution (1)
40 volumes of acetonitrile and 60 volumes of solutien A and
shake a quantity of the powdered tablets containing 20 mg of
Enalapril Maleate with 10 mL of ethanol (90%) for
10 minutes, centrifuge and use the clear supernatant liquid
Gif necessary, filter through a 0.45 im membrane filter).
to enalaprilat and enalapril diketopiperazine is at least 3.0
Solution (2) contains 0.2% w/v of enalapril maleate BPCRS in
and the resolution factor between the peaks due to enalapril
ethanol (90%). After removal of the plate, allow it to dry in
diketopiperazine and enalapril is at least 2.0. If necessary,
air, spray with a solution prepared by mixing equal volumes
adjust the ratio of the components of the mobile phase.
of a 40% w/v solution of potassium todide in water and a
solution prepared by dissolving 0.85 g of bismuth oxynitrate in In the chromatogram obtained with solution (1) the area of
a mixture of 10 mL of glacial acetic acid and 40 mL of water any peak corresponding to enalaprilat is not greater than the
and diluting 10 volumes of the mixture with 20 volumes of area of the principal peak in the chromatogram obtained with
glacial acetic acid and 70 volumes of water immediately before solution (3) (1.5%), the area of any peak corresponding to
use, then spray with dilute hydrogen peroxide solution. enalapril diketopiperazine is not greater than the area of the
084 The principal spot in the chromatogram obtained with principal peak in the chromatogram obtained with solution
oe solution (1) is similar in position, colour and size to that in (4) (0.5%), the area of any other secondary peak is not greater
mee the chromatogram obtained with solution (2). than 1.5 times the area of the principal peak in the
2016 Enoxaparin Sodium Preparations ITII-515
chromatogram obtained with solution (2) (0.3%) and the IDENTIFICATION

sum of the areas of any secondary peaks other than any peak A. Carry out the method for szze-exclusion chromatography,
corresponding to enalaprilat or enalapril diketopiperazine is Appendix III C, using the following solutions in the mobile
not greater than 5 times the area of the principal peak in the phase.
chromatogram obtained with solution (2) (1%). (1) Dilute the injection to contain 1000 IU of anti-factor Xa
ASSAY per mL.
Weigh and powder 20 tablets. Carry out the method for (2) 1% w/v of heparin low-molecular-mass for
hquid chromatography, Appendix III D, using the following calibration EPCRS.
solutions. Dissolve 0.136 g of potassium dihydrogen CHROMATOGRAPHIC CONDITIONS
orthophosphate in 800 mL of water, adjust the pH of the
(a) Use a column (30 cm x 7.5 mm) packed with
solution to 2.0 with orthophosphoric acid, add sufficient water
appropriate porous silica beads (5 um) with a fractionation
to pr dtice 1000 mL and filter through a 0.45 um filter
range for proteins of approximately 15 000 to 100 000
) solution (1) shake a quantity of the
(Waters Protein-Pak is suitable).
containing 10 mg of Enalapril Maleate with
below.
(e) For detection use a differential refractometer (RI)
detector connected 1n series to an ultraviolet
spectrophotometer (UV) set at 234 nm such that the UV
and 1 volume of solution ( ) monitor is connected to the column outlet and the RI
solution (1). detector to the UV-monitor outlet. It is necessary to measure
The chromatographic proceduredescri a the time lapse between the 2 detectors accurately so that
substances may be used. . their chromatograms can be aligned correctly. The retention
The test is not valid unless,in the chromat times used in the calibration must be those from the RI
with solution (5), the resolution factor between¢ detector.
to enalaprilat and enalapril diketopiperazine is at: (f) Inject 25 uwL of each solution.
and the resolution factor between the peaks due to eng The normalisation factor used to calculate the relative
diketopiperazine and enalaprilis at least 2.0. If necessa molecular mass from the RI/UV ratio is obtained as follows.
adjust the ratio of the components of the mobile phase culate the total area under the UV234 ()UV234) and the
Calculate the content of C29H».3N,05,C,H4O, in the table ) curves by numerical integration over the range of
using the declared content of C29H23N205,C,H4O, in
enalapril maleate BPCRS.
STORAGE
Enalapril Tablets should be protected from light and
moisture.
Enoxaparin Sodium Injection

Action and use
Low molecular weight heparin.
DEFINITION
Enoxaparin Sodium Injection isa sterile solution of
Enoxaparin Sodium in Water for Injections. It may contain,
Ss in multidose containers, a suitable antimicrobial preservative.
wo Mna = assigned number-average relative molectilar mass of
Se PRODUCTION the heparin low-molecular-mass for calibration EPCRS
es The final product is produced by methods of manufacturing found in the leaflet supplied with the EPCRS.
24 designed to ensure that substances lowering blood pressure Provided the UVs34 and the RI responses are aligned, the
ES are not introduced and to ensure freedom from i,
eat Ne
Brass - relative molecular mass M at any point is calculated using the

Se contamination by over-sulfated glycosaminoglycans.
oe oo a following expression:
Activity f RI
The estimated activity for anti-factor Xa is not less than 90% UV
and not more than 110% of the stated activity. 234
The ratio of anti-factor Xa to anti-factor IIa is not less than
3.3 and not more than 5.3. The resulting table of retention times and relative molecular
masses may be used to derive a calibration curve for the
chromatographic system by fitting a suitable mathematical
relationship to the data. A polynomial of the 3° degree is
IWI-516 Enoxaparin Sodium Preparations 2016
recommended. It must be stressed that the extrapolation of this The International Units for anti-Xa and anti-IIa activity are
eerie d
fitted calibration curve to higher molecular masses 1s not valid. the activities contained in a stated amount of the
syed
ea we 4 Inject 25 wL of the test solution and record the International Standard for low-molecular-mass heparin.
rane d
chromatogram for a period of time, ensuring complete Heparin low-molecular-mass for assay EPBRP, calibrated in
elution of sample and solvent peaks. International Units by comparison with the International
The mass-average relative molecular mass is defined by the Standard using the two assays given below, is used as the
following expression: reference preparation.
For anti-factor Xa activity
Test solutions (1) to (4) Prepare a series of 4 independent
> (RLM) dilutions of the injection being examined in tris-chloride buffer
pH 7.4; the concentration range of the solutions should be
>I. within 0.025 IU to 0.2 IU of anti-factor Xa activity per mL
and the dilutions chosen should give a linear response when
results are plotted as absorbance against log concentration.
Reference solutions (1) to (4) Preparea series of 4 dilutions of
the reference preparation of low-molecular-mass heparin in
tris-chloride buffer pH 7.4; the concentration range of the
solutions should be within 0.025 IU to 0.2 IU of anti-factor
Xa activity per mL and the dilutions chosen should give a
pH 5.0 with dilute sulfuric a linear response when results are plotted as absorbance against
SYSTEM SUITABILITY
log concentration.
The test is not valid unless, in tt am obtained Label 16 tubes in duplicate: T1, T2, T3, T4 for the dilutions
with solution (2), the column efficiency t least 20 000 of the injection being examined and R1, R2, R3, R4 for the
theoretical plates per metre. dilutions of the reference preparation. To each tube add
50 uL of anuthrombin IT solution R1 and 50 uL of the
CONFIRMATION appropriate dilution of the injection being examined, or the
The mass-average relative molecular mass ranges reference preparation. After each addition, mix but do not
3800 and 5000. The mass percentage of chains low allow bubbles to form. Treating the tubes in the
2000 is between 12.0 and 20.0%. The mass percentageof - order R1, R2, R3, R4, T1, T2, T3, 14, T1, T2, T3,
chains between 2000 and 8000 ranges between 68.0 and. . 14, R1, R2, R3, R4, allow to equilibrate at 37° Gin a water-
82.0%. heating block) for 1 minute and add to each tube
B. The ratio of anti-factor Xa activity to anti-factor Ila f bovine factor Xa solution. Incubate for exactly
activity, determined as described under Assay, is not less nd add 250 uL of chromophore substrate R1. Stop
than 3.3 and not more than 5.3. 1 after exactly 4 minutes by adding 375 uL of
C. Yields reaction A characteristic of sodium salts, ‘Transfer the mixtures to semi-micro cuvettes and
Appendix VI. sudsorbance at 405 nm, Appendix II B, using a
TESTS f g and at the end of the procedure in a

Clarity and colour of solution 2 -chloride buffer pH 7.4 in place of the
The solution is clear, Appendix IV A, and not more intensely
coloured than reference solution Y4 or BY, Appendix IV B,
Method II.
ee
Light absorption
The light absorption, Appendix II B, of a solution containing activity per mL using the usual stati
the total contents of a single dose container, or 0.4 mL from parallel-line assays.
a multi-dose container, diluted to 100.0 mL with a solution For anti-factor Ia activity
of 0.01m hydrochloric acid exhibits a maximum at 231 nm. Test solutions (1) to (4) Preparea series of 4<
Sodium dilutions of the injection being examined in tns#
10.2 to 16.9% of Enoxaparin Sodium, when determined by pH 7.4; the concentration range should be within 6.015 IU
atomic absorption spectrophotometry, Appendix II D Method I. to 0.075 IU of anti-factor Ila activity per mL and the
For the purposes of this test, assume that 100 IU of anti- dilutions chosen should give a linear response when results
factor Xa is equivalent to 1 mg of Enoxaparin Sodium. are plotted as absorbance against log concentration.
Reference solutions (1) to (4) Prepare a series of 4 independent
dilutions of the reference preparation of low-molecular-mass
heparin in tris-chloride buffer pH 7.4; the concentration range
The endotoxin limit concentration is less than 0.01 IU per
should be within 0.015 IU to 0.075 IU of anti-factor Ia
International Unit of anti-Xa activity.
activity per mL and the dilutions chosen should give a linear
ASSAY response when results are plotted as absorbance against log
The anticoagulant activity of low-molecular-mass heparins is concentration.
determined in vitro by two assays which determine its ability Label 16 tubes in duplicate: T1, T2, T3, T4 for the dilutions
to accelerate the inhibition of factor Xa (anti-Xa assay) and of the injection being examined and R1, R2, R3, R4 for the
at nw thrombin, factor IIa (anti-IIa assay), by antithrombin III. dilutions of the reference preparation. To each tube add
50 wL of antithrombin II solution R2 and 50 uL of the
2016 Ephedrine Preparations TII-517
appropriate dilution of the injection being examined or the (1) Add sufficient 5m ammonia to 50 mL of the elixir to
reference preparation. After each addition, mix but do not make it alkaline, extract with two 100-mL quantities of ether,
AN A
allow bubbles to form. Treating the tubes in the wash the combined extracts with 10 mL of water, dry with
order R1, R2, R3, R4, T1, 12, 13, T4, T1, T2, 13, anhydrous sodium sulfate, filter and evaporate the filtrate to
T4, Rl, R2, R3, R4, allow to equilibrate at 37° Gin a water- dryness. Dissolve the oily residue in sufficient methanol to
bath or heating block) for 1 minute and add to each tube produce 5 mL.
100 pL of human thrombin solution. Incubate for exactly (2) Dilute 1 volume of solution (1) to 10 volumes with
1 minute and add 250 uL of chromophore substrate R2. Stop methanol.
the reaction after exactly 4 minutes by adding 375 uL of
acetic acid. Transfer the mixtures to semi-micro cuvettes and
methanol.
measure the absorbance at 405 nm, Appendix II B, using a
gseading device. Determine the blank amidolytic (4) 0.30% w/v of ephedrine hydrochloride BPCRS in methanol.
ising trs-chloride buffer pH 7.4 in place of the
NaN all
solutions; the 2 blank values do not differ suitable).
significantly e the regression of the absorbance on (b) Use the mobile phase as described below.
log concentrati
being examined in Intern: Jnits of anti-factor Ila (e) After removal of the plate, allow it to dry in air, spray
activity per mL using the tistical methods for with ninhydrin solution and heat at 100° for 5 minutes.
parallel-line assays. » MOBILE PHASE
LABELLING 5 volumes of chloroform, 15 volumes of 13.5M ammonia and
The label states the number of IU (Uni ti-factor Xa 80 volumes of propan-2-ol.
per unit volume.
LIMITS

chromatogram obtained with solution (3). Disregard any spot
Ephedrine Elixir of lighter colour than the background.
Ephedrine Oral Solution ASSAY
‘yout the method for liquid chromatography,
Action and use endix III D, using the following solutions.
Adrenoceptor agonist.
a weighed quantity of the elixir containing 60 mg
DEFINITION ne Hydrochloride to 50 mL with methanol (65%).
Ephedrine Elixir is an oral solution containing 0.3% w/v of
Ephedrine Hydrochloride in a suitable flavoured vehicle
containing a sufficient volume of Ethanol (96%) or of an
appropriate Dilute Ethanol to give a final concentration of
12% v/v of ethanol.
The ehxir comphes with the requirements stated under Oral (b) Use isocratic elut
Liquids and with the following requirements. below.
Content of ephedrine hydrochloride, C,;>)H,;NO,HCI (c) Use a flow rate of 1.5
0.27 to 0.33% wiv.
(d) Use an ambient column temg
IDENTIFICATION (e) Use a detection wavelength O
A. To 30 mL of the elixir add 2 mL of 2m hydrochlonc acid, (f) Inject 20 uL of each solution.
extract with two 20-mL quantities of ether and discard the
MOBILE PHASE
ether. Add sufficient 5M ammonia to the aqueous phase to
make it alkaline, extract with two 30-mL quantities of ether, 0.005m dioctyl sodium sulfosuccinate in a mixtute off volume
wash the combined ether extracts with three 15-mL lumes of
quantities of water, dry with anhydrous sodium sulfate, filter methanol.
and evaporate the filtrate to dryness. The infrared absorption DETERMINATION OF CONTENT
Determine the weight per mL of the elixir, Appendix V G,
the reference spectrum of ephedrine (RS 121).
afore
‘awe al
and calculate the content of C;)>)H,;NO,HC1, weight in

B. In the test for Related substances, the principal spot in the volume, using the declared content of C;j>H,;5;NO,HCI in
chromatogram obtained with solution (2) corresponds to that ephedrine hydrochloride BPCRS.
TESTS
Ethanol content
Related substances
etn!
a Carry out the method for thin-layer chromatography,
II-518 Ephedrine Preparations 2016
vpn wd
Ephedrine Injection MOBILE PHASE

solution of ammonium acetate adjusted to pH 4.0 using glacial
i
Action and use

Adrenoceptor agonist; reversal of hypotension from spinal or acetic acid.
epidural anaesthesia. SYSTEM SUITABILITY

DEFINITION
Ephedrine Injection is a sterile solution of Ephedrine
to ephedrine and pseudoephedrine is at least 2.0.
Hydrochloride. It is supplied as a ready-to-use solution in
Water for Injections or it is prepared immediately before use LIMITS
in accordance with the manufacturer’s instructions from In the chromatogram obtained with solution (1):
ine Concentrate. the area of any secondary peak is not greater than the area of
LAWA
esquith the requirements stated under the principal peak in the chromatogram obtained with
s and with the following requirements. solution (2) (0.2%);
Content of ephedri obtained with solution (2) (0.5%).
95.0 to 105.0% of the Disregard any peak with an area less than the area of the
IDENTIFICATION
(4) (0.02%).
ASSAY
eared
dichloromethane. Add 5m ammonia uritil Appendix III D, using the following solutions.
alkaline, extract with two 30-mL quantities (1) Dilute the injection with methanol (80%) to produce a
3 volumes of dichloromethane and 1 volume 6 solution containing 0.1% w/v of Ephedrine Hydrochloride.
(2) 0.1% w/v of ephedrine hydrochloride BPCRS in methanol
evaporate to dryness at a pressure of 2 kPa, heating gé (65%).
remove the last traces of solvent. The infrared absorptioné
spectrum of the residue, Appendix II A, is concordant wi
the reference spectrum of ephedrine hydrochloride (RS 436) (a) Use a stainless steel column (20 cm x 4.6 mm) packed
ad-capped octadecylsilylsilica get for chromatography
TESTS
Related substances
(1) Dilute a volume of the injection, if necessary, with
sufficient of the mobile phase to produce a solution
containing 0.75% w/v of Ephedrine Hydrochloride. MOBILE PHASE
(2) Dilute 1 volume of solution (1) to 500 volumes with 0.005m dioctyl sodium sulfes dte in a mixture of 1 volume
mobile phase. | of glacial acetic acid, 35 vol es @f water and 65 volumes of
(3) 0.01% w/v of ephedrine hydrochloride BPCRS and methanol.
0.01% wv of pseudoephedrine hydrochlonde BPCRS in mobile DETERMINATION OF CONTENT
phase.
Calculate the content of C;>)H,;5NO;H¢ i injection
(4) Dilute 1 volume of solution (2) to 10 volumes with using the declared content of C)gH,5N HCI
mobile phase. hydrochloride BPCRS.
(a) Use a stainless steel column (15 cm x 4.6 mm) packed STERILE EPHEDRINE CONCENTRATE
with particles of silica the surface of which has been modified
by chemically bonded phenyl groups (5 um) (Spherisorb DEFINITION
Phenyl] is suitable). Sterile Ephedrine Concentrate is a sterile solution of
Ephedrine Hydrochloride in Water for Injections.
below. The concentrate complies with the requirements for Concentrates
for Injections or Infusions stated under Parenteral Preparations
Content of ephedrine hydrochloride, C,;9H,;NO,HC1
IDENTIFICATION
(g) Allow the chromatography to proceed for three times the
To a quantity of the concentrate containing 10 mg of
retention time of the peak due to Ephedrine.
Ephedrine Hydrochloride add 2 mL of 2m hydrochloric acid,
Under the prescribed conditions, the retention time of shake with two 20-mL quantities of dichloromethane and
ephedrine is about 13 minutes and the retention time of discard the dichloromethane. Add 5M ammonia until the
pseudoephedrine is about 16 minutes.
2016 Ephedrine Preparations III-519
Lt fo ee,
aqueous layer is alkaline, extract with two 30-mL quantities the plate, allow it to dry in air, spray with ninhydrin solution
‘
of a mixture of 3 volumes of dichloromethane and 1 volume of and heat at 100° for 5 minutes. Any secondary spot in the
ees veo be
ethanol, dry the combined extracts over anhydrous sodium chromatogram obtained with solution (1) is not more intense
sulfate, filter and evaporate to dryness at a pressure of 2 kPa, than the spot in the chromatogram obtained with solution
heating gently to remove the last traces of solvent. (3). Disregard any spot of lighter colour than the background
The infrared absorption spectrum of the residue, Appendix II A, and any spot remaining on the line of application.
is concordant with the reference spectrum of ephedrine
ASSAY
TESTS Appendix III D, using the following solutions. Solution (1) is
Acidity a 0.1% w/v solution of ephedrine hydrochloride BPCRS in
pH, 4.5 to 7.0, Appendix V L. methanol (65%). For solution (2) dilute the nasal drops with
methanol (80%) to contain 0.1% w/v of Ephedrine
Hydrochloride.
end-capped octadecylsilyl silica gel for chromatography (10 pm)
(Nucleosil C18 is suitable), (b) 0.005m dioctyl sodium
sulfosuccinate in a mixture of 65 volumes of methanol,
35 volumes of water and 1 volume of glacial acetic acid as the
mobile phase with a flow rate of 2 mL per minute and (c) a
Ephedrine Nasal Dr Calculate the content of C;)>H,;;NO,HCI in the nasal drops

using the declared content of C;>H,;5;5NO,HCI in ephedrine
Action and use hydrochloride BPCRS.
Adrenoceptor agonist. When ephedrine nasal drops are prescribed or demanded no
strength being stated, nasal drops containing 0.5% w/v of
DEFINITION &
ephedrine hydrochloride shall be dispensed or supplied.
Ephedrine Nasal Drops are a solution of Ephedry
Hydrochloride in a suitable aqueous vehicle.
,
The nasal drops comply with the requirements stated undersN
Content of ephedrine hydrochloride, C,j>H,;NO,HC1 1edrine Hydrochloride Tablets
IDENTIFICATION
A. To a quantity of the nasal drops containing 0.1 g of
Ephedrine Hydrochloride add 2 mL of 2m hydrochloric acid,
shake with two 20 mL quantities of chloroform and discard
the chloroform. Add 5m ammonia until the aqueous layer is
alkaline, extract with two 30 mL quantities of a mixture of
3 volumes of chloroform and 1 volume of ethanol, dry the
combined extracts over anhydrous sodium sulfate, filter and
rae ad
Ven esd evaporate to dryness at a pressure of 2 kPa, heating gently to 92.5 to 107.5%ofthe s :
Foes
remove the last traces of solvent. The infrared absorption
Tete ete
Sony -
spectrum of the residue, Appendix II A, is concordant with IDENTIFICATION

the reference spectrum of ephedrine (RS 121).
B. In the test for Related substances, the principal spot in the Ephedrine Hydrochloride with 20%
chromatogram obtained with solution (2) corresponds to that acid, filter, wash the filtrate with two
in the chromatogram obtained with solution (4). chloroform and discard the chloroform. Mak
layer alkaline with 5M ammonia and extract
TESTS
Acidity or alkalinity 1 volume of ethanol (96%). Dry the combined extracts over
pH, 4.0 to 7.0, Appendix V L. anhydrous sodium sulfate, filter and evaporate to a low volume
zai’
wn
Related substances at a pressure of 2 kPa. Prepare a disc using 0.3 g of potassium
Carry out the method for thin-layer chromatography, bromide, apply the chloroform solution to the surface of the
Appendix III A, usinga silica gel precoated plate (Merck disc and heat at 50° for 2 minutes. The infrared absorption
silica gel 60 plates are suitable) and a mixture of 80 volumes spectrum, Appendix II A, is concordant with the reference
of propan-2-ol, 15 volumes of 13.5M ammonia and 5 volumes spectrum of ephedrine (RS 121).
of chloroform as the mobile phase. Apply separately to the B. In the test for Related substances, the principal spot in the
plate 20 uwL of each of the following solutions. For solution chromatogram obtained with solution (2) corresponds to that
(1) use the nasal drops diluted, if necessary, with water to in the chromatogram obtained with solution (3).
contain 0.5% w/v of Ephedrine Hydrochloride. For solution C. Triturate a quantity of the powdered tablets containing
(2) dilute 1 volume of solution (1) to 5 volumes with 0.4 g of Ephedrine Hydrochloride with two 10 mL quantities
ae ae
methanol. For solution (3) dilute 1 volume of solution (1) to of chloroform and discard the chloroform. Macerate the
a a
200 volumes with water. Solution (4) contains 0.1% w/v of

ee
residue with 30 mL of warm ethanol (96%) for 20 minutes,

wm we
we
ephedrine hydrochloride BPCRS in methanol. After removal of

wae
filter, evaporate the filtrate to dryness on a water bath and

IW-520 Epirubicin Preparations 2016
dry the residue at 80°. Dissolve 10 mg of the residue in

1 mL of water and add 0.1 mL of weak copper sulfate solution
Epirubicin Injection
ee)
followed by 1 mL of 5M sodium hydroxide; a violet colour is Action and use

ea et produced. Add 1 mL of ether and shake; the ether layer is Anthracycline antibacterial; cytostatic.
purple and the aqueous layer is blue.
Carry out the method for thin-layer chromatography, Epirubicin Injection is a sterile solution of Epirubicin
Appendix IIT A, using the following solutions. Hydrochloride in Water for Injections.
(1) Extract a quantity of the powdered tablets containing The injection complies with the requirements stated under
0.10 g of Ephedrine Hydrochloride with 5 mL of methanol, Parenteral Preparations and with the following requirements.
filter and use the filtrate. Content of epirubicin hydrochloride, C,,H,.NO,,;,HCl
area
vans 4
IDENTIFICATION
A. Dilute a volume of the injection containing 10 mg of
(4) Dilute 1 vok Epirubicin Hydrochloride to 100 mL with water and further
methanol. dilute 5 mL to 50 mL with water. The light absorption of the
resulting solution, Appendix II B, in the range 220 to
350 nm exhibits three maxima at 233, 253 and 292 nm.
(b) Use the mobile phase a below.
(c) Apply 10 uL of each solu that of the principal peak in the chromatogram obtained with
(d) Develop the plate to 15 cm solution (2).
(e) After removal of the plate, allow it« TESTS
with ninhydrin solution and heat at 110° fe
Acidity
MOBILE PHASE pH, 2.5 to 4.0, Appendix V L.
5 volumes of chloroform, 15 volumes of 13.5m am Related substances
80 volumes of propan-2-ol. Carry out the method for liquid chromatography,
LIMITS Appendix III D, using the following solutions. Allow the
Any secondary spot in the chromatogram obtained with olutions to stand for 3 hours before use.
solution (1) is not more intense than the spot in the te a volume of the injection with sufficient of the
chromatogram obtained with solution (4). Disregard any spot | se to produce a solution containing 0.1% w/v of
of lighter colour than the background. Hydrochloride.
ASSAY
liquid chromatography, Appendix III D, using the following ach of doxorubicin hydrochloride BPCRS
solutions.
(1) Shake a quantity of the powdered tablets containing (4) Dissolve 10 meg xorubicin hydrochloride BPCRS in a
50 mg of Ephedrine Hydrochloride with 30 mL of methanol mixture of 5 mLo 5 mL of orthophosphoric acid
for 10 minutes, add sufficient water to produce 50 mL, filter and allow to stand for $0 minutes. Adjust the pH of the
through glass-fibre paper (Whatman GF/C is suitable) and solution to 2.6 with an 8: ‘sealution of sodium hydroxide,
use the filtrate. add 15 mL of acetomtrile ang 10 mL of methanol and mix
(generation of impurity A). °
(2) 0.1% w/v of ephedrine hydrochloride BPCRS in
methanol (60%). CHROMATOGRAPHIC CONDITIONS
CHROMATOGRAPHIC CONDITIONS (a) Use a stainless steel column (25 ‘era -6.mm) packed
with trimethylsilyl silica gel for chromatography (é
TMS is suitable).
(10 um) CNucleosil C18 is suitable) (b) Use isocratic elution and the mobile phase d
below. :
below. (c) Use a flow rate of 2.5 mL per minute.
(c) Use a flow rate of 2 mL per minute. (d) Use a column temperature of 35°.
aw ead (d) Use an ambient column temperature. (e) Use a detection wavelength of 254 nm.
A AN
(e) Use a detection wavelength of 263 nm. (f) Inject 10 uwL of each solution.
(f) Inject 20 wL of each solution. (g) For solution (1), allow the chromatography to proceed
for 3.5 times the retention time of epirubicin.
MOBILE PHASE
MOBILE PHASE
0.005m dioctyl sodium sulfosuccinate in a mixture of 1 volume
of glacial acetic acid, 35 volumes of water and 65 volumes of 17 volumes of methanol, 29 volumes of acetonitrile and
methanol. 54 volumes of a solution containing 0.37% w/v of sodium
dodecyl sulfate and 2.8% v/v of 1M orthophosphonic acid.
Calculate the content of Cyy~H,;NO,HCI using the declared
conditions the retention times relative to epirubicin (retention
content of C;9H,;NO,HCI1 in ephedrine hydrochlonde BPCRS.
time about 9.5 minutes) are: impurity A, about 0.3;
2016 Ergocalciferol Preparations TT-521
impurity B, about 0.4; impurity C, about 0.8; impurity E, SYSTEM SUITABILITY

about 1.1; impurity D, about 1.5; impurity F, about 1.7; The test is not valid unless, in the chromatogram obtained
impurity G, about 2.1. with solution (3), the resolution factor between the peaks due
SYSTEM SUITABILITY to doxorubicin and epirubicin is at least 2.0.
The test is not valid unless, in the chromatogram obtained DETERMINATION OF CONTENT
with solution (3), the resolution factor between the peaks due Calculate the content of C27H»,NO,,,HCI in the injection
to doxorubicin and epirubicin is at least 2.0. using the declared content of C,7H29NO,;,HCI in epirubicin
LIMITS hydrochloride BPCRS.
Identify any peak in the chromatogram obtained with STORAGE
solution (1) corresponding to impurity A using the second Kpirubicin Injection should be stored at a temperature of 2°
most abundant peak 1in the chromatogram obtained with to 8°.
IMPURITIES
rection factor: 0.7.
eran

m obtained with solution (1): monograph include those listed under Epirubicin
corresponding to impurity A Hydrochloride.
(doxorubicin) is not greater Ergocalciferol Injection

peakin the chromatogram «
Action and use
greater than
tA ws
Vitamin D analogue (Vitamin D,).

chromatogram
DEFINITION
Ergocalciferol Injection is a sterile solution of Ergocalciferol
in Ethyl Oleate.
of the principal peakin the chromatogram obtained wi Content of ergocalciferol, C;3;H,,O
solution (2) (0.05%). to 110.0% of the stated amount.
CHARACTERISTICS
Carry out the test for bacterial endotoxins, Appendix XIV C
less to pale yellow, oily liquid.
Dilute the injection, if necessary, with water BET to give a
solution containing 2 mg per mL of Epirubicin FICATION
Hydrochloride (solution A). The endotoxin limit | 0.2% v/v solution of the injection in ethanol-
concentration of solution A is not more than 2.2 IU per mL. &mL of antimony trichloride solution. The
resulting solution, Appendix II B,
ASSAY
a at 500 nm.
Appendix III D, using the following solutions. Allow the
solutions to stand for 3 hours before use.
wen ae
(1) Dilute a volume of the injection with sufficient of the
mobile phase to produce a solution containing 0.1% w/v of
Epirubicin Hydrochloride.
trichloride in dichloroethane soluti
(2) 0.1% w/v of epirubicin hydrochloride BPCRS in the mobile
of the solution at 500 and 550
phase.
(3) 0.01% w/v of each of doxorubicin hydrochloride BPCRS
and epirubicin hydrochlonde BPCRS in the mobile phase.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed Calculate the result of the assay from the difference between
with trimethylsilyl silica gel for chromatography (6 um) (Zorbax the absorbances at 500 and 550 nm and using the declared
wenn
TMS is suitable). content of Cz3H4,O in ergocalciferol BPCRS. Calculate the
percentage w/v of ergocalciferol taking 0.87 g as the value of
below. the weight per mL of the injection.
STORAGE
ale ete

(d) Use a column temperature of 35°. Ergocalciferol Injection should be protected from light.
(e) Use a detection wavelength of 254 nm. LABELLING
(f) Inject 10 pL of each solution. The label states (1) that the preparation is for intramuscular
use only; (2) the equivalent number of IU (units) of
MOBILE PHASE
antirachitic activity (vitamin D) in I mL.
Each pg of ergocalciferol is equivalent to 40 IU of
54 volumes of a solution containing 0.37% w/v of sodium
dodecyl sulfate and 2.8% v/v of 1M orthophosphoric acid.
IW-522 Ergocalciferol Preparations 2016
When calciferol injection is prescribed or demanded, deflection. Repeat the operation using solution (2) and
Colecalciferol Injection or Ergocalciferol Injection shall be injecting the same volume.
dispensed or supplied. MOBILE PHASE
8 volumes of pentan-1-ol and 992 volumes of hexane.

SYSTEM SUITABILITY
Inject 20 uL of solution (3) and record the chromatogram
Ergocalciferol Tablets using a sensitivity such that the height of the peak due to
colecalciferol is more than 50% of full-scale deflection. When
Action and use
the chromatogram is recorded under the prescribed
Vitamin D analogue (Vitamin D2).
conditions, approximate retention times relative to
DEFINITION colecalciferol are 0.4 for precolecalciferol and 0.5 for trans-
colecalciferol. The test is not valid unless the resolution factor
contain Ergocalciferol.
tan oa between the peaks corresponding to precolecalciferol and
1 the requirements stated under Tablets and
twee
trans-colecalciferol is at least 1.0. If necessary, adjust the

proportions of the constituents and the flow rate of the
mobile phase to obtain this resolution.
Calculate the content of ergocalciferol, C.3H,,O, in each
tablet using the declared content of C2gH4,O in
obtained with solution (2) sk ergocalciferol BPCRS and using peak heights.
retention time as the principal e chromatogram
ASSAY
B. Extract one tablet, in powder, with §°m
2% w/w of Ergocalciferol
dichloromethane, filter and to 1 mL of the fi add 9 mL of
antimony trichloride solution. A brownish red ¢ol
produced. |
For tablets containing 2 mg or more and 2% w/w or
TESTS more of Ergocalciferol
Uniformity of content Carry out the following procedure in subdued light. Weigh
Tablets containing less than 2 mg and/or less than 2% w/ nd powder 25 tablets, or more if necessary. To a quantity of
of Ergocalciferol comply with the requirements stated unde vdered tablets containing 6 mg of Ergocalciferol add
Tablets using the following method of analysis. Carry out the al 6£ ethanol (96%), 14 mL of glycerol and 20 mL of a
following procedure protected from light. Carry out the : solution of potassium hydroxide. Boil under a reflux
method for liquid chromatography, Appendix III D, using the for 30 minutes, swirling occasionally, add 110 mL
(1) 0.001% w/v of ergocalciferol BPCRS in hexane.
(2) For tablets containing more than 0.25 mg of
ergocalciferol prepare the solution in the following manner. range, 40° to‘
Add 4 mL of water to one tablet in an amber flask and 5 mL portions
disperse with the aid of ultrasound. Add 12 mL of dimethyl
sulfoxide, mix, extract with 100 mL of hexane by shaking for
30 minutes, centrifuge the hexane layer and use the clear solution and measure the
supernatant liquid. 500 nm and at 550 nm, 90
For tablets containing 0.25 mg or less carry out the same
procedure but using 2 mL of water, 6 mL of dimethyl sulfoxide
and 25 mL of hexane.
(3) Dissolve 0.5 g of cholecalciferol for performance test EPCRS
in 2 mL of toluene and dilute to 10 mL with the mobile
phase; heat under a reflux condenser in a water bath at 90°
for 45 minutes and cool.
from the amount of ergocalciferol in the reference $
CHROMATOGRAPHIC CONDITIONS using the declared content of Cy,gH4,O in
(a) Use a stainless steel column (20 cm x 4.6 mm) packed ergocalciferol BPCRS.
with silica gel for chromatography (5 um) (Partisil is suitable).
owe any
LABELLING
ed
Tete Nee

wane
The label states the equivalent number of IU (units) of

Aw at
~~ enw!
below. antirachitic activity (vitamin D) per tablet.

(c) Use a flow rate of 2 mL per minute. Each ug of ergocalciferol is equivalent to 40 IU of
(d) Use an ambient column temperature. antirachitic activity (vitamin D).
(e) Use a detection wavelength of 254 nm. When calciferol tablets are prescribed or demanded,
(f) Inject 20 wL of each solution. Colecalciferol Tablets or Ergocalciferol Tablets shall be
Inject a suitable volume of solution (1) and record the
chromatogram using a sensitivity such that the height of the
peak due to ergocalciferol is more than 50% of full-scale
he eG
wor Ro
Me ee
2h ees LA
2016 Ergometrine Preparations III-523
Ergometrine Injection (1) Dilute a suitable volume with sufficient water to produce
a solution containing 0.004% w/v of Ergometrine Maleate.
~ aye?
vatw st
Action and use To 3 mL add 6 mL of dimethylaminobenzaldehyde solution R6,
Oxytocic. mix, cool to room temperature and allow to stand for
30 minutes.
DEFINITION (2) To 3 mL of a 0.004% w/v solution of ergometrine
Ergometrine Injection is a sterile solution of Ergometrine maleate BPCRS add 6 mL of dimethylaminobenzaldehyde
Maleate in Water for Injections. The acidity of the solution is solution R6, mix, cool to room temperature and allow to
adjusted to pH 3 by the addition of maleic acid. stand for 30 minutes.
The injection complies with the requirements stated under Measure the absorbance of solution (2) at the maximum at
Parenteral Preparations and with the following requirements. 545 nm, Appendix IT B, using in the reference cell a solution
prepared by mixing 6 mL of dimethylaminobenzaldehyde
solution R6 and 3 mL of water. Without delay replace solution
(2) with solution (1), using the same cell, and measure the
absorbance of solution (1) at the same wavelength. Calculate
the content of C;9H.3N30,,C,H4O, using the declared
IDENTIFICATIO content of C19H23N302,C4H4O, in ergometrine
A. In the test for Related substances, the principal spot in the maleate BPCRS.
chromatogram obtainéd ‘solution (1) corresponds to that STORAGE
in the chromatogram obta Ergometrine Injection should be protected from light and
B. Exhibits a blue fluoresc stored at a temperature of 2° to 8°.
C. To a volume containing @-1" metrine Maleate,
add 0.5 mL of water and 2 mL of d& thyiaminobenzaldehyde
solution R6. A deep blue colour is prod
5 minutes. Ergometrine and Oxytocin Injection
TESTS
Action and use
Acidity
Oxytocic.
Appendix III A, in subdued light, using the following
solutions in methanol. Protect from light any solutions not n Concentrated Solutionin Water for Injections.
used immediately. dity of the solution is adjusted to pH 3.3 by the
(1) Evaporate a volume of the injection containing 1 mg of n of maleic acid.
Ergometrine Maleate to dryness at 20° at a pressure of 2 kPa
and dissolve the residue in 0.25 mL.
(2) 0.010% w/v of ergometrine maleate BPCRS. rinemaleate, CyeH,-N,0,,C,H.0,
(3) 0.020% w/v of ergometrine maleate BPCRS. : ted amount.
(4) 0.040% w/v of ergometrine maleate BPCRS.
(5) 0.40% w/v of ergometrine maleate BPCRS.
CHROMATOGRAPHIC CONDITIONS CHARACTERISTICS
(a) Use a suspension of sadica gel G in 0.1M sodium hydroxide A colourless solution.
to prepare the plate. IDENTIFICATION
(b) Use the mobile phase as described below. A. In the test for Substances rela etrine, the
(c) Apply 5 pwL of each solution. principal spot in the chromatogram obtas solution
(d) Develop the plate to 15 cm. (1) corresponds to that in the chromatogrg obtained with
solution (2).
ultraviolet light (365 nm). B. To a volume containing 0.1 mg of Ergometrine Maleate,
add 0.5 mL of water and 2 mL of dimethylaminobenzaldehyde
MOBILE PHASE
solution R6. After about 5 minutes a deep blue colour is
10 volumes of methanol and 90 volumes of chloroform. produced.
LIMITS C. In the Assay for oxytocin a peak in the chromatogram
Assess the intensities of any secondary spots in the obtained with solution (2) corresponds to the peak due to
chromatogram obtained with solution (1) by reference to the oxytocin in the chromatogram obtained with solution (1).
spots in the chromatograms obtained with solutions (2), (3) TESTS
and (4). The total of the intensities so assessed does not Acidity
exceed 10% of the intensity of the principal spot. pH, 2.9 to 3.5, Appendix V L.
ASSAY Substances related to ergometrine
Carry out the following procedure protected from light using Carry out in subdued light the method for thin-layer
the following two solutions prepared at the same time. chromatography, Appendix III A, using silica gel G as the
coating substance and a mixture of 75 volumes of chloroform,
25 volumes of methanol and 3 volumes of water as the mobile
II-524 Ergotamine Preparations 2016
phase but allowing the solvent front to ascend 14 cm above STORAGE

the line of application. Apply separately to the plate 5 pL of Ergometrine and Oxytocin Injection should be protected
each of the following solutions. For solution (1) add 10 mL from light and stored at a temperature of 2° to 8°.
of absolute ethanol to a volume of the injection containing
LABELLING
0.5 mg of Ergometrine Maleate and evaporate to dryness at a
The strength with respect to oxytocin is stated as the number
temperature not exceeding 30° at a pressure of 2 kPa; to the
of IU (units) per mL. The label also states the equivalent
residue add 0.2 mL of a mixture of 1 volume of
number of pg of oxytocin per mL.
13.5mM ammonia and 9 volumes of ethanol (80%), mix,
centrifuge and use the supernatant liquid. Solutions (2), (3),
(4), (5) and (6) contain 0.250% w/v, 0.0250% w/v,
0.0125% w/v, 0.0050% w/v and 0.00250% w/v of ergometrine
maleate Bl @RS respectivelyin a mixture of 1 volume of Ergotamine Sublingual Tablets
3.5M amit olumes of ethanol (80%). After
see wd / ry it in a current of cold air, spray with Action and use
dimethylamin be lehyde solution R7 and dry the plate at Oxytocic.
105° for 2 min ss the intensities of any secondary
DEFINITION
Ergotamine Sublingual Tablets contain Ergotamine Tartrate.
They may be flavoured.
Rf values. The sum of the The tablets comply with the requirements stated under Oromucosal
0% of the intensity Preparations and with the following requirements.
of the principal spot. .
Content of ergotamine tartrate, (C33H3;N;0;)2.,C4,H,O¢
note te
ASSAY 90.0 to 105.0% of the stated amount.
For ergometrine maleate
IDENTIFICATION
sxe ad
Carry out the method for liquid chromatograpé

Append III D, using the following solutions.
containing 0.05% w/v of Ergometrine Maleate. B. Triturate a quantity of the powdered tablets containing
2 mg of Ergotamine Tartrate with 5 mL of petroleum spirit
The chromatographic procedure may be carried out usin
oiling range, 40° to 60°), discard the petroleum spirit and
(a) a stainless steel column (10 cm x 4.6 mm) packed wit
arate the residue with 10 mL of chloroform saturated with
mW onia. Filter and evaporate the chloroform.
(Nucleosil C18 is suitable) and maintained at 40°, (b) a
“| mg of the residuein a mixture of 5 mL of glacial
mixture of 92 volumes of a 0.2% v/v solution of
orthophosphoric acid and 8 volumes of acetonitrile as the mobile
phase with a flow rate of 1 mL per minute and (c) a
chloride solution R1 previously diluted
Calculate the content of Cj;>H23N302,C4H,O, from the gé of water; the red tinge becomes less
declared content of C}9H.3N302,C,H4O, in ergometrine apparent and the-blue ¢
maleate BPCRS.
TESTS
For oxytocin
Related substances
Appendix III D, injecting 0.2 mL of each of the following
as possible. Carry out the methed
solutions. Solution (1) contains 8 pg of oxytocin EPCRS per
chromatography, Appendix III A, asi
mL. Solution (2) is the injection diluted, if necessary, to give
in a mixture of equal volumes of dic
a solution containing about 8 pg of Oxytocin per mL.
methanol.
The chromatographic procedure may be carried out using a
(1) Extract a quantity of the powdered t
stainless steel column (10 cm x 4.6 mm) packed with end-
1 mg of Ergotamine Tartrate with 2 mL ofa
capped octadecylsilyl silica gel for chromatography (5 wm)
equal volumes of dichloromethane and methanol as
(Nucleosil C18 is suitable) and maintained at 40°, (b) a
Remove the supernatant liquid, extract the residues
mixture of 85 volumes of a 0.2% v/v solution of
1-mL quantities of a mixture of equal volumes of
orthophosphoric acid and 15 volumes of acetonitrile as the
dichloromethane and methanol, evaporate the combined
mobile phase with a flow rate of 1 mL per minute and (c) a
extracts to dryness at 20° at a pressure of 2 kPa and dissolve
detection wavelength of 220 nm. If necessary adjust the
the residue in 0.25 mL of a mixture of equal volumes of
content of acetonitrile in the mobile phase so that the
dichloromethane and methanol. Centrifuge and use the
retention time of oxytocin is about 14 minutes. Record the
supernatant.
chromatogram for sufficient time to ensure elution of any
preservatives. (2) 0.010% w/v of ergotamine tartrate BPCRS.
The column efficiency, determined using the peak due to (3) 0.020% w/v of ergotamine tartrate BPCRS.
oxytocin in the chromatogram obtained with solution (1), (4) 0.040% w/v of ergotamine tartrate BPCRS.
should be not less than 50,000 theoretical plates per metre. (5) 0.40% w/v of ergotamine tartrate BPCRS.
Calculate the content of C43H¢6N12012S2 from the declared CHROMATOGRAPHIC CONDITIONS
content of peptide in oxytocin EPCRS.
eee
ANA
algal.
ew
NRA
Set re te SAR
Ae ee Ode
ce
2016 Erythromycin Preparations IH-525
(c) Apply 5 pL of each solution. CHROMATOGRAPHIC CONDITIONS

Nae
eeu ed
(d) Develop the plate to 15 cm. The chromatographic procedure described under Uniformity
- an a'd
“1
(e) After removal of the plate, dry in air and examine under of content may be used.
ultraviolet ight (365 nm). DETERMINATION OF CONTENT
MOBILE PHASE Calculate the content of (C33H35N505)2,C4H,O, using the
10 volumes of methanol and 90 volumes of dichloromethane. declared content of (C33H35N505)2,C4H.O¢ in ergotamine
tartrate BPCRS.
LIMITS
Assess the intensities of any secondary spots in the
chromatogram obtained with solution (1) by reference to the
spots in the chromatograms obtained with solutions (2), (3)
eae
and e sum of the intensities so assessed does not Gastro-resistant Erythromycin Capsules
ste Nw
btained with solution (1). In addition, any Action and use

pot in the chromatogram obtained with Macrolide antibacterial.
‘ere intense than the spot in the
DEFINITION
ith solution (2) (2.5%).
Gastro-resistant Erythromycin Capsules contain
Erythromycin. They are manufactured using gastro-resistant
capsule shells or prepared by filling capsules with granules or
of Ergotamine Tartrate ¢
particles covered with a gastro-resistant coating.
under Oromucosal Preparati
of analysis. Carry out the The capsules comply with the requirements stated under Capsules
IDENTIFICATION
A. Shake a quantity of the mixed capsule contents containing
0.1 g of Erythromycin with 5 mL of dichloromethane,
volume of the same solvent to produce a solution géntaining decolourise, if necessary, with activated charcoal, filter through
0.008% w/v of Ergotamine Tartrate and filter. a 0.45-um PTFE filter and evaporate the filtrate to dryness.
(2) 0.008% w/v of ergotamine tartrate BPCRS. The infrared absorption spectrum of the residue, Appendix II A,
after drying in vacuo at 60° for 10 minutes, is concordant
ith the reference spectrum of erythromycin (RS 123).
(a) Use a stainless steel column (12.5 cm x 4.6 mm) pa issolve a quantity of the mixed capsule contents
with particles of silica 5 um in diameter the surface of whic ing 3 mg of Erythromycin as completely as possible in
has been modified with chemically bonded hexyl groups { acetone and add 2 mL of hydrochloric acid; an orange
(Spherisorb C6 is suitable). produced which changes to red and then to deep
below.
(d) Use an ambient column temperature. Dissolution «
(e) Use a detection wavelength of 210 nm. Carry out the d
(f) Inject 20 uL of each solution. Appendix XII B1.
MOBILE PHASE TEST CONDITIONS
(a) Use Apparatus 1, rotatitig the

New anead
aw and
5 volumes of a 9.0% w/v solution of disodium hydrogen et at 50 revolutions per
orthophosphate adjusted to pH 5.0 with orthophosphoric acid, minute. eo
45 volumes of water and 50 volumes of methanol. The mobile (b) Use 900 mL of 0.06m hydro t a temperature
phase should be adjusted to pH 3.5 with orthophosphoric acid. of 37°, as the medium.
DETERMINATION OF CONTENT PROCEDURE
Calculate the content of (C33H35N5;O05)2,C,H,O, in each Place one capsule in the basket. After 1 ho
tablet using the declared content of (C33H35;N505)5,C,sH,O¢ basket from the dissolution medium, replace ths
in ergotamine tartrate BPCRS. 0.06m hydrochloric acid with 900 mL of a 0.05m phosphate
buffer solution pH 6.8, prepared as described below,
ASSAY
--awer dy
previously held at 37° and immediately lower the basket into
‘wer ny
2 wha ey
the dissolution medium and rotate at 50 revolutions per
vaAw ey
iN wn

minute. After 1 hour withdraw a sample of the medium, filter
solutions in methanol (50%) containing 1% v/v of
(discarding the first 2 mL of filtrate), transfer 5 mL of the
1m hydrochloric acid.
filtered solution to each of 2 volumetric flasks and then carry
(1) Shake a quantity of powdered tablets containing 8 mg of out the following procedures (A and B). Prepare the
Ergotamine Tartrate with 50 mL of methanol (50%) 0.05m phosphate buffer solution pH 6.8 in the following
containing 1% v/v of 1m hydrochloric acid for 15 minutes, add manner: Dissolve 136 g of potasstum dihydrogen orthophosphate
a sufficient volume of the same solvent to produce 100 mL in 1000 mL of water; separately dissolve 17.9 g of sodium
and filter. hydroxide in 1000 mL of water; mix the two solutions and
(2) 0.008% w/v of ergotamine tartrate BPCRS. dilute to 20 litres with water; the pH of the final solution is
about 6.8.
IWI-526 Erythromycin Preparations 2016
Procedure A Add 1 mL of 0.5m sulfuric acid, mix well and For solution (1) allow the chromatography to proceed for
stand at room temperature for 1 hour. Add 1 mL of 5 times the retention time of the peak corresponding to
+ Ne ele
1m sodium hydroxide and mix. Add 2 mL of a solution erythromycin A.
ene
containing 2.76% w/v of sodium hydroxide and 6.24% wiv of When the chromatograms are recorded using the prescribed
anhydrous disodium hydrogen orthophosphate 1n water, mix, heat conditions the retention time of erythromycin A is about
at 60° for 15 minutes and cool to room temperature in an ice 15 minutes. The retention times relative to erythromycin A
bath. Add sufficient water to produce 25 mL and measure are: impurity A, about 0.3; impurity B, about 0.45;
the absorbance of the final solution at the maximum at erythromycin C, about 0.5; impurity C, about 0.9;
236 nm, Appendix II B, using water in the reference cell. impurity D, about 1.4; impurity F, about 1.5;
Procedure B Add 2 mL ofa solution containing 2.76% w/v erythromycin B, about 1.8; impurity E, about 4.3.
of sodium hydroxide and 6.24% w/v of anhydrous disodium SYSTEM SUITABILITY
hydrogen ortgphosphate i1 n water, mix, heat at 60° for
room temperature in an ice bath.
NA
corresponding to N-demethylerythromycin A and
erythromycinC is at least 0.8 and the resolution factor
between the peaks corresponding to
N-demethylerythromycin A and erythromycinAis at least
Measure the absorbances « 5.5. If necessary, adjust the concentration of 2-methylpropan-
A BPCRS in dissolution ‘ 2-ol in the mobile phase (180 mL has been found to be
i inni words “‘transfer 5 mL of suitable) or reduce the flow rate to 1.5 or
the filtered solution to each of 2_volut etricflasks ... and 1.0 mL per minute.
calculate the content of C37H,7NQ); 1 medium from LIMITS
the differencein absorbance obtaine g precedures A
and B and using the declared content of C37FigzNOj3 in
solution (1) corresponding to impurities E and F using
erythromycin A BPCRS.
solution (6) and multiply the areas of these peaks by the
The amount of erythromycin released is not k corresponding correction factors: impurity E, 0.09;
the stated amount.
impurity F, 0.15.
Related substances In the chromatogram obtained with solution (1):
he area of any peak other than those peaks corresponding to
rythromycinA, erythromycin B and erythromycinC,
(1) Dissolve a quantity of the mixed capsule contents : d fi
containing 40 mg of Erythromycin in 10 mL of a mixture of
1 volume of methanol and 3 volumes of citro-phosphate buffer
pH 7.0 (solvent A), filter and use the filtrate.
(2) 0.4% w/v of erythromycin. A BPCRS in solvent A.
(3) 0.02% wiv of each of erythromycin B BPCRS and
erythromycin C BPCRS in solvent A.
(4) 0.012% w/v of erythromycin A BPCRS in solvent A. O excipients and any peak with an
(5) Dissolve 5 mg of N-demethylerythromycin A BPCRS in ».area of the principal peak in the
solution (3), add 1 mL of solution (2) and sufficient of chromatogram obtain:
solution (3) to produce 25 mL. Water
(6) Transfer 40 mg of erythromycin. A BPCRS to a glass vial The contents of the capsule 3in not more than 7.5%
-e ned
and spread evenly such that it forms a layer not more than w/w of water, Appendix IX C, w/v of imidazole in
about 1 mm thick. Heat at 130° for 4 hours, allow to cool methanol in the titration vessel.
and dissolve in sufficient of solvent A to produce 10 mL ASSAY
(generation of impurities E and F). Dissolve a quantity of the mixed content
CHROMATOGRAPHIC CONDITIONS containing the equivalent of 25 mg of erythron#ycit
(a) Use a column (25 cm x 4.6 mm) packed with styrene- completely as possible in sufficient methanol to
divinylbenzene copolymer (8 um) with a pore size of 100 nm 100 mL and carry out the microbiological assay of a
(PLRP-S is suitable). for erythromycin, Appendix XIV A. The precision of the
(b) Use isocratic elution and the mobile phase described assay is such that the fiducial limits of error are not less than
below. 95% and not more than 105% of the estimated potency.
Calculate the content of erythromycin in the capsules, taking
each 1000 IU found to be equivalent to 1 mg of
(d) Maintain the temperature of the column and at least one erythromycin. The upper fiducial limit of error is not less
third of the tubing preceding the column at 70°. than 95.0% and the lower fiducial limit of error is not more
(e) Use a detection wavelength of 215 nm. than 110.0% of the stated content.
(f) Inject 100 pL of each solution. STORAGE
MOBILE PHASE Gastro-resistant Erythromycin Capsules should be protected
To 50 mL of a 3.5% w/v solution of dipotassium hydrogen from light.
orthophosphate, adjusted to pH 9.0 with 1m orthophosphoric IMPURITIES
acid, add 400 mL of water, 165 mL of 2-methylpropan-2-ol The impurities limited by the requirements of this
and 30 mL of acetonitrile and dilute to 1000 mL with water. monograph include those listed under Erythromycin.
2016 Erythromycin Preparations III-527

LANA]
Gastro-resistant Erythromycin Tablets with solution (4) (7%). Disregard any peak with an area less
ca lt
Erythromycin Tablets than 0.02 times the area of the principal peak in the
Action and use
Macrolide antibacterial. The content of each of erythromycin B and erythromycin C,
as determined under Assay, is not more than 5%.
DEFINITION ASSAY
Gastro-resistant Erythromycin Tablets contain Erythromycin. Carry out the method for liguid chromatography,
They are made gastro-resistant by enteric-coating or by other Appendix III D, using the following solutions. Weigh and
means. powder 20 tablets (if necessary, remove the coating from
The tablets comply with the requirements stated under Tablets and 20 tablets using a sharp blade, taking care not to damage the
with. win, requirements. cores, weigh the cores and powder). For solution (1) dissolve
Content hromycins, calculated as the sum of a quantity of the powdered tablets containing 40 mg of
erythromyc C37H,,NO,3), erythromycin B Erythromycin in 10 mL of a mixture of 1 volume of methanol
(C3,H.;NO Y rythromycin C (C3¢6H,.s5NO,3) and 3 volumes of citro-phosphate buffer pH 7.0, filter and use
90.0 to 110.0% tated amount of Erythromycin. the filtrate. Solution (2) contains 0.4% w/v of erythromycin
A BPCRS in a mixture of 1 volume of methanol and
IDENTIFICA 3 volumes of citro-phosphate buffer pH 7.0 (solvent A).
A. Shake a quantity of, powdered tablets containing 0.1 g Solution (3) contains 0.02% w/v of each of erythromycin
of Erythromycin with 5 mi: hloromethane, decolourise, if B BPCRS and erythromycin C BPCRS in solvent A. Solution
necessary, with activated c r and evaporate the (4) contains 0.012% w/v of erythromycin. A BPCRS in solvent
spectrum of the A. For solution (5) dissolve 5 mg of N-demethylerythromycin
residue, Appendix II A, afte A BPCRS in solution (3), add 1 mL of solution (2) and
exceeding 0.7 kPa, is concordant with sufficient of solution (3) to produce 25 mL. For solution (6)
erythromycin (RS 123). transfer 40 mg of erythromycin A BPCRS toa glass vial and
spread evenly such that it forms a layer not more than about
3 mg of Erythromycin as completely as possik | 1 mm thick. Heat at 130° for 4 hours, allow to cool and
acetone and add 2 mL of hydrochloric acid; an ora dissolve in sufficient of solvent A to produce 10 mL
(generation of impurities E and F). The solutions can be
used within one day if stored at 5°.
becomes purple. chromatographic procedure may be carried out using
TESTS olumn (25 cm x 4.6 mm) packed with styrene-
Disintegration benzene copolymer (8 um) with a pore size of 100 nm
Tablets covered with a gastro-resistant coating comply with is suitable), (b) as mobile phase at a flow rate of
the requirements stated under Tablets but operating the er minute a solution prepared in the following
apparatus for 1 hour in 0.1m hydrochloric acid.
Related substances
d 30 mL of acetomitrile and dilute to
Appendix III D, using solutions (1), (2), (3), (4) and (6)
(c) a detection wavelength of
described under Assay.
215 nm. Maintain } nperature of the column at 70°
be used.
Inject 0.1 mL of each solution. For solution (1) allow the
chromatography to proceed for 5 times the retention time of
the peak corresponding to erythromycin A.
conditions the retention time of erythromycin A is about erythromycin A and erythromycin B. *
15 minutes. The retention times relative to erythromycin A unless the resolution factor between the péaks @o'
are: impurity A, about 0.3; impurity B, about 0.45; N-demethylerythromycin A and erythromyci
erythromycin C, about 0.5; impurity C, about 0.9; 0.8 and the resolution factor between the peaks’
impurity D, about 1.4; impurity F, about 1.5; to N-demethylerythromycin A and erythromycin A is at least
erythromycin B, about 1.8; impurity E, about 4.3. 5.5. If necessary, adjust the concentration of 2-methylpropan-
Identify any peaks in the chromatogram obtained with 2-ol in the mobile phase (180 mL has been found to be
oe
solution (1) corresponding to impurities E and F using suitable) or reduce the flow rate to 1.5 or 1.0 mL per
solution (6) and multiply the areas of these peaks by the minute.
corresponding correction factors: impurity E, 0.09; Inject alternately 0.1 mL of solutions (1), (2) and (3).
impurity F, 0.15. In the chromatogram obtained with Calculate the content of erythromycin A using the
solution (1) the area of any peak other than those peaks chromatograms obtained with solutions (1) and (2) and from
corresponding to erythromycin A, erythromycin B and the declared content of C37H¢7NOj3 in erythromycin
erythromycin C, identified from the peaks in the A BPCRS. Calculate the contents of erythromycin B and
chromatograms obtained with solutions (2) and (3), is not erythromycin C using the chromatograms obtained with
greater than the area of the principal peak in the solutions (1) and (3) and from the declared contents of
aeone
we
neal
aeoe mal chromatogram obtained with solution (4) (3%) and the sum C37H67NO12 and C36H65NO13 in erythromycin B BPCRS
Pa
Be
oe,
of the areas of any such peaks is not greater than 2.3 times and erythromycin C BPCRS respectively. |
Nte ot ee

Gastro-resistant Erythromycin Tablets should be protected The test is not valid unless the chromatogram obtained with
meee at
wee Ne
re
raw ed
ate tee!
from light. solution (4) shows two clearly separated spots.
IMPURITIES LIMITS
The impurities limited by the requirements of this Any secondary spot in the chromatogram obtained with
monograph include those listed under Erythromycin. solution (1) is not more intense than the spot in the
chromatogram obtained with solution (5) (2.5%, with respect
to erythromycin).
ASSAY
Erythromycin Estolate Capsules Dissolve a quantity of the mixed contents of 20 capsules
containing the equivalent of 0.25 g of erythromycin in
Action af 400 mL of methanol and add 200 mL of sterile phosphate
buffer pH 7.0 and sufficient water for injections to produce
1000 mL. Maintain the solution at 60° for 3 hours, cool,
filter and carry out the microbiological assay of antibiotics for
erythromycin, Appendix XIV A. The precision of the assay is
such that the fiducial limits of error are not less than 95%
and not more than 105% of the estimated potency.
Calculate the content of erythromycin in a capsule of average
IDENTIFICATION content weight, taking each 1000 IU found to be equivalent
A. The infrared absorption spect to 1 mg of erythromycin. The upper fiducial limit of error is
not less than 95.0% and the lower fiducial limit of error is
not more than 110.0% of the stated content.
LABELLING
chromatogram obtained with solution (2) is si The quantity of active ingredient is stated in terms of the
position and colour to that in the chromatogra equivalent amount of erythromycin.
with solution (3).
TESTS
Disintegration
Maximum time, 30 minutes, Appendix XII Al. Use a romycin Ethyl Succinate Oral
0.6% v/v solution of hydrochloric acid in place of water.
Water
The contents of the capsules contain not more than
5.0% w/w of water, Appendix IX C. Use 0.5 g.
Related substances
Appendix III A, using the following solutions. Erythromycin Ethyk nate Oral Suspension is a
suspension of Erythro, J
in. Ethyl Succinate in a suitable
flavoured vehicle. It is prepared by dispersing the dry
containing the equivalent of 0.4 g of erythromycin with
ingredients in the specified.volwme of water just before issue
100 mL of acetone, filter and use the filtrate.
for use.
The dry ingredients comply with thé requi nts for Powders and
acetone.
Granules for Oral Solutions and Orél sions stated under
(3) 0.13% w/v of erythromycin estolate BPCRS in acetone. Oral Liquids.
ee
(4) 0.1% w/v each of erythromycin estolate BPCRS and For the following tests prepare the oral suspeision ¢ directed on
erythromycin ethylsuccinate BPCRS in acetone. the label. The suspension examined immediatéls: re preparation,
——
(5) 0.01% w/v of erythromycin A BPCRS in acetone. unless otherwise indicated, complies with the requirem ed
tee,
CHROMATOGRAPHIC CONDITIONS under Oral Liquids and with the following requiremé
(a) Usea silica gel precoated plate (Merck silica gel 60 plates IDENTIFICATION
Dos,
are suitable). Dilute a quantity of the oral suspension containing the

(b) Use the mobile phase described below. equivalent of 0.1 g of erythromycin to 25 mL with water and
a ts
extract with two 10 mL quantities of dichloromethane. Wash

react hehe

the combined extracts with five 10 mL quantities of water,
filter using silicone-treated filter paper (Phase Separator
(e) After removal of the plate allow it to dry in air, spray with paper is suitable) and evaporate to dryness. The residue, after
anisaldehyde solution, heat at 110° for 5 minutes and allow to drying at 105° for 15 minutes complies with the following
cool. tests.
MOBILE PHASE A. The infrared absorption spectrum, Appendix II A, is
1 volume of a 15% w/v solution of ammonium acetate, concordant with the reference spectrum of erythromycin ethyl
previously adjusted to pH 7.0, 15 volumes of ethanol (96%) succinate (RS 125).
and 85 volumes of chloroform. B. Carry out the method for thin-layer chromatography,
and a mixture of 1 volume of a 15% w/v solution of
ea ee! SLE SER
ammonium acetate previously adjusted to pH 7.0, 15 volumes of equal volumes of chloroform and methanol for 15 minutes.
of ethanol (96%) and 85 volumes of chloroform as the mobile Centrifuge and evaporate the upper layer to dryness. Dissolve
ene phase. Apply separately to the plate 10 uL of each of the the residue in a minimum volume of dichloromethane,
following solutions. For solution (1) dissolve a quantity of the evaporate to dryness and dry at 105° for 15 minutes. The
residue in acetone to produce a solution containing the infrared absorption spectrum of the residue, Appendix II A, is
equivalent of 0.1% w/v of erythromycin. Solution (2) concordant with the reference spectrum of erythromycin ethyl
contains 0.1% w/v of erythromycin ethylsuccinate BPCRS in succinate (RS 125).
acetone. Solution (3) contains 0.1% w/v of erythromycin B. In the test for Related substances, the principal spot in the
ethylsuccinate BPCRS and 0.1% w/v of erythromycin chromatogram obtained with solution (2) is similar in
estolate BPCRS in acetone. After removal of the plate, allow it position and colour to that in the chromatogram obtained
to dry in air, spray with anisaldehyde solution, heat at 110° for with solution (3).
5 min d allow to cool. The principal spot in the
‘im.e@btained with solution (1) is similar in TESTS
indeeolgur to that in the chromatogram obtained Related substances
“The test is not valid unless the Carry out the method for thin-layer chromatography,
ed with solution (3) shows two clearly Appendix III A, using the following solutions.
equivalent of 0.1 g of erythromycin with 25 mL of a mixture
of equal volumes of chloroform and methanol for 15 minutes,
pH, 6.5 to 9.5, Appendix
mixture of equal volumes of chloroform and methanol.
re eewd
To a weighed quantity of thé’or (3) 0.1% w/v of erythromycin ethylsuccinate BPCRS in acetone.
equivalent of 0.25 g of erythromyciri’ad
(4) 0.1% w/v of erythromycin ethylsuccinate BPCRS and
0.1% w/v of erythromycin estolate BPCRS in acetone.
(5) 0.020% w/v of erythromycin A BPCRS in acetone.
(a) Use silica gel G as the coating substance.

95% and not more than 105% of the estimated poten
Apply 10 uL of each solution.
Repeat the procedure using a portion of the oral suspensio
that has been stored at the temperature and for the period evelop the plate to 15 cm.
stated on the label during which it may be expected to be removal of the plate allow it to dry in air, spray with
Calculate the content of erythromycin in the oral suspension
taking each 1000 IU found to be equivalent to 1 mg of
erythromycin. When freshly constituted the lower fiducial
limit of error is not more than 120.0% of the stated amount previously adjusted
and when stored at the temperature and for the period stated and 85 volumes of
on the label during which the oral suspension may be
expected to be satisfactory for use, the upper fiducial limit of
error is not less than 90.0% of the stated content.
STORAGE
The oral suspension should be stored at the temperature and
LIMITS a
used within the period stated on the label. Any secondary spot in the chroma
solution (1) is not more intense than
LABELLING
chromatogram obtained with solution
equivalent amount of erythromycin. ASSAY
Weigh and powder 20 tablets. To a quantity ofte powdered
tablets containing the equivalent of 0.25 g of erythromycin
add 200 mL of methanol, shake for 1 hour and dilute to
Erythromycin Ethyl Succinate Tablets 500 mL with methanol. Dilute 10 mL to 100 mL with
phosphate buffer pH 8.0, stand at room temperature for
Action and use 16 hours and carry out the microbiological assay of antibiotics
Macrolide antibacterial. for erythromycin, Appendix XIV A. The precision of the
assay is such that the fiducial limits of error are not less than
DEFINITION 95% and not more than 105% of the estimated potency.
Erythromycin Ethyl Succinate Tablets contain Erythromycin Calculate the content of erythromycin in the tablets taking
Ethyl Succinate. each 1000 IU found to be equivalent to 1 mg of
The tablets comply with the requirements stated under Tablets and erythromycin. The upper fiducial limit of error is not less
with the following requirements. than 97.0% and the lower fiducial limit of error is not more
than 110.0% of the stated content.
IDENTIFICATION
\ oa4

equivalent of 0.1 g of erythromycin with 20 mL of a mixture
IW-530 Erythromycin Preparations 2016
STORAGE (e) Remove the plate, allow it to dry in air and spray with a
Erythromycin Ethyl Succinate Tablets should be protected 0.5% w/v solution of potasstum permanganate in 1M sodium
MeN
ve Nw A
from light. hydroxide and heat at 110° for 5 minutes.
LABELLING MOBILE PHASE
The quantity of active ingredient is stated in terms of the A mixture of 3 volumes of glacial acetic acid, 10 volumes of
equivalent amount of erythromycin. water and 90 volumes of methanol.
CONFIRMATION
spots, one of which corresponds in position, colour and size
Erythromycin Lactobionate Infusion to the principal spot in the chromatogram obtained with
Erythrom T_actobionate Intravenous Infusion solution (2) and the other to the principal spot in the
:
Action
an U
C. To a quantity of the contents of a sealed container
b
Macrolide anti containing the equivalent of 5 mg of erythromycin add 5 mL
of a 0.02% w/v solution of xanthydrol in a mixture of
DEFINITION 1 volume of hydrochloric acid and 99 volumes of 5M acetic
sion is a sterile solution acid. A red colour develops.
TESTS
erythromycin, 6.5 to 7.5, Appendix V L.
see snd
The infusion complies with the requitemerth Related substances
Parenteral Preparations and with the followr Carry out the method for liguid chromatography,
Appendix III D, using solutions (1), (3) and (6) described
STORAGE under Assay.
ErythromycinLactobionate Infusion should be
period recommended by the manufacturer when prepar The chromatographic conditions described under Assay may
and stored strictly in accordance with the manufacturer’s e used. For solution (1) allow the chromatography to
instructions. = for 5 times the retention time of the peak
ERYTHROMYCIN LACTOBIONATE FOR

INFUSION
Erythromycin Lactobionate for Intravenous Infusion
DEFINITION
Erythromycin Lactobionate for Infusion is a sterile material cnpurity F, about 1.5;
consisting of Erythromycin Lactobionate with or without erythromycin B, aout| ; impurity E, about 4.3.
excipients. It is supplied in a sealed container. LIMITS
The contents of the sealed container comply with the requirements Identify any peaks in th atogram obtained with
for Powders for Injections or Infusions stated under Parenteral solution (1) corresponding té impurities E and F using
Preparations and with the following requirements. solution (6) and multiply the’areds of these peaks by the
Content of erythromycins, calculated as the sum of corresponding correction factors:ampusitit
erythromycin A (C3,H,;;NO;3), erythromycin B impurity F, 0.15.
(C37H67NO,2) and erythromycin C (C36H65;NO},3) In the chromatogram obtained with solution (
90.0 to 110.0% of the stated amount of erythromycin. the area of any peak other than those peaks sponding to
IDENTIFICATION erythromycin A, erythromycin B and erythrorfiyci
A. The infrared absorption spectrum, Appendix II A, is greater than the area of the principal peak in the
concordant with the reference spectrum of erythromycin chromatogram obtained with solution (3) (3%);
lactobionate (RS 126). the sum of the areas of any such peaks is not greater than
B. Carry out the method for thin-layer chromatography, 2.3 times the area of the principal peak in the chromatogram
Appendix III A, using the following solutions. obtained with solution (3) (7%).
(1) Dissolve a quantity of the contents of a sealed container Disregard any peak with an area less than 0.02 times the area
in sufficient methanol to produce a solution containing the of the principal peak in the chromatogram obtained with
equivalent of 0.2% w/v of erythromycin. solution (3) (0.06%).
(2) 0.2% w/v of erythromycin. A BPCRS in methanol. The content of each of erythromycin B and erythromycin C,
as determined under Assay, is not more than 5%.
(3) 0.1% w/v of lactobionic acid in water.
(a) Use silica gel H as the coating substance. Dissolve the contents of the sealed container in water BET to
Pe LN
tee Nw ol
(b) Use the mobile phase described below. give a solution containing the equivalent of 50 mg of
(c) Apply 5 pL of each solution. erythromycin per mL; further dilute this solution with water
‘et ad
ate)
(d) Develop to 15 cm. BET to give a solution containing the equivalent of 0.2 mg of
erythromycin per mL (solution A). The endotoxin limit DETERMINATION OF CONTENT

|
concentration of solution A is 0.07 IU of endotoxin per mL. Calculate the percentage content of erythromycin A using the
ASSAY chromatograms obtained with solutions (1) and (2) and from
Determine the weight of the contents of 10 containers as the declared content of C37H¢7NOj,3 in erythromycin
described in the test for uniformity of weight, A BPCRS. Calculate the percentage contents of
Appendix XII C1, Powders for Parenteral Administration. erythromycin B and erythromycin C using the
chromatograms obtained with solutions (1) and (4) and from
the declared contents of C37H¢7NO,, and C3,H,¢5NOj,;3 in
erythromycin B BPCRS and erythromycin C BPCRS
can be used within one day if stored at 5°.
respectively.
containing the equivalent of 40 mg of LABELLING
The label of the sealed container states the quantity of active
phosphate buffer pH 7.0 and dilute to ingredient contained in it in terms of the equivalent amount
e mixture of solvents. of erythromycin.
Erythromycin Stearate Tablets

1 volume of methanol ‘an .
pH 7.0. Action and use
Macrolide antibacterial.
TA e mg DEFINITION
Erythromycin Stearate Tablets contain Erythromycin
(5) Dissolve 5 mg of N-demethylerythro !
Stearate.
solution (4), add 1 mL of solution (2) an
solution (4) to produce 25 mL.
and spread evenly such that it forms a layer not m © thd | IDENTIFICATION
about 1 mm thick. Heat at 130° for 4 hours, allow to ¢ A. To a quantity of the powdered tablets containing the
and dissolve in sufficient of solvent A to produce 10 m valent of 0.1 g of erythromycin add 10 mL of water and
(generation of impurities E and F). ell. Decant the supernatant liquid and discard.
the residue by shaking with 10 mL of methanol, filter
t and evaporate to dryness. The infrared absorption
(a) Use a column (25 cm x 4.6 mm) packed with styrene- Tung Appendix II A, of the residue after drying at a
divinylbenzene copolymer (8 tum) with a pore size of 100 nm
(PLRP-S is suitable).
(b) Use isocratic elution and the mobile phase described of the powdered tablets containing the
below. erythromycinin 2 mL of acetone and
(c) Use a flow rate of 2.0 mL per minute. ycid; an orange colour is produced
(d) Maintain the temperature of the column at 70° using a then to deep violet-red. Add 2 mL
Ne aed water bath for the column and at least one third of the
tubing preceding the column.
tee Ae
MOBILE PHASE
To 50 mL of a 3.5% w/v solution of dipotassium hydrogen
orthophosphate, adjusted to pH 9.0 with 1M orthophosphoric
acid, add 400 mL of water, 165 mL of 2-methylpropan-2-ol
and 30 mL of acetonitrile R1 and dilute to 1000 mL with To 1 mL add a 10% w/v solution of calcium ch rides
water. a granular precipitate is produced which is insoluble in
rae ad SYSTEM SUITABILITY hydrochloric acid.
AN aa
Inject solution (5). Adjust the sensitivity of the system so that TESTS
the height of the peaks is at least 25% of the full-scale of the Dissolution
recorder. The substances are eluted in the following order: Comply with the requirements for Monographs of the British
N-demethylerythromycin A, erythromycin C, erythromycin A Pharmacopoeia in the dissolution test for tablets and capsules,
and erythromycin B. The test is not valid unless the resolution Appendix XII B1, using Apparatus 2. Use as the medium
jactor between the peaks corresponding to 900 mL of a 2.722% w/v solution of sodium acetate, the pH
N-demethylerythromycin A and erythromycin C is at least of which has been adjusted to 5.0 with glacial acetic acid and
0.8 and the resolution factor between the peaks corresponding rotate the paddle at 50 revolutions per minute. Transfer
to N-demethylerythromycin A and erythromycin A is at least 5 mL of a filtered sample to a graduated flask, add 40 mL of
5.5. If necessary, adjust the concentration of 2-methylpropan- glacial acetic acid and 10 mL of a 0.5% w/v solution of
2-ol in the mobile phase or reduce the flow rate to 1.5 or 4-dimethylaminobenzaldehyde in glacial acetic acid and dilute to
1.0 mL per minute. 100 mL with a mixture of 35 volumes of glacial acetic acid
awe
wave
and 70 volumes of hydrochlonc acid. Allow to stand for IDENTIFICATION

15 minutes and measure the absorbance of the resulting A. In the Assay for erythromycin, the retention time of the
So
ae ts
solution at the maximum at 485 nm, Appendix II B, using in principal peak in the chromatogram obtained with solution
the reference cell dissolution medium that has been subjected (1) corresponds to that in the chromatogram obtained with
to the conditions of the test. Prepare a suitable solution of solution (2).
erythromycin stearate BPCRS in the dissolution medium and B. Mix a quantity of the powder with sufficient water to
filter. Transfer 5 mL of the filtered solution to a graduated produce a 5% w/v solution and filter. Add 0.5 mL of a
flask, add 40 mL of glacial acetic acid and 10 mL of a 0.25M solution of potasstum hexacyanoferrate(u) to 5 mL of
0.5% w/v solution of 4-dimethylaminobenzaldehyde in glacial the resulting solution and mix; a white precipitate is
acetic acid and dilute to 100 mL with a mixture of produced. Add 5 mL of 4m hydrochloric acid; the precipitate
35 volumes of glacial acetic acid and 70 volumes of does not dissolve.
hydrochloric.acid. Allow to stand for 15 minutes and measure
be +Busin solution at the maximum at TEST
Related substances
Appendix III D, using solutions (1), (2), (3), (4) and (6)
described under Assay for erythromycin.
content of C37H¢7NO: The chromatographic conditions described under the Assay
for erythromycin may be used.
ASSAY
Inject 100 uL of each solution. For solution (1) allow the
chromatography to proceed for 6 times the retention time of
al to produce the peak corresponding to erythromycin A.
ve ane
yy of antibiotics When the chromatograms are recorded using the prescribed
cision of the conditions the retention time of erythromycin A is about
‘less than 15 minutes. The retention times relative to erythromycin A
renicy. are: impurity A, about 0.3; impurity B, about 0.45;
erythromycin C, about 0.5; impurity C, about 0.9;
each 1000 IU found to be equivalent to 1 mg of impurity D, about 1.4; impurity F, about 1.5;
erythromycin. The upper fiducial limit of error is n erythromycin B, about 1.8; impurity E, about 4.3.
than 97.0% and the lower fiducial limit of error is not m dentify any peaks in the chromatogram obtained with
than 110.0% of the stated content. olution (1) corresponding to impurities E and F using
STORAGE
ing correction factors: impurity E, 0.09;
Erythromycin Stearate Tablets should be protected from
0.15. In the chromatogram obtained with
light.
the area of any ONother than those peaks
LABELLING
equivalent amount of erythromycin.
e principal peakin the
ith solution (4) (3%) and the sum
le is not greater than 2.3 times
inethe chromatogram obtained
Erythromycin and Zinc Acetate Lotion
Erythromycin and Zinc Acetate Cutaneous Solution
Action and use

Macrolide antibacterial.
DEFINITION ASSAY
Erythromycin and Zinc Acetate Lotion is a cutaneous solution. For erythromycin
It contains 4% w/v of Erythromycin and 1.2% w/v of Zinc Carry out the method for liquid chromatography,*
Acetate in a suitable ethanolic vehicle. It 1s prepared by Appendix II D, using the following solutions. For*solution
dissolving the dry ingredients in the requisite volume of the (1) add 20 mL of a mixture of 1 volume of methanol and
vehicle provided before use. 3 volumes of citro-phosphate buffer pH 7.0 (solvent A) to a
The lotion complies with the requirements stated under Liquids for quantity of the powder containing 80 mg of Erythromycin,
Cutaneous Application. mix with the aid of ultrasound for 5 minutes and allow to
The dry ingredients comply with the requirements for Powders for stand until phase separation has been completed. Centrifuge
Lotions stated under Liquids for Cutaneous Application and with the lower layer and use the resulting clear solution. Solution
the following requirements. (2) contains 0.4% w/v of erythromycin. A BPCRS in solvent A.
Solution (3) contains 0.02% w/v of each of erythromycin
Content of erythromycins, calculated as the sum of
B BPCRS and erythromycin C BPCRS in solvent A. Solution
erythromycin A (C3,H,,NQ,3), erythromycin B
(4) contains 0.012% w/v of erythromycin A BPCRS in solvent
(C37H67NO;2) and erythromycin C (C3¢6H.6sNO;3)
A. For solution (5) dissolve 5 mg of N-demethylerythromycin
95.0 to 105.0% of the stated amount of Erythromycin.
A BPCRS in solution (3), add 1 mL of solution (2) and
Content of zinc acetate, C,H,;,O,Zn,2H,O sufficient of solution (3) to produce 25 mL. For solution (6)
95.0 to 105.0% of the stated amount. transfer 40 mg of erythromycin A BPCRS to a glass vial and
2016 Erythropoietin Preparations TI-533
spread evenly such that it forms a layer not more than about a white precipitate is produced. Add 10 mL of
1 mm thick. Heat at 130° for 4 hours, allow to cool and 4m hydrochloric acid; the precipitate does not dissolve.
dissolve in sufficient of solvent A to produce 10 mL
TEST
(generation of impurities E and F). The solutions can be
used within one day if stored at 5°.
The solution is clear, Appendix IV A, and colourless,
The chromatographic procedure may be carried out using Appendix IV B, Method I.
styrene-divinylbenzene copolymer (8 um) with a pore size of ASSAY
100 nm (PLRP-S is suitable), (b) as the mobile phase with a For erythromycin
flow rate of 2.0 mL per minute a solution prepared in the Carry out the Assay for erythromycin described in the
following manner: to 50 mL of a 3.5% w/v solution of requirements for the dry ingredients. For solution (1) use a
dipotasst , hydrogen orthophosphate adjusted to pH 9.0 with volume of the lotion containing 80 mg of Erythromycin in
cid add 400 mL of water, 165 mL of place of the powder.
vw wa
and 30 mL of acetonitrile and dilute to For zinc acetate

ater and (c) a detection wavelength of To a volume of the lotion containing 0.2 g of Zinc Acetate
e temperature of the column at 70° add 5 mL of dilute acetic acid. Carry out the complexometric
titration of zinc, Appendix VII D. Each mL of 0.1m disodium
edetate VS is equivalent to 21.95 mg of C,H,O,Zn,2H.O.
STORAGE
Erythromycin and Zinc Acetate Lotion should be stored at
full scale of the recorder. the temperature and used within the period stated on the
following order: N-demethyl } label.
erythromycin C, erythromy
IMPURITIES
peaks corresponding to N-demethyle The impurities limited by the requirements of this
erythromycin Cis at least 0.8 and the reso monograph include those listed under Erythromycin.
between the peaks corresponding to N-de
concentration of 2-methylpropan-2-ol in the mo Sile B

(180 mL has been found to be suitable) or reduce fi
rate to 1.5 or 1.0 mL per minute.
Erythropoietin Injection
Inject alternately 100 uL of solutions (1), (2) and (3).
Calculate the content of erythromycin A using the
chromatograms obtained with solutions (1) and (2) and fro
the declared content of C37Hg7NO};3 1n erythromycin
A BPCRS. Calculate the contents of erythromycin B and
erythromycin C using the chromatograms obtained with
solutions (1) and (3) and from the declared contents of supplied
C37H67NO}1>2 and C36H._65NO13 in erythromycin B BPCRS dissolving
and erythromycin C BPCRS respectively. the label.
For zinc acetate
To a quantity of the powder containing 0.2 g of Zinc Acetate Where the product c
swe
tee
add 5 mL of dilute acetic acid. Carry out the complexometric not comply with the test i
warwad
Stevan.
mye aA
titration of zinc, Appendix VIII D. Each mL of 0.1m disodium of higher molecular weight; "ho
edetate VS is equivalent to 21.95 mg of C,sH,O4Zn,2H,O. processisvalidated to show ai
For the following tests prepare the lotion as directed on the label.
AN AY
Cutaneous Application and with the following requirements. solution, with the following requirements.
Content of erythromycins, calculated as the sum of Potency
erythromycin A (C37H,;7;NO,3), erythromycin B The estimated potency is not less than 80% a n
(C3,H.7NO,2) and erythromycin C (C3¢H.¢;NO;3) than 125% of the stated potency.
90.0 to 110.0% of the stated amount of Erythromycin.
CHARACTERISTICS
Sate AS,
Content of zinc acetate, C,H,0O,Zn,2H,O
A clear, colourless solution virtually. free from particles.
Aran
ee Pa e
ewaAw ad
Ate
SOA 90.0 to 110.0% of the stated amount.

IDENTIFICATION
IDENTIFICATION
A. It gives the appropriate response when examined using the
A. In the Assay for erythromycin, the retention time of the
conditions under Assay.
B. Carry out the method for polyacrylamide gel electrophoresis,
(1) corresponds to that in the chromatogram obtained with
Appendix III F, using slab gels 0.75 mm thick and about
solution (2).
16 cm square (or 7 cm x 8 cm) and 12% acrylamide as the
B. Evaporate a suitable volume of the lotion to dryness on a
resolving gel. For solution (1) concentrate or dilute, if
water bath, add 20 mL of water to the residue, mix, with
necessary, the injection being examined to give a solution
shaking, and filter. Add 1 mL of a 0.25 solution of containing 2000 IU per mL in water and then add 1 volume
potassium hexacyanoferrate(u) to the resulting filtrate and mix; of SDS-PAGE sample buffer (concentrated). For solution (2)
dissolve the contents of a vial of erythropoietin EPBRP in
ee A
WWI-534 Erythropoietin Preparations 2016
water to give a solution containing 3012 IU per mL and then (e) Use fluorimetric detection with an excitation wavelength
add 1 volume of SDS-PAGE sample buffer (concentrated). of 280 nm and an emission wavelength of 340 nm.
Solution (3) is a solution of pre-stained molecular weight (f) Inject 100 uwL of each solution.
markers suitable for calibrating SDS-polyacrylamide gels in
Lwin
(g) Allow the chromatography to proceed for a minimum of

the range of 10 to 70 kDa and suitable for the electrotransfer
1 hour.
to an appropriate membrane. Boil solutions (1), (2) and (3)
for 2 minutes. Apply 20 wL (or 15 uL for 7 cm x 8 cm slab MOBILE PHASE
gels) of the solutions separately to the surface of the gel in 0.115% w/v of anhydrous disodium hydrogen orthophosphate,
the following order: solution (2), solution (1), solution (3). 0.02% w/v of potassium dihydrogen orthophosphate and
At the end of the separation, remove the gel-cassette from 2.34% wiv of sodium chloride in water; if necessary, adjust to
the apparatus. pH 7.4.
ting is carried out as follows. Transfer the gel SYSTEM SUITABILITY

available electrotransfer equipment and
in the chromatogram obtained with solution (3) aggregates
says
facturer’s instructions. After

are present, the resolution factor between the aggregate and
monomer peaks is at least 0.8 and the relative standard
deviation is less than 10%;
4 viv foetal calf serum), for 1 to
4on for 1 to 14 hours in the in the chromatogram obtained with solution (2) the area of
same blocking solution w the principal peak is 1.5 to 2.5% of the area of the principal
polyclonal or monoclonal afit peak in the chromatogram obtained with the solution (1).
Detect erythropoietin-bound afyti LIMITS
enzyme or radiolabelled antibos e, an alkaline In the chromatogram obtained with solution (1) the total
ne precise details area of any peaks eluting before the principal peak is not
should be optimised using theprinciples ‘ : chromatogram obtained with solution (2) (2.0%).
Immunochemical methods, Appendix XIV B.
B. Carry out the method for size-exclusion chromatography,
Appendix III C, using the following solutions.
(1) Prepare aggregated erythropoietin by heating a 0.1% w/v
resolved on the membrane into discrete bands, with a‘linear
_solution of erythropoietin EPBRP in citrate buffered saline for
relationship between distance migrated and logarithm, 6
4 days at 55°. Dilute 0.1 mL to 1 mL with the sample
the molecular weight.
The electrophoretogram obtained with solution (1) shows a
single broad band corresponding in position and intensity to
the single band seen in the electrophoretogram obtained with
solution (2). 28% wiv dipotassium hydrogen orthophosphate
9% wiv potassium chloride, adjusted to
TESTS
Dimers and related substances of higher molecular
weight
Use method A or method B.
te aye
A. Carry out the method for size-exclusion chromatography, Sample solution 9 Per Final Injection
cee ad
Appendix III C, using the following solutions. IU per ml mi ncentration of |volume

olysorbate 80 ul
(1) Dilute the injection, if necessary, with the mobile phase
to give a solution containing 1,000 IU of Erythropoietin per 2000 16.67 Undiluted Not 50
applicable
mL.
4000 33.33 Undiluted Not 50
(2) Dilute 0.02 mL of solution (1) to 1 mL with the mobile applicable
phase. 10,000 83.33 1:3 Solution A 0.01%, 00
(3) Prepare aggregated erythropoietin by heating a 0.1% w/v 40,000 333.33 1:6 Sample 0.01% 50
solution of erythropoietin EPBRP in citrate buffered saline for dilution
buffer
14 days at 55°. Dilute 0.1 mL to 1 mL with the mobile
aN al
phase.
va wd
Beate
The sample dilution buffer contains 2 volumes of solution A
ste gees
(a) Use a stainless steel column (60 cm x 7.5 mm) packed and 1 volume of solution B.
with hydrophilic sihca gel for chromatography of a grade suitable
(3) Dilute 0.02 mL of solution (2) to 1 mL with the sample
for fractionation of globular proteins in the molecular weight
dilution buffer.
range of 20,000 to 200,000 (TSK G 3000 SW is suitable).
below. (a) Use a stainless steel column (30 cm x 7.8 mm) packed
(c) Use a flow rate of 0.5 mL per minute. with hydrophilic silica gel for chromatography of a grade suitable
for fractionation of globular proteins in the molecular weight
range of 20,000 to 200,000 (TSK G 3000 SWxI is suitable).
BN eta
state el
2016 Erythropoietin Preparations TTH-535
(b) Use isocratic elution and the mobile phase described Reference solution (1) Dissolve erythropoietin EPBRP in
below. phosphate-albumin buffered saline pH 7.2 R1 to obtain a
(c) Use a flow rate of 0.3 mL per minute. concentration of 0.2 IU per mL.
(d) Use an ambient column temperature. Reference solution (2) Mix equal volumes of reference solution
(e) Use fluorimetric detection with an excitation wavelength (1) and phosphate-albumin buffered saline pH 7.2 R1,
of 280 nm and an emission wavelength of 345 nm. Reference solution (3) Mix equal volumes of reference solution
(f) Use injection volumes as stated in the sample preparation (2) and phosphate-albumin buffered saline pH 7.2 R1.
table. Radiolabelled ferric [°’Fe] chloride solution, concentrated Usea
(g) Allow the chromatography to proceed for a minimum of commercially available solution of [?’Fe] ferric chloride
1 hour. (approximate specific activity: 100 to 1000 MBq per mg of
Fe).
Radiolabelled [°?Fe] ferric chloride solution Dilute the
concentrated radiolabelled [°’Fe] ferric chloride solution in
sodium citrate buffer solution pH 7.8 to obtain a solution with
an activity of 3.7 x 10* Bq per mL.
The concentrations of the test solutions and reference
solutions may need to be modified, based on the response
range of the animals used.
are present and the resaluton faetor between the aggregate and
monomer peaks is at leas : Three days after returning the animals to atmospheric
pressure, inject each animal subcutaneously with 0.2 mL of
one of the solutions. The 6 animals in each cage must each
LIMIT ah.
In the chromatogram with solutie total area of any receive one of the 6 different treatments (3 test solutions and
peaks eluting before the principal pea is Mot greater than the 3 reference solutions); the order of injection must be
area of the principal peak in the chrom; obtained with separately randomised for each cage. A minimum of 8 cages
solution (3) (2.0%). is recommended. Two days after injection of the test or
Bacterial endotoxins reference solution, inject each animal intraperitoneally with
Carry out the test for bacterial endotoxins, AppendixXIVC. 0.2 mL of radiolabelled [°’Fe] ferric chloride solution. The order
The endotoxin limit concentration is less than 20 IU, of the injections must be the same as that of the
volume containing 10,000 IU of Erythropoietin. erythropoietin injections, and the time interval between
administration of the erythropoietin and the radiolabelled
ASSAY
hloride solution must be the same for each animal.
Carry out the Assay using method A or method B.
rther 48 hours, anaesthetise each animal by
The activity of the preparation is compared with that of of a suitable anaesthetic, record body weights and
erythropoietin EPBRP and expressed in International Units ‘blood samples (0.65 mL) into haematocrit
dU).
The confidence limits of the estimated potency (P = 0.95)
are not less than 64% and not more than 156% of the stated
potency. e (percentage of °’Fe in total circulating
A. In polycythaemic mice ing the expression:
The activity of the preparation is estimated by examining,
under given conditions, its effect in stimulating the
re
incorporation of °’Fe into circulating red blood cells of mice
oe se 4
made polycythaemic by exposure to reduced atmospheric
pressure.
The following schedule, using treatment in a hypobaric
chamber, has been found to be suitable.
A, = radioactivity in the sample,
Induce polycythaemia in female mice of the same strain, A, = total radioactivity injected,
weighing 16 to 18 g. Place the mice in a hypoxic chamber 7.5 = total blood volume as per cent body
and reduce the pressure to 0.6 atmospheres. After 3 days at M = body weight, in grams,
0.6 atmospheres, further reduce the pressure to 0.4 to 0.5 V; sample volume.
atmospheres and maintain the animals at this pressure for a
further 11 days (the partial vacuum is interrupted daily for a Calculate the potency by the usual statistical methods for a
maximum of 1 hour at about 11:00 a.m., in order to clean parallel line assay. Eliminate from the calculation any animal
where the packed cell volume is less than 54%, or where the
Ne ANG
Ste
Leet ate
A wae the cages and feed the animals). At the end of the specified
period, return the mice to normal atmospheric conditions. body weight is more than 24 g.
Randomly distribute the mice into cages, each containing B. In normocythaemic mice
6 animals, and mark them. The Assay is based on the measurement of stimulation of
Test solution (1) Dilute the substance to be examined in reticulocyte production in normocythaemic mice.
phosphate-albumin buffered saline pH 7.2 R1 to obtain a The Assay may be carried out using the following procedure:
concentration of 0.2 IU per mL. Test solution (1) Dilute the preparation being examined in
Test solution (2) Mix equal volumes of test solution (1) and phosphate-albumin buffered saline pH 7.2 R1 to obtain a
phosphate-albumin buffered saline pH 7.2 R1. concentration of 80 IU per mL.
Test solution (3) Mix equal volumes of test solution (2) and Test solution (2) Mix equal volumes of test solution (1) and
phosphate-albumin buffered saline pH 7.2 R1. phosphate-albumin buffered saline pH 7.2 R1.
vote od
aoe ed
ste ted
IWI-536 Estradiol Preparations 2016
Test solution (3) Mix equal volumes of test solution (2) and contents of a vial of erythropoietin EPBRP in water to give a
phosphate-albumin buffered saline pH 7.2 R1. solution containing 3012 IU per mL. Add 1 volume of SDS-
Reference solution (1) Dissolve erythropoietin EPBRP in PAGE sample buffer (concentrated) to each solution.
phosphate-albumin buffered saline pH 7.2 R1 to obtain a TESTS
concentration of 80 IU per mL. Dimers and related substances of higher molecular
Reference solution (2) Mix equal volumes of reference weight
solution (1) and phosphate-albumin buffered saline pH 7.2 R1. Comply with the test described for Erythropoietin Injection
Reference solution (3) Mix equal volumes of reference using the following solutions.
solution (2) and phosphate-albumin buffered saline pH 7.2 R1. (1) Dissolve a quantity of the powder in the mobile phase to
The exact concentrations of the test solutions and reference give a solution containing 1,000 IU of erythropoietin per mL.
solutions may need to be modified, based on the response (2) Dilute 0.02 mL of solution (1) to 1 mL with the mobile
t ls used. phase.
e assay procedure, randomly distribute Water
ve and strain (8-week old B6D2F1 mice Not more than 4.0% w/w, Appendix IX C, Method 1.
s. A minimum of 8 mice per cage is
animal subcutaneously with
reatment (one solution per cage)
The endotoxin limit concentration is less than 20 IU ina
volume containing 10,000 IU of Erythropoietin.
freated mice contains one
its (3 test solutions and ASSAY
Carry out the Assay as described for Erythropoietin Injection
using the following solutions:
A. In polycythaemic mice
procedure. Test solution (1) 0.2 IU per mL 1n phosphate-albumin buffered
The following method may be employed: saline pH 7.2 R1,
The volume of blood, dilution procedure and fly B. In normocythaemic mice
reagent may need to be modified to ensure maximug Test solution (1) 80 IU per mL in phosphate-albumin buffered
development and stability of fluorescence. saline pH 7.2 R1.
Colorant solution, concentrated Use a solution of thiazole
orange suitable for the determination of reticulocytes. Prep
at a concentration twice that necessary for the analysis. ealed container in the liquid stated on the label should
Proceed with the following dilution steps. Dilute whole blood himmediately after preparation but, in any case,
500-fold in the buffer used to prepare the colorant solution.
Dilute this solution 2-fold in the concentrated colorant
solution. After staining for 3 to 10 minutes, determine the
reticulocyte count microfluorometrically in a flow cytometer.
The percentage of reticulocytes is determined using a
The label of the ontainer states the number of IU
biparametric histogram: number of cells/red fluorescence
(620 nm). (Units) contained i
Calculate the potency by the usual statistical methods for a
parallel line assay.
STORAGE
Erythropoietin Injection should be protected from light.
Estradiol Injection
LABELLING Action and use
The label states the number of IU (Units) in a suitable dose- Estrogen.
volume.
DEFINITION
Estradiol Injection is a sterile solution of Estradiol B
ERYTHROPOIETIN FOR INJECTION in Ethyl Oleate or other suitable ester, in a suitablé
DEFINITION or in any mixture of these. It may contain suitable alcohols.
Erythropoietin for Injection is a freeze-dried, sterile The injection complies with the requirements stated under
preparation prepared from Erythropoietin Concentrated Parenteral Preparations and with the following requirements.
Solution. It is supplied in a sealed container. Content of estradiol benzoate, C,;H,;03
The contents of the sealed container comply with the requirements 90.0 to 110.0% of the stated amount.
IDENTIFICATION
IDENTIFICATION Appendix III A, using the following solutions.
A. It gives the appropriate response when examined using the (1) Add 10 mL of 2,2,4-trimethylpentane to a volume of the
conditions under Assay. injection containing 2 mg of Estradiol Benzoate and extract
B. Comply with Identification test B as described for with three 10 mL quantities of ethanol (70%). Wash the
Erythropoietin Injection. Prepare solution (1) by dissolving a combined extracts with 15 mL of 2,2,4-trimethylpentane,
quantity of Erythropoietin for Injection in water to contain evaporate the ethanolic extract to dryness using a rotary
2000 IU per mL. Prepare solution (2) by dissolving the evaporator and dissolve the residue in 2 mL of chloroform.
2016 Estradiol Preparations II-537
(2) 0.1% w/v of estradiol benzoate BPCRS in chloroform. MOBILE PHASE
CHROMATOGRAPHIC CONDITIONS A mixture of 1 volume of 1,4-dioxan and 9 volumes of

cyclohexane.
(b) Use the mobile phase as described below. SYSTEM SUITABILITY
(c) Apply 5 wL of each solution. The assay is not valid unless the resolution factor between the
peaks due to benzyl alcohol (if present) and estradiol
benzoate and between the peaks due to estradiol benzoate
(e) After removal of the plate, dry in air, spray with ethanolic and the internal standard is more than 1.5.
sulfuric acid (20%), heat at 105° for 10 minutes and examine
under ultraviolet hght (365 nm).
Calculate the content of C25H»,03 using the declared
MOBILE PHASE
content of C,5H»2 O03 in estradiol benzoate BPCRS.
STORAGE
Estradiol Injection should be protected from light. If solid
matter separates on standing it should be redissolved by
the chromatogram obtained with warming before use.
; in position and colour to that in the
chromatogram ob : LABELLING
The label states (1) that the preparation is for intramuscular
ASSAY injection only; (2) that any solid matter that has separated on
Carry out the method for* standing should be redissolved by warming before use.
Appendix II D.
For injections containing 6.2
benzoate :
Dissolve 15 mg of 4-hydroxybenzaldehydé (j
in 5 mL of 1,4-dioxan, add sufficient cyclah Estradiol Transdermal Patches
10 mL (solution A) and use the following 6
Action and use
(1) Add 1.0 mL of solution A to 10 mg of estradia] Estrogen.
benzoate BPCRS and add sufficient of a mixture
of cyclohexane and 1 volume of 1,4-dioxan to produce 1 DEFINITION
(2) Prepare in the same manner as solution (1) using a adiol Transdermal Patches contain Estradiol
quantity of the injection containing 10 mg of Estradiol ‘hydrate in a suitable matrix or reservoir presentation.
Benzoate but omitting the addition of solution A.
CTION
(3) Prepare in the same manner as solution (1) using a fe test 1s carried out to demonstrate the appropriate
quantity of the injection containing 10 mg of Estradiol
Benzoate.
For injections containing less than 0.2% w/v of
estradiol benzoate
Content of estra
Dissolve 15 mg of the internal standard in 10 mL of
1,4-dioxan, add sufficient cyclohexane to produce 100 mL
(solution B) and use the following solutions.
(1) Add 10 mL of solution B to 10 mg of estradiol
benzoate BPCRS and add sufficient of a mixture of 9 volumes
of cyclohexane and 1 volume of 1,4-dioxan to produce rom
100 mL.
(2) Dilute a quantity of the injection containing 1 mg of
Estradiol Benzoate to 10 mL with a mixture of 9 volumes of
cyclohexane and 1 volume of 1,4-dioxan. equivalent of 2 mg of estradiol in 5 mL
the aid of ultrasound, shake for 15 minut
(3) Add 1 mL of solution B to a quantity of the injection
containing 1 mg of Estradiol Benzoate and dilute to 10 mL
with the same solvent mixture.
(2) 0.04% w/v of estradiol hemihydrate BPCRS in absolute
=~ ya 4
ethanol, dissolved with the aid ofultrasound.
with szdica gel for chromatography (10 um) (uwPorasil is
suitable). (a) Use as the coating silica gel F254 (100 mm x 100 mm)
(Merck plates are suitable).
below. (b) Use the mobile phase as described below.
(c) Use a flow rate of 2 mL per minute. (c) Apply 10 uL of each solution.
(d) Use an ambient column temperature. (d) Develop the plate to 7 cm.
(e) Use a detection wavelength of 254 nm. (e) After removal of the plate, dry in a stream of warm air for
5 minutes, spray with methanolic sulfuric acid (50%) and heat
at 110° for 10 minutes. Allow to cool and examine under
~_ me ool
II-538 Estradiol Preparations 2016
MOBILE PHASE (1) Remove the release liner from a patch, score the exposed
2 volumes of acetone and 8 volumes of dichloromethane. surface and cover the sticky surface with a small piece of
glass wool. Place the patch in a flask containing sufficient
CONFIRMATION
ew awd
mobile phase to produce a solution containing the equivalent
The principal spot in the chromatogram obtained with of 0.01% w/v of estradiol, mix with the aid of ultrasound for
solution (1) corresponds in position and colour to that in the 10 minutes, shake mechanically for 1 hour and, if necessary,
chromatogram obtained with solution (2). filter through a glass-fibre filter paper (Whatman GF/Cis
B. In the test for Uniformity of content, the chromatogram suitable). Using a disposable syringe, collect part of the
obtained with solution (1) shows a peak with the same supernatant liquid and filter through a membrane filter with
retention time as the principal peak in the chromatogram a pore size of 0.45 um.
obtained with solution (2). (2) Dilute 1 volume of a 0.1% w/v solution of estradiol
hemthydrate BPCRS in acetonitrile to 10 volumes with the
mobile phase.
5 for liquid chromatography, CHROMATOGRAPHIC CONDITIONS
Appendix I p, ig the following solutions.
(1) Remove thé release “liners from 10 patches, score the substances may be used but inject 20 wL of each solution.
exposed surfaces an e sticky surfaces with small
pieces of glass wool. Pla atches iin a flask containing
sufficient mobile phase ‘ solution containing the Calculate the content of C;gH»,O, in the transdermal patch
equivalent of 0.01% w/v of § ,mix with the aid of using the declared content of C,gH»,O>, in estradiol
ultrasound for 10 minutes, s ake me hanically for 1 hour hemthydrate BPCRS.
and filter through a glass-fibre ASSAY
is suitable). If the filtrate is not‘cle : Use the average of the 10 results obtained in the test for
membrane filter with a pore size of 0.4 Uniformity of content.
(2) Dilute 1 volume of solution (1) to 1
LABELLING
mobile phase.
CHROMATOGRAPHIC CONDITIONS equivalent amount of estradiol per patch.
(a) Use a stainless steel column (25 cm x 4.6 mm) pack
with octadecysilyl silica gel for chromatography (10 um)
below.
idiol Vaginal Tablets
aginal Tablets from different manufacturers, whilst
with the requirements of the monograph, are not
(d) Use an ambient column temperature. unless otherwise justified and authorised.
(f) Inject 50 wL of each solution. Acti
Estrogen.
retention time of the principal peak. DEFINITION
MOBILE PHASE Estradiol Vaginal Ta tain Estradiol Hemihydrate.
35 volumes of acetonitrile and 65 volumes of water. They are formulated so dicament is released over
a period of several hours.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained PRODUCTION |
with solution (2), the signal to-notise ratio for the peak due to
Estradiol is at least 10.
LIMITS

the principal peak in the chromatogram obtained with Vaginal Preparations and with the following requirements.
solution (2) (1%);
Content of estradiol, C,3;H,,0,
the sum of the areas of any such peaks is not greater than 95.0 to 105.0% of the stated amount.
obtained with solution (2) (2%). IDENTIFICATION
Disregard any peak due to diethyltoluamide.
(1) To a quantity of vaginal tablets containing the equivalent
Comply with the requirements stated under uniformity of
of 0.38 mg of estradiol, add 50 mL of propan-2-ol and allow
content, Appendix XII C3, Test C, with respect to the
to disintegrate by stirring overnight. Centrifuge the resulting
individual content of each dosage unit and using the
suspension, evaporate an aliquot of 40 mL of the supernatant
following method of analysis. Carry out the method for liquid
to dryness and dissolve the residue in 3 mL of propan-2-ol.
Evaporate to dryness, reconstitute with 300 pL of absolute
solutions.
Saw
a
ethanol to produce a solution containing the equivalent of
2016 Estradiol Preparations ITI-539
0.1% w/v of estradiol, centrifuge and use the supernatant Time Mobile phase A Mobile phase B Comment
liquid. (Minutes) (% viv) (% viv)
(2) 0.1% w/v of estradiol hemihydrate BPCRS in absolute

wen
ae 0-35 80-15 20-85 linear gradient

ene)
ethanol. 35-49 15 85 isocratic
CHROMATOGRAPHIC CONDITIONS 49-50 1580 85-20 linear gradient
(a) Use as the coating silica ge (Kieselgel 60 HPTLC plates 50-55 80 20 re-equilibration
are suitable).
(c) Apply 5 uL of each solution. conditions the retention times relative to estradiol (retention
(d) Develop the plate to 8 cm. time about 26 min) are: impurity 2, about 0.7, impurity 3,
oval of the plate, dry in air and spray with about 0.96 and estrone, about 1.13.
acid (S%). Heat the plate at 105° for SYSTEM SUITABILITY
Ne

with solution (3), the resolution between estradiol and estrone
is at least 7.0.
LIMITS
ogram obtained with Identify any peaks in the chromatogram obtained with
yn and colour to that in the solution (1) due to impurity 3 and multiply the peak area by
4tiGt the correction factor 0.32.
the area of any peak corresponding to impurity 2 is not
retention time as the peak due to estradi greater than 1.5 times the area of the peak in the
chromatogram obtained with solution chromatogram obtained with solution (2) (1.5%);
TESTS the area of any peak corresponding to impurity 3 is not
Related substances greater than 1.3 times the area of the peak in the
Carry out the method for liquid chromatography, chromatogram obtained with solution (2) (1.3%);
Appendix III D, using the following solutions. the area of any other secondary peak is not greater than the
(1) To a quantity of vaginal tablets, add absolute ethano area of the principal peak in the chromatogram obtained with
produce a solution containing the equivalent of ion (2) (1.0%);
0.00024% w/v of estradiol. Stir for a minimum of 16 hours, urn of the areas of all secondary peaks is not greater than
shake thoroughly, and centrifuge. Evaporate 10 mL of the
supernatant to dryness. Dissolve the residue in 1.0 mL of
water and add 7.0 mL of a mixture of 2 volumes of acetone
and 5 volumes of toluene. Mix using a vortex mixer at
12 minute intervals for 1 hour and allow the mixture to stand
for 15 minutes before evaporating 5.0 mL of the organic
phase to dryness. Reconstitute the residue in 2 mL of absolute ,
Tablets containing
ethanol to produce a solution containing the equivalent of
0.00086% w/v of estradiol. Centrifuge and use the
stated under Tablets
tye oad supernatant liquid.
Carry out the method fo
(2) Dilute 1 volume of solution (1) to 100 volumes with Appendix III D, using the utions in solvent A.
absolute ethanol.
Solvent A equal volumes of acet °R1 and water.
(3) 0.0025% w/v of estradiol hemihydrate BPCRS and
(1) Add 7 mL of solvent A to on
0.0000125% w/v of estrone BPCRS in absolute ethanol.
absolute ethanol.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed (2) 0.0001% w/v of estradiol hemihydrate BPCRS in solvent A
with end-capped octadecylsilyl silica gel for chromatography (3) 0.0002% w/v of estradiol hemihydrate BPCRS and
Ne te
(5 um) (Waters Symmetry C18 is suitable). 0.00007% w/v of estrone BPCRS in solvent A.
tawas
(b) Use gradient elution and the mobile phase described CHROMATOGRAPHIC CONDITIONS
below.
(c) Use a flow rate of 1 mL per minute. with end-capped octadecylsilyl silica gel for chromatography
(d) Use an ambient column temperature. (4 um) (Nova-Pak C18 is suitable).
(e) Use a detection wavelength of 220 nm. (b) Use isocratic elution and the mobile phase described
(f) Inject 100 uL of each solution. below.
MOBILE PHASE (c) Use a flow rate of 1 mL per minute.
Mobile phase A acetomitrile. (d) Use an ambient column temperature.
Mobile phase B_ water. (e) Use a detection wavelength of 205 nm.
. Estradiol and Norethisterone Tablets

MOBILE PHASE 1 1
wg 450 volumes of water and 550 volumes of acetonitrile R1.

ae SYSTEM SUITABILITY Action and use
oe The test is not valid unless, in the chromatogram obtained Estrogen.
mh on) he nnbetween che Pais due © a

rNETION
Estradiol and Norethisterone Tablets contain Estradiol
DETERMINATION OF CONTENT Hemihydrate and Norethisterone. They are coated.
Calculate the content of CisH2402 in each tablet using the The tablets comply with the requirements stated under Tablets and
hemthydrate BPCRS. Content of estradiol, C,3H,,0,

Fthe 10 individual results obtained in the Content of norethisterone, C,,H>,O>
test for Unito f content. 95.0 to 105.0% of the stated amount.
STORAGE <« IDENTIFICATION
Kstradiol Vaginal A. Carry out the method for thin-layer chromatography,
LABELLING Appendix III A, using the following solutions.
The quantity of active ingy (1) Add 0.2 mL of water to two tablets and shake to disperse.
equivalent amount of estrady Add sufficient ethanol (96%) to produce a solution containing
IMPURITIES . 0.035% wiv ofNorethisterone, centrifuge and use the clear
£ this supernatant liquid.
The impurities limited by the réqui
oe monograph include those listed underg (2) A suitable concentration of estradiol hemihydrate BPCRS
we and: and norethisterone BPCRS in ethanol (96%).
(a) Use as the coating szlica gel F254 (Merck silica gel 60 Fos,4
elop the plate to 8 cm.
emoval of the plate, dry in air and spray with
furic acid (5%). Heat the plate at 105° for
and examine under wltraviolet ight (365 nm).
1. estra-1,3,5(10)-triene-3,6«,17{-triol (60-hydroxy-
estradiol),
clearly separated spéts with’ Ry values corresponding to those

observed in the chromatogram,.obtained with solution (2).
Nem,
fone] , , TESTS
eet I PCO ee G-one (6-keto- Dissolution |
Comply with the requirements for Monogra
Pharmacopoeia in the dissolution test for tablets atid
Appendix XII B1.
TEST CONDITIONS

per minute.
HO (b) Use 500 mL of a 0.3% w/v solution of sodium lauryl

sulfate in water, at a temperature of 37°, as the medium.
os 3. estra-1,3,5(10),6-tetraene-3,17B-diol (A6-estradiol). PROCEDURE

we Carry out the method for liquid chromatography,
“ Appendix III D, using the following solutions.
filter, discarding the first 5 mL of the filtrate. Use the filtered
os medium.
Poe (2) Dissolve a sufficient quantity of estradiol
ms hemihydrate BPCRS and norethisterone BPCRS in methanol
2016 Estradiol Preparations II-541
(80%) and dilute an aliquot with a 0.3% w/v solution of Carry out the method for liquid chromatography,
sodium lauryl sulfate in water; the concentration of the final Appendix III D, using the following solutions.
solution should be the same as that expected for solution (1). (1) Add 20 mL of the mobile phase to one tablet, mix with
(3) 0.0017% w/v of estradiol hemihydrate BPCRS, the aid of ultrasound, cool, add sufficient of the mobile phase
0.00084% w/v of norethisterone acetate BPCRS, 0.00066% w/v to produce 25 mL and centrifuge. Dilute the supernatant
of estrone BPCRS and 0.00034% w/v of norethisterone BPCRS liquid, if necessary, with the mobile phase to produce a
in the mobile phase. solution containing the equivalent of 0.002% w/v of estradiol.
CHROMATOGRAPHIC CONDITIONS (2) Dissolve sufficient quantities of estradiol
(a) Use a stainless steel column (25 cm x 4.6 mm) packed hemthydrate BPCRS and norethisterone BPCRS in the mobile
with end-capped octadecylsilylsilica gelier chromatography phase and dilute an aliquot with the mobile phase;
the concentrations in the final solution are the same as those
expected for solution (1).
(3) 0.0017% w/v of estradiol hemihydrate BPCRS,
0.00084% w/v of norethisterone acetate BPCRS, 0.00066% w/v
of estrone BPCRS and 0.00034% w/v of norethisterone BPCRS
The chromatographic conditions described under Dissolution
MOBILE PHASE may be used, but using an injection volume of 20 uL.
450 volumes of water and SYSTEM SUITABILITY
SYSTEM SUITABILITY The test is not valid unless, in the chromatogram obtained
with solution (3), the resolution factor between each pair of
peaks (estradiol and norethisterone, and estrone and
peaks (estradiol and norethisterone, an norethisterone acetate) is at least 1.0.
norethisterone acetate) is at least 1.0. DETERMINATION OF CONTENT
DETERMINATION OF CONTENT Calculate the content of C;3H24O02 and Cz9.H26O> in each
Calculate the total content of estradiol, C;gH»,O>, tablet using the declared content of C,;gH»,O> 1n estradiol
norethisterone, C59H»,¢O>, in the medium from the hemthydrate BPCRS and the declared content of C29H»2.O. in
chromatograms obtained and using the declared conte norethisterone BPCRS.
C18H240> in estradiol hemihydrate BPCRS and C29H2,6O> 1
norethisterone BPCRS.
Estrone
(1) Powder 20 tablets. Add 20 mL of the mobile phase to a
quantity of the powdered tablets containing the equivalent of
cong ing the equivalent of 2 mg or more
5 mg of estradiol, mix with the aid of ultrasound and add
and 2% w/w 6r mE estradiol
sufficient mobile phase to produce 25 mL. Centrifuge and
Weigh and powd
use the clear supernatant liquid.
(2) 0.0001% w/v of estrone BPCRS in the mobile phase. solutions.
(3) 0.0017% w/v of estradiol hemihydrate BPCRS,
0.00084% w/v of norethisterone acetate BPCRS, 0.00066% w/v
in the mobile phase. Dilute 1 volume of the clear superna
CHROMATOGRAPHIC CONDITIONS 10 volumes with mobile phase.
The chromatographic conditions described under Dissolution (2) 0.002% w/v of estradiol hemthydrate B
may be used, but using an injection volume of 20 uL. phase.
SYSTEM SUITABILITY (3) 0.0017% w/v of estradiol hemihydrate BPCRS¢
0.00084% w/v of norethisterone acetate BPC.RS, 0.00066% w/v
with solution (3), the resolution factor between each pair of
away
Ua
norethisterone acetate) is at least 1.0. CHROMATOGRAPHIC CONDITIONS
LIMITS
The chromatographic conditions described under Dissolution
may be used, but using an injection volume of 20 UL.
SYSTEM SUITABILITY
the area of any peak corresponding to estrone is not greater
than the area of the principal peak in the chromatogram The test is not valid unless, in the chromatogram obtained
obtained with solution (2) (0.5%). with solution (3), the resolution factor between each pair of
norethisterone acetate) is at least 1.0.
Tablets containing less than the equivalent of 2 mg and/or
ALN
less than 2% w/w of estradiol comply with the requirements
stated under Tablets using the following method of analysis.
DETERMINATION OF CONTENT (e) After removal of the plate, dry in air and spray with
Calculate the total content of estradiol, C;3H»,O>, in the ethanolic sulfuric acid (5%). Heat the plate at 105° for
aN,
tablets using the declared content of C,;gH24O> in estradiol 15 minutes and examine under wltraviolet ight (365 nm).
hemihydrate BPCRS. MOBILE PHASE
For norethisterone 10 volumes of acetone and 90 volumes of dichloromethane.
SYSTEM SUITABILITY
STORAGE solution (1) shows two clearly separated spots.
Estradiol and Norethisterone Tablets should be protected
CONFIRMATION
from light.
ra ad
wt AN chromatogram obtained with solution (2).
B. In the test for Uniformity of content, the chromatogram
obtained with solution (1) shows two peaks having the same
retention times as the peaks due to estradiol and
norethisterone acetate in the chromatogram obtained with
A. Estrone. solution (2).
TESTS
Dissolution
Estradiol and Norethist Appendix XII B1.
Tablets TEST CONDITIONS
Action and use (a) Use Apparatus 2, rotating the paddle at 50 revolutions
Estrogen. per minute.
(b) Use 500 mL of a 0.3% w/v solution of sodium lauryl
DEFINITION sulfate, at a temperature of 37°, as the medium.
Estradiol and Norethisterone Acetate Tablets contain
Estradiol Hemihydrate and Norethisterone Acetate. They
it the method for liquid chromatography,
coated.
die III D, using the following solutions.
minutes withdraw a sample of the medium and
e filtered medium, diluted with a 0.3% w/v
Content of estradiol, C,;;H,,O0, and norethisterone ssdium lauryl sulfate if necessary, to produce a
acetate, C,7H>3;03
(2) Dissolve’ cier antities of estradiol

Content Limits hemihydrate BPCRS | norethisterone acetate BPCRS ina
Norethisterone Norethisterone 0.3% w/v solution of
Estradiol Acetate Estradiol Acetate
mg mg % of stated amount % of stated amount
sulfate to produce conc
2 1 95.0 to 105.0 92.5 to 105.0 same as those expected for
1 1 95.0 to 105.0 92.5 to 105.0
1 0.5 95.0 to 105.0 92.5 to 105.0
Pon wd
0.5 0.1 95.0 to 105.0 90.0 to 105.0 with end-capped octadecylsilyl silica gel'fo
(b) Use isocratic elution and the mobile p ase de
IDENTIFICATION below.
(1) Add 0.2 mL of water to two tablets and shake to disperse.
aes Add sufficient ethanol (96%) to produce a solution containing (e) Use a detection wavelength of 235 nm.
0.035% w/v of Norethisterone Acetate, centrifuge and use (f) Inject 200 wL of each solution.
the clear supernatant liquid. MOBILE PHASE
(2) A suitable concentration of estradiol hemthydrate BPCRS 450 volumes of water and 550 volumes of acetonitrile.
and norethisterone acetate BPCRS in ethanol (96%).
SYSTEM SUITABILITY
(a) Use as the coating silica gel F254 (Merck silica gel 60 Fos, with solution (2), the resolution factor between each pair of
plates are suitable). peaks (estradiol and norethisterone, and estrone and
(b) Use the mobile phase as described below. norethisterone acetate) is at least 1.0.
nw and (c) Apply 2 wL of each solution.
ryt
rN eae
2016 Estradiol Preparations III-543
DETERMINATION OF CONTENT (2) Dissolve sufficient quantities of estradiol

Calculate the total content of estradiol, C;gH»,0>., and of hemthydrate BPCRS and norethisterone acetate BPCRS in the
norethisterone acetate, C»H»g03, in the medium using the mobile phase and dilute with sufficient mobile phase to
declared content of C,;gH»4O>, in estradiol hemthydrate BPCRS produce concentrations in the final solution the same as
and the declared content of C.H» 803 in norethisterone those expected for solution (1).
acetate BPCRS. (3) 0.0017% w/v of estradiol hemihydrate BPCRS,
Estrone and norethisterone 0.00084% w/v of norethisterone acetate BPCRS, 0.00066% w/v
Weigh and powder 20 tablets. Carry out the method for of estrone BPCRS and 0.00034% w/v of norethisterone BPCRS
liquid chromatography, Appendix III D, using the following in the mobile phase.
solutions in mobile phase. CHROMATOGRAPHIC CONDITIONS
(1) Add 20 mL of the mobile phase to a quantity of the The chromatographic conditions described under Dissolution
may be used but injecting 20 uL of each solution.
wee aed nd add sufficient mobile phase to produce
SYSTEM SUITABILITY
L and use the clear supernatant liquid.
(2) Add20 n with solution (3), the resolution factor between each pair of
powdered tablets: containing 2.5 mg of Norethisterone
A f ultrasound and add sufficient
L. Centrifuge and use the
clear supernatant liquic DETERMINATION OF CONTENT
(3) 0.0001% w/v of estron Calculate the content of C;g3H,»,O, and of C22H».03 in each
tablet using the declared content of C;gH»,O> in estradiol
hemthydrate BPCRS and the declared content of C.,H»,03 in
norethisterone acetate BPCRS.
0.00084% w/v of norethisterone aceta C
of estrone BPCRS and 0.00034% w/v of ASSAY
For estradiol
2% v/w of estradiol
may be used but injecting 20 pL of each solution:
SYSTEM SUITABILITY test for Uniformity of content.
The test is not valid unless, in the chromatogram obtaine} ablets containing 2 mg or more and 2% w/w or
with solution (5), the resolution factor between each pair of * »f estradiol
LIMITS
In the chromatogram obtained with solution (1) quantify the
area of any peak due to estrone using the principal peak in coptaining the equivalent of 10 mg of
the chromatogram obtained with solution (3). estradiol, ‘the aid of ultrasound and centrifuge.
In the chromatogram obtained with solution (2) quantify the Dilute 10 mL ¢
area of any peak due to norethisterone using the principal the mobile phase.
acetate BPCRS, 0.00066% w/v

Content of Limits
norethisterone BPCRS.
Estradiol Norethisterone Acetate Estrone Norethisterone
mg mg % %
CHROMATOGRAPHIC CONDITIO?
The chromatographic conditions desc be der Dissolution
2 1 0.5 0.5
may be used but injecting 20 pL of eac:
1 1 0.5 0.5
SYSTEM SUITABILITY
1 0.5 0.5 0.5 The test is not valid unless, in the chromatogram®*obtained
0.5 0.1 0.5 1.0 with solution (5), the resolution factor between each pair of
Uniformity of content DETERMINATION OF CONTENT
Calculate the content of C,;gH»,O> in each tablet using the
of estradiol or less than 2 mg and/or less than 2% w/w of
declared content of C,g3H»4,O> in estradiol
Norethisterone Acetate comply with the requirements stated
hemthydrate BPCRS.
out the method for liquid chromatography, Appendix III D, For norethisterone acetate
using the following solutions. For tablets containing less than 2 mg and/or less than
(1) Add 20 mL of the mobile phase to one tablet, mix with 2% w/w of estradiol
the aid of ultrasound, cool, add sufficient of the mobile phase Use the average of the 10 individual results obtained in the
to produce 25 mL and centrifuge. Dilute the supernatant test for Uniformity of content.
liquid if necessary, with the mobile phase to produce a
solution containing the equivalent of 0.002% w/v of estradiol.
seyret
Sata
II-544 Estramustine Preparations 2016
STORAGE MOBILE PHASE

Estradiol and Norethisterone Acetate Tablets should be Equal volumes of butan-2-one, propan-2-ol and triethylamine
awa
tet et! protected from light. hydrogen carbonate solution.
hala
|
LABELLING LIMITS
The label states the quantity of estradiol hemihydrate in In the chromatogram obtained with solution (1):
terms of the equivalent amount of estradiol. any secondary spot due to 176,17’B-bis {3-
IMPURITIES [bis(2-chloroethyl)carbamoyloxy]estral,3,5(10)-trienyl}
The impurities limited by the requirements of this pyrophosphate is not more intense than the corresponding
monograph include: spot in the chromatogram obtained with solution (3) (2%);
A. Estrone, any secondary spot due to estramustine is not more intense
B. Noreth than the corresponding spot in the chromatogram obtained
Any other secondary spot is not more intense than the spot in
ASSAY
Estramustin Shake a quantity of the mixed contents of 20 capsules
Action and use containing the equivalent of 0.28 g of Estramustine
Cytotoxic alkylating agent? Phosphate with 20 mL of water, dilute to 50 mL with water
and filter. Dilute 5 mL of the filtrate to 100 mL with ethanol
DEFINITION (50%) and measure the absorbance of the resulting solution at
Estramustine Phosphate Capsul the maximum at 275 nm, Appendix II B. Calculate the
Sodium Phosphate. content of C23H32Cl,NO¢P taking 15.4 as the value of
The capsules comply with the requirements St Capsules A(1%, 1 cm) at the maximum at 275 nm.
and with the following requirements. LABELLING
Content of estramustine phosphate, C,3;H3,GI The quantity of active ingredient is stated in terms of the
92.5 to 107.5% of the stated amount. | equivalent amount of estramustine phosphate.
IDENTIFICATION
A. Shake a quantity of the contents of the capsules
containing the equivalent of 0.2 g of Estramustine Phosphat
with 10 mL of methanol, filter and evaporate the filtrate to
estramustine sodium phosphate (RS 128). In preparing the
potassium bromide disc precautions should be taken to
exclude moisture and avoid excessive grinding; if necessary
heat the prepared disc at 90° for 2 minutes. Estriol in a suitable basis.
B. A 1% ww solution of the residue obtained in test A yields e requirements stated under Topical
the reactions characteristic of sodium salts, Appendix VI. Semi-solid Preparati th the following requirements.
TESTS Content of estriol, C

Related substances 95.0 to 105.0% of the
Carry out the method for thin-layer chromatography, IDENTIFICATION
Appendix III A, using the following solutions in a mixture of A. Carry out the method for thin-layer
1 volume of triethylamine and 49 volumes of methanol. Appendix III A, using the following soluti
(1) 4.0% w/v of the residue obtained in test A for (1) To a quantity of cream containing
Identification. 50 mL of solvent, heat on a water bath 4!
(2) 0.020% w/v of the residue obtained in test A for cream has completely dispersed, cool the con
Identification. centrifuge and use the supernatant liquid.
(3) 0.080% w/v of 178,17’ B-bis{3- (2) 0.004% w/v of estriol BPCRS.
[bis (2-chloroethyl) carbamoyloxy]estral,3,5(10)-trienyl\ (3) 0.004% w/v each of estriol BPCRS and
pyrophosphate BPCRS. prednisolone BPCRS.
(4) 0.040% of estramustine BPCRS. CHROMATOGRAPHIC CONDITIONS
CHROMATOGRAPHIC CONDITIONS (a) Use a silica gel 60 high performance precoated plate
(a) Use as the coating silica gel. (Merck HPTLC silica gel 60 is suitable).
(b) Use the mobile phase as described below. (b) Use the mobile phase as described below.
(c) Apply 10 uL of each solution. (c) Apply 5 uL of each solution.
(d) Develop the plate to 15 cm. (d) Develop the plate to 15 cm.
(e) After removal of the plate, dry in air, spray with (e) After removal of the plate, dry the plate in a horizontal
methanolic sulfuric acid (20%) and heat at 110° for position at 100 to 105°. Dilute 2 mL of sulfuric acid to
10 minutes. 100 mL with ethanol (96%) and spray the solution evenly
onto the plate. Examine the plate in daylight.
2016 - Estropipate Preparations TI-545
MOBILE PHASE ; the sum of the areas of any secondary peaks is not greater than
10 volumes of methanol and 90 volumes of dichloromethane. twice the principal peak in the chromatogram obtained with
solution (2) (1%).
SYSTEM SUITABILITY
(3) (0.05%).
CONFIRMATION
ASSAY
The principal spot in the chromatogram obtained with Carry out the method for liquid chromatography,
solution (1) is similar in position, colour and size to that in Appendix III D, using the following solutions in methanol.
(1) To a quantity of cream containing 0.5 mg of Estriol add
20 mL of methanol, heat on a water bath and mix until the
-waNe
cream has completely dispersed, allow to cool to room
-vas 4 temperature and add sufficient methanol to produce 25 mL,
transfer to a centrifuge tube and cool the contents in ice for
15 minutes, centrifuge and dilute 5 volumes of the
supernatant liquid to 100 volumes with methanol.
(2) 0.0001% w/v of estriol BPCRS.
(3) 0.01% w/yv of estriol impurity standard BPCRS.
continuous stirring throug! CHROMATOGRAPHIC CONDITIONS
Related substances The chromatographic procedure described under Related
Carry out the method for lig substances may be used.
SYSTEM SUITABILITY
to estriol and 16-epi-estriol is at least 2.5.
temperature and add sufficient solvent to prod, en
Cool the contents in ice for 15 minutes, centrifuge’ and ise
the supernatant liquid. Calculate the content of C;g3H»,O3 in the cream using the
(2) Dilute 5 volumes of solution (1) to 100 volumes, fug declared content of C,;3H»4O03 in estriol BPCRS.
dilute 10 volumes of this solution to 100 volumes.
(4) 0.01% w/v of estriol impurity standard BPCRS.
below.
(c) Use a flow rate of 1 mL per minute. with the following requi S...
(d) Use a column temperature of 35°. Content of estropipate, isl: O;S,C,HoN2

(e) Use a detection wavelength of 280 nm. 95.0 to 105.0% of the sta amount.
(f) Inject 10 nL of each solution. IDENTIFICATION a

MOBILE PHASE In the Assay, the chromatogram 6 ith solution (1)
shows a peak with the same retention time ; the principal
peak in the chromatogram obtained w jon (2).
For solutions (3) and (4), when the chromatograms are TESTS
recorded under the prescribed conditions, the retention times Free estrone
for estriol and 16-epi-estriol are about 5 minutes and about Carry out the method for liquid chromatography,
7 minutes respectively. Appendix ITI D, using the following solutions.
SYSTEM SUITABILITY
(1) Shake a quantity of the powdered tablets containing 5 mg
of Estropipate with 20 mL of methanol (50%) for 30 minutes,
The test is not valid unless, (a) in the chromatogram
centrifuge and filter the supernatant liquid.
peaks due to estriol and 16-epi-estriol is at least 2.5 and (b) (2) 0.0005% w/v of estrone BPCRS in methanol (50%).
in the chromatogram obtained with solution (3) the signal-to- CHROMATOGRAPHIC CONDITIONS
noise ratio of the principal peak is at least 10. | (a) Use a stainless steel column (30 cm x 3.9 mm) packed
LIMITS with end-capped octadecylsilyl silica gel for chromatography
In the chromatogram obtained with solution (1): (10 um) (uBondapak C18 is suitable).
the area of any secondary peak is not greater than the area of (b) Use isocratic elution and the mobile phase described
twee AY the principal peak in the chromatogram obtained with below.
solution (2) (0.5%); (c) Use a flow rate of 1.5 mL per minute.
IWI-546 Ethambutol Preparations 2016

(f) Inject 20 wL of each solution. A. Extract a quantity of the powdered tablets containing
MOBILE PHASE
50 mg of ethambutol hydrochloride with 5 mL of methanol,
filter and evaporate the filtrate to dryness. The infrared
35 volumes of acetonitrile and 65 volumes of 0.025M potassium
concordant with the reference spectrum of ethambutol
SYSTEM SUITABILITY hydrochloride (RS 134).
The peak due to estrone has a retention time, relative to the B. Shake a quantity of the powdered tablets containing 0.1 g
peak due to estropipate, of about 5. of ethambutol hydrochloride with 10 mL of water, filter and
LIMITS add to the filtrate 2 mL of a 1% w/v solution of copper(m)
In the chromatogram obtained with solution (1): sulfate followed by 1 mL of 1M sodium hydroxide. A blue
colour is produced.
corresponding to estrone is not greater
‘peak in the chromatogram obtained with 2-Aminobutanol
2 mg and/or less than 2% w/w and a mixture of 10 volumes of 13.5m ammonia, 15 volumes
requirements stated under of water and 75 volumes of methanol as the mobile phase.
Tablets using the following thod of analysis. Carry out the Apply separately to the plate 2 uL of each of the following
method for liquid chromato; , Appendix III D, using the solutions. For solution (1) shake a quantity of the powdered
following solutions. tablets containing 0.50 g of ethambutol hydrochloride for
5 minutes with sufficient methanol to produce 10 mL.
(1) Add 20 mL of water to on
Solution (2) contains 0.050% w/v of 2-aminobutan-1-ol in
30 minutes, add 20 mL of met:
methanol. After removal of the plate, allow it to dry in air,
for a further 30 minutes, dilute to 504
heat at 110° for 10 minutes, cool, spray with ninhydrin
(50%) and filter. Dilute 10 mL of the fil:
solution R1 and heat at 110° for 5 minutes. Any spot
methanol (50%).
corresponding to 2-aminobutanol in the chromatogram
(2) 0.0015% w/v of estropipate BPCRS in metha obtained with solution (1) is not more intense than the spot
CHROMATOGRAPHIC CONDITIONS in the chromatogram obtained with solution (2) (1%).
The chromatographic procedure described under Fre ASSAY
estrone may be used. Weigh and powder 20 tablets. Add 20 mL of 2m sodium
DETERMINATION OF CONTENT voxade to a quantity of the powdered tablets containing
Calculate the content of C;gH»,05S,C,H),9N> in each tablet | thambutol hydrochloride, mix with the aid of
using the declared content of C,gH2205S8,C4H) 9Ne2 in d for 5 minutes and extract with three successive
estropipate BPCRS. antities of a mixture of 3 volumes of chloroform and
pan-2-ol. Filter each extract successively
ASSAY
filter consisting of anhydrous sodium sulfate
tom plug moistened with a mixture of
iq and 1 volume of propan-2-ol and
solutions.
wash the plug L of the same solvent mixture.
(1) Shake a quantity of the powdered tablets containing 3 mg Add 100 mL of ank etic acid to the combined
of Estropipate with 40 mL of methanol (50%) for 30 minutes, wry out Method I for non-
dilute to 100 mL with the same solvent and filter. aqueous titration, Append using 1-naphtholbenzein
(2) 0.003% w/v of estropipate BPCRS in methanol (50%). solution as indicator. Each £0.1m perchloric acid VS is
The chromatographic procedure described under Free

estrone may be used.
Calculate the content of C;3H..05S,C,Hj9N> in the tablets Ethanolamine Oleate Injection

using the declared content of C;3H2.05S,C4,Hj9N> in DEFINITION :
estropipate BPCRS. Ethanolamine Oleate Injection is a sterile solution containing
5% wiv of Ethanolamine Oleate, prepared by the interaction
of Ethanolamine and Oleic Acid, in Water for Injections.
Ethambutol Tablets The injection complies with the requirements stated under
Action and use Content of oleic acid, C,;3H3;,0,
Antituberculosis drug. 3.9 to 4.5% wiv.
DEFINITION Content of ethanolamine, C;,H;NO

Ethambutol Tablets contain Ethambutol Hydrochloride. 0.85 to 0.95% w/v.
The tablets comply with the requirements stated under Tablets and TESTS
with the following requirements. Alkalinity
Content of ethambutol hydrochloride,
C,9H24N,02,2HCI1
vo we eye
2016 Ethosuximide Preparations TII-547
ASSAY filter, acidify the filtrate with 0.15 mL of sulfuric acid, add
For oleic acid 3 mL of ether, shake and allow to separate. Evaporate the
To 10 mL add 20 mL of 0.05m sulfuric acid VS and extract ether layer to dryness and heat the residue on a water bath
with three 25 mL volumes of chloroform, washing each extract for 5 minutes with 0.2 mL of glacial acetic acid and 2 mL of
with the same 10 mL of water. Reserve the aqueous solution orthophosphoric acid. A pink colour with an intense orange
and washings for the Assay for ethanolamine. Evaporate the fluorescence is produced.
combined extracts to dryness, dissolve the residue in ethanol TESTS
(96%) previously neutralised to phenolphthalein solution R1
and titrate with 0.1M sodium hydroxide VS using
phenolphthalein solution R1 as indicator. Each mL of
of Ethinylestradiol comply with the requirements stated
0.1M sodium hydroxide VS is equivalent to 28.25 mg of
out the method for liquid chromatography, Appendix III D,
ine
of acid in the combined aqueous solution (1) Add 2 mL of the mobile phase to one tablet, allow to
d in the Assay for oleic acid with stand for 5 minutes, mix with the aid of ultrasound for
0.1m sodium hy S using methyl orange solution as 5 minutes and centrifuge. Dilute the supernatant liquid with
indicator. Each mJ M sulfuric acid VS is equivalent to the mobile phase, if necessary, to produce a solution
expected to contain 0.0005% w/v of Ethinylestradiol.
STORAGE % (2) 0.0005% w/v of ethinylestradiol BPCRS in the mobile
Ethanolamine Oleate Injeéiion’s d be protected from phase.
wo fat
light. CHROMATOGRAPHIC CONDITIONS
(5 um) (Zorbax ODS is suitable).
Ethinylestradiol Tablets (b) Use isocratic elution and the mobile phase described
below.
Action and use
Estrogen. (c) Use a flow rate of 1.5 mL per minute.
DEFINITION
Ethinylestradiol Tablets contain Ethinylestradiol.
t 20 uL of each solution.
The tablets comply with the requirements stated under Tablets ani
PHASE
s of water and 60 volumes of acetonitrile.
Content of ethinylestradiol, C,)H,,0,
90.0 to 110.0% of the stated amount. ON OF CONTENT
IDENTIFICATION
0.25 mg of Ethinylestradiol with four 20-mL quantities of.
acetone, filter each extract in turn, evaporate the combined STORAGE
filtrates to dryness on a water bath in a current of nitrogen Ethinylestradiol tablets shouldbe protected from light.
and dissolve the residue in 0.25 mL of acetone.
(2) 0.1% w/v of ethinylestradiol BPCRS in acetone.

Ethosuximide Capsules
(c) Apply 20 uL of each solution. Action and use
Antiepileptic.
(e) After removal of the plate, dry in air, spray with ethanolic DEFINITION
teww 4 sulfuric acid (20%), heat at 110° for 10 minutes and examine Ethosuximide Capsules contain Ethosuximide.
ran a
under ultraviolet light (365 nm) and in daylight.
evan
d
MOBILE PHASE and with the following requirements.
10 volumes of ethanol (96%) and 90 volumes of toluene. Content of ethosuximide, C;H,,NO,
eo Nt
CONFIRMATION
By each method of visualisation the principal spot in the IDENTIFICATION
chromatogram obtained with solution (1) corresponds in A. Heat a quantity of the contents of the capsules containing
position and colour to that in the chromatogram obtained 0.1 g of Ethosuximide with 0.2 g of resorcinol and 0.1 mL of
with solution (2). sulfuric acid at 140° for 5 minutes, add 5 mL of water, make
wa
aiwt
ay
te B. Triturate a quantity of the powdered tablets containing alkaline with 5m sodium hydroxide and add 0.2 mL to a large
0.1 mg of Ethinylestradiol with 0.5 mL of 0.1M sodium volume of water. A bright green fluorescence is produced.
hydroxide and 5 mL of water, allow to stand for 5 minutes,
ewe ay
IW-548 Ethosuximide Preparations 2016
B. To a quantity of the contents of the capsules containing 10 mL of the internal standard solution, shake with 10 g of
tes eel
0.5 g of Ethosuximide add 15 mL of a 40% w/v solution of anhydrous sodium sulfate and filter.
"hee ld
wwe mal sodium hydroxide. Boil under a reflux condenser for The chromatographic procedure may be carried out using a
30 minutes, cool, acidify with hydrochloric acid and extract glass column (1.5 m x 4 mm) packed with acid-washed,
with three 30 mL quantities of ether. Wash the combined silanised diatomaceous support (80 to 100 mesh) coated with
extracts with 5 mL of water and evaporate to dryness. The 3% w/w of cyanopropylmethyl phenyl methyl silicone fluid
melting point of the residue, after recrystallisation from toluene (OV-225 is suitable) and maintained at 165°.
and petroleum spirit (boiling range, 40° to 60°), is about 102°,
Appendix V A.
Appendix V G, and calculate the content of C7H,,;NOz,,
ASSAY weight in volume, using the declared content of C7H,,NO,
Weigh 20 capsules. Open the capsules carefully without loss in ethosuximide BPCRS.
of shell l, express as much of the contents as possible
ether, discard th
temperatur
Etidronate Tablets
quantity of the contents Action and use
idein 30 mL of Bisphosphonate; treatment of osteoporosis; Paget’s disease.
thod II for non-aqueous
gneson solution as DEFINITION
IM, hydroxide VS as Etidronate Tablets contain Etidronate Disodium.
Content of etidronate disodium, C,H;Na,0-P,
IDENTIFICATION
Ethosuximide Oral Solution A. To a quantity of the powdered tablets containing 1 g of
Etidronate Disodium, add 10 mL of water and shake for
Action and use
5 minutes. Filter the solution (Whatman No.4 filter is
Antiepileptic.
uitable) and collect thefiltrate. Add 15 mL of methanol to
DEFINITION
Ethosuximide Oral Solution is a solution of Ethosuximide in
a suitable flavoured vehicle.
Content of ethosuximide, C,H,,NO,
IDENTIFICATION
A. Extract a quantity containing 0.5 g of Ethosuximide with
Dissolution
two 30 mL quantities of chloroform, filter the combined
Comply with the requirem
extracts through absorbent cotton and evaporate the filtrate
and capsules, Appendix XII
to dryness. Heat 0.1 g of the residue with 0.2 g of resorcinol
and 0.1 mL of sulfuric acid at 140° for 5 minutes, cool, add TEST CONDITIONS &
5 mL of water, make alkaline with 5m sodium hydroxide and
add 0.2 mL to a large volume of water. A bright green per minute.
fluorescence is produced. (b) Use 900 mL of water, at a temperatute:
B. In the Assay, the chromatogram obtained with solution medium.
(2) shows a peak with the same retention time as that due to PROCEDURE
ethosuximide BPCRS in the chromatogram obtained with
solution (1).
ASSAY (1) After 30 minutes withdraw a sample of the medium and
Carry out the method for gas chromatography, filter. Use the filtered medium, diluted with water, if
Appendix III B, using the following solutions. For solution necessary, to produce a solution expected to contain
(1) add 2 mL of a 3.0% w/v solution of dimethyl phthalate 0.0222% w/v of Etidronate Disodium.
(internal standard) in chloroform to 25 mL of a 0.2% w/v
(2) 0.0222% w/v of etidronate disodium BPCRS in water.
solution of ethosuximide BPCRS in chloroform. Prepare
solution (2) in the same manner as solution (3) but omit the CHROMATOGRAPHIC CONDITIONS
internal standard. For solution (3) add 10 mL of water and (a) Use a stainless steel column (15 cm x 4.6 mm) packed
2 g of sodium hydrogen carbonate to a weighed quantity of the with anion exchange resin (10 um) (Waters IC-Pak 1s
oral solution containing 0.25 g of Ethosuximide and extract suitable).
with five 25 mL quantities of chloroform, washing each extract (b) Use isocratic elution and the mobile phase described
with the same 10 mL of water. To the combined extracts add below.
aint ata
4
2016 Etodolac Preparations III-549
(d) Use an ambient column temperature. Centrifuge an aliquot of this solution for 10 minutes and
siete ey
(e) Use a detection wavelength of 240 nm. filter (a 0.45-um HVLP filter is suitable).
awe wl
(f) Inject 200 wL of each solution. (2) 0.022% w/v of ettdronate disodium BPCRS in water.
(g) Allow the chromatography to proceed for 15 minutes. CHROMATOGRAPHIC CONDITIONS
MOBILE PHASE The chromatographic conditions described under Dissolution

may be used.
0.0454% v/v solution of mitric acid in water.
Calculate the total content of etidronate disodium, Calculate the content of C,HsNa2O7P, in the tablets using
the declared content of C,H¢Na2O7P, in etidronate
C2H6Na207P2, in the medium from the chromatograms
disodium BPCRS.
IMPURITIES
monograph include those listed under Etidronate Disodium.
Etodolac Capsules
Action and use
DEFINITION
Etodolac Capsules contain Etodolac.
acid and dilute to 50 volumes with water
CHROMATOGRAPHIC CONDITIONS and with the following requirements.
Content of etodolac C,,H,,;NO;3
with anion exchange resin (5 um) (Allsep anion is suit 95.0 to 105.0% of the stated amount.
(b) Use isocratic elution and the mobile phase describe
IDENTIFICATION
below.
Q a quantity of the contents of the capsules containing
(c) Use a flow rate of 1.0 mL per minute. 0.1 g of Etodolac add 4 mL of 0.01m hydrochloric acid
(d) Use a column temperature of 35°. with the aid of ultrasound for 5 minutes, shaking
(e) Use a differential refractometer for detection. ally, centrifuge for 10 minutes, discard the
(f) Inject 100 wL of each solution. tdiquid and wash the residue with 4 mL of water.
1 Bes conemnge for 10minutes and discard the
MOBILE PHASE
0.2 volumes of anhydrous formic acid and 1000 volumes of th the aid of ultrasound for 5 minutes,
water, adjust to pH 3.5 with an 8% w/v solution of sodium d centrifuge for 10 minutes. Transfer
hydroxide.
When the chromatograms are recorded in the prescribed
conditions, the retention times are: phosphate, about liquid should be 2 or eSs
9.4 minutes; phosphite, about 11.5 minutes. discard the supernatant li
SYSTEM SUITABILITY
to phosphate and phosphite is at least 2.5.
LIMITS

the area of any peak corresponding to phosphite is not due to etodolac in the chromatogram obtained with
greater than the area of the corresponding peak in the solution (2).
chromatogram obtained with solution (2) (1%); TESTS
aA aN
the area of any peak corresponding to phosphate is not Dissolution
greater than the area of the corresponding peak in the
|

chromatogram obtained with solution (2) (1%). Pharmacopoeia in the dissolution test for tablets and capsules,
ASSAY Appendix XII B1, using as the medium 900 mL of phosphate
Weigh and powder 20 tablets. Carry out the method for buffer pH 7.5 and rotating the basket at 100 revolutions per
liquid chromatography, Appendix III D, using the following minute. Withdraw a 10 mL sample of the medium and
solutions. measure the absorbance of the filtered sample, suitably diluted
if necessary, at the maximum at 278 nm, Appendix II B.
(1) Weigh a quantity of the powdered tablets containing
Measure the absorbance of a suitable solution of
44 mg of Eudronate Disodium, add 190 mL of water,
etodolac BPCRS prepared by dissolving 30 mg in 100 mL of
aAwe
dissolve with the aid of ultrasound for 5 minutes and shake
A
the dissolution medium and diluting to a suitable volume

for 10 minutes. Dilute to 200 mL with water and mix well.
with the dissolution medium and using dissolution medium
III-550 Etodolac Preparations 2016
in the reference cell. Calculate the total content of etodolac, ODS1is suitable), (b) a mixture of 13 volumes of
C17H2;NO3; in the medium from the absorbances obtained acetonitrile, 19 volumes of methanol and 68 volumes of a
Faw eo 4
and from the declared content of C,;7H2,;NO3 in 1.74% w/v solution of dipotasstum hydrogen orthophosphate as
etodolac BPCRS. the mobile phase with a flow rate of 1.0 mL per minute and
Related substances (c) a detection wavelength of 225 nm. Adjust the mobile
Carry out the method for thin-layer chromatography, phase, if necessary, to give a retention time of 14 to
Appendix III A, using a silica gel F254 precoated plate 20 minutes for etodolac. The order of elution of peaks in the
(Merck silica gel 60 F254 plates are suitable), previously chromatogram obtained with solution (2) is etodolac
activated by heating at 105° for 1 hour, and a mixture of 8-methyl analogue and etodolac 1-methyl analogue.
0.5 volumes of glacial acetic acid, 30 volumes of absolute For solution (1) allow the chromatography to proceed for
ethanol and 70 volumes of toluene as the mobile phase. Place twice the retention time of the principal peak.
unlined tank containing a solution prepared The test is not valid unless, in the chromatogram obtained
with solution (2), the resolution factor between the two methyl
analogue impurities is at least 0.75.
Calculate the percentage content of etodolac 1-methy]l
analogue and etodolac 8-methyl analogue in etodolac by
reference to the corresponding peaks in the chromatogram
acetone.
solutions in obtained with solution (2). The total content is not greater
capsul
contents of the than 1.0%.
ASSAY
5 minutes and filter. For soluty
solution (1) to 200 volumes wi
dilute 1 volume of solution (2)
After removal of the plate, allow it to «ry
containing 50 mg of Etodolac with about 70 mL of
under ultraviolet light (254 nm). Any secoré
0.1m sodium hydroxide for 30 minutes, dilute to 100 mL with
chromatogram obtained with solution (1) is
0.1m sodium hydroxide, mix and filter through a glass-fibre
filter (Whatman GF/C is suitable) and dilute 2 mL of the
filtrate to 100 mL with the mobile phase. For solution (2)
than the spot in the chromatogram obtained with s¢ dilute 2 mL of a 0.05% w/v solution of etodolac BPCRS in
(0.25%).
0.1m sodium hydroxide to 100 mL with the mobile phase.
Etodolac acid dimer tion (3) add 2 mL of a 0.05% w/v solution of
Carry out the method for thin-layer chromatography, methyl analogue BPCRS in 0.1M sodium hydroxide to
Appendix III A, usinga silica gel F,5, precoated plate 0.05% w/v solution of etodolac BPCRS in
(Merck silica gel 60 Fy54 plates are suitable), previously hydroxide and dilute to 100 mL with the mobile
activated by heating at 105° for 1 hour, and a mixture of
3 volumes of glacial acetic acid, 17 volumes of 1,4-dioxan and
60 volumes of toluene as the mobile phase. Place the plate in
an unlined tank containing a solution prepared by dissolving
0.5 g of L-ascorbic acid in 20 mL of water and adding 80 mL
(Spherisorb OD$ "1
of methanol. Allow the solution to ascend 1 cm above the line
of acetonitrile and 5% 3 of phosphate buffer pH 4.75 as
of application on the plate, remove the plate and allow it to
‘rate of 1 mL per minute and
dry for at least 30 minutes. Apply separately to the plate
mM.
20 pL of each of the following solutions. For solution (1)
shake a quantity of the contents of the capsules containing
eave all
a as
0.6 g of Etodolac with 20 mL of acetone, mix with the aid of

ultrasound for 5 minutes and filter. Solution (2) contains
0.003% w/v of etodolac acid dimer BPCRS in acetone. After Calculate the content of C;7H2,;N
removal of the plate, allow it to dry in air and examine under content of C,;7H,,NO3 in etodolac BPCRS
ultraviolet light (254 nm). Any secondary spot in the
the acid dimer is not more intense than the spot in the
Etodolac Tablets
Total methyl analogue impurities
Carry out the method for liguid chromatography, Action and use
Appendix III D, using the following solutions. For solution Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.
(1) shake a quantity of the contents of the capsules
containing 0.1 g of Etodolac with 40 mL of methanol, mix DEFINITION
with the aid of ultrasound for 5 minutes, filter and dilute Etodolac Tablets contain Etodolac.
10 mL of the filtrate to 25 mL with water. For solution (2) The tablets comply with the requirements stated under Tablets and
dilute 1 volume of a solution containing 0.025% w/v each of with the following requirements.
etodolac 1-methyl analogue BPCRS and etodolac 8-methyl
Content of etodolac C,;H,,NO;3
analogue BPCRS in methanol to 50 volumes with water.
(a) a stainless steel column (20 cm x 4.6 mm) packed with IDENTIFICATION
octadecylsilyl silica gel for chromatography (5 um) (Spherisorb A. Shake a quantity of the powdered tablets containing 0.5 g
of etodolac with 30 mL of hexane for 5 minutes, centrifuge,
2016 Etodolac Preparations T-551
discard the clear hexane layer and add about 40 mL of ether (e) After removal of the plate, dry in air and examine under
to the residue; shake for 5 minutes, centrifuge for 5 minutes, ultraviolet light (254 nm).
decant the ether layer and filter if necessary. Evaporate the MOBILE PHASE
solution to dryness under nitrogen and add about 5 mL of
Nate ate
0.5 volumes of glacial acetic acid, 30 volumes of absolute

0.1m hydrochloric acid to the residue. Warm on a water bath
ethanol and 70 volumes of toluene.
until the residue begins to crystallise and triturate with a glass
rod to promote crystallisation. Cool the mixture in an ice LIMITS
bath, filter through a glass-fibre filter (Whatman GF/C is Any secondary spot in the chromatogram obtained with
suitable) and dry the crystals at a pressure of 2 kPa at 60° for solution (1) is not more intense than the spot in the
1 hour. The infrared absorption spectrum of the residue, chromatogram obtained with solution (2) (0.5%) and not
Appendix II A, is concordant with the reference spectrum of more than one such spot is more intense than the spot in the
S 139). chromatogram obtained with solution (3) (0.25%).
the chromatogram obtained with solution Etodolac acid dimer
with the same retention time as the peak Carry out the method for thin-layer chromatography,
due to etodoél/, the chromatogram obtained with Appendix IT A, using the following solutions in acetone.
solution (2) (1) Shake a quantity ofthe powdered tablets containing 0.6 g
TESTS of Etodolac with 20 mL of solvent, mix with the aid of
Dissolution ultrasound for 5 minutes and filter.
Comply with the requ Monographs of the British (2) 0.003% w/v of etodolac acid dimer BPCRS.
Pharmacopoeia in the diss st for tablets and capsules,
Appendix XII Bl.
TEST CONDITIONS substances may be used injecting 20 wL of each solution and
(a) Use Apparatus 1, rotating the basket a: 00 revolutions using the mobile phase as described below.
per minute. MOBILE PHASE
(b) Use 900 mL of phosphate buffer pH 7.5,. temperature 3 volumes of glacial acetic acid, 17 volumes of 1,4-dioxan and
of 37°, as the medium.
60 volumes of toluene.
PROCEDURE
LIMITS
(1) After 45 minutes withdraw a 10 mL sample of tk
medium and measure the absorbance of the filtered samp
solution (1) corresponding to the acid dimer is not more
suitably diluted with the dissolution medium if necessary
se than the spot in the chromatogram obtained with
the maximum at 278 nm, Appendix II B using dissolution
hm (2) (0.1%).
thyl analogue impurities
etodolac BPCRS prepared by dissolving 20 mg in 100 mL of
the dissolution medium, suitably diluted with the dissolution
medium, using dissolution medium in the reference cell. of the powdered tablets containing 0.1 g
L of methanol, mix with the aid of
Calculate the total content of etodolac, C;7H»,;NOz3 in the
medium from the absorbances obtained and from the
declared content of C,;7H.,;NO3 in etodolac BPCRS.
each of etodolac 1-met
Related substances 8-methyl analogue BPCRS'
Carry out the method for thin-layer chromatography, water.
Appendix III A, using the following solutions in acetone.
CHROMATOGRAPHIC CONDITIO!
(a) Use a stainless steel column (20°C
of etodolac with 20 mL of solvent, mix with the aid of
with octadecylsilyl silica gel for chromato
ultrasound for 5 minutes and filter.
(b) Use isocratic elution and the mobile phas;
(3) Dilute 1 volume of solution (2) to 2 volumes. below. Adjust the mobile phase, if necessary, to¢
CHROMATOGRAPHIC CONDITIONS retention time of 14 to 20 minutes for etodolac.
(a) Use a silica gel F254 precoated plate (Merck silica gel 60 (c) Use a flow rate of 1.0 mL per minute.
F554 plates are suitable), previously activated by heating at (d) Use an ambient column temperature.
105° for 1 hour. Place the plate in an unlined tank (e) Use a detection wavelength of 225 nm.
containing a solution prepared by dissolving 0.5 g of
L-ascorbic acid in 20 mL of water and adding 80 mL of
methanol. Allow the solution to ascend 1 cm above the line of (g) For solution (1) allow the chromatography to proceed for
application on the plate, remove the plate and allow it to dry twice the retention time of the principal peak.
for at least 30 minutes. MOBILE PHASE
(b) Use the mobile phase as described below. 13 volumes of acetonitrile, 19 volumes of methanol and
(c) Apply 10 uL of each solution. 68 volumes of a 1.74% w/v solution of dipotasstum hydrogen
(d) Develop the plate to 15 cm. orthophosphate.
IWI-552 Etoposide Preparations 2016
SYSTEM SUITABILITY The capsules comply with the requirements stated under Capsules
oN 4
The order of elution of peaks in the chromatogram obtained and with the following requirements.
yAnNe4
Niet. 4te
with solution (2) is etodolac 8-methyl analogue and etodolac Content of etoposide, C,.H3,0;3
"wand 1-methyl analogue. 95.0 to 105.0% of the stated amount.
The test is not valid unless, in the chromatogram obtained IDENTIFICATION
with solution (2), the resolution factor between the two methyl
Add a quantity of the contents of the capsules containing
analogue impurities is at least 0.75.
0.1 g of Etoposide to a separating funnel containing 100 mL
LIMITS of water, extract with two 20 mL quantities of
In the chromatogram obtained with solution (1): dichloromethane, dry the combined organic extracts over
Calculate the percentage content of etodolac 1-methy]l anhydrous sodium sulfate and filter. Extract the filtrate with
analogueand etodolac 8-methyl analoguein etodolac by 30 mL of water, filter the dichloromethane layer through
sto ti sponding peaksin the chromatogram anhydrous sodium sulfate and evaporate to dryness at 25° to
eae As
(2). The total content is not greater 35° under reduced pressure. Dissolve the oily residue in
5 mL of water, shake gently and allow to stand for
30 minutes. Filter through a sintered-glass funnel, wash the
precipitate in the funnel with three 20 mL quantities of water
3 Carry out the method for and dry the precipitate in the funnel at 40° at a pressure of
liquid chromatograph ix III D, using the following 2 kPa for 90 minutes. The infrared absorption spectrum of the
solutions. dried precipitate, Appendix II A, is concordant with the
reference spectrum of etoposide (RS 396).
50 mg of etodolac with about
TESTS
hydroxide for 30 minutes, dilut
Dissolution
hydroxide, mix, filter through agla
GF/C is suitable) and dilute 2 mL of th
100 mL with the mobile phase.
900 mL of a pH 4.5 buffer prepared by dissolving 2.99 g of
sodium acetate and 14 mL of 2M acetic acid in sufficient water
(3) Add 2 mL of a 0.05% w/v solution of etodolac to produce 1000 mL and rotate the paddle at 50 revolutions
analogue BPCRS in 0.1M sodium hydroxide to 2 mL of # per minute. Withdraw a sample of 10 mL of the medium
0.05% w/v solution of etodolac BPCRS in 0.1M sodium and filter. Carry out the method for liquid chromatography,
hydroxide and dilute to 100 mL with the mobile phase. adix III D, using the following solutions. For solution
CHROMATOGRAPHIC CONDITIONS he filtrate diluted, if necessary, with dissolution
produce a solution expected to contain about
y of Etoposide. Solution (2) contains 0.005% w/v
below.
(d) Use an ambient column temperature. phenyl silica gel for ch:
(e) Use a detection wavelength of 225 nm. phenylis suitable), (b).
(f) Inject 20 uL of each solution. of 1.0 mL per minute a m
and 74 volumes of a 0.272
MOBILE PHASE
adjusted to pH 4.0 with glacz
45 volumes of acetonitrile and 55 volumes of phosphate buffer wavelength of 254 nm.
pH 4.75. The test is not valid unless, in the c
SYSTEM SUITABILITY with solution (3), the resolution factor be
The test is not valid unless the resolution factor between principal peaks is at least 2.0.
etodolac and etodolac 1-methyl analogue in the
chromatogram obtained with solution (3) is at least 1.5. medium using the declared content of CroH320 134
DETERMINATION OF CONTENT etoposide BPCRS.
Calculate the content of C;7H.,;NO3 using the declared cis-Etoposide
ye a
content of C,;7H».;NO3 in etodolac BPCRS. Carry out the method for liguid chromatography,
(1) add 80 mL of the mobile phase to 10 whole capsules and
stir mechanically for 15 minutes with occasional shaking.
Add sufficient mobile phase to produce 100 mL and stir for
Etoposide Capsules a further 5 minutes. Dilute, if necessary, a volume of the
solution with the mobile phase to give a solution containing
Action and use 0.5% w/v of Etoposide; use immediately. For solution (2)
Inhibitor of DNA topoisomerase type II; cytotoxic. dilute 1 volume of solution (1) to 50 volumes with the
mobile phase. For solution (3) prepare a 0.5% w/v solution
DEFINITION of etoposide BPCRS in a mixture of 50 volumes of acetonitrile,
Etoposide Capsules contain a solution of Etoposide in a
suitable water-miscible vehicle.
2016 Etoposide Preparations II-553
50 volumes of water and 0.1 volume of triethylamine and The concentrate complies with the requirements for Concentrates
allow to stand for 40 minutes. for Injections or Infusions stated under Parenteral Preparations
eed
The chromatographic procedure described under Dissolution and with the following requirements.
may be used. Content of etoposide, C,.H320;3
The test is not valid unless, in the chromatogram obtained 95.0 to 105.0% of the stated amount.
with solution (3), the resolution factor between the principal IDENTIFICATION
peak and the peak immediately following the principal peak A. Carry out the method for thin-layer chromatography,
(cis-etoposide) is at least 1.0. Appendix III A, using the following solutions.
In the chromatogram obtained with solution (1) the area of (1) Dilute a volume of the concentrate containing 20 mg of
any peak corresponding to cis-etoposide is not greater than Etoposide to 25 mL with a mixture of 9 volumes of
the area of the peak in the chromatogram obtained with dichloromethane and 1 volume of methanol.
(2) 0.08% w/v of etoposide BPCRS in a mixture of 9 volumes
of dichloromethane and 1 volume of methanol.
od for liquid chromatography,
g the following solutions. For solution
(a) Use a TLC sihca gel F254 plate (Merck plates are suitable)
etoposide BPCRS in the mohile' phas:
0.005% w/v of etoposide BPCRS a 0Q025% w/v of ethyl MOBILE PHASE
0.5 volume of water, 2.5 volumes of ethanol (96%),

The chromatographic procedure describ 25 volumes of acetone and 80 volumes of dichloromethane.
may be used. CONFIRMATION

with solution (3), the resolution factor between the twe¢ solution (1) corresponds to that in the chromatogram
principal peaks is at least 2.0. obtained with solution (2).
Calculate the content of C29H320)3 in the capsules B. In the Assay, the principal peak in the chromatogram
chromatograms obtained and using the declared content 61 d with solution (1) has the same retention time as the
C49H32013 in etoposide BPCRS. al peak in the chromatogram obtained with
STORAGE
Etoposide capsules should not be refrigerated.
ofthe concentrate containing 0.1g of

with carbon dioxide-free water. The pH of
the solution ig’ 3. 4.0, Appendix V L.
Etoposide Infusion
cis-Etoposide
Etoposide Intravenous Infusion
Carry out the meth id chromatography,
Appendix TI D, using wing solutions.
Action and use
Inhibitor of DNA topoisomerase type II; cytotoxic. (1) Dilute the concentratéwith the mobile phase to produce
a solution containing 0.5% wey of
DEFINITION (2) Dilute 1 volume of solution
Etoposide Infusion is a sterile solution containing Etoposide. mobile phase.
It is prepared by diluting Sterile Etoposide Concentrate with (3) 0.5% w/v solution of etoposide B
a suitable diluent in accordance with the manufacturer’s 50 volumes of acetonitrile, 50 volumes of #
instructions. 0.1 volume of triethylamine and allow to star
The infusion complies with the requirements stated under 40 minutes.
STORAGE (a) Use a stainless steel column (30 cm x 3.9 mm) packed
Etoposide Infusion should be used immediately after with phenyl silica gel for chromatography (10 um) (uBondapak
preparation. phenyl is suitable).
STERILE ETOPOSIDE CONCENTRATE below.
DEFINITION (c) Use a flow rate of 1.0 mL per minute.
Sterile Etoposide Concentrate is a sterile solution of (d) Use an ambient column temperature.
Etoposide in a suitable ethanolic vehicle. (e) Use a detection wavelength of 254 nm.
II-554 Etynodiol Preparations 2016
MOBILE PHASE PROCEDURE

26 volumes of acetonitrile and 74 volumes of a 0.272% w/v (1) After 45 minutes withdraw a sample of the medium and
‘Awe 4
solution of sodium acetate adjusted to pH 4.0 with glacial filter. Dilute a quantity of the filtrate with dissolution
acetic acid. medium, if necessary, to produce a solution expected to
SYSTEM SUITABILITY contain 0.0001% w/v of Etynodiol Diacetate.
The test is not valid unless, in the chromatogram obtained (2) 0.0001% w/v of etynodiol diacetate BPCRS in water.
with solution (3), the resolution factor between the principal CHROMATOGRAPHIC CONDITIONS
peak and the peak immediately following the principal peak The chromatographic conditions described under Uniformity
(cis-etoposide) is at least 1.0. of content may be used.
LIMITS DETERMINATION OF CONTENT
Calculate the total content of etynodiol diacetate, C2,H320,,
in the medium from the chromatogram obtained and using
of the peak in the chromatogram the declared content of C2,H3 20,4 in etynodiol
(2) (2%).
diacetate BPCRS.
LIMITS
bs guid chromatography, The amount of C2,H320, released is not less than 75% (Q)
Appendix III D, using the fol solutions. of the stated amount.
Related substances
CHROMATOGRAPHIC CONDITIONS (1) Shake a quantity of powdered tablets containing 10 mg of
The chromatographic procedure describe Etynodiol Diacetate with 30 mL of acetonitrile R1, add
cis-Etoposide may be used. sufficient water to produce 50 mL and filter.
mixture of 40 volumes of water and 60 volumes of
Calculate the content of Cz9H320;3 in the concenttrat¢ acetontrile R1. Further dilute 1 volume of this solution to
the declared content of C9H3.0)3 in etoposide BPCRS. 5 volumes with the same solvent mixture.
STORAGE ) 0.02% w/v of etynodiol diacetate BPCRS and
Sterile Etoposide Concentrate should be protected from ligh % w/v of estrone BPCRS in a mixture of 40 volumes
‘and 60 volumes of acetonitrile R1.
GRAPHIC CONDITIONS
ainless steel column (25 cm x 4.6 mm) packed
Etynodiol Tablets debutylsilyl silica gel for chromatography (5um)
As suitable).
Action and use tio
Progestogen.
DEFINITION
Etynodiol Tablets contain Etynodiol Diacetate.
with the following requirements. (f) Inject 150 wL of each sol
Content of etynodiol diacetate, C,,H3,0, MOBILE PHASE é
95.0 to 105.0% of the stated amount. Mobile phase A water.
IDENTIFICATION Mobile phase B_ acetonitrile R1
Add 50 mL of ethanol (96%) to a quantity of powdered te € prescribed
tablets containing 20 mg of Etynodiol Diacetate. Mix with etate
the aid of ultrasound, filter and evaporate the filtrate to (retention time about 63 minutes) are: estrone, 2
dryness at a temperature not exceeding 40°. The infrared and impurity 1, about 0.8.
concordant with the reference spectrum of etynodiol diacetate
(RS 138).
TESTS
Dissolution
Appendix XII B1. 65-66 25-70 7530 isocratic
TEST CONDITIONS 66-75 70 30 re-equilibration

per minute.
SYSTEM SUITABILITY
sulfate in water, at a temperature of 37°, as the medium.
estrone and etynodiol diacetate is at least 5.0.
2016 Famotidine Preparations DUT-555
LIMITS
nee Nn In the chromatogram obtained with solution (1):
identify any peak corresponding to impurity 1 and multiply
nN NY
the area of this peak by a correction factor of 2.0;

the area of any peak corresponding to impurity | is not
the sum:of the areas of any other secondary peaks is not
imes the area of the principal peak in the
Famotidine Tablets
tained with solution (2) (0.5%).
Action and use
ulceration.
DEFINITION
Famotidine Tablets contain Famotidine.
under Tablets using theow The tablets comply with the requirements stated under Tablets and
out the method for liguid ch with the following requirements.
using the following solutions. Content of famotidine, C,gH,;N7O,S;
IDENTIFICATION
(1) shows a peak with the same retention time as the peak in
(2) 0.005% w/v of etynodiol diacetate BPCRSin a
40 volumes of water and 60 volumes of acetonitrile R Appendix III A, usinga silica gel F254 precoated plate
(3) 0.02% w/v of etynodiol diacetate BPCRS and 0.0004% scher Silica Gel GF plates are suitable) and a mixture of
of estrone BPCRSin a mixture of 40 volumes of water and es of 13.5mM ammonia, 20 volumes of toluene,
60 volumes of acetonitrile R1. mes of methanol and 40 volumes of ethyl acetate as the
(a) Use a stainless steel column (25 cm x 4.6 mm) packed Ing solutions. For solution (1) shake a quantity of
with end-capped butylsilyl silica gel for chromatography (5m) ablets$ containing 40 mg of Famotidine with
(YMC-Pack Pro C4 is suitable). He id with the aid of ultrasound, dilute to
solvent, centrifuge and use the clear
supernatant liqui lution (2) contains 0.4% w/v of
below.
famotidine BPCRS i al acetic acid. After removal of the
(c) Use a flow rate of 1.5 mL per minute. plate, allow it to dr r and examine under ultraviolet light
(d) Use a column temperature of 30°. (254 nm). The prin the chromatogram obtained
(e) Use a detection wavelength of 220 nm. with solution (1) correspe to that in the chromatogram
(f) Inject 150 wL of each solution. obtained with solution (2).
MOBILE PHASE
TESTS
Dissolution
30 volumes of water and 70 volumes of acetonitrile R1.
Comply with the requirements for Me
SYSTEM SUITABILITY Pharmacopoeia in the dissolution test for tagiets «
The test is not valid unless, in the chromatogram obtained Appendix XII B1, using Apparatus 2. Rotate
with solution (3), the resolution between the peaks due to 50 revolutions per minute and use as the medigm 900 mL of
estrone and etynodiol diacetate is at least 1.5. phosphate buffer pH 4.5 preparedin the following manner.
Dissolve 13.61 g of potassium dihydrogen orthophosphate in
water, adjust the pH of the solution with orthophosphoric acid
Calculate the content of C,4,H320,, in each tablet using the
or 1M potasstum hydroxide as necessary and add sufficient
declared content of C2,H3,0, in etynodiol diacetate BPCRS
water to produce 1000 mL. Withdraw a sample of 10 mL of
ASSAY the medium, filter and centrifuge at 2000 revolutions per
Use the average of the 10 individual results obtained in the minute for 20 minutes. Carry out the method for liguid
test for Uniformity of content. : chromatography, Appendix III D, using the following
solutions. Solution (1) contains 0.001% w/v of
IMPURITIES
famotidine BPCRS in the dissolution medium. For solution
(2) use the filtered and centrifuged dissolution medium,
monograph include:
diluted if necessary, to give a solution expected to contain
1. etynodiol 17-monoacetate about 0.001% w/v of Famotidine.
substances may be used. Inject 50 uwL of each solution.
II-556 Famotidine Preparations 2016
Calculate the total content of famotidine, CgH,;;N7O0.S3, in Calculate the contents of each of impurity C and degradation
awe
the medium using the declared content of CgH,;5N7O2S3 in impurities 1 and 2 using the chromatogram obtained with
AN AN
te net
famotdine BPCRS. solution (4) and the nominal content of any other impurities
Related substances using the chromatograms obtained with solution (2) and (3).
Carry out the method for liguid chromatography, The sum of the contents of all the impurities so calculated is
Appendix III D, using the following solutions. For solution not greater than 2.5%. Disregard any peak with an area less
(1) add 200 mL of 0.05m potassium dihydrogen orthophosphate than 0.25 times the area of the principal peak in the
adjusted to pH 6.0 with 1m potassium hydroxide (solution A) chromatogram obtained with solution (3) (0.05%).
to a quantity of whole tablets containing 0.2 g of Famotidine, ASSAY
mix with the aid of ultrasound for 5 minutes, add about Carry out the method for liquid chromatography,
200 mL of methanol, shake for 60 minutes and add sufficient Appendix III D, using the following solutions. For solution
solutionA té roduce 500 mL. For solution (2) dilute (1) add 200 mL of 0.05M potassium dihydrogen orthophosphate
ieee
(1) to 100 volumes with solution A. adjusted to pH 6.0 with 1M potassium hydroxide (solution A)
For soluti te 1 volume of solution (1) to to a quantity of whole tablets containing 0.2 g of Famotidine,
10 volumes it on A and dilute 1 volume of the mix with the aid of ultrasound for 5 minutes, add about
resulting solutioii to 200 mL of methanol, shake for 60 minutes and add sufficient
For solution (4) adé. acetonitrile to a mixture of solution A to produce 500 mL. Dilute 1 volume of this
rity C BPCRS, famotidine solution to 5 volumes with solution A. For solution (2)
€2
dissolve 8 mg of famotidine BPCRS in 4 mL of methanol, mix
wmpurity 2 BPCRS, mix with. with the aid of ultrasound for 5 minutes and add sufficient
2 minutes, cool, add 40 mL solution A to produce 20 mL. Dilute 1 volume of this
solution A to produce 200 mL. ime of the solution to 5 volumes with solution A.
resulting solution to 5 volumesWi uy For solution
(5) dissolve 8 mg offamotidine BPCRS4n substances may be used. Inject 50 wL of each solution.
A with the aid ofultrasound, cool and ad
Calculate the content of CgH;;N7O,S; in the tablets using
the declared content of CgH,5N7O2S3 in famotidine BPCRS.
IMPURITIES
1 volume of solution B with 100 volumes of solution’ A ag The impurities limited by the requirements of this
further dilute a suitable volume with an equal volume of onograph include impurity C listed under famotidine and
solution (4). e following degradation impurities.
(Inertsil ODS-2 is suitable) maintaining the column
temperature at 40°, (b) a mixture of 7 volumes of acetonitrile
and a mixture of 93 volumes of 0.1M sodium acetate
containing 0.1% v/v of triethylamine the pH adjusted to 6.0
with glacial acetic acid and as the mobile phase with a flow
rate of 1.4 mL per minute and (c) a detection wavelength of
275 nm. Condition the column for approximately 30 minutes
before the first injection.
Inject separately 50 wL of each solution. The substances are
ss es eluted in the following order: famotidine degradation
impurity 3, famotidine degradation impurity 1, famotidine
impurity C, famotidine and famotidine degradation
impurity 2. The test is not valid unless, in the chromatogram
peaks due to famotidine and famotidine impurityC is at least
2. 3-[2-(Diaminomethyleneamino)-1,3-thiazof=4-
1.4 and that between the peaks due to famotidine and
ylmethylthio]propanamide,
famotidine degradation impurity 2 is at least 1.4. If this
resolution is not achieved adjust the content of acetonitrile or Corresponds to impurity D listed under Famotidin
decrease the concentration of sodium acetate in the mobile
phase. NH,
A,
wn ee
In the chromatogram obtained with solution (1) the areas of

wtaete ted
any peaks corresponding to famotidine impurity C or HN seN..-NHz

famotidine degradation impurities 1 and 2 are not greater
than the areas of the corresponding peaks in the 4x
O O
chromatogram obtained with solution (4) (0.5% of each), the
area of any peak with a relative retention time of about 0.4
with reference to famotidine in the chromatogram obtained 3. 3-[2-(Diaminomethyleneamino)-1,3-thiazol-4-
with solution (5) (famotidine degradation impurity 3) is not ylmethylsulfinyl|-N-sulfamoylpropanamidine.
greater than the area of the peak in the chromatogram
eA ea
obtained with solution (2) (1%) and the area of any other
Am rt
rat weary secondary peak is not greater than the area of the principal
peak in the chromatogram obtained with solution (3) (0.2%).
tae
ewes d
2016 Felbinac Preparations III-557

Felbinac Cutaneous Foam mobile phase and further dilute 1 volume of this solution to
Action and use 10 volumes with the same solvent.
Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory. (3) 0.00006% w/v of 4-acetylbiphenyl and 0.00006% w/v of
biphenyl in methanol.
DEFINITION (4) 0.001% w/v of felbinac BPCRS and 0.001% w/v of
Felbinac Cutaneous Foam is a fluid foam containing o-phenylbenzoic acid in the mobile phase.
Felbinac in solution in a suitable pressurised container.
The cutaneous foam complies with the requirements stated under
Medicated Foams and with the following requirements.
(10 um) (Partisil ODS3 is suitable).
wing tests, discharge a: quantity of the foam into below.
uth the can upright. Quantitatively transfer the
etermine the sample weight by difference.
(1) Dissolve aweighed G:
at least twice the retention time of the principal peak.
60 mg of Felbinac in meth
to break the foam, and add MOBILE PHASE
100 mL. . : 45 volumes of a 0.1% v/v solution of glacial acetic acid and
(2) 0.06% w/v solution offelbinac B 55 volumes of methanol.
(a) Use as the coating silica gel F254 (Merc The test is not valid unless, in the chromatogram obtained
plates are suitable) with solution (4), the resolution factor between the two
(b) Use the mobile phase as described below. principal peaks is at least 3.0.
(c) Apply 10 nL of each solution. LIMITS
(d) Develop the plate to 10 cm. the chromatogram obtained with solution (1):
(e) After removal of the plate, dry in air and examine unde . rea of any peak corresponding to 4-acetylbiphenyl is not
ultraviolet light (254 nm) (first examination). Spray the plate than the area of the corresponding peak in the
with a mixture of equal volumes offormaldehyde solution and togram obtained with solution (3) (0.1%);
sulfuric acid and heat at 110° for 10 minutes (second
examination).
MOBILE PHASE
1 volume of glacial acetic acid, 25 volumes of acetone and x secondary peak is not greater than the
50 volumes of hexane. peak in the chromatogram obtained with
solution (2) (0.
CONFIRMATION
ASSAY
the principal spot in the chromatogram obtained with
the principal spots in the chromatograms obtained with
solutions (1) and (2) are an intense purple colour.
B. In the Assay, the chromatogram obtained with solution (2) 0.0015% wy offelbinac BPCRS in the robilé phase.
(3) 0.0015% w/v each offelbinac BPCRS and 0-phenylbenzoic
acid in the mobile phase.
solution (2).
TESTS
Use the chromatographic conditions described under Related
Alkalinity
substances, with the exception of the run time. Inject 20 pL
pH of the foam, 7.0 to 8.6, Appendix V L. Ensure good
of each solution.
contact between the foam and the electrode.
SYSTEM SUITABILITY
Related substances
Carry out the method for liquid chromatography, The assay is not valid unless, in the chromatogram obtained
Appendix III D, using the following solutions. with solution (3), the resolution factor between the two
(1) Dissolve a weighed quantity of the foam containing
30 mg of Felbinac in methanol, warming slightly if necessary DETERMINATION OF CONTENT
to break the foam, and add sufficient methanol to produce Calculate the content of C;,4H,2O> in the foam using the
50 mL. declared content of C,4H) 20>, in felbinac BPCRS.
IWI-558 Felbinac Preparations 2016
STORAGE (2) Dilute 1 volume of solution (1) to 100 volumes with

Felbinac Cutaneous Foam should be kept protected from mobile phase and further dilute 1 volume of this solution to
light. It should not be refrigerated. 10 volumes with the same solvent.
(3) 0.00006% w/v of 4-acetylbiphenyl and 0.00006% w/v of
biphenyl in methanol
(4) 0.001% wv offelbinac BPCRS and 0.001% w/v of
o-phenylbenzoic acid in mobile phase.
Felbinac Gel
Action and use (a) Use a stainless steel column (10 cm x 4.6 mm) packed
Cyclo-oxygenase inhibitor; analgesic; antinflammatory. with end-capped octadecylsilyl silica gel for chromatography
(10 um) (Partisil ODS3 is suitable).
below.
Content of felbinac; (e) Use a detection wavelength of 254 nm.
95.0 to 105.0% of the s (f) Inject 50 wL of each solution.
IDENTIFICATION (g) For solution (1) allow the chromatography to proceed for
at least twice the retention time of the principal peak.
MOBILE PHASE
(1) Dilute a quantity of the gel c mg of Felbinac 45 volumes of a 0.1% v/v solution of glacial acetic acid and
~ rN we
with sufficient acetone to produce 5 mL‘and.gni 55 volumes of methanol.

(2) 0.6% w/v solution offelbinac BPCRS in« SYSTEM SUITABILITY
CHROMATOGRAPHIC CONDITIONS The test is not valid unless, in the chromatogram obtained
(a) Use as the coating silica gel F254 (Merck silica gel with solution (4), the resolution between the two principal
plates are suitable). peaks is at least 3.0.
(b) Use the mobile phase as described below. IMITS
(c) Apply 5 uL of each solution. h the chromatogram obtained with solution (1):
(d) Develop the plate to 12 cm. any peak corresponding to 4-acetylbipheny] is not
(e) After removal of the plate, dry in air and examine under the area of the corresponding peak in the
ultraviolet light (254 nm) (first examination). Spray the plate obtained with solution (3) (0.1%);
with a mixture of equal volumes offormaldehyde solution and peak corresponding to biphenyl is not greater
sulfuric acid and heat at 110° for 10 minutes (second
examination).
MOBILE PHASE
1 volume of glacial acetic acid, 25 volumes of acetone and
50 volumes of hexane.
CONFIRMATION
ASSAY

Appendix III D, using the follt
(1) Dissolve a quantity of the gel €O
Felbinacin 70 mL of mobile phase, add.
phase to produce 100 mL, mix anddilu
resulting solution to 20 volumes with mobi
The principal spots in the chromatograms obtained with (2) 0.0015% w/v offelbinac BPCRS in mobile'p ase.
solutions (1) and (2) are an intense purple colour.
(3) 0.0015% w/v offelbinac BPCRS and 0.0015% wi of
B. In the Assay, the chromatogram obtained with solution o-phenylbenzotc acid in mobile phase. |
tees
Me
solution (2). Use the chromatographic conditions described under Related
substances, with the exception of the run time. Inject 20 pL
Nat etl
TESTS
of each solution.
pH, 7.0 to 8.0, Appendix V L. SYSTEM SUITABILITY
Ley
Related substances The Assay is not valid unless, in the chromatogram obtained
Carry out the method for liquid chromatography, with solution (3), the resolution between the two principal
Appendix III D, using the following solutions. peaks is at least 3.0.
(1) Dissolve a weighed quantity of the gel containing 30 mg DETERMINATION OF CONTENT

of Felbinac in methanol and add sufficient methanol to Calculate the content of C,;,H;,O> in the gel from the
produce 50 mL. chromatograms obtained using the declared content of
C14H20>2 in Jelbinac BPCRS.
2016 Felodipine Preparations III-559
Prolonged-release Felodipine Tablets SOLVENT A

A mixture of 0.08% w/v of orthophosphoric acid R and
Prolonged-release Felodipine Tablets from different manufacturers,
wn we
0.8% w/v of sodium dihydrogen orthophosphate.

interchangeable unless otherwise justified and authorised. (1) Mix with the aid of ultrasound a quantity of the
powdered tablets containing 10 mg of Felodipine with 10 mL
Action and use of methanol and 20 mL of acetonitrile for 5 minutes, add
Calcium channel blocker. 15 mL of solvent A and continue to disperse with the aid of
ultrasound for a further 30 minutes. Cool, dilute to 50 mL
DEFINITION with solvent A and filter through a 0.45-um PTFE filter.
Prolonged-release Felodipine Tablets contain Felodipine. (2) Dilute 1 volume of solution (1) to 100 volumes with the
They are formulated so that the medicament is released over mobile phase.
soe several hours. (3) Dilute 1 volume of solution (2) to 10 volumes with the
mobile phase.
ion test is carried out to demonstrate the (4) 0.006% w/v offelodipine impurity standard BPCRS in
appropriate. ¢ Felodipine. The dissolution profile mobile phase.
reflects the in vivo mance which in turn is compatible
with the dosages commended by the manufacturer.
The tablets comply wit! gearements stated under Tablets and
with octadecylsilyl silica gel for chromatography (5 wm) (Waters
with the following require
Nova-Pak is suitable).
Content of felodipine, C; (b) Use isocratic elution using the mobile phase described
92.0 to 105.0% of the state below.
IDENTIFICATION é (c) Use a flow rate of 1.0 mL per minute.
A. Extract a quantity of the powdered ontaining (d) Use ambient column temperature.
15 mg of Felodipine with 100 mL of et. %), filter,
and dilute 5 mL of the filtrate to 50 mL wit
The light absorption, Appendix II B, in the ratig (f) Inject 20 wL of each solution.
250 to 450 nm exhibits a maximum at 362 nm. MOBILE PHASE
B. Carry out the method for chin-layer chromatography 20 volumes of methanol, 40 volumes of acetonitrile and
40 volumes of solvent A.
(1) Shake a quantity of the powdered tablets containing M SUITABILITY
10 mg of Felodipine with 10 mL of methanol and filter st is not valid unless, in the chromatogram obtained
through a 0.45-um filter. lution (4), the resolution factor between the two
(2) 0.1% w/v of felodipine BPCRS in methanol. peaks is at least than 2.5.
(3) 0.1% w/v each of felodipine BPCRS and nifedipine BPCRS
in methanol.
orresponding to Impurity A is not
(a) Use as the coating substance silica gel F54. s.the area of the principal peak in the
(d) Develop to 15 cm.
(e) Dry the plate in air and examine under ultraviolet light
the area of the
(254 nm).
principal peak in the chromato ined with solution
MOBILE PHASE
(2);
40 volumes of ethyl acetate and 60 volumes of cyclohexane. the area of any other secondary peak is*
SYSTEM SUITABILITY the area of the principal peak in the chror
The test is not valid unless the chromatogram obtained with with solution (3) (0.2%); ‘
solution (3) shows two clearly separated spots of different the sum of the areas of any other secondary peaks is not
colours. greater than 0.5 times the area of the principal peak in the
CONFIRMATION
The principal spot in the chromatogram obtained with ASSAY
solution (1) corresponds in position and colour to that in the SOLVENT A
chromatogram obtained with solution (2). A mixture of 0.08% w/v of orthophosphoric acid R and
C. In the Assay, the chromatogram obtained with solution 0.8% wv of sodium dihydrogen orthophosphate.
(1) shows a principal peak with the same retention time as Weigh and powder 20 tablets. Carry out the method for
the principal peak in the chromatogram obtained with liquid chromatography, Appendix III D, using the following
solution (2). solutions.
TESTS (1) Mix with the aid of ultrasound a quantity of the
Related substances powdered tablets containing 10 mg of Felodipine with 10 mL
Carry out the method for liguid chromatography, of methanol and 20 mL of acetonitrile for 5 minutes, add
Appendix II D, using the following solutions. 15 mL of solvent A and mix with the aid of ultrasound for a
II-560 Fenbufen Preparations 2016
further 30 minutes. Cool, add sufficient solvent A to produce is suitable) and dilute 1 mL of the filtrate to 50 mL with the
50 mL and filter through a 0.45-um PTFE filter. Dilute dissolution medium. Measure the absorbance of this solution,
1 volume of the resulting solution to 10 volumes with the Appendix IT B, at 285 nm using dissolution medium in the
mobile phase. reference cell. Measure the absorbance of a suitable solution
(2) 0.002% w/v offelodipine BPCRS in mobile phase. offenbufen BPCRS prepared by dissolving 50 mg in 50 mL of
methanol and diluting to a suitable volume with the
(3) 0.006% w/v offelodipine impurity standard BPCRS in
dissolution medium and using dissolution medium in the
mobile phase.
reference cell. Calculate the total content of fenbufen,
CHROMATOGRAPHIC CONDITIONS C16H403 in the medium from the absorbances obtained and
The chromatographic conditions described under Related from the declared content of C,,H 403 in fenbufen BPCRS.
substances may be used. Related substances
inless, in the chromatogram obtained Appendix III D, using the following solutions. For solution
resolution factor between the two (1) add to a quantity of the contents of the capsules
containing 0.25 g of fenbufen 20 mL of dimethylformamide,
mix with the aid of ultrasound for 20 minutes, dilute to
ENT
50 mL with the initial mobile phase and filter (Whatman
sFiyoCI,NO, in the tablets using GF/F paper is suitable). For solution (2) dilute 1 volume of
lgNO,4 in felodipine BPCRS. solution (1) to 100 volumes with the initial mobile phase and
IMPURITIES : further dilute 1 volume of this solution to 10 volumes with
The impurities limited by the réequi 1eqts of this the initial mobile phase. Solution (3) contains 0.0025% w/v
monograph include those impuri icder Felodipine. offenbufen BPCRS and 0.0006% w/v of
3-(4-chlorobenzoyl)propionic acid.
The chromatographic procedure may be carried out using a
stainless steel column (10 cm x 4.6 mm) packed with end-
capped octadecylsilyl silica gel for chromatography (5 um)
Fenbufen Capsules (Spherisorb ODS 2 is suitable). Use as the initial mobile
phase a mixture of 32 volumes of acetonitrile and 68 volumes
Action and use
of a solution consisting of 1 volume of glacial acetic acid and
Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory:
5 volumes of water and as the final mobile phase a mixture
f 45 volumes of acetonitrile and 55 volumes of a solution
DEFINITION
tig of 1 volume of glacial acetic acid and 55 volumes of
Fenbufen Capsules contain Fenbufen.
4imtain the initial mobile phase for 15 minutes, carry
The capsules comply with the requirements stated under Capsules gradient elution with a flow rate of 2 mL per
and with the following requirements. minutes and maintain the final mobile phase for
Content of fenbufen, C,<~H,,03
IDENTIFICATION
A. To a quantity of the contents of the capsules containing with solution (3 the
0.9 g of fenbufen add 10 mL of acetone, triturate using a principal peaks is at
glass pestle, filter through filter paper wetted with acetone into
100 mL of petroleum spirit (boiling point, 40° to 60°), stir
rapidly with a glass rod to induce crystallisation and allow to
stand for 15 minutes. Filter through a fine porosity sintered-
glass funnel, rinse the crystals with 25 mL of petroleum spirit
(boiling point, 40° to 60°), remove the solvent under reduced
pressure and dry the crystals at 105° for 15 minutes. The
infrared absorption spectrum of the dried crystals,
Appendix III D, using the following solutions. For'so
fenbufen (RS 140).
(1) add to a quantity of the mixed contents of 20 capsu
B. In the Assay, the retention time of the principal peak in containing 0.1 g of fenbufen 30 mL of methanol, mix with the
the chromatogram obtained with solution (1) is the same as aid of ultrasound for 15 minutes, add sufficient of the mobile
that of the peak in the chromatogram obtained with phase to produce 100 mL and dilute 1 volume of this
wend
tate
eet
solution (2). solution to 10 volumes with the mobile phase. For solution
INN
TESTS (2) dissolve fenbufen BPCRS in methanol, add sufficient of the

Dissolution mobile phase to produce a 0.1% w/v solution and dilute
Comply with the requirements for Monographs of the British 1 volume of this solution to 10 volumes with the mobile
Pharmacopoeia in the dissolution test for tablets and capsules, phase.
Appendix XII B1, using Apparatus 2. Use as the medium The chromatographic procedure may be carried out using
900 mL of a phosphate buffer prepared by dissolving 6.69 g (a) a stainless steel column (30 cm x 3.9 mm) packed with
of potasstum dihydrogen orthophosphate and 1.63 g of sodium end-capped octadecylsilyl silica gel for chromatography (10 um)
hydroxide in sufficient water to produce 1000 mL, adjusting (uBondapak C18 is suitable), maintained about 40°, (b) a
the pH to 7.5 with 5m sodium hydroxide if necessary, and mixture of 1 volume of glacial acetic acid, 44 volumes of
acetonitrile and 55 volumes of water as the mobile phase with
he am,
vane
~
rate et
Met ae
s
rotate the paddle at 100 revolutions per minute. Withdraw a
oe Le
aw ee
wh,
sample of 10 mL of the medium, filter (Whatman 541 paper
2016 Fenbufen Preparations III-561
a~ wn!
a flow rate of 1.5 mL per minute and (c) a detection Related substances
wavelength of 280 nm. Carry out the method for liquid chromatography,
Calculate the content of C;,H,,03 in the capsules using the Appendix III D, using the following solutions.
declared content of C,;¢H,,03 in fenbufen BPCRS. (1) To a quantity of the powdered tablets containing 0.25 g
of Fenbufen add 20 mL of dimethylformamide, mix with the
aid of ultrasound for 20 minutes, add sufficient of the initial
mobile phase to produce 50 mL and filter (Whatman GF/F
is suitable).
Fenbufen Tablets (2) Dilute 1 volume of solution (1) to 100 volumes with the
Action and use initial mobile phase and further dilute 1 volume of this
Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory. solution to 10 volumes with the initial mobile phase.
(3) 0.0025% w/v offenbufen BPCRS and 0.0006% w/v of
3-(4-chlorobenzoyl)propionic acid.
(5 um) (Spherisorb ODS 2is suitable).
95.0 to 105.0% of th (b) Use gradient elution and the mobile phases described
IDENTIFICATION below. |
MOBILE PHASE
a solution consisting of 1 volume of glacial acetic acid and
pressure and dry the crystals at 105° for 15 minutes? The’ 55 volumes of water.
infrared absorption spectrum of the dried crystals, Mobile phase B 45 volumes of acetonitrile and 55 volumes of
Appendix I A, is concordant with the reference spectrum wution consisting of 1 volume of glacial acetic acid and
fenbufen (RS 140). evolumes of water.
Mobile phase Mobile phase Comment
that of the peak in the chromatogram obtained with A% B%
solution (2).
0 isocratic
TESTS
Dissolution 0-100 linear gradient
Comply with the requirements for Monographs of the British 100 isocratic
Pharmacopoeia in the dissolution test for tablets and capsules, 100-0 linear gradient
Appendix XII Bl.
0 re-equilibration
TEST CONDITIONS
per minute. SYSTEM SUITABILITY
(b) Use 900 mL of a phosphate buffer prepared by dissolving The test is not valid unless in th egram obtained
6.69 g of potassium dihydrogen orthophosphate and 1.63 g of with solution (3) the resolution factor en the two
sodium hydroxide in sufficient water to produce 1000 mL, principal peaks is at least 10.0.
adjusting the pH to 7.5 with 5M sodium hydroxide if necessary, LIMITS
at a temperature of 37°, as the medium.
In the chromatogram obtained with solution (13.
PROCEDURE the area of any secondary peak is not greater than the area of
(1) After 45 minutes withdraw a 10 mL sample of the the principal peak in the chromatogram obtained with
medium, filter (Whatman 541 paper is suitable) and dilute solution (2) (0.1%);
1 mL of the filtrate to 50 mL with the dissolution medium. the sum of the areas of any such peaks is not greater than
Measure the absorbance of this solution, Appendix II B, at five times the area of the principal peak in the chromatogram
285 nm using dissolution medium in the reference cell. obtained with solution (2) (0.5%).
ASSAY
fenbufen BPCRS prepared by dissolving 50 mg in 50 mL of
methanol and diluting to volume with the dissolution medium
and using dissolution medium in the reference cell.
solutions.
(1) To a quantity of the powdered tablets containing 0.1 g of
Calculate the total content of fenbufen, C,,~H,403, in the Fenbufen add 30 mL of methanol, mix with the aid of
medium from the absorbances obtained and using the ultrasound for 15 minutes, add sufficient of the mobile phase
declared content of C,¢6H 403, in fenbufen BPCRS. to produce 100 mL, filter through a 0.45-um filter
IWI-562 Fenoprofen Preparations 2016
(Whatman GF/C is suitable) and dilute 1 volume to (4) Dilute 1 volume of solution (2) to 5 volumes with the
10 volumes with the mobile phase. mobile phase.
tet Net
(2) Dissolve fenbufen BPCRS in methanol, add sufficient of CHROMATOGRAPHIC CONDITIONS
the mobile phase to produce a 0.1% w/v solution and dilute (a) Use a stainless steel column (25 cm x 4.6 mm) packed
1 volume of this solution to 10 volumes with the mobile with end-capped octadecylsilyl silica gel for chromatography (7 to
phase. 8 um) (Zorbax ODS is suitable).
with end-capped octadecylsilyl silica gel for chromatography (c) Use a flow rate of 2 mL per minute.
(10 um) (uBondapak C18 is suitable).
3 times the retention time of the peak due to fenoprofen.
MOBILE PHASE
(f) Inject 20 pL of ea
2 volumes of glacial acetic acid, 7 volumes of tetrahydrofuran,
MOBILE PHASE
1 volume of glacial acetic act fumes of acetonitrile and
SYSTEM SUITABILITY
Calculate the content of CicH 403 in capsules using the corresponding to fenoprofen calcium and
declared content of C;6H 403 in fenbujfen J 4’,4'-dimethoxybenzophenone is at least 3.0.
LIMITS

Fenoprofen Tablets the area of any secondary peak is not greater than twice the
area of the peak in the chromatogram obtained with solution
Action and use
2) (1.0%);
than one such peak has an area greater than the
DEFINITION peak in the chromatogram obtained with solution
Fenoprofen Tablets contain Fenoprofen Calcium. They are
coated. ‘he areas of all such peaks is not greater than four
The tablets comply with the requirements stated under Tablets and of the peak in the chromatogram obtained
Content of fenoprofen, C;;H,,03
95.0 to 105.0% of the stated amount. principal peak ii matogram obtained with solution
IDENTIFICATION
(4) (0.1%).
A. The light absorption, Appendix IT B, in the range 230 to ASSAY
350 nm of the final solution obtained in the Assay exhibits Weigh and powder 20 table quantity of the powder
two maxima, at 272 nm and 278 nm, and a shoulder at containing the equivalent of 0.2 g.of fenoprofen add 5 mL of
266 nm. glacial acetic acid and shake for*¥*minute. Add 100 mL of
B. Suspend a quantity of the powdered tablets containing the
equivalent of 0.3 g of fenoprofen in 10 mL of
0.1m hydrochloric acid. Extract with 20 mL of chloroform, filter
the extract through anhydrous sodium sulfate and evaporate the
filtrate to dryness. The infrared absorption spectrum of a thin Calculate the content of C,5;H,403 taking 80 : alue
film of the residue, Appendix II A, is concordant with the of A(1%, 1 cm) at the maximum at 272 nm.
reference spectrum of fenoprofen (RS 141). LABELLING
C. Ignite a quantity of the powdered tablets. The residue The quantity of active ingredient is stated in terms of the
yields the reactions characteristic of calcium salts, equivalent amount of fenoprofen.
Appendix VI.
Related substances
(1) To a quantity of the powdered tablets containing the
Fentanyl Injection
equivalent of 0.5 g of fenoprofen add 80 mL of the mobile Action and use
phase, mix with the aid of ultrasound, allow to cool, add Opioid receptor agonist; analgesic.
sufficient mobile phase to produce 100 mL and filter.
(2) Dilute 1 volume of solution (1) to 200 volumes with the DEFINITION
mobile phase. Fentanyl Injection is a sterile solution of Fentanyl Citrate in
teh a
ane (3) 0.04% w/v offenoprofen calcium and 0.0015% w/v of Water for Injections.
4,4'-dimethoxybenzophenone in the mobile phase.
eae
2016 Ferrous Fumarate Preparations III-563
The injection complies with the requirements stated under the area of any peak corresponding to fentanyl impurity D is
Parenteral Preparations and with the following requirements. not greater than twice the area of the peak in the
Content of fentanyl, C,,H,,N,O chromatogram obtained with solution (2) (0.5%);
95.0% to 105.0% of the stated amount. the area of any other secondary peak is not greater than the
IDENTIFICATION
solution (2) (0.25%);
350 nm of the injection diluted, if necessary, to contain the the sum of the areas of any secondary peaks apart from any
equivalent of 0.005% w/v of fentanyl exhibits two maxima at peaks corresponding to fentanyl impurity A and fentanyl
251 and 257 nm and a shoulder at 262 nm. impurity D is not greater than three times the area of the
(2) (0.75%).
obtainedswith solution (1) has the same retention time as the
Disregard any peak obtained with the blank solution and any
peak with an area less than 0.2 times the area of the principal
peak in the chromatogram obtained with solution (2)
(0.05%).
ASSAY
diluted with the mobile
phase.
phase if necessary, to cont uivalent of 0.005% w/v
of fentanyl. (1) The injection diluted, if necessary, to contain the
equivalent of 0.005% w/v of fentany].
(2) Dilute 1 volume of solu volumes with the
mobile phase and dilute 5 volumes ¢ resulting solution (2) 0.008% w/v solution offentanyl citrate BPCRS.
to 20 volumes with the mobile phase. , CHROMATOGRAPHIC CONDITIONS
(3) 0.00005% w/v offentanyl impurity A’ The chromatographic conditions described under Related
mobile phase. substances may be used.
(4) Dissolve 10 mg offentanyl citrate BPCRS in 1Q DETERMINATION OF CONTENT
2m hydrochloric acid, heat on a waterbath under a ref} Calculate the content of C2,H»gN.0 in the injection using
condenser for 4 hours and neutralise with 10 mL of the declared content of C2,H» ,N,0O in fentanyl
2M Sodium hydroxide. Evaporate to dryness on a water curate BPCRS.
cool, dissolve the residue in 10 mL of methanol and filter.
Dilute 1 volume of the filtrate to 10 volumes with the mobile
phase (generation of impurity D). :
(10 um) (Bondclone C18 10h is suitable).
below.
(f) Inject 100 wL of each solution. Inject methanol as a blank
prior to the solutions.
(g) For solutions (1) and (2) allow the chromatography to
proceed for twice the retention time of the principal peak.
MOBILE PHASE The capsules comply with the requirements stated, i
0.3% wv of potassium dihydrogen orthophosphate in a mixture and with the following requirements. |
of 4 volumes of acetonitrile, 40 volumes of methanol and Content of ferrous iron, Fe(n)
56 volumes of water, the solution adjusted to pH 3.2 with 95.0 to 105.0% of the stated amount.
IDENTIFICATION
SYSTEM SUITABILITY
A. Heat 1 g of the contents of the capsules with 25 mL of a
The test is not valid unless, in the chromatogram obtained mixture of equal volumes of hydrochloric acid and water on a
with solution (4), the retention time of fentanyl impurity D is water bath for 15 minutes, cool and filter. Retain the residue
about 0.8 relative to fentanyl. for test B. The filtrate yields reaction A characteristic of iron
LIMITS salts, Appendix VI.
In the chromatogram obtained with solution (1): B. Wash the residue reserved in test A with a mixture of
1 volume of 2m hydrochloric acid and 9 volumes of water and
the area of any peak corresponding to fentanyl impurity A is
dry at 105°. Suspend 0.1 g of the residue in 2 mL of dilute
not greater than half the area of the peak in the
sodium carbonate solution and add dilute potassium
permanganate solution drop wise. The permanganate is
decolourised and a brownish solution is produced.
IWI-564 Ferrous Fumarate Preparations 2016
C. Mix a quantity of the contents of the capsules containing IDENTIFICATION

0.5 g of ferrous fumarate with 1 g of resorcinol. To 0.5 g of A. Mix a volume of the oral suspension containing about
the mixture in a crucible add 0.15 mL of sulfuric acid and 0.6 g of ferrous fumarate with 20 mL of water, centrifuge and
heat gently; a deep red, semi-solid mass is produced. Add the discard the supernatant liquid. Repeat with a further 20 mL
mass to a large volume of water; an orange—yellow solution is of water. Add 15 mL of 3m hydrochloric acid to the residue,
produced which exhibits no fluorescence. dissolve with minimum warming, cool and extract with two
TESTS 50 mL quantities of ether. Wash the combined ether extracts
with two 20 mL quantities of water, shake with anhydrous
Ferric iron
sodium sulfate, filter and evaporate to dryness. The infrared
In a flask with a ground-glass stopper dissolve a quantity of
the mixed contents of 20 capsules prepared for the Assay
concordant with the reference spectrum of fumaric acid
containing 1.5 g of ferrous fumarate in a mixture of 10 mL
(RS 163).
of hydro 1 cid and 100 mL of water by heating rapidly to
boiling. Bout econds. Cool rapidly, add 3 g of B. Mix a volume of the oral suspension containing about
0.3 g of ferrous fumarate in 10 mL of water, centrifuge and
wot
potassium 10dideg er the flask and allow to stand

protected frorii light f8 15 minutes. Add 2 mL of starch discard the supernatant liquid. To 0.2 g of the residue add
solution as indicator. fe the liberated iodine with 10 mL of a mixture of equal volumes of hydrochloric acid and
0.05m sodium thiosué S..Carry out a blank test. water, dissolve with minimum warming, cool and filter.
The difference betwee volumes used in the two The filtrate yields reaction A characteristic of iron salts,
titrations corresponds to the.amownt of iodine liberated by Appendix VI.
ferric ion. The difference be ietitrations is not more TESTS
than 5.4 mL (1%). Ferric iron
Dissolution Disperse a quantity of the oral suspension containing 0.28 g
of ferrous fumarate in 20 mL of water, centrifuge and decant
the supernatant liquid into a 500 mL graduated flask.
Appendix XII Bl. Dissolve the residue in 20 mL of 1M sulfuric acid with
TEST CONDITIONS minimum warming, cool and transfer the resulting solution
to the same graduated flask, dilute to 500 mL with water and
(a) Use Apparatus 2, rotating the paddle at 50 revo
filter. To 5 mL of the filtrate in a Nessler cylinder add 40 mL
per minute.
of water and 5 mL of a 10% w/v solution of ammonium
(b) Use 900 mL of 0.1m hydrochloric acid, at a temperature.@t thiocyanate and mix. Any red colour produced is not more
PROCEDURE
medium and titrate the filtered sample with 0.01M ammonium
cerum(iv) sulfate VS using ferroin solution as indicator.
DETERMINATION
OFCONTENT
Calculate the total content of Fe(i1), in the medium taking
each mL of 0.01M ammonium cerium(1v) sulfate VS to be
equivalent to 0.5585 mg of Fe(i). acid, carefullywarfn u
a further 25 mL of nit isevaporate to about 10 mL and
ASSAY mL, of sulfuric acid to the
Dissolve a quantity of the mixed contents of 20 capsules
containing 0.3 g of ferrous fumarate in 7.5 mL of 1M sulfuric
fags ete
RA acid with gentle heating. Cool, add 25 mL of water and

titrate immediately with 0.1M ammonium cerium(iv) sulfate VS
using ferroin solution as indicator. Each mL of
0.1M ammonium cerium(1v) sulfate VS is equivalent to
5.585 mg of Fei).
LABELLING
The quantity of the active ingredient is stated both as the
amount of ferrous fumarate and in terms of the equivalent colour persists for 10 seconds. Add 10 mL of hydrochloric acid
amount of ferrous iron. and 3 g of potassium iodide, allow to stand for 15 minutes
protected from light, add 10 mL of chloroform and titrate the
liberated iodine with 0.1m sodium thiosulfate VS, with vigorous
shaking, until the chloroform layer becomes colourless.
Repeat the procedure without the preparation being
Ferrous Fumarate Oral Suspension examined. The difference between the titrations represents
the amount of sodium thiosulfate required. Each mL of
DEFINITION
0.1m sodium thiosulfate VS is equivalent to 5.585 mg of Fe(a).
Ferrous Fumarate Oral Suspension is a suspension of ferrous
fumarate in a suitable flavoured vehicle. STORAGE
The oral suspension complies with the requirements stated under Ferrous Fumarate Oral Suspension should be protected from
Oral Liquids and with the following requirements. light.
Content of ferrous iron, Fe(m)

2016 Ferrous Fumarate Preparations III-565
LABELLING liberated by ferric ion. The difference between the titrations

The quantity of the active ingredient is stated both as the is not more than 13.4 mL (5%).
amount of ferrous fumarate and in terms of the equivalent ASSAY
amount of ferrous iron.
powder containing 0.3 g of ferrous fumarate in 7.5 mL of
1m sulfuric acid with gentle heating. Cool, add 25 mL of water
and titrate immediately with 0.1M ammonium cerium(1v)
Ferrous Fumarate Tablets sulfate VS using ferroin solution as indicator. Each mL of
0.1M ammonium certum(iv) sulfate VS is equivalent to
DEFINITION 5.585 mg of Fe().
Ferrous Fumarate Tablets contain Ferrous Fumarate.
LABELLING
The quantity of the active ingredient is stated both as the
amount of ferrous fumarate and in terms of the equivalent
amount of ferrous iron.
bath for 15 minutes, cool

Ferrous Fumarate and Folic Acid Tablets
test B. The filtrate yields Action and use
salts, Appendix VI. Vitamin B component.
B. Wash the residue reserved i ath a mixture of
1 volume of 2m hydrochloric acid and 9 1 of water and DEFINITION
dry at 105°. Suspend 0.1 g of the resi aL of dilute Ferrous Fumarate and Folic Acid Tablets contain Ferrous
sodium carbonate solution and add dilute pot Fumarate and Folic Acid. They are coated.
permanganate solution drop wise. The permanggnat The tablets comply with the requirements stated under Tablets and
decolourised and a brownish solution is produced: with the following requirements.
C. Mix a quantity of the powdered tablets containing’ 0.58 Carry out the tests avoiding exposure to actinic light.
of ferrous fumarate with 1 g of resorcinol. To 0.5 g of th
Content of ferrous fumarate, C,H,FeO,
mixture in a crucible add 0.15 mL of sulfuric acid and he
<0 105.0% of the stated amount.
gently; a deep red, semi-solid mass is produced. Add the
mass to a large volume of water; an orange—yellow solution 1 teat of folic acid, Cys5H,5N7O,
produced which exhibits no fluorescence.
TESTS
Dissolution
Appendix XII Bl. solution (2). «
B. Heat a quanti
TEST CONDITIONS

volumes of hydrochloric’a
per minute.
15 minutes, cool and filt
(b) Use 900 mL of 0.1m hydrochloric acid, at a temperature of The filtrate yields reaction
37°, as the medium. Appendix VI.
PROCEDURE C. Wash the residue reserved in
After 45 minutes withdraw a sample of 100 mL of the 1 volume of 2m soarocone acid and‘
medium and filter. Titrate the filtrate with 0.01M ammonium
cerum(Iv) sulfate VS using ferroin solution as indicator.
solution is produced.
Calculate the total content of Fe(r) in the medium taking
each mL of 0.01M ammonium cerium(1v) sulfate VS to be TESTS
equivalent to 0.5585 mg of Fe(1). Ferric iron
Dissolve a quantity of the powder prepared for the Assay for
Ferric iron
ferrous fumarate containing 1.5 g of Ferrous Fumarate in a
In a flask with a ground-glass stopper dissolve a quantity of
mixture of 100 mL of water and 10 mL of hydrochloric acid
the powder prepared for the Assay containing 1.5 g of ferrous
by heating rapidly to the boiling point. Boil for 15 seconds,
fumarate in a mixture of 10 mL of hydrochloric acid and
cool rapidly, add 3 g of potassium todide, stopper, allow to
100 mL of water by heating rapidly to boiling. Boil for
stand in the dark for 15 minutes and titrate the liberated
15 seconds. Cool rapidly, add 3 g of potassium iodide, stopper
iodine with 0.1M sodium thiosulfate VS using starch mucilage as
the flask and allow to stand protected from light for
indicator. Repeat the operation without the substance being
15 minutes. Add 2 mL of starch solution as indicator. Titrate
examined. The difference between the titrations is not more
the liberated iodine with 0.1M sodium thiosulfate VS. Carry
than 13.4 mL (5% ferric iron in Ferrous Fumarate).
out a blank test. The difference between the volumes used in
the two titrations corresponds to the amount of iodine
W-566 Ferrous Gluconate Preparations 2016
Uniformity of Content (b) Use isocratic elution and the mobile phase described
For folic acid below.
Tablets containing less than 2mg and/or less than 2% w/w of (c) Use a flow rate of 1 mL per minute.
Folic Acid comply with the requirements stated under (d) Use an ambient column temperature.
wend
Tablets using the following method of analysis. Carry out the (e) Use a detection wavelength of 277 nm.
method for liguid chromatography, Appendix III D, using the
following solutions in 135 volumes of methanol and
800 volumes of a 0.57% w/v solution of dipotasstum hydrogen MOBILE PHASE
orthophosphate (solvent A). 135 volumes of methanol and 800 volumes of a solution
(1) Place one tablet in 40 mL of solvent A, shake for a containing 0.938% w/v of sodium perchlorate and 0.075% wiv
further 15 minutes, dilute to 50 mL with solvent A and filter of potassium dihydrogen orthophosphate adjusted to pH 7.2 with
on filter is suitable). 0.1m potassium hydroxide and diluted to 1000 volumes with
water.
Calculate the content of Cyg>H19N7O¢ in the tablets using the

declared content of Cj9Hj9N7O¢ in folic acid BPCRS.
(Spherisorb ODS 1 STORAGE
(b) Use isocratic elutio Ferrous Fumarate and Folic Acid Tablets should be
below. protected from light.
304 mg of ferrous fumarate is equivalent to 100 mg of
(d) Use an ambient column te & ferrous iron.
(e) Use a detection wavelength
MOBILE PHASE
135 volumes of methanol and 800 volumes o Ferrous Gluconate Tablets

DEFINITION
Ferrous Gluconate Tablets contain Ferrous Gluconate. They
0.1m potassium hydroxide and diluted to 1000 volumes
water.
owing requirements.
Calculate the content of C;g)H,9N7O¢ in each tablet using
f ferrous iron, Fe(n)
the declared content of Cj9H,9N7Og¢ in folic acid BPCRS.
ASSAY
For ferrous fumarate
Disperse a quantity of the powder containing 0.3 g of
Ferrous Fumarate in 7.5 mL of 1m sulfuric acid with gentle
heating. Cool, add 25 mL of water and titrate immediately
produced.
with 0.1M ammonium cerum(iv) sulfate VS using ferroin
solution as indicator. Each mL of 0.1M ammonium certum(1v)
B. The powdered tablets*yi
sulfate VS is equivalent to 16.99 mg of CygH,FeQO,. iron salts, Appendix VI.
For folic acid TESTS
Ferric iron
2% w/w offolic acid
potassium iodide. Close the vessel, allow to stand’
more offolic acid
for 5 minutes and titrate the liberated iodine with
0.1M sodium thiosulfate VS using starch mucilage as indicator.
Appendix III D, using the following solutions in 135 volumes
Repeat the operation without the powder. The difference
of methanol and 800 volumes of a 0.57% w/v solution of
between the titrations represents the amount of iodine
dipotasstum hydrogen orthophosphate (solvent A).
liberated by the ferric iron. Not more than 11.2 mL of
(1) Mix a quantity of the powdered tablets containing 0.1m sodium thiosulfate VS is required.
0.35 mg of Folic Acid in 40 mL of solvent A, shake for
5 minutes with the aid of ultrasound, shake for a further ASSAY
15 minutes and dilute to 50 mL with solvent A and filter (a Weigh and powder 20 tablets. Dissolve a quantity of the
0.45 ym nylon filter is suitable) powder containing 1 g of ferrous gluconate as completely as
possible in a mixture of 30 mL of water and 20 mL of
(2) 0.0007% w/v of folic acid BPCRS solvent A.
1m sulfuric acid and titrate with 0.1M ammonium
CHROMATOGRAPHIC CONDITIONS certum(1v) sulfate VS using ferroin solution as indicator. Each
‘ew
(a) Use a stainless steel column (25 cm x 4.6 mm) packed mL of 0.1M ammonium cerium(iv) sulfate VS is equivalent to
a.
wow
atietesy
vee A with octadecylsilyl silica gel for chromatography (5 um) 5.585 mg of Fe(i).
elt aS gad ph Geet tad el pe i gt a en FIGS
A Ew Se
2016 Fexofenadine Preparations III-567

weaned
LABELLING
The quantity of active ingredient is stated both as the
Prolonged-release Ferrous Sulfate
amount of ferrous gluconate and in terms of the equivalent Tablets
amount of ferrous iron. Prolonged-release Ferrous Sulphate Tablets
Prolonged-release Ferrous Sulfate Tablets from different
manufacturers, whilst complying with the requirements of the
authorised.
Paediatric Ferrous Sulfate Oral Solution
Paediatric Ferrous Sulphate Oral Solution DEFINITION
Prolonged-release Ferrous Sulfate Tablets contain Dried
Ferrous Sulfate. They are formulated so that the medicament
is released over a period of several hours. They are coated.
saves
w/v of Ferrous Sulfate Heptahydrate and a

ant in a suitable vehicle with an orange PRODUCTION
appropriate release of ferrous sulfate. The dissolution profile
should reflect the 1m vivo performance which in turn 1s
compatible with the dosage schedule recommended by the
manufacturer.
Content of ferrous s
1.10 to 1.30% w/v.
ASSAY
oer Ne
Content of ferrous iron, Fe()
eee 95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. The powdered tablets yield reaction A characteristic of
iron salts, Appendix VI.
chlonde VS maintaining a steady flow of carbon di6x1 B. Extract a quantity of the powdered tablets containing
through the flask. Each mL of 0.1M titantum(m) chlée 0.15 g of Dried Ferrous Sulfate with 10 mL of
equivalent to 27.80 mg of FeSO,4,7H2O. 2m hydrochloric acid and filter. The filtrate yields reaction A
Paediatric Ferrous Sulfate Oral Solution contains in 5 m cteristic of sulfates, Appendix VI.
about 12 mg of ferrous iron.
and powder 20 tablets. Dissolve a quantity of the
dercontaining 0.5 g of Dried Ferrous Sulfate as
i possible in a mixture of 30 mL of water and
Ferrous Sulfate Tablets

Ferrous Sulphate Tablets
DEFINITION
Ferrous Sulfate Tablets contain Dried Ferrous Sulfate. They LABELLING
are coated. The quantity of active’ snt is stated both as the
wane The tablets comply with the requirements stated under Tablets and amount of dried ferrous nd in terms of the
with the following requirements. equivalent amount of Fe(1
Content of ferrous iron, Fe(n)
IDENTIFICATION
A. The powdered tablets yield reaction A characteristic of Fexofenadine Tablets
iron salts, Appendix VI.
B. Extract the powdered tablets with 2m hydrochloric acid and Action and use
filter. The filtrate yields reaction A characteristic of sudfates,
Appendix VI.
DEFINITION
ASSAY Fexofenadine Tablets contain Fexofenadine Hydrochloride.
Weigh and powder 20 tablets. Dissolve a quantity of the They may be coated.
powder containing 0.5 g of dried ferrous sulfate as
completely as possible in a mixture of 30 mL of water and
20 mL of 1m sulfuric acid and titrate with 0.1M ammonium
certum(1v) sulfate VS using ferroin solution as indicator. Each PRODUCTION
mL of 0.1m ammonium cerium(1v) sulfate VS is equivalent to The manufacturing process of Fexofenadine Hydrochloride,
5.585 mg of Fe(). used in the formulation of Fexofenadine Tablets, is validated
to ensure that the content of the enantiomer impurity B is
LABELLING
not more than 0.1%.
The quantity of active ingredient is stated both as the
TA amount of dried ferrous sulfate and in terms of the Content of fexofenadine hydrochloride, C3,H3,NO,,HCI
ins
Sa ag
beseLC
aa tee s
ato equivalent amount of ferrous iron. 95.0 to 105.0% of the stated amount.
eA ae
IWI-568 Fexofenadine Preparations 2016
IDENTIFICATION (e) Use a detection wavelength of 220 nm.

Shake a quantity of the powdered tablets containing 30 mg (f) Inject 20 uL of each solution.
of Fexofenadine Hydrochloride with 10 mL of methanol for
MOBILE PHASE
5 minutes, filter and evaporate the filtrate to dryness. The
infrared absorption spectrum of the dried residue, 350 volumes of acetonitrile and 650 volumes of a buffer
Appendix II A, is concordant with the reference spectrum of solution containing 0.05M sodium dihydrogen orthophosphate
fexofenadine hydrochloride (RS 459). monohydrate and 0.006M sodium perchlorate the pH of which is
adjusted to 2.0 with orthophosphoric acid. To the resulting
TESTS solution add 3 volumes of triethylamine and mix.
Dissolution
SYSTEM SUITABILITY
Appendix XJI B1. The test is not valid unless, in the chromatogram obtained
with solution (3), the resolution factor between the principal
peaks due to Fexofenadine and impurity A is at least 10.
LIMITS
of 37°, as the In the chromatogram obtained with solution (1):

PROCEDURE multiply the peak area of any peak corresponding to
impurity A by 1.4;
Appendix III D, using th the area of any secondary peak corresponding to impurityA is
not greater than 3 times the area of the principal peak in the
(1) After 45 minutes withdr:
the area of any secondary peak corresponding to impurityC is
not greater than 1.5 times the area of the principal peak in
the chromatogram obtained with solution (2) (0.3%);
(2) 0.003% w/v offexofenadine hydrochlo
0.001M hydrochloric acid. the area of any other secondary peak is not greater than the
The chromatographic conditions described underRelat
substances may be used. 5 times the area of the principal peak in the chromatogram
DETERMINATION OF CONTENT btained with solution (2) (1.0%).
Calculate the total content of fexofenadine hydrochloride, wd any peak with an area less than 0.5 times the area
C32H39NO,,HCI, in the medium from the chromatograms principal peak in the chromatogram obtained with
obtained and using the declared content of C32H3)9NO,,HC1l
in fexofenadine hydrochloride BPCRS.
LIMITS
The amount of fexofenadine hydrochloride released is not
less than 75% (Q) of the stated amount.
Related substances
SOLVENT A
solvent A.
Equal volumes of acetonitrile and a buffer solution containing
0.05m sodium dihydrogen orthophosphate monohydrate and (3) 0.1% w/v of fexofenadine impupit U7 dard BPCRS in
0.006M sodium perchlorate. The pH of the buffer solution is solvent A.
adjusted to 2.0 with orthophosphoric acid before the addition CHROMATOGRAPHIC CONDITIONS
of acetonitrile. The chromatographic conditions describe 7 Related
(1) Shake a quantity of powdered tablets containing 25 mg of substances may be used.
Fexofenadine Hydrochloride with 25 mL of solvent A and
SYSTEM SUITABILITY
filter.
with solution (3), the resolution factor between the principal
solvent A and further dilute 1 volume of the resulting
peaks due to Fexofenadine and impurity A is at least 10.
solution to 5 volumes with solvent A.
(3) 0.1% w/v of fexofenadine impurity standard BPCRSin
solvent A. Calculate the content of C3.H3)NO,,HCI in the tablets using
the declared content of C3,H3,)NO,4,HCI in fexofenadine
with phenylsilyl silica gel for chromatography (5 um) (Zorbax IMPURITIES
SB Phenyl is suitable). The impurities limited by the requirements of this
monograph include impurities A and C listed under
Fexofenadine Hydrochloride.
below.
Weve wey
POR
WO neeteMr
me re Kot,
hr et itad rege Ca
rose? TTT EAE
EE NR a Ire Oe
eR ee “ f,0 ee
A
Poll 2.0
7 meeSte
my oe
a
eee ee aesPS
2016 Finasteride Preparations III-569
Related substances
Finasteride Tablets Carry out the method for liguid chromatography,
Action and use Appendix III D, using the following solutions.
5-Alpha reductase inhibitor; treatment of benign prostatic (1) Add 30 mL of a mixture of equal volumes of acetonitrile
hyperplasia. and water to a quantity of powdered tablets containing
100 mg of Finasteride, dilute to 50 mL with the same
DEFINITION mixture of solvents, centrifuge and filter the supernatant
Finasteride Tablets contain Finasteride. They are coated. liquid. (0.2%)
The tablets comply with the requirements stated under Tablets and (2) Dilute 2 volumes of solution (1) to 100 volumes with a
with the following requirements. mixture of equal volumes of acetonitrile and water, dilute
Content of finasteride, C,3H3;,N,O, 1 volume of this solution to 10 volumes with a mixture of
equal volumes of acetonitrile and water.
whe ete
(3) 0.2% w/v offinasteride for peak identification EPCRS in a

NL yt
mixture of equal volumes of acetonitrile and water.

Dissolution, the chromatogram obtained
s a peak with the same retention time (4) Dilute 25 volumes of solution (2) to 100 volumes with
equal volumes of acetonitrile and water.

peak with the same with end-capped octadecylsilyl silica gel for chromatography
retention time as the pea inasteridein the (5 um) (Spherisorb ODS 2 is suitable).
chromatogram obtained wi (b) Use isocratic elution and the mobile phase described
below.
chet Ne
TESTS
Dissolution (c) Use a flow rate of 1.5 mL per minute.
Comply with the requirements for Mono (d) Use a column temperature of 60°.
Pharmacopoeiain the dissolution test for tab (e) Use a detection wavelength of 210 nm.
Appendix XII Bl.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 50 revolutigsi conditions the retention time of finasteride is
per minute. about 28 minutes. The retention times relative to finasteride
(b) Use 900 mL of water, at a temperature of 37°, as the purity A, about 0.9; impurity B, about 1.2;
medium. C, about 1.4. For solution (1) allow the
PROCEDURE

medium and filter. Use the filtered medium.
(2) A suitable solution offinasteride BPCRS in a mixture of
3 volumes of water and 7 volumes of acetonitrile. s in the chromatogram obtained
CHROMATOGRAPHIC CONDITIONS alley ratio between finasteride
ste NTS
with octadecylsilyl silica gel for chromatography (3 wm) (Hypersil
ODS is suitable).
below. than 0.3%, calculated using the area
(c) Use a flow rate of 1.5 mL per minute. finasteride impurity A in solution (3)
(d) Use a column temperature of 45°. content of finasteride impurity Ainfinastenid é or
identification EPCRS;
the area of any peak corresponding to finasteride impurity B
is not greater than 1.5 times the area of the principal peak in
MOBILE PHASE solution (2) (0.3%);
21 volumes of water and 29 volumes of acetonitrile. the area of any peak corresponding to finasteride impurity C
SYSTEM SUITABILITY is not greater than 1.5 times the area of the principal peak in
The test is not valid unless, in the chromatogram obtained the chromatogram obtained with solution (2) (0.3%);
with solution (2), the symmetry factor of the peak the area of any other secondary peak is not greater than
corresponding to finasteride is less than 2.0. 0.5 times the area of the principal peak in the chromatogram
Calculate the content of C,3H3,.N2O>, in the medium from
the chromatograms obtained using the declared content of
C33H36N20> infinasteride BPCRS.
we NY
“Nv Aw
IWI-570 Flavoxate Preparations
Disregard any peak with an area less than 0.25 times the area SYSTEM SUITABILITY
of the peak due to finasteride in the chromatogram obtained The assay is not valid unless, in the chromatogram obtained
eas
with solution (2) (0.05%). with solution (2), the symmetry factor of the peak due to
wa
Uniformity of content finasteride is less than 2.0.

Tablets containing less than 2 mg and/or less than 2% w/w DETERMINATION OF CONTENT
of Finasteride comply with the requirements stated under
Calculate the content of C23H3.5N.,O> in the tablets from the
Tablets using the following method of analysis. Carry out the
chromatograms obtained and using the declared content of
method for liquid chromatography, Appendix III D, using the C43H36N20> in finasteride BPCRS.
following solutions in a mixture of 3 volumes of water and
7 volumes of acetonitrile (solvent A). IMPURITIES
(1) Add 2.5 mL of water to one tablet, shake with the aid of The impurities limited by the requirements of this
til the tablet is completely dispersed. monograph include those listed in the monograph for
ea OA
Finasteride.
sways
Flavoxate Tablets
Action and use
(a) Usea stainless steel cél m x 4.6 mm) packed
Anticholinergic.
with octadecylsilyl silica gel fe aphy (5 um) (Hypersil
ODS is suitable). & DEFINITION
eae (b) Use isocratic elution and thi Flavoxate Tablets contain Flavoxate Hydrochloride. They are
below. ( coated.
(c) Use a flow rate of 1.5 ml per minute. The tablets comply with the requirements stated under Tablets and
(d) Use a column temperature of 45°. with the following requirements.
(e) Use a detection wavelength of 240 nm. Content of flavoxate hydrochloride, C,,H,;NO,,HCl
(f) Inject 20 wL of each solution. 95.0 to 105.0% of the stated amount.
Equal volumes of acetonitrile and 0.0025m of orthophosph Extract a quantity of the powdered tablets containing
acid. sf, Flavoxate Hydrochloride with 10 mL of
) hane, filter and evaporate the filtrate to dryness.
SYSTEM SUITABILITY
d absorption spectrum of the residue, Appendix II A,
with solution (2), the symmetry factor of the peak due to
finasteride is less than 2.0.
Calculate the content of C.3H3¢N2O, in each tablet using
the declared content of C,3H3,N.O> in finasteride BPCRS.
ASSAY
2% w/w of Finasteride
owes
Use the average of the 10 individual results obtained in the 8M ammonia,
test for Uniformity of content. 80 volumes of propan-2-ol and 260 of ethyl acetate as
Ne
For tablets containing 2 mg or more and 2% w/w or the mobile phase. Apply separately
more of Finasteride
we ove

liquid chromatography, Appendix III D, using the following 10 mL of chloroform and filtering, (2) 10 uL*
solutions in a mixture of 3 volumes of water and 7 volumes solution of 3-methylflavone-8-carboxylic acid BPG:
of acetonitrile (solvent A). chloroform, (3) 10 uL of a 0.015% w/v solution of
3-methylflavone-8-carboxylic acid ethyl ester BPCRS in
(1) Add 25 mL of water to a quantity of the powdered tablets
chloroform, (4) 25 uL of a solution obtained by diluting one
containing 50 mg of Finasteride, add 350 mL of solvent A,
volume of solution (1) to 500 volumes with chloroform, (5)
|
mix with the aid of ultrasound for 30 minutes. Allow to

10 uL of a solution obtained by diluting 1 volume of solution
aN
wn ete
ree AY
attain room temperature and dilute to 500 mL with
(1) to 20 volumes with chloroform and (6) 10 uL of a
solvent A, centrifuge and use the clear supernatant liquid.
0.1% w/v solution offlavoxate hydrochloride BPCRS in
(2) 0.010% w/v offinasteride BPCRS in solvent A. chloroform. After removal of the plate, allow it to dry in air
CHROMATOGRAPHIC CONDITIONS and examine under wltraviolet ight (254 nm). Any spot
The chromatographic conditions described under Uniformity corresponding to 3-methylflavone-8-carboxylic acid ethyl
of content may be used. ester in the chromatogram obtained with solution (1) 1s not
more intense than the spot in the chromatogram obtained
with solution (3) (0.15%) and any other secondary spot in the
Ae chromatogram obtained with solution (1), other than the
2.
eS Tee
See ee spot corresponding to 3-methyflavone-8-carboxylic acid, is
ape
2016 Flecainide Preparations III-571
not more intense than the spot in the chromatogram TESTS

obtained with solution (4) (0.1%). Acidity
FAN aN
3-Methylflavone-8-carboxylic acid
Carry out the method for thin-layer chromatography, (Piperidin-2-yl)methanamine
Appendix III A, using a TLC silica gel GF 254 plate (Merck Carry out the method for thin-layer chromatography,
silica gel 60 F254 plates are suitable) and a mixture of Appendix III A, usinga silica gel F254 precoated plate
4 volumes of glacial acetic acid, 25 volumes of ethyl acetate (Merck plates are suitable) and a mixture of 2 volumes of
and 70 volumes of cyclohexane as the mobile phase. Apply methanol, 5 volumes of 18M ammonia, 100 volumes of acetone
separately to the plate 50 wL of each of the following and 100 volumes of dichloromethane as the mobile phase but
solutions. For solution (1) shake a quantity of the powdered allowing the solvent front to ascend 10 cm above the line of
tablets containing 0.2 g of Flavoxate Hydrochloride with application. Apply separately to the plate 1 uwL of solution (1)
10 mL, loroform and filter. Solution (2) is a 0.010% w/v and 5 uL of each of solutions (2) and (3). Solution (1)
contains 0.025% w/v offlecainide acetate impurity B EPCRS
[(piperidin-2-yl)methanamine] in methanol. For solution (2)
dilute pota ismuthate solution. Any spot dilute the injection, if necessary, with methanol to contain
corresponding toé “mm thylflavone-8-carboxylic acidin the 1% w/v of flecainide acetate. Solution (3) contains 1% w/v of
chromatogram sd with solution (1) 1i S not more intense flecainide acetate BPCRS in methanol. After removal of the
than the spot in plate, allow it to dry in air and examine under wiltraviolet light
(0.5%). (254 nm) (for Identification test B). Spray the plate with a
ASSAY freshly prepared 0.2% w/v solution of ninhydrin in methanol,
heat the plate at 105° for approximately 5 minutes and
Weigh and finely powder 20
examine immediately. In the chromatogram obtained with
powdered tablets containing.
solution (2) any bluish-purple spot corresponding to
BS
(piperidin-2-yl)methanamine is not more intense than the

Related substances
0.1m hydrochloric acid and measure the absorba: Carry out the method for liquid chromatography,
resulting solution at 293 nm, Appendix II B. Cak Appendix III D, using the following solutions. Solution (1) 1s
content of C.4H.;NO,,HC! from the absorbance obtai the injection diluted, if necessary, with a mixture of
repeating the measurement using a 0.002% w/v solutiogi of, 29 volumes of acetonitrile and 71 volumes of water to contain
flavoxate hydrochloride BPCRSin 0.1m hydrochloric acid an 1.0% w/v of flecainide acetate. For solution (2) dilute
from the declared content of C24H.»5NO,4,HCIin flavoxate | e of solution (1) to 100 volumes with a mixture of
hydrochlonde BPCRS. umes of acetonitrile and 71 volumes of water and
ilute 1 volume of this solution to 5 volumes with the
STORAGE
sgivent mixture. Solution (3) contains 0.01% w/v of
Flavoxate tablets should be protected from light. ide acetate BPCRS and dlflecainide
procedure may be carried out using

Flecainide Injection n (15 cm x 4.6 mm) packed with
1 for chromatography (5 um)
Action and use
Class I antiarrhythmic.
DEFINITION
Flecainide Injection is a sterile solution of Flecainide Acetate the mixture adjusted to pH 5.8 us
in Water for Injections. a detection wavelength of 254 nm.
The injection complies with the requirements stated under Inject 20 uL of each solution. The te
Parenteral Preparations and with the following requirements. the chromatogram obtained with solution *{3)
Content of flecainide acetate, C,7H, )F;>N,03,C,H,O, factor between the peaks corresponding to fle
95.0 to 105.0% of the stated amount. flecainide impurity A is at least 3.5.
CHARACTERISTICS For solution (1) allow the chromatography to proceed for

nine times the retention time of the principal peak. In the
A clear, colourless or almost colourless solution.
chromatogram obtained with solution (1) the area of any
IDENTIFICATION secondary peak is not greater than the area of the peak in the
A. The light absorption, Appendix II B, of the solution chromatogram obtained with solution (2) (0.2%) and the
obtained in the Assay in the range 230 nm to 350 nm sum of the areas of any such peaks is not greater than two
exhibits a maximum at 296 nm. and a half times the area of the principal peak in the
B. In the test for (Piperidin-2-yl)methanamine, examine the chromatogram obtained with solution (2) (0.5%). Disregard
chromatograms under ultraviolet light (254 nm) before any peak with an area less than 0.05 times the area of the
spraying. The principal spot in the chromatogram obtained peak in the chromatogram obtained with solution (2)
with solution (2) corresponds to that in the chromatogram (0.01%).
obtained with solution (3). ASSAY
Dilute the injection with a 0.2% v/v solution of lactic acid to
produce a solution containing 0.01% w/v of flecainide acetate
IWI-572 Flecainide Preparations 2016
and measure the absorbance of the resulting solution at the following solutions. For solution (1) add 2 mL of methanol to
maximum at about 296 nm, Appendix II B, using a 0.2% v/v a quantity of the powdered tablets containing 0.2 g of
solution of /actic acid in the reference cell. Calculate the flecainide acetate, shake, centrifuge and use the supernatant
content of C;7H»oFgN203,C2H,4O> in the injection from the liquid. Solution (2) contains 0.05% w/v offlecainide
absorbance obtained with a solution containing 0.01% w/v of acetate BPCRS in methanol. Solution (3) contains 0.05% w/v
flecainide acetate BPCRS in a 0.2% v/v solution of lactic acid offlecainide impurity A EPCRS in methanol. Solution (4)
and using the declared content of C)7H2)F,N,03,C2H4O> in contains 0.02% w/v of flecainide impurity B EPCRS in
flecainide acetate BPCRS. methanol. After removal of the plate, allow it to dry in air and
examine under ultraviolet light (254 nm). In the
STORAGE
Flecainide Injection should not be allowed to freeze.
corresponding to 3-[2,5-bis(2,2,2-trifluoroethoxy)pheny]]-
1,5,6,7,8,8ahexahydroimidazo[1,5-a]pyridine (impurity A) is
not more intense than the principal spot in the
chromatogram obtained with solution (3) (0.5%). Spray the
plate with a freshly prepared 0.2% w/v solution of ninhydrin
in absolute ethanol, heat the plate at 105° for approximately
5 minutes and examine immediately. In the chromatogram
obtained with solution (1) any bluish-purple spot
corresponding to (piperidin-2-yl)methanamine (impurity B) is
not more intense than the principal spot in the
Action and use chromatogram obtained with solution (4) (0.2%) and any
Class I antiarrhythmic. & other secondary spot is not more intense than the principal
DEFINITION é
ASSAY
Flecainide Tablets contain Flecainide Ac
Shake 20 tablets with 100 mL of a 2% v/v solution of lactic
The tablets comply with the requirements stated acid until the tablets have disintegrated, add 650 mL of
with the following requirements. water, Shake with the aid of ultrasound for 30 minutes, add
Content of flecainide acetate, C,7,H2oF5N203,Cz 2 sufficient water to produce 1000 mL, mix and filter
95.0 to 105.0% of the stated amount. , (Whatman GF/F paper is suitable), discarding the first
100 mL of filtrate. Dilute the filtrate with a 0.2% v/v solution
IDENTIFICATION
lactic acid to producea solution containing 0.01% w/v of
A. The light absorption, Appendix II B, of the solution
é acetate and measure the absorbance of the resulting
obtained in the Assay in the range 230 nm to 350 nm
the maximum at about 296 nm, Appendix II B,
exhibits a maximum at 296 nm.
% viv solution of lactic acid in the reference cell.
B. Shake a quantity of the powdered tablets containing 0.1 g
of flecainide acetate with 10 mL of methanol for 10 minutes,
filter and evaporate the filtrate to dryness. The infrared
concordant with the reference spectrum of flecainide acetate
(RS 397).
STORAGE |
TESTS
Flecainide Tablets shoi
Dissolution exceeding 30°.
Pharmacopoeia in the dissolution test for tablets and capsules, IMPURITIES
Appendix XII B1, using Apparatus 2. Use as the medium The impurities limited by the reg
900 mL of 0.1m hydrochloric acid and rotate the paddle at monograph include impurities A, B nd ]
100 revolutions per minute. Withdraw a sample of 5 mL of Flecainide Acetate. » 6
the medium, filter and dilute the filtered solution, if
necessary, with sufficient 0.1m hydrochloric acid to produce a
solution expected to contain about 0.005% w/v of flecainide
acetate. Measure the absorbance of the solution at the
maximum at 298 nm, Appendix II B, using 0.1m hydrochloric
Flucloxacillin Capsules
acid in the reference cell. Calculate the total content of Action and use
oe flecainide acetate, Cy7H29F5N203,C2H.4O>, in the medium Penicillin antibacterial.
“oy from the absorbance of a 0.005% w/v solution offlecainide
25) acetate BPCRS in 0.1m hydrochloric acid using the declared DEFINITION
ce content of C)7H2pF6N203,C2H4O> in flecainide Flucloxacillin Capsules contain Flucloxacillin Sodium.
acetate BPCRS.
ae Related substances . and with the following requirements.
a
on
_ Carry out the method for thin-layer chromatography;
Appendix III A, using a TLC silica gel F254 plate (Merck
Content of flucloxacillin,
0
C;5H,;CIFN;0<S
plates are suitable) and a mixture of 2 volumes of methanol,
ma] 5 volumes of 18M ammonia, 100 volumes of acetone and IDENTIFICATION
S253)
A
100 volumes of dichloromethane as the mobile phase but The infrared absorption spectrum of the contents of the
eSney allowing the solvent front to ascend 10 cm above the line of capsules, Appendix II A, is concordant with the reference
spectrum of flucloxacillin sodium (RS 145).
er
application. Apply separately to the plate 1 wL of each of the

2016 Flucloxacillin Preparations II-573
TESTS LABELLING
tN ad
Related substances The quantity of active ingredient is stated in terms of the
venue
Carry out the method for liguid chromatography, equivalent amount of flucloxacillin.
(1) shake a quantity of the contents of the capsules
containing the equivalent of 0.1 g of flucloxacillin with
80 mL of the mobile phase for 15 minutes, add sufficient of
the mobile phase to produce 100 mL and filter. For solution Flucioxacillin Injection
(2) dilute 1 volume of solution (1) to 100 volumes with the
Action and use
mobile phase. Solution (3) contains 0.01% w/v of each of
flucloxacillin sodium BPCRS and cloxacillin sodium BPCRS in
DEFINITION
ra eS
wer el Flucloxacillin Injection is a sterile solution of Flucloxacillin
Sodium in Water for Injections. It is prepared by dissolving
Flucloxacillin Sodium for Injection in the requisite amount of
the mobile phase with a flow rate of Water for Injections before use.
e of 25 volumes of acetonitrile and
solution of potasstum dihydrogen
“5.0 with 2m sodium hydroxide
STORAGE
Flucloxacillin Injection should be used immediately after
For solution (1) allow the chromatogra
times the retention time of the principa
FLUCLOXACILLIN SODIUM FOR
INJECTION
peak in the chromatogram obtained with solution: {2)
DEFINITION
and the sum of the areas of any such peaks is not gréat
than 5 times the area of the principal peak in the Flucloxacillin Sodium for Injection is a sterile material
chromatogram obtained with solution (2) (5%). Disregars consisting of Flucloxacillin Sodium with or without
any peak with an area less than 0.05 times the area of the : nts. It is supplied in a sealed container.
principal peak in the chromatogram obtained with solution tents of the sealed container comply with the requirements
(2) (0.05%). s for Injections or Infusions stated under Parenteral
rations and with the following requirements.
ASSAY
containing the equivalent of 50 mg of flucloxacillin with
40 mL of the mobile phase for 15 minutes, add sufficient of
the mobile phase to produce 50 mL, filter and dilute
5 volumes of the resulting solution to 50 volumes with the
mobile phase. Solution (2) contains 0.011% w/v of Appendix VI.
flucloxacillin sodium BPCRS in the mobile phase. Solution (3)
contains 0.01% w/v of each of flucloxacillin sodium BPCRS TESTS
and cloxacillin sodium BPCRS in the mobile phase. Acidity or alkalinity
The chromatographic procedure may be carried out using pH of a solution containing the equi
(a) a stainless steel column (25 cm x 4.6 mm) packed with flucloxacillin, 5.0 to 7.0, Appendix V
octadecylsilyl silica gel for chromatography (5 um) (Hypersil 5 Related substances
ODS is suitable), (b) as the mobile phase with a flow rate of Comply with the test described under Fluc Capsules
1 mL per minute a mixture of 25 volumes of acetonitrile and but using a solution prepared in the following manner as
75 volumes of a 0.27% w/v solution of potassium dihydrogen solution (1). Shake a quantity of the contents of the sealed
orthophosphate adjusted to pH 5.0 with 2m sodium hydroxide container containing the equivalent of 0.1 g of flucloxacillin
and (c) a detection wavelength of 225 nm. with 80 mL of the mobile phase for 15 minutes, add
The test is not valid unless, in the chromatogram obtained sufficient of the mobile phase to produce 100 mL and filter.
with solution (3), the resolution factor between the first peak Water
(cloxacillin) and the second peak (flucloxacillin) is at least Not more than 4.5% w/w, Appendix IX C. Use 0.3 g.
2.5. Bacterial endotoxins
Calculate the content of C;)H;7CIFN305S in the capsules Carry out the test for bacterial endotoxins, Appendix XIV C.
using the declared content of Cjj)H,;¢CIFN3NaQO5S in Dissolve the contents of the sealed container in water BET to
flucloxacillin sodium BPCRS. Each mg of give a solution containing the equivalent of 9 mg of
C,9H).CIFN3NaQ5S is equivalent to 0.9538 mg of flucloxacillin per mL (solution A). The endotoxin limit
C19H,7CIFN305S. concentration of solution A is 3.5 IU per mL.
II-574 Flucloxacillin Preparations 2016
ASSAY silanised silica gel 60 plates are suitable) and a mixture of

peut es
Determine the weight of the contents of 10 containers as 30 volumes of acetone and 70 volumes of a 15.4% w/v
described in the test for uniformity of weight, solution of ammonium acetate adjusted to pH 5.0 with glacial
ee wel
vee nd
Appendix XII C1, Powders for Parenteral Administration. acetic acid as the mobile phase. Apply separately to the plate
Carry out the method for liguid chromatography, 1 wL of each of the following solutions. For solution (1)
Appendix III D, using the following solutions. For solution dilute a quantity of the oral solution containing the
(1) dissolve a quantity of the mixed contents of 10 containers equivalent of 50 mg of flucloxacillin to 20 mL with phosphate
containing the equivalent of 50 mg of flucloxacillin in buffer pH 7.0. Solution (2) contains 0.25% w/v offlucloxacillin
sufficient of the mobile phase to produce 50 mL and dilute sodium BPCRS in phosphate buffer pH 7.0. Solution (3)
5 volumes of the resulting solution to 50 volumes with the contains 0.25% w/v of each of cloxacillin sodium BPCRS,
mobile phase. Solution (2) contains 0.011% w/v of dicloxacillin sodium BPCRS and flucloxacillin sodium BPCRS in
sadium BPCRS in the mobile phase. Solution (3) phosphate buffer pH 7.0. After removal of the plate, allow it to
: of each offlucloxacillin sodium BPCRS dry in air, expose to iodine vapour until the spots appear and
examine in daylight. The principal spot in the chromatogram
obtained with solution (1) is similar in position, colour and
cedure may becarried out
0 using
size to that in the chromatogram obtained with solution (2).
in (25 cm x 4.6 mm) packed with
TESTS
orthophosphate adjusted to pH pH, 4.0 to 7.0, Appendix V L.
and (c) adetectionwavelength
ASSAY
vate tats

(1) dilute a weighed quantity of the oral solution containing
the equivalent of 50 mg of flucloxacillin to 50 mL with the
mobile phase and dilute 5 volumes of this solution to
average content weight using the declared content ef 50 volumes with the mobile phase. Solution (2) contains
CjoH,.CIFN3Na0O;S in flucloxacilin sodium BPCRS. Each , 0.011% w/v offlucloxacillin sodium BPCRS in the mobile
mg of Cj9H;,CIFN3Na0OsS is equivalent to 0.9538 mg of hase. Solution (3) contains 0.01% w/v of each of
Cj9H,7CIFN305S. cilin sodium BPCRS and cloxacillin sodium BPCRS in
LABELLING
The label of the sealed container states the quantity of
Flucloxacillin Sodium contained in it in terms of the
equivalent amount of flucloxacillin.
5éwhy solution of potassium dihydrogen

pH 5.0 with 2m sodium hydroxide
Flucloxacillin Oral Solution and (c) a detection :
The test is not valid u
Action and use
with solution (3), the resolu
(cloxacillin) and the secon
mee ad
DEFINITION 2.5.
Flucloxacillin Oral Solution is a solution of Flucloxacillin
ate ne, Sodium in a suitable flavoured vehicle. It is prepared by
dissolving the dry ingredients in the specified volume of
water just before issue for use.
The dry ingredients comply with the requirements for Powders and
equivalent to 0. 9538 mg of C,oH,;CIFN;0;S. |
Granules for Oral Solutions and Oral Suspensions stated under
Oral Liquids. Repeat the procedure using a portion of the oral solution that
has been stored at the temperature and for the period stated
For the following tests prepare the oral solution as directed on the
ot
on the label during which it may be expected to be
label. The solution, examined immediately after preparation unless
TAAL
wasp.
otherwise indicated, complies with the requirements stated under
Oral Liquids and with the following requirements. STORAGE
Content of flucloxacillin, C,,H,;CIFN30,;S The oral solution should be stored at the temperature and
When freshly constituted, not more than 120.0% of the used within the period stated on the label.
stated amount. When stored at the temperature and for the LABELLING
period stated on the label during which the oral solution may The quantity of active ingredient is stated in terms of the
be expected to be satisfactory for use, not less than 80.0% of equivalent amount of flucloxacillin.
the stated amount.
Veta eal
IDENTIFICATION
Sone ew)
nae
Appendix III A, using a TLC silica gel silanised plate (Merck
a a
.
.a
te
yee
2016 Fluconazole Preparations T-575

wae
Flucloxacillin Oral Suspension octadecylsilyl sihca gel for chromatography (5 um) (Hypersil 5
ODS is suitable), (b) as the mobile phase with a flow rate of
Action and use 1 mL per minute a mixture of 25 volumes of acetonitrile and
Penicillin antibacterial. 75 volumes of a 0.27% w/v solution of potassium dihydrogen
orthophosphate adjusted to pH 5.0 with 2m sodium hydroxide
DEFINITION and (c) a detection wavelength of 225 nm.
Flucloxacillin Oral Suspension is a suspension of The test is not valid unless, in the chromatogram obtained
Flucloxacillin Magnesium Octahydrate in a suitable flavoured with solution (3), the resolution factor between the first peak
vehicle. It is prepared by dispersing the dry ingredients in the (cloxacillin) and the second peak (flucloxacillin) is at least
specified volume of water just before issue for use. 2.5.
The dry ingredients comply with the requirements for Powders and Determine the weight per mL of the oral suspension,
6x, Oral Solutions and Oral Suspensions stated under Appendix V G, and calculate the content of
Cj9H,7CIFN30;S, weight in volume, using the declared
content of C;j>H;.CIFN3Na05;S in flucloxacillin
examined immediately after preparation, sodium BPCRS. Each mg of C,9H,.6CIFN3Na0O:S is
l, complies with the requirements stated equivalent to 0.9538 mg of C,9H,7CIFN30;S.
with the following requirements. Repeat the procedure using a portion of the oral suspension
Content of flucloxaéillin, 19H 7CIFN30;S
When freshly constituted: nore than 120.0% of the stated on the label during which it may be expected to be
stated amount. When sto \e:temperature and for the satisfactory for use.
h the oral suspension STORAGE
may be expected to be satisfa; use, not less than The oral suspension should be stored at the temperature and
80.0% of the stated amount. used within the period stated on the label.
IDENTIFICATION LABELLING
Appendix III A, using a TLC silica gel silanised gi equivalent amount of flucloxacillin.
silanised silica gel 60 plates are suitable) and a mi
solution of ammonium acetate adjusted to pH 5.0 wi ;

acetic acid as the mobile phase. Apply separately tothe pl
1 wL of each of the following solutions. For solution (1) conazole Capsules
dilute a quantity of the oral suspension containing the
equivalent of 50 mg of flucloxacillin to 20 mL with phosphate
buffer pH 7.0. Solution (2) contains 0.25% w/v offlucloxacillin
sodium BPCRS in phosphate buffer pH 7.0. Solution (3)
contains 0.25% w/v of each of cloxacillin sodium BPCRS,
dicloxacillin sodium BPCRS and flucloxacillin sodium BPCRS in contain Fluconazole.
phosphate buffer pH 7.0. After removal of the plate, allow it to ply eeath the requirements stated under Capsules
dry in air, expose to iodine vapour until the spots appear and and with the foklowi uirements.
examine in daylight. The principal spot in the chromatogram Content of flucén C,3H)2.F,N,O
obtained with solution (1) is similar in position, colour and 95.0 to 105.0% of
t ount.
size to that in the chromatogram obtained with solution (2).
IDENTIFICATION
A. Carry out the method for'thin-layer chromatography,
Appendix II A, using the foll6winig soluti
B. Dilute a quantity of the oral suspension containing the
equivalent of 50 mg of flucloxacillin to 20 mL with water,
containing 100 mg of Fluconazole wi |
shake to dissolve and filter if necessary. The filtrate yields
Filter and use the filtrate.
reaction B characteristic of magnesium salts, Appendix VI.
TESTS
Acidity
ketoconazole BPCRS in methanol.
ASSAY
Carry out the method for liquid chromatography, (a) Use as the coating stlca gel F254.
Appendix III D, using the following solutions. For solution (b) Use the mobile phase as described below.
(1) dilute a weighed quantity of the oral suspension (c) Apply 10 uL of each solution.
containing the equivalent of 50 mg of flucloxacillin to 50 mL (d) Develop the plate to 15 cm.
with the mobile phase and dilute 5 volumes of the solution to
(e) After removal ofthe plate, dry in air and examine under
50 volumes with the mobile phase. Solution (2) contains
0.011% w/v offlucloxacillin sodium BPCRS in the mobile
phase. Solution (3) contains 0.01% w/v of each of MOBILE PHASE
flucloxacilin sodium BPCRS and cloxacillin sodium BPCRS in 1 volume of 13.5m ammonia, 20 volumes of methanol and
the mobile phase. 80 volumes of dichloromethane.
IWI-576 Fluconazole Preparations 2016

sa a
The test is not valid unless the chromatogram obtained with 14 volumes of acetonitrile and 86 volumes of
solution (3) shows two clearly separated spots. 0.01M ammonium formate.
CONFIRMATION When the chromatograms are recorded under the prescribed
The principal spot in the chromatogram obtained with conditions, the retention times relative to fluconazole
solution (1) corresponds to that in the chromatogram (retention time about 11 minutes) are: impurity B, about 0.4;
obtained with solution (2). impurity A, about 0.5 and impurity C, about 0.8.
B. In the Assay, the retention time of the principal peak in SYSTEM SUITABILITY
the chromatogram obtained with solution (1) corresponds to The test is not valid unless, in the chromatogram obtained
that of the principal peak in the chromatogram obtained with with solution (3), the resolution between the peaks due to
impurity C and fluconazole is at least 3.0.
wtet vt 4 LIMITS

the area of any peak due to impurityA is not greater than
TEST CONDITIONS «, obtained with solution (2) (0.4%);
(a) Use Apparatus lla the area of any peak due to impurity B is not greater than
per minute. 3 times the area of the principal peak in the chromatogram
(b) Use 900 mL of 0.1m hyd obtained with solution (2) (0.3%);
37°, as the medium. the area of any other secondary peak is not greater than twice
PROCEDURE
(1) After 45 minutes withdraw a sample of |
the total content of impurities is not greater than 10 times
measure the absorbance of the filtered sanipl
containing 0.0056% w/v of Fluconazole, at 26F nim,
Appendix II B using dissolution medium in the refe Disregard any peak with an area less than the area of the
cell. | principal peak in the chromatogram obtained with
solution (2) (0.1%)
(2) Measure the absorbance of a 0.0056% w/v solution of «
fluconazole BPCRS in dissolution medium at 261 nm using |
liquid chromatography, Appendix III D, using the
lutions in the mobile phase.
Calculate the total content of fluconazole, C;3H,2F.N,O, in
the medium from the absorbances obtained and using the ity of powdered capsule contents containing
declared content of C,;3H,2F,N,O in fluconazole BPCRS. ole add 50 mL, mix with the aid of
LIMITS
The amount of fluconazole released is not less than 75% (Q) (2) 0.05% w/vof flucc
(3) 0.1% w/vof fluc
Related substances
CHROMATOGRAPHIC
NY
phase. substances may be used.
(1) To a quantity of powdered capsule contents containing SYSTEM SUITABILITY
0.5 g of Fluconazole, add 25 mL and mix with the aid of
ultrasound. Dilute to produce 50 mL, filter and use the
filtrate. impurity C and fluconazole is at least 3.0.
(2) Dilute 1 volume of solution (1) to 100 volumes and DETERMINATION OF CONTENT
Calculate the content of C,3H,.F,N,O in the capéiles using
(3) 0.1% w/v of fluconazole impurity standard BPCRS. the declared content of C,;3H,.F,N,0 in fluconazole BPCRS.
IMPURITIES
(a) Use a stainless steel column (15 cm x 4.6 mm) packed The impurities limited by the requirements of this
“way 4
with octadecylsilyl silica gel for chromatography (5 um) (Waters monograph include those listed under Fluconazole.
below.
(g) Allow the chromatography to proceed for 3.5 times the
retention time of fluconazole.
2016 Fluconazole Preparations TI-577

Fluconazole Infusion below.
Action and use (c) Use a flow rate of 1.0 mL per minute.
Antifungal. (d) Use a column temperature of 40°.
DEFINITION
Fluconazole Infusion is a sterile solution containing
Fluconazole. It is supplied as a ready-to-use solution. (g) Allow the chromatography to proceed for 3.5 times the
retention time of fluconazole.
Parenteral Preparations and with the following requirements. MOBILE PHASE
f fluconazole, C13H12F,N,O 14 volumes of acetonitrile and 86 volumes of

0.01M ammonium formate.
conditions, the retention times relative to fluconazole
: method for thin-layer chromatography,
(retention time about 11 minutes) are: impurity B, about 0.4;
: the following solutions.
impurity A, about 0.5 and impurity C, about 0.8.
(1) Dilute a voli
necessary, to prodt SYSTEM SUITABILITY
Fluconazole. The test is not valid unless, in the chromatogram obtained
(2) 0.2% w/v offluconaz RS in methanol. with solution (3), the resolution between the peaks due to
RS ‘and 0,1% wiv of impurity C and fluconazole 1s at least 3.0.
(3) 0.2% w/v offluconazole B
ketoconazole BPCRS in metha LIMITS
CHROMATOGRAPHIC CONDITIONS:
(a) Use as the coating silica gel F254. the area of any peak due to impurity A is not greater than
the area of any peak due to impurity B is not greater than
(d) Develop the plate to. 15 cm. 3 times the area of the principal peak in the chromatogram
(e) After removal of the plate, dry in air and examiri obtained with solution (2) (0.3%);
ultraviolet ight (254 nm). | the area of any other secondary peak is not greater than twice
MOBILE PHASE “area of the principal peak in the chromatogram obtained
1 volume of 13.5m ammonia, 20 volumes of methanol and ‘ tion (2) (0.2%);
80 volumes of dichloromethane. alcontent of impurities is not greater than 10 times
SYSTEM SUITABILITY
of the principal peak in the chromatogram obtained
yori (2) (1.0%).
&
CONFIRMATION (2) 8 ,
solution
The principal spot in the chromatogram obtained with ,
ASSAY
dd f
Carry out the meth
using
B. In the Assay, the retention time of the principal peak in ndix HI D,
Appee.
phas
solution (2).
wee al
TESTS
Acidity or alkalinity (3) 0.1% w/v offluconazole impurity sta
pH, 4.0 to 8.0, Appendix V L. CHROMATOGRAPHIC CONDITIONS
d under’R
Related substances The chromatographic conditions describe
Carry out the method for liguid chromatography, substances may be used.
Appendix III D, using the following solutions in the mobile SYSTEM SUITABILITY
phase. The test is not valid unless, in the chromatogram obtained
(1) Dilute the infusion, if necessary, to produce a solution with solution (3), the resolution between the peaks due to
containing 0.2% w/v of Fluconazole. impurity C and fluconazole is at least 3.0.
ae ee (2) Dilute 1 volume of solution (1) to 100 volumes and DETERMINATION OF CONTENT
further dilute 1 volume to 10 volumes. Calculate the content of C,;3H,.F,N,O in the infusion using
(3) 0.1% w/v offluconazole impurity standard BPCRS. the declared content of C,;3H,2F,N,O in fluconazole BPCRS.
CHROMATOGRAPHIC CONDITIONS STORAGE
vee (a) Use a stainless steel column (15 cm x 4.6 mm) packed Fluconazole Infusion should be stored at a temperature not
with octadecylsilyl sihca gel for chromatography (5 um) (Waters exceeding 30°. It should not be refrigerated or allowed to
y
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II-578 Fluconazole Preparations

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IMPURITIES Related substances

The impurities limited by the requirements of this Carry out the method for liguid chromatography,
s F
monograph include A, B and C listed under Fluconazole. Appendix III D, using the following solutions in the
o
mobile phase.
ae
wae)
(1) To a quantity of the oral suspension containing 0.1 g of

Fluconazole, add 25 mL and mix with the aid of ultrasound.
Dilute to produce 50 mL, filter and use the filtrate.
Fluconazole Oral Suspension (2) Dilute 1 volume of solution (1) to 200 volumes.
Action and use (3) 0.1% w/v offluconazole impurity standard BPCRS.
Antifungal. (4) Dilute 1 volume of solution (2) to 5 volumes.
with octadecylsilyl silica gel for chromatography (5 um) (Waters
ingredients Symmetry C18 is suitable).
for use. (b) Use isocratic elution and the mobile phase described
weth the requirements for Powders and below.
Granules for Oral Solutio ‘pensions stated under Oral (c) Use a flow rate of 1.0 mL per minute.
Liquids. (d) Use a column temperature of 40°.
For the following tests prepare’ (e) Use a detection wavelength of 260 nm.
ly after preparation
wrements stated
eae
for 3.5 times the retention time of fluconazole.

Content of fluconazole, C,;3H,.F.N.
MOBILE PHASE
14 volumes of acetonitrile and 86 volumes of
IDENTIFICATION é
0.01M ammonium formate.
Appendix III A, using the following solutions. When the chromatograms are recorded under the prescribed
conditions, the retention times relative to fluconazole
(1) Shake a quantity of the oral suspension containing 1
(retention time about 11 minutes) are: impurity B, about 0.4;
of Fluconazole with 3 mL of methanol. Add sufficient
y A, about 0.5 and impurity C, about 0.8.
methanol to produce 5 mL, filter and use the filtrate.
(2) 0.2% w/v offluconazole BPCRS in methanol.
(3) 0.2% w/v offluconazole BPCRS and 0.1% w/v of
ketoconazole BPCRS in methanol.

the area of any pea
(c) Apply 20 uL of each solution. 0.8 times the area
ultraviolet light (254 nm). 0.6 times the area of theprintipal pet
MOBILE PHASE obtained with solution (2) (0.3%); |
1 volume of 13.5mM ammonia, 20 volumes of methanol and
SYSTEM SUITABILITY

CONFIRMATION
The principal spot in the chromatogram obtained with principal peak in the chromatogram obtained with
solution (1) corresponds to that in the chromatogram solution (4) (0.1%)
1
we a
ASSAY
phase.
solution (2).
TESTS 25 mg, add 20 mL and shake. Dilute to 50 mL, filter and
Acidity use the filtrate.
pH, 3.0 to 5.0, Appendix V L. (2) 0.05% w/v of fluconazole BPCRS.
(3) 0.1% w/v of fluconazole impurity standard BPCRS.
PP Rem
ee
2016 Fludrocortisone Preparations III-579
CHROMATOGRAPHIC CONDITIONS allow to stand for 15 minutes. Remove the plate and place it
The chromatographic conditions described under in a current of cold air until the excess of chlorine is removed
Related substances may be used. and an area of the coating substance below the line of
application does not give a blue colour with a drop of
SYSTEM SUITABILITY
potassium todide and starch solution. Spray the plate with
The test is not valid unless, in the chromatogram obtained potassium iodide and starch solution and examine the plate in
with solution (3), the resolution between the peaks due to daylight.
impurity C and fluconazole is at least 3.0.
MOBILE PHASE
1 volume of anhydrous formic acid, 15 volumes of water,
Determine the weight per mL of the oral suspension, 25 volumes of methanol and 60 volumes of ethyl acetate.
Appendix V G, and calculate the content of C,;3H).F2,N,.O,
ight imevolume, using the declared content of SYSTEM SUITABILITY
LIMITS
stated on thé’label Any secondary spot in the chromatogram obtained with
satisfactory for solution (1) is not more intense than the spot in the
IMPURITIES chromatogram obtained with solution (2) (0.1%).
The impurities limite ASSAY
monograph include A, B : under Fluconazole. Weigh and powder 20 tablets. To a quantity of the powder
containing 0.1 g of Flucytosine add 80 mL of
0.1m hydrochloric acid and shake for 15 minutes. Dilute to
100 mL with 0.1m hydrochloric acid and filter. Dilute 10 mL
of the filtrate to 100 mL with 0.1m hydrochloric acid and
Flucytosine Tablets further dilute 10 mL of the solution to 100 mL with
0.1m hydrochloric acid. Measure the absorbance of the resulting
Action and use
solution at the maximum at 286 nm, Appendix II B.
Antifungal.
Calculate the content of C,H,FN30 taking 709 as the value
DEFINITION of A(1%, 1 cm) at the maximum at 286 nm.
Flucytosine Tablets contain Flucytosine. STORAGE
The tablets comply with the requirements stated under Tablets a ytosine tablets should be protected from light.
Content of flucytosine, C,H,FN3;0
IDENTIFICATION
Flucytosine with 100 mL of methanol for 30 minutes, filter
and evaporate the filtrate to dryness. The infrared absorption
the reference spectrum of flucytosine (RS 146).
Fludrocortisone Tab! ¢ Fludrocortisone Acetate.
TESTS
The tablets comply with th
Related substances
90.0 to 110.0% of the stated amo
0.10 g of Flucytosine with 10 mL of a mixture of equal IDENTIFICATION
volumes of 13.5mM ammonia and methanol and filter.
methanol (60%) and dilute 1 volume of the resulting solution phase B. Apply separately to the plate 20 uL of éach of the
to 100 volumes with methanol (60%). following solutions. For solution (1) shake a quantity of the
powdered tablets containing 1 mg of fludrocortisone acetate
with 20 mL of chloroform for 5 minutes, filter, evaporate the
dissolve 5 mg offluorouracil BPCRS in 5 mL of the resulting
filtrate to dryness and dissolve the residue in 4 mL of a
solution.
mixture of 9 volumes of chloroform and 1 volume of methanol.
CHROMATOGRAPHIC CONDITIONS Solution (2) contains 0.025% w/v offludrocortisone
(a) Use as the coating silica gel. acetate BPCRS in a mixture of 9 volumes of chloroform and
(b) Use the mobile phase as described below. 1 volume of methanol.
(c) Apply 10 uL of each solution. B. In the Assay, the chromatogram obtained with solution
(d) Develop the plate to 12 cm in an unsaturated tank. (1) shows a peak with the same retention time as the peak
due to fludrocortisone acetate in the chromatogram obtained
(e) After removal of the plate, allow the solvent to evaporate,
with solution (2).
stand the plate in a tank of chlorine vapour prepared by the
addition of hydrochloric acid to a 5% w/v solution of potassium
aw as
permanganate contained in a beaker placed in the tank and
IlI-580 Flumetasone Preparations 2016
TESTS
Flumetasone and Clioquinol Ear Drops
Tablets containing less than 2 mg and/or less than 2% w/w Action and use
of Fludrocortisone Acetate comply with the requirement Glucocorticoid and antibacterial.
Carry out the method for liquid chromatography, DEFINITION
Appendix III D, using the following solutions protected from Flumetasone and Clioquinol Ear Drops contain Flumetasone
light. Solution A contains 0.002% w/v of Pivalate and Clioquinol.
norethisterone BPCRS in acetonitrile. The ear drops comply with the requirements stated under Ear
(1) Place a single tablet in a centrifuge tube, add 1 mL of Preparations and with the following requirements.
water, shake on a vortex-type mixer for 1 minute, add
Content of flumetasone pivalate, C,7H3,F,0O,
elution A and shake again for 1 minute. Shake
95.0 to 105.0% w/v of the stated amount.
utes on a mechanical shaker, centrifuge
Content of clioquinol, C)H;CIINO
95.0 to 105.0% w/v of the stated amount.
IDENTIFICATION
(a) Use a stainless steel :
with octadecylsilyl silica g (1) Disperse a quantity of the ear drops containing 1 mg of
Flumetasone Pivalate in acetone, add sufficient acetone to
produce 10 mL and filter.
(b) Use isocratic elution and
below. (2) 0.01% w/v offlumetasone pivalate BPCRS in acetone.
(c) Use a flow rate of 2 mL per minute: CHROMATOGRAPHIC CONDITIONS
(d) Use an ambient column temperature (a) Use as the coating silica gel F54.
(e) Use a detection wavelength of 240 nm. (b) Use the mobile phase as described below.
(f) Inject 20 pL of each solution. (c) Apply 50 uL of each solution.
MOBILE PHASE
40 volumes of acetonitrile and 60 volumes of water. (e) After removal of the plate, dry in air, heat at 105° for
minutes and examine under ultraviolet light (254 nm).
Calculate the content of C,3H3,FO, in each tablet using the
declared content of C23H3,FO. in fludrocortisone : s of water, 8 volumes of methanol, 15 volumes of
acetate BPCRS. volumes of dichloromethane.
ASSAY
Weigh and powder 20 tablets. Carry out the method for yt in the chromatogram obtained with
liquid chromatography, Appendix III D, using the following jonds in position and size to that in the
solutions. Solution A contains 0.01% w/v of ified, with solution (2).
norethisterone BPCRS (internal standard) in acetonitrile. B. In the Assay forfluzt sone pivalate, the chromatogram
(1) Shake a quantity of the powdered tablets containing obtained with solut ) sHows a peak with the same
0.5 mg of fludrocortisone acetate with 2 mL of water for retention time as the p due.to flumetasone pivalate in the
1 minute, add 4 mL of solution A and 4 mL of acetonitrile chromatogram obtained wi
TN eR Y and shake on a mechanical shaker for 40 minutes. Dilute the C. In the Assay for clioquinoljt chromatogram obtained
hae
mixture to 20 mL with acetomitrile, centrifuge and use the with solution (1) shows a peak with4 ame retention time
supernatant liquid. as the peak due to clioquinol in the chr Aatogram obtained
(2) 20 mL of solution A, 25 mL of a 0.01% w/v solution of with solution (2).
fludrocortisone acetate BPCRS in acetonitrile and 10 mL of TESTS
water diluted to 100 mL with acetonitnile. Related substances
(3) Prepare in the same manner as solution (1) but using For flumetasone pivalate
8 mL of acetomitrile in place of 4 mL of solution A and 4 mL Carry out the method for liquid chromatography,
of acetonitrile. Appendix III D, using the following solutions prepared in
CHROMATOGRAPHIC CONDITIONS methanol (80%).
(Aww
ae
wwe 4
The chromatographic conditions described under Uniformity (1) Shake a volume of the ear drops containing 1.2 mg of
of content may be used. Flumetasone Pivalate with 50 mL of methanol (80%), add
40 mg of copper(m) acetate and dilute to 100 mL. Place the
solution in an ice bath for 1 hour, centrifuge and use the
Calculate the content of C,3H3,FOg, in the tablets using the
supernatant liquid.
declared content of C23H3,;FO, in fludrocortisone
acetate BPCRS. (2) Dilute 1 volume of solution (1) to 100 volumes.
(3) 0.001% w/v of flumetasone pivalate BPCRS and
0.00001% w/v of flumetasone acetate.
yea,
NN ae
Ne ee eS
2016 Flumetasone Preparations III-581
CHROMATOGRAPHIC CONDITIONS MOBILE PHASE
(a) Use a stainless steel column (15 cm x 4.6 mm) packed 20 volumes of water and 80 volumes of methanol.
with octadecylsilyl silica gel for chromatography (5 um) When the chromatograms are recorded under the prescribed
(Nucleosil C18 is suitable). conditions the retention times relative to clioquinol
(b) Use isocratic elution and the mobile phase described (retention time about 5 min) are: 5-chloroquinolin-8-ol,
below. about 0.6; 5,7-diiodoquinolin-8-ol, about 0.8 and
(c) Use a flow rate of 1.5 mL per minute. 5,7-dichloroquinolin-8-ol, about 1.1.
(d) Use an ambient column temperature. SYSTEM SUITABILITY
(e) Use a detection wavelength of 235 nm. The test is not valid unless, in the chromatogram obtained
clioquinol and 5,7-dichloroquinolin-8-ol is at least 1.5.
LIMITS

ete att
the area of any peak corresponding to 5-chloroquinolin-8-ol

is not greater than twice the area of the principal peak in the
the area of any peak corresponding to 5,7-diiodoquinolin-8-ol
or 5,7-dichloroquinolin-8-ol is not greater than the area of
with solution (3), the 1res the principal peak in the chromatogram obtained with
flumetasone acetate and solution (2) (1%);
eran
LIMITS the area of any other secondary peak is not greater than the
twice the area of the principal peakin the chromatog Disregard any peak with an area less than half that of the
obtained with solution (2) (2%). : principal peak in the chromatogram obtained with
Disregard any peak: solution (3) (0.1%).
that elutes before 1.5 minutes;
with an area less than the area of the principal peak in the etasone pivalate
chromatogram obtained with solution (4) (0.1%). t the method for liguid chromatography,
For choquinol
Appendix III D, using the following solutions. . g
phase, ad
Solution A 0.1 volume of orthophosphoric acid, 10 volumes of
with the m
water, 30 volumes of acetonitrile and 60 volumes of methanol.
(1) Dilute a volume of the ear drops containing 18 mg of
(2) 0.0024% w/v o
Clioquinol with 1 mL of tetrahydrofuran, add sufficient
phase.
solution A to produce 100 mL, centrifuge and use the
supernatant liquid. ” 0.001% w/v of flumetas valate BPCRS and
the mobile phase.
solution A. CHROMATOGRAPHIC conprrio
(3) Dilute 1 volumes of solution (2) to 5 volumes with (a) Use a stainless steel column (
solution A.
(4) 0.018% w/v of choguinol BPCRS and 0.00018% w/v each
of 5-chloroquinolin-8-ol, 5,7-dichloroquinolin-8-ol and
5,7-dnodoquinolin-8-ol in solution A. below.
CHROMATOGRAPHIC CONDITIONS (c) Use a flow rate of 1 mL per minute.
x
(a) Use a stainless steel column (25 cm x 4.6 mm) packed (d) Use an ambient column temperature.
“ore
aie
we
with octadecylsilyl silica gel for chromatography (10 um) (e) Use a detection wavelength of 254 nm.
(Nucleosil C18 is suitable). (f) Inject 20 wL of each solution.
(b) Use isocratic elution and the mobile phase described MOBILE PHASE
below.
SYSTEM SUITABILITY
(e) Use a detection wavelength of 260 nm. with solution (3) the resolution between the peaks due to
(f) Inject 20 wL of each solution. flumetasone acetate and flumetasone pivalate is at least 1.5.
(g) Allow the chromatography to proceed for twice the If necessary adjust the concentration of methanol in the
retention time of the peak due to clioquinol. mobile phase.
Ja al
IWI-582 Fluocinolone Preparations 2016
DETERMINATION OF CONTENT cool in ice for 15 minutes, centrifuge at 3000 revolutions per
Determine the weight per mL of the ear drops, minute for 15 minutes, decant the clear, supernatant liquid,
Appendix V G, and calculate the content of C.7H3.F.0,, evaporate to dryness on a water bath in a current of nitrogen
\we aw
wet
a
weight in volume, using the declared content of C27H36F20¢ and dissolve the residue in 1 mL of chloroform.
marin
in flumetasone pivalate BPCRS. (2) 0.025% w/v solution offluocinolone acetonide BPCRS in
For choquinol chloroform.
Appendix III D, using the following solutions. (a) Use as the coating silica gel G.
(1) To a weighed quantity of the ear drops containing 18 mg (b) Use the mobile phase as described below.
of Clioquinol add 5 mL of a solution containing 1 volume of
triethylamine and 1 volume of tetrahydrofuran, add sufficient of
weary (e) After removal of the plate, dry in air until the solvent has
evaporated, heat at 105° for 5 minutes and spray whilst hot
with alkaline tetrazolium blue solution.
MOBILE PHASE
5,7-dichloroquinolin-8 1 volume of triethylamine, 10 volumes of methanol,
CHROMATOGRAPHIC Ci 40 volumes of chloroform and 60 volumes of n-hexane.
(a) Use a stainless steel colu: cm x 4.6 mm) packed CONFIRMATION
with octadecylsilyl silica gel for ch ropraph (10 yum) The principal spot in the chromatogram obtained with
(Nucleosil C18 is suitable). solution (1) corresponds to that in the chromatogram
ae
|
(b) Use isocratic elution and the mo 1 se described
below. B. In the Assay, the chromatogram obtained with solution
(c) Use a flow rate of 1 mL per minute. (2) shows a peak with the same retention time as the peak
(d) Use an ambient column temperature. due to fluocinolone acetonide in the chromatogram obtained
with solution (1).
(f) Inject 10 pL of each solution. ASSAY
MOBILE PHASE
0.1 volume of orthophosphoric acid, 10 volumes of water, eams containing 0.025% to 0.2% w/w of
30 volumes of acetonitrile and 60 volumes of methanol.
lone acetonide
SYSTEM SUITABILITY w/v of fluocinolone acetonide BPCRS and
with solution (3), the resolution between clioquinol and
5,7-dichloroquinolin-8-ol is at least 1.5. If necessary adjust
the concentration of methanol in the mobile phase.
Determine the weight per mL of the ear drops,
Appendix V G, and calculate the content of Cj)H5CIINO, ethanolic layer, taking care to
weight in volume, using the declared content of Cp)H5CIINO arates at the interface.
cate ea in choguinol BPCRS. Repeat the extraction usinga further 25 mL of the lithium
chloride solution. To the corti¥ified extracts add a solution of
11 g of aluminium potassium sulfate i :
Fluocinolone Cream chloroform extract through filter paper (Whe

suitable), previously moistened with chlorofory:
Action and use excluding any solid matter at the interface. Reps
Glucocorticoid. extraction with 50- and 10-mL quantities of chloraf
filtering the extracts as before. Evaporate the combined
DEFINITION extracts to dryness on a water bathin a current of nitrogen,
Fluocinolone Cream contains Fluocinolone Acetonide or dissolve the residue in 5 mL of chloroform, transfer to a
Fluocinolone Acetonide Dihydrate in a suitable basis. 10-mL graduated flask with the aid of chloroform and add
The cream complies with the requirements stated under Topical sufficient chloroform to produce 10 mL.
Semi-solid Preparations and with the following requirements. (3) Prepare in the same manner as solution (2) but add
Content of fluocinolone acetonide, C,,H3)F,O, 1.0 mL of a 0.050% w/v solution of phenacetin to the
90.0 to 110.0% of the stated amount. chloroform solution before dilution to 10 mL.
IDENTIFICATION For creams containing 0.01% w/w offluocinolone
A. Carry out the method for thin-layer chromatography, acetonide
Appendix III A, using the following solutions. (1) 0.01% w/v offluocinolone acetonide BPCRS and
0.002% w/v of phenacetin (internal standard) in chloroform.
(1) Disperse, by shaking, a quantity of the preparation being
(2) Prepare as described above but using a quantity of the
"AN oa
examined containing 0.25 mg of Fluocinolone Acetonide in

2 mL of chloroform, add 10 mL of methanol, shake vigorously, cream containing 1 mg of Fluocinolone Acetonide.
ae
a Cees
2016 Fluocinolone Preparations III-583
(3) Prepare in the same manner as solution (2) but add

1 mL of a 0.02% w/v solution of phenacetin to the chloroform
Fluocinolone Ointment
solution before diluting to 10 mL. Action and use
For creams containing 0.00625% w/w offluocinolone Glucocorticoid.
acetonide
(1) 0.00625% w/v of fluocinolone acetonide BPCRS and DEFINITION
0.00125% w/v of phenacetin (internal standard) in chloroform. Fluocinolone Ointment contains Fluocinolone Acetonide or
(2) Prepare as described above but using a quantity of the Fluocinolone Acetonide Dihydrate in a suitable basis.
cream containing 0.62 mg of Fluocinolone Acetonide. The ointment complies with the requirements stated under Topical
(3) Prepare in the same manner as solution (2) but add Semi-solid Preparations and with the following requirements.
1 mL of.a 0.0125% w/v solution of phenacetin to the Content of fluocinolone acetonide, C3,H3.9F,0,
) ion before diluting to 10 mL. 90.0 to 110.0% of the stated amount.
Swen wf
i tning 0.0025% w/w offluocinolone IDENTIFICATION

and a mixture of 60 volumes of n-hexane, 40 volumes of
(2) Prepare as descrit chloroform, 10 volumes of methanol and 1 volume of
cream containing 0.2! triethylamine as the mobile phase. Apply separately to the
plate 5 wL of each of the following solutions. For solution (1)
1 mL of a 0.005% w/v soluti disperse, by shaking, a quantity of the preparation being
chloroform solution before examined containing 0.25 mg of fluocinolone acetonide in
2 mL of chloroform, add 10 mL of methanol, shake vigorously,
CHROMATOGRAPHIC CONDITIONS, cool in ice for 15 minutes, centrifuge at 3000 revolutions per
(a) Use a stainless steel column (20 c minute for 15 minutes, decant the clear, supernatant liquid,
evaporate to dryness on a water bath in a current of nitrogen
and dissolve the residue in 1 mL of chloroform. Solution (2)
contains 0.025% w/v solution offluocinolone acetonide BPCRS
below. in chloroform. After removal of the plate, allow it to dry in air
(c) Use a flow rate of 1.8 mL per minute. until the solvent has evaporated, heat at 105° for 5 minutes
(d) Use an ambient column temperature. and spray whilst hot with alkaline tetrazolium blue solution.
sprincipal spot in the chromatogram obtained with
tin (1) corresponds to that in the chromatogram
MOBILE PHASE
58 volumes of hexane, 40 volumes of chloroform, 2 volumes of
methanol and 0.1 volume of glacial acetic acid. fluweitio
solution (4).
SYSTEM SUITABILITY
The assay is not valid unless the resolution factor (R,) between
the peaks due to fluocinolone acetonide and phenacetin is
more than 2, and the capacity factors (k') of fluocinolone
acetonide and phenacetin are about 3 and 2, respectively. contains 0.0050% w
If these conditions are not achieved, adjust the concentration 0.40% v/v of toluene (int
of methanol in the mobile phase, increasing its concentration ‘w..or less of fluocinolone
to reduce the value of k’ and reducing its concentration to e following manner. To a
increase the value of k’. If the correct values cannot be rig. of fluocinolone
obtained by this means, the column is faulty and must be
repacked. If, when the correct k’ values have been obtained,
the value of R, is less than 2, reduce the concentration of
chloroform in the mobile phase by 5% to obtain an increased
retention time for both fluocinolone acetonide and the
phenacetin and re-adjust the k’ values to the specified values washing to the previous extract. To the combined extracts
by increasing the concentration of methanol. Repeat the add sufficient methanol (80%) to produce 10 mL. Prepare
adjustment of chloroform and methanol concentrations until solution (3) in the same manner as solution (2) but adding
correct values for both R, and k’ have been obtained. 1 mL of a 4% v/v solution of the internal standard in
DETERMINATION OF CONTENT methanol to the combined extracts before dilution to 10 mL.
Calculate the content of C24H3)F2O. in the cream using the For ointments containing 0.025% w/w of fluocinolone
declared content of C,,H39F206¢ in fluocinolone acetonide, prepare solution (2) in the following manner. To a
acetonide BPCRS. quantity of the ointment containing 1.25 mg of fluocinolone
acetonide add 50 mL of 2,2,4-trimethylpentane and 20 mL of
LABELLING methanol (80%), warm gently on a water bath until the
When the active ingredient is Fluocinolone Acetonide preparation is dispersed and shake vigorously for 2 minutes.
Dihydrate, the quantity is stated in terms of the equivalent Separate the lower, aqueous methanolic layer and wash the
amount of fluocinolone acetonide. upper layer with 2 mL of methanol (80%), adding the
washing to the previous extract. To the combined extracts
II-584 Fluocinonide Preparations 2016
add sufficient methanol (80%) to produce 25 mL. Prepare B. In the Assay, the retention time of the principal peak in
solution (3) in the same manner as solution (2) but adding the chromatogram obtained with solution (1) is similar to
1 mL of a 10% vw/W solution of the internal standard in that of the principal peak in the chromatogram obtained with
solution (2).
awe tS
methanol to the combined extracts before dilution to 25 mL.

Av eal
The chromatographic procedure may be carried out using ASSAY

(a) a stainless steel column (20 cm x 5 mm) packed with Carry out the method for liquid chromatography,
octadecylsilyl silica gel for chromatography (5 um) (Spherisorb Appendix III D, using the following solutions.
ODS1is suitable), (b) a mixture of 55 volumes of water,
(1) Disperse a quantity of the cream containing 1.5 mg of
45 volumes of acetonitrile and 0.1 volume of glacial acetic acid
Fluocinonide in 20 mL of methanol (80%), warming gently
as the mobile phase with a flow rate of 1 mL per minute and
over a water bath if necessary. Add 50 mL of
2,2,4-trimethylpentane, shake for 2 minutes and transfer the
ntent of C,,H39F.O0, in the ointment using lower aqueous methanol layer to a 50-mL flask. Repeat the
tetit.of Co4H39F20¢ in fluocinolone extraction with a further 20 mL of methanol (80%). Dilute
the combined extracts to volume with the same solvent.
(2) 0.003% w/v of fluocinonide BPCRS in methanol (80%).
below.
Fluocinonide Cream (c) Use a flow rate of 2 mL per minute.
Action and use (d) Use an ambient column temperature.
Glucocorticoid. (e) Use a detection wavelength of 238 nm.
DEFINITION
MOBILE PHASE
Fluocinonide Cream contains Fluocinonide in a suitabl
basis. 0.1 volume of glacial acetic acid, 45 volumes of acetonitrile and
The cream complies with the requirements stated under Topica 5 volumes of water.
Semi-solid Preparations and with the following requirements. MINATION OF CONTENT
Content of fluocinonide, C,,H3,F,0, e content of C2,H3,F,O7 in the cream using the
90.0 to 110.0% of the stated amount. ntent of C.5H32F,07 in fluocinonide BPCRS.
IDENTIFICATION
(1) Disperse a quantity of the cream containing 2.5 mg of Fluocinoni
Fluocinonide in 25 mL of methanol (80%), add 50 mL of
ether and shake vigorously to produce a clear, homogeneous Action and use
solution. Add 15 mL of water, shake and transfer the lower Glucocorticoid.
layer to a second separating funnel. Add 100 mL of water,
DEFINITION
extract with 10 mL of chloroform, filter the chloroform layer
through filter paper and evaporate to a volume of about Fluocinonide Ointment contaifis
1 mL in a current of air on a water bath. basis.
(2) 0.1% w/v offluocinonide BPCRS in a mixture of 1 volume ted under Topical
of methanol and 9 volumes of dichloromethane. Semi-solid Preparations and with the following regur
Content of fluocinonide, C,,H3,F,O7
(a) Use as the coating silica gel Fo54.
IDENTIFICATION
(1) Disperse a quantity of the ointment containing 2 mg of
ae als
ve nw
(e) After removal of the plate, dry in air and examine under fluocinonide in 20 mL of methanol (80%) in a 100-mL
ultraviolet light (254 nm). separating funnel containing 50 mL of 2,2,4-trimethylpentane.
MOBILE PHASE Warm the contents over a water bath and shake gently.
12 volumes of water, 80 volumes of methanol, 150 volumes of Allow the layers to separate and transfer the lower layer to a
ether and 770 volumes of dichloromethane. Mix the water and 250-mL separating funnel containing 100 mL of water.
the methanol before adding to the remaining solvents of the Add 10 mL of chloroform and shake for 3 minutes. Allow the
mobile phase. layers to separate, evaporate the lower layer to dryness on a
water bath in a current of air and dissolve the residue in
CONFIRMATION
1 mL of chloroform.
(2) 0.2% wiv offluocinonide BPCRS in chloroform.
Lea ed

2016 Fluocortolone Preparations JTII-585
CHROMATOGRAPHIC CONDITIONS The cream complies with the requirements stated under Topical
(a) Use as the coating silica gel Fs54. Semi-solid Preparations and with the following requirements.
(b) Use the mobile phase as described below. Content of fluocortolone pivalate, C,,H3;,FO,;
(c) Apply 10 pL of each solution. 90.0 to 110.0% of the stated amount.
(d) Develop the plate to 15 cm. Content of fluocortolone hexanoate, C,,H39FO;
(e) After removal of the plate, allow it to dry in air until the 90.0 to 110.0% of the stated amount.
solvent has evaporated. Heat at 105° for 5 minutes and spray IDENTIFICATION
while hot with alkaline tetrazolium blue solution. A. Carry out the method for thin-layer chromatography,
MOBILE PHASE Appendix III A, using a silanised silica gel precoated plate
the surface of which has been modified by chemically-bonded
12 volumes of water, 80 volumes of methanol, 150 volumes of
octadecylsilyl groups (Whatman KC18F plates are suitable)
ether and..770 volumes of dichloromethane. Mix the water and
and a mixture of 35 volumes of water and 65 volumes of
acetonitrile as the mobile phase. Apply separately to the plate
10 wL of each of the following solutions. For solution (1),
,
transfer a quantity of the preparation being examined

ts
i
os
containing 1 mg of fluocortolone pivalate to a separating

te
funnel with the aid of 10 mL of methanol, add 50 mL of

'
2,2,4-trimethylpentane and shake vigorously for 1 minute.

B. In the Assay, the f Allow to stand, separate the lower methanol layer, add
the chromatogram obtaiti 100 mL of water and 50 mL of dichloromethane, shake
vigorously for 1 minute and centrifuge at 1500 revolutions
AN ten
|
solution (2). per minute for 5 minutes. Evaporate 25 mL of the
dichloromethane layer to dryness on a water bath in a
ASSAY .
current of nitrogen and dissolve the residue in 1 mL of a
Carry out the method for liquid chrom mixture of 1 volume of methanol and 9 volumes of
Appendix III D, using the following sol dichloromethane. For solution (2), mix 0.5 mL of a 0.1% wiv
solution offluocortolone pivalate BPCRS in a mixture of
1 volume of methanol and 9 volumes of dichloromethane with
0.5 mL of a 0.1% w/v solution offluocortolone
hexanoate BPCRS in the same solvent mixture. Solution (3) is
2 minutes. Allow the layers to separate and transfer the: ixture of equal volumes of solutions (1) and (2). After
layer to a 50 mL flask. Repeat the extraction with a furth val of the plate, allow it to dry in air for 10 minutes and
20 mL of methanol (80%). Dilute the combined extracts to e under ultraviolet light (254 nm). Two principal spots
50 mL with the same solvent. hromatogram obtained with solution (1) correspond
(2) 0.003% w/v offluocinonide BPCRS in methanol (80%). : in the chromatogram obtained with solution (2).
a t valid unless the chromatogram obtained with
below.
oN ee
rs
mee At

MOBILE PHASE
0.1 volume of glacial acetic acid, 45 volumes of acetonitrile and

50 mL of 2,2,4-trimethylpentane to a ouantit of. {
DETERMINATION OF CONTENT preparation being examined containing 2 mg of fluocortolone
Calculate the content of C25H32F2O7 in the ointment using pivalate and heat on a water bath, shaking intermittently,
the declared content of C.¢.H3.F,0,7 in fluocinonide BPCRS. until the preparation is completely dispersed. Remove from
the water bath, shake vigorously for 3 minutes, allow to
separate and transfer the lower, aqueous acetonitrile layer to
a flask. Repeat the extraction of the 2,2,4-trimethylpentane
solution with a further 20 mL of the acetonitrile—-water
Fluocortolone Cream mixture and again transfer the lower, aqueous acetonitrile
layer to the flask. Dilute the combined extracts to 50 mL
Action and use
with a mixture of 4 volumes of acetonitrile and 1 volume of
Glucocorticoid.
water and filter a portion using a pressure filter (a Swinnex
filter holder prepared with a double thickness of Whatman
DEFINITION
No. 42 filter paper is suitable). Prepare solution (3) in the
Fluocortolone Cream contains Fluocortolone Pivalate and
same manner as solution (2) but adding 2 mL ofa
Fluocortolone Hexanoate in a suitable basis.
0.100% v/v solution of benzyl benzoate in a mixture of
let at ee
II-586 Fluorescein Preparations 2016
4 volumes of acetonitrile and 1 volume of water to the Dimethylformamide

combined extracts before dilution to 50 mL. Carry out the method for gas chromatography,
The chromatographic procedure may be carried out using Appendix III B.
caval
(a) a stainless steel column (20 cm x 5 mm) packed with (1) 0.0020% v/v of dimethylformamide and 0.0020% v/v of
octadecylsilyl silica gel for chromatography (5 wm) (Spherisorb dimethylacetamide (internal standard).
ODS 1 is suitable), (b) as the mobile phase with a flow rate (2) Dilute the eye drops with water, if necessary, to produce
of 1 mL per minute, a mixture of acetonitrile and water each a solution containing 1.0% w/v of fluorescein sodium.
containing 1% v/v of glacial acetic acid adjusted so that the To 5 mL of this solution add, with stirring, 0.3 mL of
retention time of fluocortolone pivalate is about 9 minutes 1m hydrochloric acid, allow to stand for 15 minutes and
and baseline separation is obtained from benzyl benzoate and centrifuge; dissolve 10 mg of trisodium orthophosphate in 2 mL
fluocortolone hexanoate (retention time, about 11 minutes) of the supernatant liquid.
(3) Prepare in the same manner as solution (2) but adding
ef glacial acetic acid is usually suitable) and (c)
1 mL of a 0.010% v/v solution of dimethylacetamide before
veletigth of 238 nm. the hydrochloric acid.
(a) Use a glass column (1.5 m x 4 mm) packed with acid-
in fluocortolone hexane SRS respectively. washed, silanised diatomaceous support (80 to 100 mesh) coated
with 10% w/w of polyethylene glycol 1000.
STORAGE
(b) Use nitrogen as the carrier gas at a suitable flow rate.
Fluocortolone Cream should, d at a temperature not
exceeding 30°. (c) Use isothermal conditions maintained at 120°.
(d) Use a suitable inlet temperature.
(e) Use a flame ionisation detector at a suitable temperature.
Fluorescein Eye Drops LIMITS
In the chromatogram obtained with solution (3) the ratio of
Action and use : the area of any peak corresponding to dimethylformamide to
Detection of corneal lesions, retinal angiography an the area of the peak due to the internal standard is not
pancreatic function testing. reater than the corresponding ratio in the chromatogram
btained with solution (1) (0.2%).
DEFINITION
Fluorescein Eye Drops are a sterile solution of Fluorescein i.substances and resorcinol
Sodium in Purified Water.
‘the method for thin-layer chromatography,
I A, using the following solutions.
Content of fluorescein sodium, C,H,)Na,0;
IDENTIFICATION
A. Evaporate a volume containing 20 mg of fluorescein sodium chloride and _gxtraétwith two 25-mL quantities of
sodium and dry at 105° for 30 minutes. The infrared peroxide-free ether. Dry tk bined extracts over anhydrous
absorption spectrum of the residue, Appendix II A, is sodium sulfate, evaporate s. under reduced pressure
nN ae concordant with the reference spectrum of fluorescein sodium and dissolve the residue in 1
(RS 151). hydrochloric acid.
B. The eye drops are strongly fluorescent, even in extreme
dilution; the fluorescence disappears when the solution is
made acidic and reappears when it is made alkaline.
C. Dilute with water to produce a solution containing
0.05% w/v of fluorescein sodium. One drop of the solution,
absorbed by a piece of filter paper, colours the paper yellow. acid.
On exposing the moist paper to bromine vapour for 1 minute
(6) Mix 5 volumes of a 0.025% w/v solution of resorcinol in
and then to ammonia vapour the yellow colour becomes
0.1m methanolic hydrochloric acid with 2 volumes of solution
deep pink.
(1) and add sufficient methanol to produce 10 mL.
TESTS CHROMATOGRAPHIC CONDITIONS
(a) Usea silica gel 60 F254 precoated plate (Merck plates are
suitable).
Chloroform-soluble matter
To a volume containing 0.1 g of fluorescein sodium add
1 mL of 2m sodium hydroxide, extract with 10 mL of (c) Apply 10 pL of solution (1) and 5 uL of solutions (2) to
chloroform and dry the chloroform layer with anhydrous sodium (6).
sulfate. The absorbance of the resulting solution at 480 nm is (d) Develop the plate to 15 cm.
not more than 0.05, Appendix II B, using chloroform in the (e) After removal of the plate, dry in air, expose the plate to
reference cell. iodine vapour for 30 minutes and examine in daylight and
ea

nA Ay
aT oS
area d
ca ee Sd
2016 Fluorescein Preparations III-587
MOBILE PHASE The injection complies with the requirements stated under
10 volumes of methanol and 90 volumes of dichloromethane. Parenteral Preparations and with the following requirements.
aan
TAN AN
we At SYSTEM SUITABILITY Content of fluorescein sodium, C,.H;)Na,0,
aww NS

solution (6) shows two clearly separated spots in daylight. IDENTIFICATION
LIMITS A. Evaporate 1 mL to dryness on a water bath and dry the
In the chromatogram obtained with solution (1), under residue at 105° for 30 minutes. The infrared absorption
ultraviolet light (254 nm): spectrum of the residue, Appendix II A, is concordant with
the reference spectrum of fluorescein sodium (RS 151).
any secondary spot, other than any spot corresponding to
resorcinol, is not more intense than the spot in the B. The injection is strongly fluorescent, even in extreme
ogram obtained with solution (3) (0.5%); dilution; the fluorescence disappears when the solution is
made acidic and reappears when it is made alkaline.
me such spot is more intense than the spot in
m obtained with solution (4) (0.2%). C. Dilute with water to produce a solution containing
0.05% w/v of fluorescein sodium. One drop of the solution,
absorbed by a piece of filter paper, colours the paper yellow.
On exposing the moist paper to bromine vapour for 1 minute
», is not more intense than the spot and then to ammonia vapour the yellow colour becomes
ned with solution (5) (0.5%). deep pink.
ASSAY |
TESTS
Carry out the method for guid ch Alkalinity
Appendix III D, using the folléwing solutions.
(1) Dilute the eye drops w phase to produce a
Chloroform-soluble matter
solution containing 0.005% w/v of fluores ein sodium.
Dilute the injection with water, 1f necessary, to produce a
solution containing 1% w/v of fluorescein sodium. To 20 mL
add 5 mL of 1M sodium hydroxide, dilute to 50 mL with
water, extract with 10 mL of chloroform and dry the
chloroform layer over anhydrous sodium sulfate. The absorbance
Dilute 5 volumes of this solution to 100 volumes Ww, of the resulting solution at 480 nm is not more than 0.10,
mobile phase. Appendix II B, using chloroform in the reference cell.
CHROMATOGRAPHIC CONDITIONS imethylformamide
(a) Use a stainless steel column (25 cm x 4.6 mm) packe arry.out the method for gas chromatography,
with end-capped octadecylsilyl silica gel for chromatography ix III B.
(5 um) (Spherisorb ODS 2 is suitable). 20% viv of dimethylformamide and 0.0020% v/v of
(b) Use isocratic elution and the mobile phase described etamide (internal standard).
below. | (2) dilute the injection with water, if
(c) Use a flow rate of 1.5 ml per minute.
(d) Use an ambient column temperature. o 5 mL of this solution add, with
(e) Use a detection wavelength of 254 nm. stirring, 0.3 mL “vdrochloric acid, allow to stand for
15 minutes and ; dissolve 10 mg of trisodium
e.supematant liquid.
MOBILE PHASE
5 volumes of triethylamine, 400 volumes of acetonitrile and but adding 1.0 mL of a OT
595 volumes of water, adjust the pH to 3.0 with dimethylacetamide before the Kydré
CHROMATOGRAPHIC CONDITIO
DETERMINATION OF CONTENT (a) Use a glass column (1.5m x4 ked with acid-
Calculate the content of C2)>H; 9Na,Os; in the eye drops washed, silamised diatomaceous support (80 ‘OUemesh) coated
using the declared content of anhydrous diacetylfluorescein in with 10% w/w of polyethylene glycol 1000.
diacetylfluorescein BPCRS. Each mg of anhydrous (b) Use nitrogen as the carrier gas at a suitable. rate.
diacetylfluorescein is equivalent to 0.9037 mg of
(c) Use isothermal conditions maintained at 120°,
C59H19Na2Os.
(d) Use a suitable inlet temperature.
Niele od STORAGE
(e) Use a flame ionisation detector at a suitable temperature.
need
Fluorescein Eye Drops should be protected from light.
aw eas
LIMITS
Fluorescein Injection In the chromatogram obtained with solution (3) the ratio of
the area of any peak corresponding to dimethylformamide to
Action and use the area of the peak due to the internal standard is not
Detection of corneal lesions, retinal angiography and greater than the corresponding ratio in the chromatogram
pancreatic function testing. obtained with solution (1) (0.2%).
Related substances and resorcinol
. at el
Nowe ew
DEFINITION Carry out the method for thin-layer chromatography,
“~se Fluorescein Injection is a sterile solution of Fluorescein Appendix III A, using the following solutions.
BN
Sodium in Water for Injections.
IW-588 Fluorometholone Preparations 2016
(1) Dilute the injection with 0.1m methanolic hydrochloric acid Dilute 5 volumes of this solution to 100 volumes with the
to produce a solution containing 1.0% w/v of fluorescein mobile phase.
sodium. CHROMATOGRAPHIC CONDITIONS
(2) Dilute a quantity of the injection containing 250 mg of (a) Use a stainless steel column (25 cm x 4.6 mm) packed
fluorescein sodium to 5 mL with water, add 2 mL of with end-capped octadecylsilyl silica gel for chromatography
phosphate buffer pH 8.0, 3 mL of water and 2.5 g of sodium (5 um) (Spherisorb ODS 2 is suitable).
chloride, shake to dissolve the sodium chloride and extract
with two 25-mL quantities of peroxide-free ether. Dry the
below.
combined extracts over anhydrous sodium sulfate, evaporate to
dryness under reduced pressure and dissolve the residue in (c) Use a flow rate of 1.5 ml per minute.
10 mL of 0.1m methanolic hydrochloric acid. (d) Use an ambient column temperature.
(3) Dilute ¥* me of solution (1) to 100 volumes with (e) Use a detection wavelength of 254 nm.
ea A yarochloricacid. (f) Inject 20 pL of each solution.
tye ad
MOBILE PHASE
5 volumes of triethylamine, 400 volumes of acetonitrile and

595 volumes of water, adjust the pH to 3.0 with
orthophosphoric acid
(6) Mix 1 volume of solt
solution (5).
Calculate the content of C29H,)Na2Os; in the eye drops
CHROMATOGRAPHIC CONDITEEK using the declared content of anhydrous diacetylfluorescein in
(a) Usea silica gel 60 F254 pre diacetylfiuorescen BPCRS. Each mg of anhydrous
en aa
suitable). ‘ diacetylfluorescein is equivalent to 0.9037 mg of
(b) Use the mobile phase as described ‘be C49H)9Na.0s.
(c) Apply 5 wL of each solution. STORAGE
(d) Develop the plate to 15 cm. Fluorescein Injection should be protected from light.
(e) After removal of the plate, dryin air, expose the plate
iodine vapour for 30 minutes and examine in daylighit ang
MOBILE PHASE luorometholone Eye Drops
10 volumes of methanol and 90 volumes of dichloromethane.
SYSTEM SUITABILITY
solution (6) shows two clearly separated spots in daylight.
LIMITS
In the chromatogram obtained with solution (1), under
ultraviolet light (254 nm):
any secondary spot, other than any spot corresponding to
resorcinol, is not more intense than the spot in the
not more than one such spot is more intense than the spot in
In the chromatogram obtained with solution (2), in daylight:
any spot corresponding to resorcinol in the chromatogram the filtrate to dryness. Dissolvethetresidue
obtained with solution (2) is not more intense than the spot acetone, filter and evaporate the filtrate t
in the chromatogram obtained with solution (5) (0.5%). infraredabsorption spectrum of the residue,
On examination in daylight, any spot corresponding to
(RS 152).
resorcinol in the chromatogram obtained with solution (2) is
not more intense than the spot in the chromatogram B. In the Assay, the principal peak in the chromatogram
obtained with solution (5) (0.5%). obtained with solution (1) has the same retention time as the
ASSAY
pawns
ata ae
awn
owe solution (2).
Appendix III D, using the following solutions. TESTS
(1) Dilute the injection with water, if necessary, to produce a
solution containing 1.0% w/v of fluorescein sodium and |
dilute 1 volume of this solution to 200 volumes with the Related substances
mobile phase. Carry out the method for liquid chromatography,
(2) Dissolve 55 mg of diacetylfluorescein BPCRS in a mixture
of 5 mL of ethanol (96%) and 1 mL of 2.5m sodium (1) Dilute a quantity of the eye drops containing 1 mg of
aon ond hydroxide, heat on a water bath for 20 minutes, mixing Fluorometholone to 10 mL with a mixture of equal volumes
wv awe
frequently, cool and add sufficient water to produce 50 mL. of methanol and water.
2016 Fluorouracil Preparations III-589

methanol and further dilute 1 volume to 10 volumes with
Fluorouracil Cream
methanol. Action and use
(3) 0.00005% w/v each of deltamedrane BPCRS and Pyrimidine analogue; cytotoxic.
fluorometholone BPCRS.
DEFINITION
Fluorouracil Cream contains Fluorouracil in a suitable basis.
with octadecylsilyl silica gel for chromatography (10 um) The cream complies with the requirements stated under Topical
(uBondapak C18 is suitable). Sem1-solid Preparations and with the following requirements.
(b) Use isocratic elution and the mobile phase described Content of fluorouracil, C,H3FN,O,
IDENTIFICATION
A. Dry a quantity containing 50 mg of Fluorouracil at a
pressure not exceeding 0.7 kPa, mix with 100 mL of ether,
decant, wash the white, crystalline residue with 50 mL of
ether and dry in air. The infrared absorption spectrum of the
spectrum of fluorouracil (RS 153).
350 nm of the final solution obtained in the Assay exhibits a
to deltamedrane and fluorometho TESTS
LIMITS
5-Hydroxyuracil
(1) Shake a quantity of the cream containing 0.10 g of
the principal peak in the chromatogram obtained ;
Fluorouracil with 10 mL of water for 5 minutes, add 10 mL
solution (2) (0.5%); |
of ethanol (96%), mix and filter through glass-fibre paper.
the sum of the areas of any secondary peaks is not greag
(2) 0.00125% w/v of 5-hydroxyuracil in methanol (50%).
obtained with solution (2) (1%). MATOGRAPHIC CONDITIONS
ASSAY a silica gel precoated plate (Merck silica gel 60 plates

ble).
Appendix III D, using the following solutions. he mobile phase as described below.
(1) Mix the eye drops thoroughly and dilute a quantity
containing 1 mg of Fluorometholone to 25 mL with a
mixture of equal volumes of methanol and water.
(2) Dilute 4 mL of a 0.05% w/v solution of
fluorometholone BPCRS in methanol to 50 mL with a mixture
of equal volumes of methanol and water. MOBILE PHASE
(3) 0.00005% w/v each of deltamedrane BPCRS and 10 volumes of water , 4 volumes of acetone and 70 volumes
fluorometholone BPCRS. of ethyl acetate.
LIMITS
The chromatographic conditions described under Related Any spot corresponding to 5-hy. n the
substances may be used. chromatogram obtained with solutio more intense
SYSTEM SUITABILITY than the spot in the chromatogram obtain
The test is not valid unless, in the chromatogram obtained solution (2).
with solution (3), the resolution factor between the peaks due Urea |
to deltamedrane and fluorometholone is at least 1.5. Carry out the method for thin-layer chromatography,
DETERMINATION OF CONTENT Appendix III A, using the following solutions.
Calculate the content of C2,H» FO, in the eye drops using (1) Shake a quantity of the cream containing 0.10 g of
the declared content of C3.H»9FO, in Fluorouracil with 10 mL of water for 5 minutes, add 10 mL
fluorometholone BPCRS. of ethanol (96%), mix and filter through glass-fibre paper.
(2) 0.0050% w/v of urea in water.
(a) Usea silica gel precoated plate (Merck silica gel 60 plates
are suitable).
IW-590 Fluorouracil Preparations 2016
(e) After removal of the plate, allow it to dry in air, spray 10 volumes of a 1% w/v solution of
with a mixture of 10 volumes of a 1% w/v solution of 4-dimethylaminobenzaldehyde in ethanol (96%) and 1 volume
4-dimethylaminobenzaldehyde in ethanol (96%) and 1 volume of hydrochloric acid and heat at 100° until maximum intensity
of hydrochloric acid and heat at 100° until maximum intensity of the spots is obtained. Any spot corresponding to urea in
of the spots is obtained. the chromatogram obtained with solution (1) is not more
MOBILE PHASE
solution (2).
10 volumes of water, 40 volumes of acetone and 70 volumes
of ethyl acetate. Related substances
LIMITS
Appendix III A, using a silica gel F254 precoated plate
Any spot corresponding to urea in the chromatogram (Merck silica gel 60 F5,4 plates are suitable) and a mixture of
olution (1) is not more intense than the spot 70 volumes of ethyl acetate, 15 volumes of methanol and
obtained with solution (2). 15 volumes of water as the mobile phase. Apply separately to
the plate 10 uwL of each of the following solutions.
For solution (1) dilute a suitable quantity of the injection
with water to produce a solution containing the equivalent of
2.0% w/v of fluorouracil. For solution (2) dilute 1 volume of
solution (1) to 400 volumes with methanol (50%). Solution
(3) contains 0.0050% w/v of 5-hydroxyuracil in methanol (50%).
suitable). Dilute 5 mL to 10Q.m: h 0.1m hydrochloric acid After removal of the plate, allow it to dry in a current
and measure the absorbance oft} iting solution at the of air and examine under witraviolet light (254 nm). Any
maximum at 266 nm, Appendix a e the content secondary spot in the chromatogram obtained with solution (1)
of C,H3FN,0, taking 552 as th %, 1 cm) at is Not more intense than the spot in the chromatogram
obtained with solution (2). Spray with a freshly prepared
en ad

0.5% w/v solution offast blue B salt and then with
0.1m sodium hydroxide. Any spot corresponding to
5-hydroxyuracil in the chromatogram obtained with solution
(1) is not more intense than the spot in the chromatogram
Fluorouracil Injection obtained with solution (3). Disregard any spots
Action and use withRf values lower than 0.2.
Pyrimidine analogue; cytotoxic ASSAY
e containing the equivalent of 75 mg of
DEFINITION add 20 mL of 1m hydrochloric acid and sufficient
Fluorouracil Injection is a sterile solution in Water for duce 200 mL. Dilute 3 mL to 100 mL with
Injections of fluorouracil sodium, prepared by the interaction oric acid and measure the absorbance of the
of Fluorouracil and Sodium Hydroxide. at the maximum at 266 nm,
The injection complies with the requirements stated under late the content of C,H3FN2O, taking
Parenteral Preparations and with the following requirements. 552 as‘the va “%,1 cm) at the maximum at 266 nm.
Content of fluorouracil, C,H,;FN,O, STORAGE
90.0 to 110.0% of the stated amount. Fluorouracil Injection be protected from light.
CHARACTERISTICS It should not be refriger
A colourless or almost colourless solution. LABELLING
ete
IDENTIFICATION The strength is stated in ter the equivalent amount of
A. Carefully acidify a volume containing the equivalent of Fluorouracil in a suitable dose-volume
0.1 g of fluorouracil with glacial acetic acid, stir, cool and
filter. Wash the precipitate with 1 mL of water and dry over
phosphorus pentoxide at 80° at a pressure of 2 kPa for 4 hours.
The infrared absorption spectrum of the residue, Appendix II A,
is concordant with the reference spectrum of fluorouracil
Fluoxetine Capsules
(RS 153). Action and use
B. The light absorption, Appendix II B, in the range 230 to Selective serotonin reuptake inhibitor; antidepressant.
350 nm of the solution obtained in the Assay exhibits a
nwo maximum only at 266 nm. DEFINITION
Jd
TESTS Fluoxetine Capsules contain Fluoxetine Hydrochloride.

Alkalinity The capsules comply with the requirements stated under Capsules
pH, 8.5 to 9.1, Appendix V L. and with the following requirements.
Urea Content of fluoxetine, C,;,H,sF;NO

Carry out the method described under Related substances 95.0 to 105.0% of the stated amount.
applying separately to the plate 20 uL of each of the IDENTIFICATION
following solutions. For solution (1) dilute a suitable quantity A. Extract a quantity of the contents of the capsules
of the injection with water to produce a solution containing containing the equivalent of 20 mg of fluoxetine with 10 mL
the equivalent of 0.50% w/v of fluorouracil. Solution (2) of methanol, filter and evaporate the filtrate to dryness. The
contains 0.020% w/v of urea in water. After removal of the infrared absorption spectrum of the residue, Appendix II A, is
plate, allow it to dry in air, spray with a mixture of
2016 Fluoxetine Preparations IJI-591
concordant with the reference spectrum of fluoxetine (b) Use isocratic elution and the mobile phase described
hydrochloride (RS 385). below.
als las!
ANAS
B. In the Assay, the chromatogram obtained with solution (c) Use a flow rate of 1 mL per minute.
(1) shows a peak with the same retention time as the (d) Use ambient column temperature.
solution (2).
TESTS
Dissolution
retention time of the peak due to fluoxetine hydrochloride.
Pharmacopoeia in the dissolution test for tablets and capsules, If necessary, adjust the composition of the mobile phase so
Appendix XII B1. Prepare a mixture of 1 volume of that, in the chromatogram obtained with solution (2), the
retention time of the peak due to fluoxetine is between 10
3.5 with orthophosphonic acid (solution A); and 20 minutes.
e may form, keep the mixture well stirred. MOBILE PHASE
containing 1 volume of tnethylamine and 99 volumes of water,
per minute. and adjusting the pH to 6.0 with orthophosphonic acid.
(b) Use 900 mL of 0. LIMITS
37°, as the medium. In the chromatogram obtained with solution (1):
PROCEDURE the area of any secondary peak is not greater than half the area
Carry out the method for of the peak in the chromatogram obtained with solution (2)
(0.25%);
the area of not more than two such peaks is greater than
medium and filter, discarding the first 5: 0.2 times the area of the peak in the chromatogram obtained
Add to 5 mL of filtered medium 2 mL with solution (2) (0.1%);
well. and the sum of the areas of all the secondary peaks is not
(2) Add to 5 mL of a 0.0022% w/v solution of fiuoxe: greater than the area of the principal peak in the
hydrochloride BPCRS, 2 mL of solution A and mix Well chromatogram obtained with solution (2) (0.5%).
(a) Use a stainless steel column (15 cm x 4.6 mm) packed ut the method for liguid chromatography,
with cyanosilyl silica gel for chromatography (5 um) (Zorbax ix IIT D, using the following solutions.
CN is suitable). Ive a quantity of the mixed contents of 20 capsules
(b) Use isocratic elution and the mobile phase described ining the equivalent of 20 mg of fluoxetine in sufficient
below. hase to produce 200 mL, filter and use the
(c) Use a flow rate of 2 mL per minute. he first 2 mL. »
(7.5 cm x 4.6 mm) packed
MOBILE PHASE
for chromatography (3.5 wm)
2 volumes of diethylamine, 200 volumes of acetonitrile and
300 volumes of water, the mixture adjusted to pH 3.5 with
orthophosphonic acid. (b) Use isocratic elution and ¢t phase described
below.
Calculate the content of C;7H;3F3NO in the medium from

(d) Use an ambient column temperatu
C,7H)sF3NO,HCI in fluoxetine hydrochloride BPCRS and (e) Use a detection wavelength of 227 nm.
taking each mg of C,7H;3F3NO,HCI to be equivalent to (f) Inject 20 wL of each solution.
0.8944 mg of C,7HisF3NO. MOBILE PHASE
Related substances 33 volumes of a solution containing 0.3% w/v of glacial acetic
Carry out the method for liquid chromatography, acid and 0.64% w/v of sodium pentanesulfonate, adjusted to
Appendix III D, using the following solutions. pH 5.0 with 5m sodium hydroxide, and 67 volumes of
(1) Dissolve a quantity of the contents of the capsules methanol.
containing the equivalent of 20 mg of fluoxetine in sufficient DETERMINATION OF CONTENT
of the mobile phase to produce 10 mL, filter and use the
Calculate the content of C,;7H,gF3NO in the capsules from
filtrate, discarding the first 2 mL.
(2) 0.001% w/v offluoxetine hydrochloride BPCRS in the C,7H)gF3NO,HCI in fluoxetine hydrochloride BPCRS and
mobile phase. taking each mg of C,7H;gF3NO,HCI to be equivalent to
CHROMATOGRAPHIC CONDITIONS 0.8944 mg of C,;7H;sF3NO.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed LABELLING
with cyanosilyl silica gel for chromatography (5 um) (DuPont The quantity of active ingredient is stated in terms of the
Zorbax SB-CN is suitable). equivalent amount of fluoxetine.
II-592 Fluoxetine Preparations 2016
IMPURITIES CHROMATOGRAPHIC CONDITIONS

The impurities limited by the requirements of this (a) Use a stainless steel column (25 cm x 4.6 mm) packed
monograph include impurities A and B listed under with octadecylsilyl silica gel for chromatography (5 um)
Fluoxetine Hydrochloride. (Supelcosil LC-18-DB is suitable).
ve aw d

below.
Fluoxetine Oral Solution (d) Use an ambient column temperature.
Action and use
(g) Equilibrate the column with mobile phase A for at least
10 minutes.
MOBILE PHASE
Mobile phase A 21 volumes of acetonitrile R1, 26 volumes of

methanol R2 and 53 volumes of solution A.
Mobile phase B 22 volumes of methanol R2, 35 volumes of
acetonitrile R1 and 43 volumes of solution A.
95.0 to 105.0% of the sta
IDENTIFICATION Time Mobile phase A Mobile phase B Comment

A. To a volume of the oral soluty (Minutes) (% viv) (% viv)
of 0.1 g of fluoxetine add 5 mL of 0-13 100 0 isocratic
extract with 10 mL of dichloromethane, *
dichloromethane layer (Whatman 1PS is

the reference spectrum of fluoxetine (RS 398). 30-40 100 0 re-equilibration
B. In the Assay, the chromatogram obtained with soluty

principal peak in the chromatogram obtained with the chromatograms are recorded under the prescribed
solution (2). ‘is the retention time of fluoxetine is about
TESTS
Acidity ETABILITY
Related substances
Carry out the method for liguid chromatography, he baseline of the peak due to impurity C
Appendix III D, using the following solutions. Add 4.33 g of veéthe baseline of the lowest point of the
sodium octanesulfonate and 13.8 g of sodium dihydrogen ak from the peak due to fluoxetine.
orthophosphate monohydrate to 1000 mL of water, adjust the
pH, if necessary, to 3.0 with orthophosphoric acid and filter
(solution A).
(1) Mix a quantity of the oral solution containing the the principal peak in the chro
equivalent of 20 mg of fluoxetine in 20 mL of a mixture of solution (2) (0.4%);
1 volume of acetonitrile, 3 volumes of methanol and 6 volumes
of solution A and use immediately.
mixture of 1 volume of acetonitrile, 3 volumes of methanol and
6 volumes of solution A and further dilute 1 volume to
10 volumes with the same solvent mixture.
solution (6).
(3) Heat a 0.2% w/v solution offluoxetine
hydrochloride BPCRS in 0.5M sulfuntc acid at 85° for 1 hour ASSAY
(generation of impurity A and 4-trifluoromethylphenol). Carry out the method for liquid chromatography,
solution containing 0.1% w/v offluoxetine (1) Dilute a quantity of the oral solution with sufficient of
hydrochloride BPCRS in a mixture of 1 volume of acetonitrile, the mobile phase to produce a solution containing the
3 volumes of methanol and 6 volumes of solution A. equivalent of 0.004% w/v of fluoxetine.
(5) 0.1% w/v offluoxetine hydrochloride BPCRS and (2) 0.0045% w/v offluoxetine hydrochloride BPCRS in the
0.0003% w/v of fluoxetine impunty C EPCRS in a mixture of mobile phase.
1 volume of acetonitrile, 3 volumes of methanol and 6 volumes CHROMATOGRAPHIC CONDITIONS
of solution A. (a) Use a stainless steel column (25 cm x 4.6 mm) packed
oe ne= (6) 0.05% w/v of benzoic acid in a mixture of 1 volume of cyanosilyl silica gel for chromatography (5 um) (Dupont Zorbax
acetonitrile, 3 volumes of methanol and 6 volumes of
Hh, lay
CN Special is suitable).
Te Ne
a inten
al
wn ete
Pe
solution A.
'
——_~
a
2016 Flupentixol Preparations II-593
(b) Use isocratic elution and the mobile phase described Appendix IT B, in the range 205 to 300 nm of the resulting
below. solution exhibits two maxima at 230 nm and 264 nm.
ae, ee (c) Use a flow rate of 1 mL per minute. B. Carry out the method for thin-layer chromatography,
Appendix III A, usinga silica gel Fo54 precoated plate
PNT ay

(e) Use a detection wavelength of 215 nm. (Merck silica gel 60 F254 plates are suitable) and a mixture of
3 volumes of diethylamine and 90 volumes of cyclohexane as
the mobile phase and an unsaturated tank. Apply separately
(g) Allow the chromatography to proceed for at least to the plate 5 wL of each of the following solutions.
10 minutes. For solution (1) dilute the injection with ethanol (96%) to
MOBILE PHASE contain 0.4% w/v of flupentixol decanoate. Solution (2)
contains 0.4% w/v of flupentixol decanoate
dihydrochlonde BPCRS in ethanol (96%). After removal of the
alee ed
plate, allow it to dry in air, spray with a 1% w/v solution of
OF CONTENT
ed
sodium molybdate in sulfuric acid, heat at 110° for 20 minutes
ht per mL of the oral solution, and examine in daylight. The principal spot in the
Appendix chromatogram obtained with solution (1) is similar in colour,
weight in volu position and size to that in the chromatogram obtained with
C;7HigF3NO,H¢ solution (2).
TESTS
C 1 7H gF3NO.
Related substances
STORAGE Carry out the method for liguid chromatography,
Appendix III D, using the following solutions in acetonitrile,
aaa eal
wwe nd
LABELLING ( protected from light. For solution (1) dilute the injection to
The quantity of active ingredient is stat contain 0.20% w/v of Flupentixol Decanoate. Solution (2)
equivalent amount of fluoxetine. contains 0.0060% w/v of cis-flupentixol BPCRS. Solution (3)
contains 0.001% w/v of 2-trifluoromethylthioxanthone BPCRS.
IMPURITIES é Solution (4) contains 0.002% w/v of trans-flupentixol
The impurities limited by the requirements of this decanoate BPCRS. Solution (5) contains 0.006% w/v of cis-
monograph include those listed under Fluoxetine flupentixol BPCRS and 0.001% w/v each of
Hydrochloride and the following: 2-trifluoromethylthioxanthone BPCRS and trans-flupentixol
anoate BPCRS in solution (1).
N hromatographic procedure may be carried out using
e
Se
y SO
1. 3-Methylamino-1-phenylprop-1-ene,
Ci~~ NHMe
sulfosuccinate (grepar
2. 3-Methylamino-1-chloropropane, sulfosuccinate in 5
(96%) and (c) a det relength of 270 nm.

tine a
Fyo7 To Inject solution (1) and a he chromatography to proceed
3. 4-Trifluoromethylphenol.
In the chromatogram obtained with solution (1)

Flupentixol Injection any peak corresponding to cis-flupentixol is notgreater than
Action and use with solution (2) (3%), the area of any peak corresponding to
Dopamine receptor antagonist; neuroleptic. 2-trifluoromethylthioxanthone is not greater than the area of
DEFINITION
solution (3) (0.5%) and the area of any peak corresponding
Flupentixol Injection is a sterile solution of Flupentixol to trans-flupentixol decanoate is not greater than the area of
Decanoate in a suitable vegetable oil. the principal peak in the chromatogram obtained with
The injection complies with the requirements stated under | solution (4) (1.0%).
ASSAY
Content of flupentixol decanoate, C33;H,3F3;N,0,S Carry out the method for liguid chromatography,
95.0 to 105.0% of the stated amount. Appendix III D, using the following solutions in acetonitrile,
IDENTIFICATION protected from light. For solution (1) dilute a volume of the
A. Dilute 1 volume of solution A obtained in the Assay to injection to contain 0.20% w/v of Flupentixol Decanoate.
2 volumes with ethanol (96%). The light absorption,
vows J
ose |
IWI-594 Flupentixol Preparations 2016
Solution (2) contains 0.22% w/w offlupentixol decanoate PROCEDURE

dihydrochloride BPCRS. Carry out the method for liquid chromatography,
ANA
The chromatographic procedure described under Related Appendix III D, using the following solutions prepared in the
substances may be used. medium.
Calculate the content of C33H43F3N20.S using the declared (1) After 45 minutes withdraw a sample of the medium and
content of C33H43F3N,0.S in flupentixol decanoate filter. Use the filtered medium, diluted with sufficient
dihydrochloride BPCRS. Each mg of flupentixol decanoate 0.1m hydrochloric acid, if necessary, to produce a solution
dihydrochloride is equivalent to 0.8897 mg of flupentixol expected to contain the equivalent of 0.0001% w/v of
decanoate. flupentixol.
STORAGE (2) 0.00012% w/v of flupentixol dihydrochloride BPCRS.
Flupentixol,Jnjection should be protected from light. (3) 0.058% w/v of flupentixol dthydrochlonde BPCRS and
0.0005% of 2-trifluoromethylthioxanthone BPCRS.
Flupentixo ak with octadecylsilyl silica gel for chromatography (5 ym) (Waters
Action and use
Dopamine receptor ant
below.
Flupentixol Tablets contain F (d) Use a column temperature of 40°.
The tablets comply with the requiremen. nder Tablets and (e) Use a detection wavelength of 270 nm.
with the following requirements. g (f) Inject 100 LL of each solution.
Content of flupentixol, C,3H,;F3N,0S Solution A Dissolve 8.89 g ofdioctyl sodium sulfosuccinate in
95.0 to 105.0% of the stated amount. 500 mL of water (by stirring for approximately 8 hours) and
IDENTIFICATION : | add sufficient water to produce 1000 mL.
A. Carry out the method for thin-layer chromatograph MOBILE PHASE
Appendix III A, using the following solutions. 0.1 volume of orthophosphoric acid, 25 volumes of solution A
(1) Shake a quantity of powdered tablets containing the and 75 volumes of ethanol (96%).
equivalent of 4 mg of flupentixol with 5 mL of methanol, adé M SUITABILITY
sufficient methanol to produce 10 mL and filter.
(2) 0.05% w/v offlupentixol dihydrochloride BPCRS in on (3), the resolution between the peaks due to
methanol.

(b) Use the mobile phase as described below. cefitent of C.3H»5F3;N.OS in Aupentixol
(d) Develop the plate twice to 15 cm. LIMITS
(e) After removal of the plate, dry in air and examine in The amount of flupenti d is not less than 75% (Q)
ultraviolet light (254 nm). of the stated amount.
Related substances
ase als
MOBILE PHASE
Carry out the method for liquid chrom dgraphy,
yew awd
1 volume of water, 4 volumes of diethylamine and 95 volumes

of methyl ethyl ketone.
(1) Shake a quantity of powdered ta
CONFIRMATION equivalent of 5 mg of flupentixol with 7 tr
solution (1) corresponds in position and size to that in the (2) Dilute 1 volume of solution (1) to 50 volumé¢
chromatogram obtained with solution (2). Doubling of the acetonitrile, further dilute 1 volume of this solution.
spots may be observed in each chromatogram. 10 volumes with acetonitrile.
B. In the Assay, the chromatogram obtained with solution (3) 0.0005% w/v of 2-trifluoromethylthioxanthone BPCRS in
Lene
~ ~
Nwaed J (1) shows a peak with the same retention time as the peak acetonitrile.
due to flupentixol in the chromatogram obtained with (4) 0.058% w/v offlupentixol dihydrochloride BPCRS and
solution (2). 0.0005% of 2-trifluoromethylthioxanthone BPCRS in
TESTS acetonitrile.
Dissolution CHROMATOGRAPHIC CONDITIONS
Comply with the requirements in the dissolution test for tablets The chromatographic conditions described under Dissolution
and capsules, Appendix XII B1. may be used. For solution (1), allow the chromatography to
TEST CONDITIONS proceed for 3 times the retention time of flupentixol.
(a) Use Apparatus 2, rotating the paddle at 50 revolutions SYSTEM SUITABILITY
per minute. The test is not valid unless, in the chromatogram obtained
ee
art (b) Use 500 mL of 0.1M hydrochloric acid, at a temperature of with solution (4), the resolution between the peaks due to
tee
37°, as the medium. flupentixol and 2-trifluoromethylthioxanthone is at least 1.5.

2016 Fluphenazine Preparations II-595
LIMITS For tablets containing the equivalent of 2 mg or more

In the chromatogram obtained with solution (1): and 2% w/w or more offlupentixol
the area of any peak corresponding to | Weigh and powder 20 tablets. Carry out the method for
2-trifluoromethylthioxanthone is not greater than the area of liquid chromatography, Appendix III D, using the following
the principal peak in the chromatogram obtained with solutions prepared in methanol.
solution (3) (1%); (1) Shake a quantity of powdered tablets containing the
the area of any other secondary peak is not greater than the equivalent of 5 mg of flupentixol with 25 mL of methanol,
area of the principal peak in the chromatogram obtained with add sufficient methanol to produce 50 mL and filter.
solution (2) (0.2%); (2) 0.012% w/v offlupentixol dihydrochloride BPCRS.
the sum of the areas of any other secondary peaks is not (3) 0.012% w/v each offlupentixol dihydrochlonde BPCRS and
greater than 2.5 times the area of the principal peakin the melitracen hydrochloride BPCRS.
ained with solution (2) (0.5%). CHROMATOGRAPHIC CONDITIONS
with an area less than half of the area of The chromatographic conditions described under Uniformity
the princiipl | ein the chromatogram obtained with of content may be used.
solution (2) ¢
SYSTEM SUITABILITY
flupentixol and melitracen is at least 3.0.
chromatography, Appendix I Calculate the content of C23H25F3N,2OS (flupentixol) in the
solutions. tablets using the declared content of C,3H,5F,;N,OS in
flupenuxol dihydrochloride BPCRS.
LABELLING
methanol, if necessary, to produce a solutie The quantity of the active ingredient is stated in terms of the
contain the equivalent of 0.005% w/v of flu equivalent amount of flupentixol.
(2) 0.0058% wiv offlupentixol dihydrochloride B
methanol.
(3) 0.0058% w/v each offlupentixol dihydrochloride B
and melitracen hydrochloride BPCRS in methanol.
phenazine Decanoate Injection

with end-capped octadecylsilyl sihca gel (5 um) (Brownlee
Analytical C18 1s suitable).
below.
MOBILE PHASE
10 volumes of a 0.34% w/v solution of potasstum dihydrogen
orthophosphate and 90 volumes of methanol, adjust the pH of
the mixture to pH 7.3 with triethylamine.
conditions, the retention time relative to flupentixol
(retention time, about 5 minutes) of melitracen is about 1.3.
SYSTEM SUITABILITY
allow it to dryin air, turn the plate through 90°in a
clockwise direction, impregnate the coating with a 5% v/v
solution of n-tetradecane in n-hexane and allow it to dry in air.
flupentixol and melitracen is at least 3.0.
Apply to the bottom right-hand corner of the plate, to the
DETERMINATION OF CONTENT right of the solvent front of the first development, 1 wL of a
Calculate the content of C.3H25F3N,OS (flupentixol) in each 2.0% w/v solution of fluphenazine decanoate EPCRS in ethanol
tablet using the declared content of C23H25F3N2OS in (96%). For the second development use methanol (90%) as
flupennxol dihydrochloride BPCRS. the mobile phase. After removal of the plate, allow it to dry
in air and examine under witraviolet light (254 nm).
ASSAY
The principal spot in the chromatogram obtained with the
For tablets containing the equivalent of less than 2 mg
injection corresponds to that in the chromatogram obtained
and/or less than 2% w/w offlupentixol
with the reference substance.
test for Uniformity of content. B. Shake a volume containing 5 mg of Fluphenazine
Decanoate with 1 mL of a 1% w/v solution of sucrose in
IW-596 Fluphenazine Preparations 2016
hydrochloric acid and allow to stand for 5 minutes. A red

colour is produced in the acid layer.
Fluphenazine Tablets
Related substances Action and use
Protect the solutions from light. Carry out the method for Dopamine receptor antagonist; neuroleptic.
solutions. For solution (1) dilute a volume of the injection DEFINITION
with sufficient chloroform to produce a solution containing Fluphenazine Tablets contain Fluphenazine Hydrochloride.
0.50% w/v of Fluphenazine Decanoate, dilute 1 volume of They are coated.
this solution to 25 volumes with acetonitrile and mix. The tablets comply with the requirements stated under Tablets and
For solution (2) dilute 1 volume of solution (1) to with the following requirements.
100 volumes with acetonitrile. For solution (3) add 0.05 mL
Content of fluphenazine hydrochloride,
of 10M sodiiii rydroxide to 2 mL of solution (1) and allow to
C,,H>.F3N;0S,2HC1
ah eR
s‘before use (generation of fluphenazine
solution (.200 IDENTIFICATION

allow to stand Autes, add sufficient chloroform to A. Carry out the method for thin-layer chromatography,
produce 1 mL, m to 100 mL with acetonitrile Appendix III A, using the following solutions.
J-oxide impurities). (1) Shake a quantity of the powdered tablets with sufficient
Fluphenazine Hydrochloride, centrifuge and use the
end-capped octadecylsilyl silica gél supernatant liquid.
(Hypersil ODS is suitable) fitted: (2) 0.2% w/v offluphenazine hydrochloride BPCRS in
(2.5 cm x 4.6 mm) packed witt methanol.
the mobile phase with a flow rate of 1°m
solution prepared by adding 450 volume
(a) Use as the coating kieselguhr G. Impregnate the dry plate
by placing it in a tank containing a shallow layer of a mixture
of 5 volumes of 2-phenoxyethanol, 15 volumes offormamide
and 180 volumes of acetone, allowing the impregnating
Inject separately 20 wL of each solution. After completion
olvent to ascend to the top, removing the plate from the
the test, flush the column with a mixture of equal volumes
ank and using it immediately.
methanol and water.
:the mobile phase as described below.
with solution (4), the resolution factor between the peaks uL of each solution.
corresponding to the two fluphenazine mono-N-oxides is at p the plate to 15 cm.
least 2. al of the plate, dry in air, examine under
In the chromatogram obtained with solution (1) the area of t nm) and observe the fluorescence
any peak corresponding to the peak due to fluphenazine ab utBeminutes. Heat the plate at 120° for
impurity in the chromatogram obtained with solution (3) is 20 minutes,
¢ . ith ethanolic sulfuric acid (20%) and
not greater than 4 times the area of the peak in the observe the colous rod ced.
chromatogram obtained with solution (2) (4%), the area of MOBILE PHASE
any other secondary peak is not greater than the area of the 2 volumes of diethylaming.atidt00 volumes of petroleum spirit
peak in the chromatogram obtained with solution (2) (1%)
(boiling range, 40° to 60°) saturated with 2-phenoxyethanol.
and the sum of the areas of any secondary peaks other than
any peak corresponding to fluphenazine is not greater than CONFIRMATION
twice the area of the peak in the chromatogram obtained
with solution (2) (2%). Disregard any peak with a retention
time relative to fluphenazine decanoate of 0.2 or less.
ASSAY
Appendix VIII A, using a volume containing 0.15 g of
Fluphenazine Decanoate diluted with 75 mL of anhydrous
acetic acid and crystal violet solution as indicator. Each mL of An orange colour is produced.
aa al
0.1m perchlonc acid VS is equivalent to 29.59 mg of C. Extract a quantity of the powdered tablets containing
Sa Nd
oe
aa
Mtoe
C32H44F3N30,S. 10 mg of Fluphenazine Hydrochloride with 10 mL of absolute
ethanol containing 0.2% v/v of 13.5M ammonia and evaporate
STORAGE
the extract to dryness. Heat 0.5 mL of chromic-sulfurtc acid
Fluphenazine Decanoate Injection should be protected from mixture in a small test tube in a water bath for 5 minutes;
light. the solution wets the side of the tube readily and there is no
LABELLING greasiness. Add 2 or 3 mg of the residue and again heat in a
The label states that the injection is for intramuscular water bath for 5 minutes; the solution does not wet the side
injection only. of the tube and does not pour easily from the tube.
TESTS
Related substances
Appendix IIT A, using the following solutions.
Neem e
2016 Flurazepam Preparations III-597
(1) Remove the coating from a suitable number of tablets; For each solution measure the amplitude from the peak at
shake a quantity of the powdered tablet cores containing about 266 nm to the trough at about 258 nm. Calculate the
we anwd
20 mg of Fluphenazine Hydrochloride with 10 mL of content of C22H»>6F3N308,2HCI in the tablets using the
0.1m methanolic sodium hydroxide for 5 minutes, centrifuge declared content of C22H25F3N30S,2HCI in fluphenazine
weaned
and use the supernatant liquid. hydrochloride BPCRS.

0.1m methanolic sodium hydroxide.
0.1M methanolic sodium hydroxide. Flurazepam Capsules
(a) Use-as.the coating silica gel GF 254. Action and use

Benzodiazepine.
we ned bile phase as described below.
DEFINITION
Flurazepam Capsules contain Flurazepam
15 cm. Monohydrochloride.
2 e, dry in air and examine under The capsules comply with the requirements stated under Capsules
ultraviolet light 05
254 and with the following requirements.
MOBILE PHASE Content of flurazepam, C,,H,3;CIFN;O
80 volumes of acetone. IDENTIFICATION
twats
LIMITS A. Shake a quantity of the contents of the capsules
containing the equivalent of 0.15 g of flurazepam with 3 mL
solution (1) is not more intense than the: of chloroform IR and filter. The infrared absorption spectrum of
the filtrate, Appendix II A, is concordant with the reference
chromatogram obtained with solution (2)
spectrum of flurazepam monohydrochloride (RS 155).
chromatogram obtained with solution (3) (0.5%) B. The light absorption, Appendix II B, in the range 220 to
any spot remaining on the line of application. 350 nm of the final solution obtained in the Assay exhibits
Uniformity of content two maxima, at 240 nm and 284 nm.
Tablets containing less than 2 mg and/or less than 2%
of Fluphenazine Hydrochloride comply with the
requirements stated under Tablets using the following
method of analysis. Carry out the following procedure
protected from light. Record second-denvative ultraviolet
absorption spectra of the following solutions in the range
230 to 300 nm, Appendix II B. For solution (1) add 2 mL of L gf each of the following solutions.
0.1M hydrochloric acid to one tablet and mix with the aid of jake vigorously a quantity of the contents
ultrasound until the tablet is dispersed. Add 60 mL ofa of the capsules’contgining the equivalent of 0.1 g of
mixture of 1 volume of 1m hydrochloric acid and 99 volumes flurazepam with 2: _ mixture of 2 volumes of
of ethanol (80%), shake for 20 minutes, dilute to 100 mL 13.5M ammonia and‘ s of methanol and centrifuge.
with the same solvent mixture, mix and filter. Solution (2) For solution (2) dilu of solution (1) to
contains 0.001% w/v offluphenazine hydrochloride BPCRS. yivent mixture. After removal of
Ran
we wed
For each solution measure the amplitude from the peak at examine under
about 266 nm to the trough at about 258 nm. Calculate the
content of C.,H»6F3N30OS8,2HCI in each tablet using the
declared content of C.,H».6F3N30S,2HC] in fluphenazine
hydrochloride BPCRS. (0.5%).
ASSAY ASSAY
For tablets containing less than 2 mg and/or less than Carry out the following procedure protected fros# light.
2% w/w of Fluphenazine Hydrochloride Transfer a quantity of the capsule contents containing the
Use the average of the 10 individual results obtained in the equivalent of 0.1 g of flurazepam into about 150 mL of
test for Uniformity of content. : 1m methanolic sulfuric acid, washing the inner surfaces of the
For tablets containing 2 mg or more and 2% w/w or capsule shells, shake for 10 minutes and add sufficient
more of Fluphenazine Hydrochloride 1m methanolic sulfuric acid to produce 250 mL. Further dilute
Carry out the following procedure protected from light. this solution with 1m methanolic sulfuric acid to produce a
Record second-denvative ultraviolet absorption spectra of the solution containing the equivalent of about 0.002% w/v of
following solutions in the range 230 to 300 nm, flurazepam and measure the absorbance of the resulting
Appendix II B. For solution (1) add 20 mL of solution at the maximum at 284 nm, Appendix II B.
0.1m hydrochloric acid to 10 tablets, mix with the aid of Calculate the content of C,,;H.3CIFN3O taking 319 as the
ultrasound until the tablets are dispersed, add 600 mL of a value of A(1%, 1 cm) at the maximum at 284 nm.
mixture of 1 volume of 1m hydrochloric acid and 99 volumes LABELLING
of ethanol (80%), shake for 20 minutes, dilute to 1000 mL The quantity of active ingredient is stated in terms of the
with the same solvent mixture, mix and filter. Solution (2) equivalent amount of flurazepam.
a!
contains 0.001% w/v offluphenazine hydrochloride BPCRS.

to
vo
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wt
,
vs oy we
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.
fe
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aire
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?
‘
II-598 Flurbiprofen Preparations 2016
not greater than the area of the peak in the chromatogram

Flurbiprofen Eye Drops obtained with solution (2) (0.5%).
Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory. Carry out the method for liquid chromatography,
DEFINITION (1) dilute the eye drops, if necessary, with a mixture of
Flurbiprofen Eye Drops are a sterile solution of Flurbiprofen 25 volumes of water and 50 volumes of methanol to produce
Sodium in purified water. a solution containing 0.015% w/v of flurbiprofen sodium.
The eye drops comply with the requirements stated under Eye Solution (2) contains 0.015% w/v of flurbiprofen
Preparations and with the following requirements. sodium BPCRS in a mixture of 25 volumes of water and
Content of flurbiprofen sodium dihydrate, 50 volumes of methanol. Solution (3) contains 0.0005% w/v
offlurbiprofen sodium BPCRS and 0.0005% w/v of
2-(biphenyl-4-yl) propionic acid BPCRS in a mixture of
The chromatographic procedure described under the test for
2-(Biphenyl-4-yl)propionic acid may be used.
olumes of propan-2-ol and The assay is not valid unless the resolution factor between the
as:the mobile phase. Apply two principal peaks in the chromatogram obtained with
separately to the plate 5 u solution (3) is at least 1.5.
solutions. For solution (1) dify Calculate the content of C,5;H,;,FNaO,,2H,O in the eye
with a mixture of 25 volumes drops using the declared content of C;5;H,;2.FNaQO.,2H,0O in
methanol to produce a solution flurbiprofen sodium BPCRS.
flurbiprofen sodium. Solution (2) cont
flurbiprofen sodium BPCRS in a mixture o
allow it to dry in air and examine under witravi

(254 nm). The principal spot in the chromatogram gt
Flurbiprofen Suppositories
with solution (1) corresponds to that in the chroma ere
Action and use
obtained with solution (1) has the same retention time as thé®
principal peak in the chromatogram obtained with en Suppositories contain Flurbiprofen in a suitable
solution (2). basis.
TESTS ositories comply with the requirements stated under Rectal
2-(Biphenyl-4-yl)propionic acid
Carry out the method for Lguid chromatography,
Appendix III D, using the following solutions. For solution ‘ in-layer chromatography,
(1) dilute the eye drops, if necessary, with a mixture of Appendix III A, using &:sik F454 precoated plate
tern 25 volumes of water and 50 volumes of methanol to produce (Merck plates are suitable) nd
a solution containing 0.030% w/v of flurbiprofen sodium.
Solution (2) contains 0.00015% w/v of 2-(biphenyl-4-
yw)propionic acid BPCRS in a mixture of 25 volumes of water
and 50 volumes of methanol. Solution (3) contains
0.00050% w/v of flurbiprofen sodium BPCRS and following solutions. For solution (1) cut'a
0.00050% w/v of 2-(biphenyl-4-yl)propionic acid BPCRS in a the suppositories into small pieces, add 50
The chromatographic procedure may be carried out using melted, shake mechanically for 10 minutes, allow t6
(a) a stainless steel column (15 cm x 3.9 mm) packed with 2° to 8°, filter (Whatman No. 1 paper is suitable) and
octadecylsilyl silica gel for chromatography (5 wm) (Resolve 5p is evaporate to dryness. Dissolve the residue in 5 mL of a
suitable), (b) a mixture of 5 volumes of glacial acetic acid, mixture of equal volumes of methanol and water. Solution (2)
awn
35 volumes of acetonitrile and 60 volumes of water as the contains 0.2% w/v of flurbiprofen sodium BPCRS in a mixture
mobile phase with a flow rate of 1 mL per minute and (c) a of equal volumes of methanol and water. After removal of the
detection wavelength of 254 nm. Adjust the sensitivity so that plate, allow it to dry in air and examine under ultraviolet light
the heights of the principal peaks in the chromatogram (254 nm). The principal spot in the chromatogram obtained
obtained with solution (3) are about 40% of full-scale _ with solution (1) corresponds to that in the chromatogram
deflection on the chart paper. obtained with solution (2).
ves ae
The test is not valid unless the resolution factor between the B. In the Assay, the principal peak in the chromatogram
two principal peaks in the chromatogram obtained with obtained with solution (1) has the same retention time as
solution (3) is at least 1.5. that in the chromatogram obtained with solution (2).
Aw AY
In the chromatogram obtained with solution (1) the area of Related substances
any peak corresponding to 2-(biphenyl-4-yl)propionic acid is
eon
we A

One Fe]
ws
e

2016 Flurbiprofen Preparations IIJ-599
(1) cut a suitable number of the suppositories into small Calculate the content of C,;5H,3FO, in the suppositories
pieces, add 50 mL of methanol to a quantity containing 0.1 g using the declared content of C,5H,3FO2 in flurbiprofen
rw AN
Aw eA!
ee Ne
of flurbiprofen, heat gently until melted, shake mechanically sodium BPCRS.
for 10 minutes and filter (Whatman No. 1 paper is suitable).
VAN st
~ oN el
Dilute the filtrate with sufficient of a mixture containing

35 volumes of acetonitrile and 65 volumes of water to produce
100 mL and filter. For solution (2) dilute 1 volume of
solution (1) to 100 volumes with a mixture of 45 volumes of
Flurbiprofen Tablets
acetonitrile and 55 volumes of water and further dilute Action and use
1 volume to 5 volumes with the same solvent mixture. Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.
Solution(3) contains 0.0005% w/v of 2-(biphenyl-4-
WW propiomuc. acid BPCRSin a mixture of 45 volumes of DEFINITION
iD olumes of water. Solution (4) contains Flurbiprofen Tablets contain Flurbiprofen. They are coated.
cetyl-2-fluorobiphenyl BPCRS in a mixture
acetonitrile and 55 volumes of water.
.
*
Content of flurbiprofen, C,;;H,;FO,

pie
;

‘
fel whe
’
IDENTIFICATION
oy
‘
eye
oe Pettey
Extract a quantity of the powdered tablets containing 0.5 g of

o.
flurbiprofen with 25 mL of acetone, filter, evaporate the

aye
ee
ety
filtrate to dryness with the aid of a current of air without

oy
‘yr
tee
.
Niet wy heating and dry at 60° at a pressure of 2 kPa. The residue

complies with the following tests.
1 mL per minute and (c) a detection wi A. The infrared absorption spectrum, Appendix II A, is
Adjust the sensitivity so that the heights concordant with the reference spectrum of flurbiprofen
(RS 156).
B. Heat 0.5 mL of chromic—sulfunic acid mixture in a small test
The test is not valid unless,in the chromatogram ob ne tube in a water bath for 5 minutes; the solution wets the side
with solution (5), the resolution factor between the tw of the tube readily and there is no greasiness. Add 2 or 3 mg
principal peaks is at least 1.5. fthe residue and heatin a water bath for 5 minutes;
In the chromatogram obtained with solution (1) the area o Olution does not wet the side of the tube and does not
any peak corresponding to 2-(biphenyl-4-yl)propionic acid is asily from the tube.
not greater than the area of the peak in the chromatogram 1g point, about 114°, Appendix V A.
obtained with solution (3) (0.5%), the area of any peak
corresponding to 4-acetyl-2-fluorobipheny]l is not greater than
solution (4) (0.5%), the area of any other secondary peak is 7 of the powdered tablets containing
not greater than the area of the peak in the chromatogram i
0.5 g of flurbip 50 mL of water, add 200 mL of
obtained with solution (2) (0.2%) and the sum of the areas acetonitrile, mix, cet
of any such peaks is not greater than 2.5 times the area of
the peak in the chromatogram obtained with solution (2) 100 volumes with a m
(0.5%). 55 volumes of water and
eae
ete ae
ASSAY
(1) cut a suitable number of the suppositories into small
pieces, add 50 mL of methanol to a quantity containing 0.1 g
of flurbiprofen, heat gently until melted, shake mechanically
for 10 minutes and filter (Whatman No. 1 paper is suitable).
Dilute the filtrate with sufficient of a mixture containing
35 volumes of acetonitrile and 65 volumes of water to produce suitable), (b) a mixture of 5 volumes of glacial acetic acid,
100 mL, filter and dilute 1 volume of the filtrate to 35 volumes of acetonitrile and 60 volumes of water as the
25 volumes with the same solvent mixture. Solution (2) mobile phase with a flow rate of 1 mL per minute and (c) a
contains 0.005% w/v offlurbiprofen sodium BPCRS in a detection wavelength of 254 nm.
mixture of 35 volumes of acetomtrile and 65 volumes of water. Adjust the sensitivity so that the heights of the principal
Solution (3) contains 0.0005% w/v each offlurbiprofen peaks in the chromatogram obtained with solution (4) are
sodium BPCRS and2-(biphenyl-4-yl)propionic acid BPCRS in a about 40% of full-scale deflection on the chart paper.
mixture of 35 volumes of acetonitrile and 65 volumes of water.
The chromatographic procedure described under Related two principal peaks in the chromatogram obtained with
substances may be used. solution (4) is at least 1.5.
The assay is not valid unless, in the chromatogram obtained In the chromatogram obtained with solution (1) the area of
with solution (3), the resolution factor between the two any peak corresponding to 2-(biphenyl-4-yl)propionic acid is
principal peaks is at least 1.5. not greater than the area of the peak in the chromatogram
obtained with solution (3) (0.5%), the area of any other
III-600 Fluticasone Preparations 2016
secondary peak is not greater than the area of the peak in the B. In the Assay, the retention time of the principal peak in
“Nw AD chromatogram obtained with solution (2) (0.2%) and the the chromatogram obtained with solution (1) is similar to
sum of the areas of any secondary peaks is not greater than that of the principal peak in the chromatogram obtained with
five times the area of the peak in the chromatogram obtained solution (2).
ASSAY
ASSAY Carry out the method for liguid chromatography,
Weigh and powder 20 tablets. Shake a quantity of the Appendix III D, using the following solutions protected from
powder containing 0.1 g of flurbiprofen with 60 mL of light.
0.1M sodium hydroxide for 5 minutes, dilute to 100 mL with (1) Transfer a quantity of the cream containing 1 mg of
0.1m sodium hydroxide, filter 1f necessary and dilute 10 mL of Fluticasone Propionate to a separating funnel, add 25 mL of
the filtrate to 100 mL with the same solvent. Further dilute ethanol (65%), stopper and shake until the cream is
completely dispersed. Add 25 mL of n-hexane, shake for
3 minutes and allow to separate, filter the lower aqueous
247 nm, Apps idix.dI B. Calculate the content of layer through an absorbent cotton plug, previously washed
C,5H,3FO, 2 as the value of A(1%, 1 cm) at the with ethanol (65%), into a graduated flask and repeat the
maximum at 247 extraction with one 5-mL and then one 2-mL quantity of
ethanol (65%), filtering the aqueous ethanol extracts into the
same graduated flask. Wash the absorbent cotton plug with
ethanol (65%), collecting the washings in the flask and dilute
Fluticasone Cream. the combined extracts to 50 mL with ethanol (65%).
Action and use (2) 0.002% w/v of fluticasone propionate BPCRS in methanol
Glucocorticoid.
(80%).
(3) 0.0004% w/v offluticasone S-methyl impurity BPCRS and
DEFINITION 0.002% w/v offluticasone propionate BPCRS in methanol
Fluticasone Cream contains Fluticasone Propi (80%).
suitable basis. CHROMATOGRAPHIC CONDITIONS
The cream complies with the requirements stated under (a) Use a stainless steel column (25 cm x 4.6 mm) packed
Semi-solid Preparations and with the following requirement with octadecylsilyl silica gel for chromatography (5 wm)
Content of fluticasone propionate, C,;H3,F3;0;S Spherisorb ODS1 is suitable).
95.0 to 105.0% of the stated amount. e isocratic elution and the mobile phase described
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, ow rate of 2 mL per minute.
Appendix III A, using the following solutions. ‘olumn temperature of 50°.
(1) Transfer a quantity of the cream containing 1 mg of
Fluticasone Propionate to a separating funnel, add 25 mL of
acetomtrile and 25 mL of n-hexane, shake for 3 minutes and
allow to separate. Filter the lower layer through an absorbent
cotton plug, previously washed with acetonitrile, into a 50-mL 15 volumes of onitys 35 volumes of 0.01M ammonium
graduated flask, repeat the extraction with one 5-mL and dihydrogen orthophosphagé previously adjusted to pH 3.5 with
then one 2-mL quantity of acetonitrile, filter and add the orthophosphonc acid a volumes of methanol.
extracts to the filtered layer; wash the absorbent cotton plug SYSTEM SUITABILITY
with 1 to 2 mL of acetonitrile, add the washings to the filtered
layer and dilute the combined extracts to 50 mL with
acetonitrile. Evaporate 4 mL of the resulting solution to
dryness using a rotary evaporator at a temperature of 40° and
dissolve the residue in 0.2 mL of acetonitrile.
(2) 0.04% w/v of fluticasone propionate BPCRS in acetonitrile.
(a) Use a silica gel F>54 precoated plate (Merck silica gel 60
F554 plates are suitable). propionate BPCRS.
PRN A

(e) After removal of the plate, dry it in a current of air and Fluticasone Nasal Drops
MOBILE PHASE
Action and use
Glucocorticoid.
1 volume of glacial acetic acid, 8 volumes of ethyl acetate and
30 volumes of dichloromethane. DEFINITION
CONFIRMATION Fluticasone Nasal Drops are a suspension of Fluticasone
The principal spot in the chromatogram obtained with Propionate in a suitable liquid in a container fitted with an
solution (1) corresponds in position and colour to that in the appropriate nasal delivery system.
2016 Fluticasone Preparations III-601
The nasal drops comply with the requirements stated under Nasal MOBILE PHASE
Preparations and with the following requirements. Mobile phase A A solution containing 0.05% v/v of
Veta wy
Content of fluticasone propionate, C,;H3;,F3;0;S orthophosphoric acid and 3.0% v/v of methanol in acetonitrile.
95.0 to 110.0% of the stated amount. Mobile phase B’ A solution containing 0.05% v/v of
Carry out all the following procedures 1n the dark or under long- orthophosphoric acid and 3.0% v/v of methanol in water.
wavelength light (greater than 420 nm). Prepare solutions Equilibrate the column with a mixture of 43 volumes of
immediately before use and protect them from light. mobile phase A and 57 volumes of mobile phase B.
IDENTIFICATION
Appendix III A, using the following solutions. Time Mobile phase Mobile phase Comment
(Minutes) A%viv B % viv
antity of the nasal drops containing 2 mg of

SYSTEM SUITABILITY

MOBILE PHASE in the chromatogram obtained with solution (3), the resolution
1 volume of glacial acetic acid, 8 volumes of € factor between the peaks due to fluticasone S-methy]l
30 volumes of dichloromethane. impurity and fluticasone propionate is at least 1.5;
CONFIRMATION
in the chromatogram obtained with solution (4), the peak
due to fluticasone propionate has a signal-to-noise ratio of at
least 10.
B. In the Assay, the retention time of the principal peak in hromatogram obtained with solution (1):
the chromatogram obtained with solution (1) is similar to ~of any secondary peak is not greater than the area of
that of the principal peak in the chromatogram obtained with « due to fluticasone propionate in the chromatogram
solution (2).
TESTS
Related substances
(1) Dilute a quantity of the nasal drops containing 1 mg of peak due to fluticaso C.J
Fluticasone Propionate to 5 mL with a mixture of equal obtained with solution (
volumes of mobile phase A and mobile phaseB and filter. ASSAY
mixture of equal volumes of mobile phase A and mobile Appendix III D, using the following.sol
phase B. (1) Mix the contents of 20 ampoules
(3) 0.02% w/v offluticasone propionate BPCRS and ethanol (65%) to a quantity of the na
0.00004% w/v offluticasone S-methyl impurity BPCRS in a
mixture of equal volumes of mobile phase A and mobile ultrasound for 10 minutes. Add sufficient ethic
phase B. produce 50 mL and filter.
(4) Dilute 1 volume of solution (2) to 10 volumes with a (2) Dilute 2 mL of a 0.05% w/v solution offluticasone
eat
mixture of equal volumes of mobile phase A and mobile propionate BPCRS in methanol (80%) to 50 mL with
phase B. ethanol (65%).
Pes?
Fy ERS!
CHROMATOGRAPHIC CONDITIONS (3) 0.0004% w/v offluticasone S-methyl impurity BPCRS and
0.002% w/v offluticasone propionate BPCRS in the mobile
en

phase.
no

(Spherisorb ODS 1 1s suitable). CHROMATOGRAPHIC CONDITIONS
(b) Use gradient elution and the mobile phase described (a) Use a stainless steel column (25 cm x 4.6 mm) packed
.
.
below. with octadecylsilyl sihca gel for chromatography (5 wm)

:

‘

a
ct,

.

wily
Grey
te
below.
Ce ey

Pe ess
eG

NG
(d) Use a column temperature of 40°. CONFIRMATION

(e) Use a detection wavelength of 240 nm. The principal spot in the chromatogram obtained with
(f) Inject 20 pL of each solution. solution (1) corresponds in position and colour to that in the
MOBILE PHASE
15 volumes of acetonitrile, 35 volumes of 0.01M ammonium the chromatogram obtained with solution (1) is similar to
dihydrogen orthophosphate previously adjusted to pH 3.5 with that of the principal peak in the chromatogram obtained with
orthophosphoric acid and 50 volumes of methanol. solution (2).
SYSTEM SUITABILITY
TESTS
The assay is not valid unless, in the chromatogram obtained Related substances
with solution (3), the resolution factor between the peaks due Carry out the method for liquid chromatography,
‘S-methyl impurity and fluticasone propionate is Appendix III D, using the following solutions.
essary, adjust the proportion of acetonitrile
(1) Dilute a quantity of the nasal spray containing 1 mg of
Fluticasone Propionate to 5 mL with a mixture of equal
volumes of mobile phase A and mobile phase B and filter.
mixture of equal volumes of mobile phase A and mobile
propionate BPCRS. phase B.
IMPURITIES (3) 0.02% w/v offluticasone propionate BPCRS and
D. 6a,9-difluoro-17-[(methylstz 0.00004% w/v offluticasone S-methyl impurity BPCRS in a
1 64-methyl-3-oxoandrosta-1,4- mixture of equal volumes of mobile phase A and mobile
(fluticasone S-methyl impurity, eq phase B.
fluticasone impurity D). (4) Dilute 1 volume of solution (2) to 10 volumes with a
mixture of equal volumes of mobile phase A and mobile
phase B.
Fluticasone Nasal Spray (a) Use a stainless steel column (25 cm x 4.6 mm) packed
Action and use (Spherisorb ODS1 is suitable).
Glucocorticoid. radient elution and the mobile phases described
DEFINITION
Fluticasone Nasal Spray is a suspension of Fluticasone
Propionate in a suitable liquid in a container fitted with an
appropriate nasal delivery system.
The nasal spray complies with the requirements stated under Nasal
Content of fluticasone propionate, C,;H3,F;0,;S ontaining 0.05% v/v of
80.0 to 120.0% of the amount stated to be delivered by viv of methanol in acetonitrile.
actuation of the valve.
Carry out all the following procedures in the dark or under long- methanol in water.
wavelength light (greater than 420 nm). Prepare solutions
43 volumes of
immediately before use and protect them from light.
IDENTIFICATION
Appendix III A, using the following solutions. Time Mobile phase Mobile ph
(1) To a quantity of the nasal spray containing 2 mg of (Minutes) A% viv B% viv
Fluticasone Propionate add sufficient acetonitrile to produce
5 mL, shake for 3 minutes and filter. 0-40 43-355 5745 linear gradient
(2) 0.04% w/v offluticasone propionate BPCRS in acetonitrile.
|
(a) Use as the coating silica gel F254 (Merck silica gel 60 Fos,
plates are suitable). 70-75 9043 10-57 linear gradient
(e) After removal of the plate, dry in air and examine under SYSTEM SUITABILITY
The test 1s not valid unless:
MOBILE PHASE
nae
SOL]
1 volume of glacial acetic acid, 8 volumes of ethyl acetate and factor between the peaks due to fluticasone S-methyl
30 volumes of dichloromethane. impurity and fluticasone propionate is at least 1.5;
ver
d
we Ney
in the chromatogram obtained with solution (4), the peak

due to fluticasone propionate has a signal-to-noise ratio of at
Fluticasone Ointment
least 10. Action and use
LIMITS Glucocorticoid.
DEFINITION
Fluticasone Ointment contains Fluticasone Propionate in a
the peak due to fluticasone propionate in the chromatogram
suitable basis.
4 times the area of the peak due to fluticasone propionate in
the chrematogram obtained with solution (2) (2%). Content of fluticasone propionate, C,;H3,F,;0;S
) duticasone propionate in the chromatogram IDENTIFICATION
(1) Transfer a quantity of the ointment containing 0.1 mg of
‘charge the container a acetonitrile and 50 mL of n-hexane, shake for 5 minutes and
m 1 mg of Fluticasone allow to separate. Filter the lower layer through an absorbent
cotton plug previously washed with acetonitrile, extract the
hexane layer with two 5 mL quantities of acetonitrile, filter
each extract through the absorbent cotton plug and wash the
(65%) to produce 50 mL,filter andsuse t
absorbent cotton plug with 2 mL of acetonitrile. Add the
(2) Dilute 2 mL of a 0.05% w/v solut
washings to the combined filtrates, evaporate the resulting
solution to dryness using a rotary evaporator at a temperature
of 40° and dissolve the residue in 0.5 mL of acetonitrile.
(2) 0.020% w/v offluticasone propionate BPCRS in acetonitrile.
phase. CHROMATOGRAPHIC CONDITIONS

(a) Use as the coating silica gel F254 (Merck silica gel 60 F254
as are suitable).
(a) Use a stainless steel column (25 cm x 4.6 mm) packe
Use the mobile phase as described below.
(Spherisorb ODS 1 is suitable). yply 20 pL of each solution.
(b) Use isocratic elution and the mobile phase described : the plate to 12 cm.
below. : 1 of the plate, allow it to dry in a current of
CONFIRMATION
MOBILE PHASE
15 volumes of acetonitrile, 35 volumes of 0.01M ammonium The principal spot in the
dihydrogen orthophosphate previously adjusted to pH 3.5 with
orthophosphoric acid and 50 volumes of methanol.
SYSTEM SUITABILITY
the chromatogram obtained with solu
The assay is not valid unless, in the chromatogram obtained that of the principal peak in the chrom m @btained with
with solution (3), the resolution factor between the peaks due solution (2).
to fluticasone S-methyl impurity and fluticasone propionate is
at least 1.5. If necessary, adjust the proportion of acetonitrile ASSAY
in the mobile phase. Carry out the method for liquid chromatography,
light.
Calculate the content of C,;H3,F305S in the nasal spray
(1) Transfer a quantity of the ointment containing 0.1 mg of
using the declared content of C,;H3,F30;S in fluticasone
propionate BPCRS.
n-hexane, previously heated to 60° in a water bath, stopper
IMPURITIES the funnel and shake until the ointment is dispersed, venting
D. 6x,9-difluoro-17-[(methylsulfanyl)carbony]]-11B-hydroxy- frequently. Wash the stopper and neck of the funnel with
1 6a-methyl-3-oxoandrosta-1,4-dien-17a-yl propanoate 5 mL of n-hexane collecting the washings in the funnel, allow
(fluticasone S-methyl impurity, equivalent to Ph. Eur. the funnel to cool to room temperature, add 10 mL of
fluticasone impurity D). methanol (80%), stopper, shake for 1 minute and allow to
separate. Filter the lower aqueous layer through an absorbent
cotton plug, previously washed with methanol (80%), into a
graduated flask; repeat the extraction with two 5-mL
quantities of methanol (80%), filtering the aqueous methanol
extracts into the same graduated flask. Wash the absorbent solution expected to contain 0.0005% w/v of Fluticasone
cotton plug with 2 mL of methanol (80%), collecting the Propionate. The light absorption, Appendix IT B, in the
washings in the flask and dilute the extract to 25 mL with range 210 to 300 nm closely resembles that of a solution
methanol (80%). containing 0.0005% w/v offluticasone propionate BPCRS in
(2) 0.0004% w/v offluticasone propionate BPCRS in methanol solvent A and exhibits a single maximum at 240 nm.
(80%). B. In the Assay, the principal peak in the chromatogram
(3) 0.0004% w/v offluticasone S-methyl impunity BPCRS and obtained with solution (1) has the same retention time as the
0.002% w/v offluticasone propionate BPCRS in methanol principal peak in the chromatogram obtained with
(80%). solution (2).
CHROMATOGRAPHIC CONDITIONS TESTS

(a) Use a stainless steel column (25 cm x 4.6 mm) packed Related substances
sw ead gel for chromatography (5 um) Carry out the method for liquid chromatography,
RA Ne
suitable). Appendix III D, using the following solutions.
tion and the mobile phase described (1) Shake a quantity of the inhalation powder containing
0.5 mg of Fluticasone Propionate in 10 mL of a mixture of
7 volumes of acetonitrile, 20 volumes of water and 23 volumes
of methanol and filter.
(2) Dilute 1 volume of solution (1) to 200 volumes in equal
(f) Inject 20 wL of each solu (3) 0.0004% w/v offluticasone S-methyl impurity BPCRS and
MOBILE PHASE 0.002% w/v offluticasone propionate BPCRS in equal volumes
of acetonitrile and water.
(4) Dilute 1 volume of solution (2) to 5 volumes in equal

b) Use gradient elution and the mobile phase described
DETERMINATION OF CONTENT ow rate of 1.5 mL per minute.
Calculate the content of C,;H3,F305S in the ointment using umn temperature of 40°.
the declared content of C,5H3,F305S in fluticasone ection wavelength of 239 nm.
propionate BPCRS.
Mobile phase A
methanol.
Fluticasone Inhalation Powder
Fluticasone Powder for Inhalation, metered-dose powder
inhaler
va eal
Action and use
Glucocorticoid.
isocratically with the chosen mobile.
elution of the apex of the fluticason: Hate peak start a
DEFINITION linear gradient elution to reach a mobile’ phas¢ atio A:B of
Fluticasone Inhalation Powder consists of Fluticasone 85:15 over a period of 10 minutes. Contiriti
Propionate in muicrofine powder either alone or combined with chromatography for 10 minutes.
a suitable carrier. It is administered by a dry-powder inhaler. SYSTEM SUITABILITY
The inhalation powder complies with the requirements stated under The test is not valid unless, in the chromatogram obtained
Preparations for Inhalation and with the following requirements. with solution (3), the resolution factor between the peaks due
yw ANS
PRODUCTION to fluticasone propionate and fluticasone S-methyl impurity is
we
Mat
at least 1.5.
The size of aerosol particles to be inhaled is controlled so
that a consistent portion is deposited in the lung. The fine- LIMITS
particle characteristics of powders for inhalation are In the chromatogram obtained with solution (1):
determined using the method described in Appendix XII C. the area of any secondary peak is not greater than the area of
7. Preparations for Inhalation: Aerodynamic Assessment of the principal peak in the chromatogram obtained with
Fine Particles. solution (2) (0.5%);
Content of fluticasone propionate, C,;H3,F,;0,;S the sum of the areas of any secondary peaks is not greater than
80.0 to 120.0% of the stated amount. 5 times the principal peak in the chromatogram obtained
Pane ae
IDENTIFICATION with solution (2) (2.5%).
Oe AN
A. Dilute a quantity of the inhalation powder in a mixture of

Sy
2 volumes of water and 8 volumes of methanol to produce a_
a
ey
2016 Fluticasone Preparations ITII-605
Disregard any peak with an area less than the area of the area The inhalation powder, pre-dispensed complies with the
7 NMA
of the principal peak in the chromatogram obtained with requirements stated under Preparations for Inhalation and with the
~Ne ag
solution (4) (0.1%). following requirements.
Uniformity of delivered dose PRODUCTION
Complies with the requirements stated under Inhalation The size of aerosol particles to be inhaled is controlled so
Powders using the following method of analysis. Carry out that a consistent portion is deposited in the lung. The fine-
the method for liguid chromatography, Appendix III D, using particle characteristics of powders for inhalation are
the following solutions in a mixture of 35 volumes of water determined using the method described in Appendix XII C.
and 65 volumes of methanol (solvent A). 7. Preparations for Inhalation: Aerodynamic Assessment of
(1) Collect single doses of the preparation being examined Fine Particles.
using the procedure described under Inhalation Powders, Content of fluticasone propionate, C,;H3;,F,;0;S
Aet e
we ned
IDENTIFICATION
300 nm of the final solution obtained in the test for
Uniformity of delivered dose closely resembles that of a
solution containing 0.0005% w/v offluticasone
propionate BPCRS in solvent A and exhibits a single
maximum at 240 nm.
(Spherisorb ODS1 is suitable). B. In the test for Uniformity of delivered dose, the retention
phase describe
(b) Use isocratic elution an d time of the principal peak in the chromatogram obtained
below. with solution (1) is similar to that of the principal peak in the
(c) Use a flow rate of 1.5 mL per min chromatogram obtained with solution (2).
(d) Use a column temperature of 40°. TESTS
(e) Use a detection wavelength of 239 nm Related substances
(f) Inject 20 uL of each solution. Carry out the method for liquid chromatography,
MOBILE PHASE
(1) Shake a quantity of the powder, containing 0.5 mg of
15 volumes of acetonitrile, 35 volumes of 0.01M ammoné Fluticasone Propionate in 10 mL of a mixture of 7 volumes
dihydrogen orthophosphate and 50 volumes of methanol wcetonitrile, 20 volumes of water and 23 volumes of
adjusted to pH 3.5 with orthophosphoric acid or dilute wiéthanol and filter.
ammonia.
SYSTEM SUITABILITY
with solution (2), the symmetry factor of the principal peak is
not greater than 2.5.
Calculate the content of Fluticasone Propionate,
C45H3);F305S, per delivered dose using the declared content
of C,5H3,F305S in fluticasone propionate BPCRS. Repeat the
(a) Use a stainlesssteel umi (25 cm x 4.6 mm) packed
procedure as described for reservoir systems under Inhalation
with octadecylsilyl silica gel foréhromatography (5 um)
Powders, Uniformity of delivered dose.
eae ey
(Spherisorb ODS1 is suita e).
ASSAY (b) Use gradient elution and the phase described
Use the average of the 10 individual results obtained in the below.
test for Uniformity of delivered dose. (c) Use a flow rate of 1.5 mL per mi
Fluticasone Inhalation Powder, pre- MOBILE PHASE
tere
dispensed Mobile phase A 23 volumes of acetonitrile and 77 volumes of
i
Fluticasone Powder for Inhalation, pre-metered units methanol.
Mobile phase B 0.01M ammonium dihydrogen orthophosphate,
Action and use
adjusted to pH 3.5 with acetic acid or dilute ammonia.
Glucocorticoid.
DEFINITION 60:40. Inject solutions (1) and (3) and start the elution
Fluticasone Inhalation Powder, pre-dispensed consists of isocratically with the chosen mobile phase. One minute after
Fluticasone Propionate in microfine powder either alone or elution of the apex of the fluticasone propionate peak start a
combined with a suitable carrier. The blister is loaded into a linear gradient elution to reach a mobile phase ratio A:B of
dry-powder inhaler to generate an aerosol. 85:15 over a period of 10 minutes. Continue the
ae
chromatography for 10 minutes.

saw as!
Ne et
eee
Fo 2s
ete me
IlI-606 Fluticasone Preparations 2016
SYSTEM SUITABILITY
aANw as The test is not valid unless, in the chromatogram obtained
Fluticasone Pressurised Inhalation
wet ete
aa as
ww ay with solution (3), the resolution factor between the peaks due Action and use
to fluticasone propionate and fluticasone S-methyl impurity is Glucocorticoid.
at least 1.5.
LIMITS
DEFINITION
Fluticasone Pressurised Inhalation is a suspension of
Fluticasone Propionate in a suitable liquid in a pressurised
the area of any secondary peak is not greater than the area of container fitted with a metering dose valve.
the sum ofsthe areas of any secondary peaks is not greater than requirements.
tan es
PRODUCTION
The size of aerosol particles to be inhaled is controlled so
that a consistent portion is deposited in the lung. The fine-
particle characteristics of pressurised metered-dose
Uniformity of deliver described in Appendix XII C. 7. Preparations for Inhalation:
Complies with the requi Aerodynamic Assessment of Fine Particles.
the method for liquid chromatog Content of fluticasone propionate, C,;H3,F;0;S

the following solutions in a mi
IDENTIFICATION
ate Ate
wend
(1) Collect single doses of the preparatio A. The light absorption, Appendix IT B, in the range 210 to
using the procedure described under Inh 300 nm of the final solution obtained in the test for
Uniformity of delivered dose closely resembles that of a
in sufficient of solvent A to producea solution e3 solution containing 0.0005% w/v offluticasone
contain 0.0005% w/v of Fluticasone Propionate. propionate BPCRS in solvent A and exhibits a single
(2) 0.0005% w/v offluticasone propionate BPCRS in maximum at 240 nm.
solvent A. B. In the test for Uniformity of delivered dose, the retention
fthe principal peak in the chromatogram obtained
ition (1) is similar to that of the principal peak in the
(a) Use a stainless steel column (25 cm x 4.6 mm) packed am obtained with solution (2).
below.
MOBILE PHASE
Fe mw
15 volumes of acetonitrile, 35 volumes of 0.01M ammonium volumes of acetonitrile and wait

a
dihydrogen orthophosphate and 50 volumes of methanol (3) 0.02% w/v offluticasone propion:
adjusted to pH 3.5 with orthophosphoric acid or dilute 0.00004% w/v offluticasone S-methy.
ammonia. volumes of acetonitrile and water.
SYSTEM SUITABILITY (4) Dilute 1 volume of solution (2) to 5 voi
with solution (2), the symmetry factor of the principal peak is CHROMATOGRAPHIC CONDITIONS
not greater than 2.5. (a) Use a stainless steel column (25 cm x 4.6 mm) packed
DETERMINATION OF CONTENT with octadecylsilyl silica gel for chromatography (5 wm)
Calculate the content of Fluticasone Propionate,
atte at a.
Otel ea
C,5H3,F30;S, per delivered dose using the declared content (b) Use gradient elution and the mobile phase described
of C,5H3,F305S in fluticasone propionate BPCRS. Repeat the below.
procedure as described for pre-dispensed systems under (c) Use a flow rate of 1.5 mL per minute.
Inhalation Powders, Uniformity of delivered dose. (d) Use a column temperature of 40°.
ASSAY (e) Use a detection wavelength of 239 nm.
Use the average of the individual results obtained in the test (f) Inject 20 pL of each solution.
for Uniformity of delivered dose.
MOBILE PHASE

a AN wl
methanol.
~ ene
| Mobile phase B 0.01M ammonium dihydrogen orthophosphate, DETERMINATION OF CONTENT

Las adjusted to pH 3.5 with acetic acid or dilute ammonia. Calculate the content of Fluticasone Propionate,
ee Equilibrate the column with a mobile phase ratio A:B of C,5H3,F305S, per delivered dose using the declared content
as 60:40. Inject solutions (1) and (3) and start the elution of C25H3,F305S in fluticasone propionate BPCRS. Repeat the
isocratically with the chosen mobile phase. One minute after procedure as described under Pressurised Metered-dose
elution of the apex of the fluticasone propionate peak start a Preparations for Inhalation, Uniformity of delivered dose.
linear gradient elution to reach a mobile phase ratio A:B of ASSAY
85:15 over a period of 10 minutes. Continue the
Use the average of the individual results obtained in the test
chromatography for 10 minutes. for Uniformity of delivered dose.
SYSTEM SUITABILITY
The test_is not valid unless,

1in the chromatogram obtained
at least
Fluticasone and Salmeterol Inhalation
LIMITS Powder, pre-dispensed
ined with solution (1):
Action and use
the area of any second R is not greater thanthe area of Glucocorticoid and betaz-adrenoceptor agonist;
the principal peakiin bronchodilator.
DEFINITION
Fluticasone and Salmeterol Inhalation Powder, pre-dispensed
consists of Fluticasone Propionate and Salmeterol Xinafoate
in microfine powder either alone or combined with a suitable
carrier. The pre-dispensed unit 1s loaded into a dry-powder
(4) (0.1%). inhaler to generate an aerosol.
The inhalation powder, pre-dispensed complies with the
requirements stated under Preparations for Inhalation and with the
Complies with the requirements stated under Pr suris
Metered-dose Preparations for Inhalation using the ‘foll following requirements.
method of analysis. Carry out the method for liquid Content of fluticasone propionate, C,;H3;,;F3;0;S
chromatography, Appendix HI D, using the following solutier to 107.5% of the stated amount.
in a mixture of 35 volumes of water add 65 volumes of tent of salmeterol, C,;H3;NO,
methanol (solvent A).
(1) Collect single doses of the preparation being examined
using the procedure described under Pressurised Metered-
dose Preparations for Inhalation, Uniformity of delivered
dose and dissolve the collected dose in sufficient of solvent A
delivered §
to produce a solution expected to contain 0.0005% w/v of
0.00005% wiv. terol xinafoate BPCRS and an
Fluticasone Propionate.
appropriate concer n.of fluticasone propionate BPCRS
: (2) 0.0005% w/v offluticasone propionate BPCRS in depending on the
| solvent A. in methanol (70%).
CHROMATOGRAPHIC CONDITIONS B. In the Assay for flutic
(a) Use a stainless steel column (25 cm x 4.6 mm) packed obtainedwith solution (1)
(Spherisorb ODS1 is suitable). the chromatogram obtained with
(b) Use isocratic elution and the mobile phase described C. In the Assay for salmeterol, the c
below.
with solution (3).
(e) Use a detection wavelength of 239 nm. TESTS
a Inject 20 pL of each ;
solution. Uniformity of delivered dose
eae ( Injec SID Complies with the requirements stated under Inhalation
ay MOBILE PHASE Powders using the following method of analysis. Carry out
ace 15 volumes of acetonitrile, 35 volumes of 0.01M ammonium the method for liquid chromatography, Appendix III D, using
dihydrogen orthophosphate and 50 volumes of methanol the following solutions.
adjusted to pH 3.5 with orthophosphonc acid or dilute (1) Collect single doses of the preparation being examined
ammonia. | using the procedure described under Inhalation Powders,
SYSTEM SUITABILITY Uniformity of delivered dose and dissolve the collected dose
The test is not valid unless, in the chromatogram obtained in sufficient methanol (70%) to p produce a solution containing
with solution (2), the symmetry factor of the principal peak is 0.00025% w/v of Fluticasone Propionate.
not greater than 2.5. (2) Collect single doses of the preparation being examined
: using the procedure described under Inhalation Powders,
ree Uniformity of delivered dose and dissolve the collected dose
in sufficient methanol (70%) to produce a solution containing (b) Use gradient elution and the mobile phase described
the equivalent of 0.00005% w/v of salmeterol. below.
(3) 0.00025% w/v of fluticasone propionate BPCRS and (c) Use a flow rate of 1.0 mL per minute.
0.00007% w/v of salmeterol xinafoate BPCRS in (d) Use a column temperature of 35°.
methanol (70%).
MOBILE PHASE
with octadecylsilyl silica gel (5 um) (Hypersil BDS C18 1s
Mobile phase A 0.05mM ammonium dihydrogen orthophosphate
suitable).
adjusted to pH 2.9 with 10% v/v of orthophosphoric acid.
Mobile phase B_ acetonitrile.
below.
tet te (c) Use 1.5 mL per minute.
(d) Use , unt _mperature of 40°.
: avelength of 239 nm anda fluorimetric
0-1 70 30 isocratic
MOBILE PHASE 62-71 70 30 re-equilibration
30 volumes of acetonitrile, 3
40 volumes of a solution conta “uimonium acetate When the chromatograms are recorded under the prescribed
sulfate in water. conditions the retention time relative to fluticasone
When the chromatograms are recorded undér prescribed propionate (retention time about 37 minutes) are: salmeterol,
conditions the retention time of salmeterol igsaby about 0.41; impurity 1, about 0.74; fluticasone propionate
4 minutes and the retention time of fluticasone. impurity D, about 0.97 and fluticasone propionate
9 minutes. impurity G, about 1.1.
The test is not valid unless, in the chromatogram obta The test is not valid unless, in the chromatogram obtained
with solution (3), the resolution between salmeterol and with solution (6), the resolution between the peaks due to
fluticasone propionate is at least 6.0. sane propionate impurity D and fluticasone propionate
Calculate the content of fluticasone propionate,
C,5H3,F305S, per delivered dose using the declared content propionate In the chromatogram obtained
of C,5H3,F30;S, in fluticasone propionate BPCRS at 239 nm.
Calculate the content of salmeterol, C2,5H37NQOx,, per
delivered dose using the declared content of C.5H37NQOz, in
salmeterol xinafoate BPCRS using fluorimetric detection.
Repeat the procedure as described for pre-dispensed systems
under Powders for Inhalation, Uniformity of delivered dose.
Related substances area of the principal peak’in
Carry out the method for guid chromatography, solution (3) (0.2%);
Appendix III D, using the following solutions in solution A.
Solution A 30 volumes of water and 70 volumes of
0.05% v/v of orthophosphonic acid in methanol.
(1) Dissolve, with the aid of ultrasound, a quantity of the
powder in sufficient solution A to produce a solution principal peak in the chromatogram obtained.
containing 0.02% w/v of Fluticasone Propionate. (3) (0.1%).
(2) Dissolve, with the aid of ultrasound, a quantity of the For salmeterol In the chromatogram obtained wit
powder in sufficient solution A to produce a solution solution (2):
containing the equivalent of 0.01% w/v of salmeterol. the area of any peak corresponding to impurity 1 is not
haw
ww Ae
(3) Dilute 2 volumes of solution (1) to 100 volumes. Further greater than the area of the principal peak in the
~warnd
dilute 1 volume of the resulting solution to 10 volumes. chromatogram obtained with solution (4) (2.5%);
(4) 0.00025% w/v of salmeterol xinafoate impurity 1 BPCRS. the area of any other secondary peak is not greater than twice
(5) 0.00001% w/v of salmeterol xinafoate impurity 1 BPCRS.
(6) 0.02% w/v offluticasone propionate BPCRS and
the sum of the areas of any other secondary peaks 1s not
0.00006% w/v offluticasone S-methyl BPCRS (fluticasone
propionate impurity D). greater than 5 times the area of the principal peak in the
(a) Use a stainless steel column (25 cm x 4.6 mm) packed principal peak in the chromatogram obtained with solution
wre
with octadecylsilyl sihca gel (5 um) (Inertsil ODS2 is suitable).

ee
Loe
eee a
(5) (0.1%).
2016 Fluticasone Preparations ITI-609
veeel
alee |
ASSAY
Weigh and powder the contents of 20 pre-dispensed units.
Fluticasone and Salmeterol Pressurised
Inhalation, Suspension
eweuyy1
ny

NAAR
eveey
haearar ars
Appendix III D, using the following solutions in

ov rte eee
methanol (70%). Action and use

Glucocorticoid and beta,-adrenoceptor agonist;
(1) Dissolve, with the aid of ultrasound, a quantity of the
bronchodilator.
powder to produce a solution containing 0.002% w/v of
DEFINITION
(2) Dissolve, with the aid of ultrasound, a quantity of the Fluticasone and Salmeterol Pressurised Inhalation,
powder to produce a solution containing the equivalent of Suspension is a suspension of Fluticasone Propionate and
0.0004% w/v of salmeterol. Salmeterol Xinafoate in a suitable liquid in a pressurised
container fitted with a metering dose valve.
Nee
eae
onditions described under Uniformity requirements.
of delivered do e used with an injection volume of Content of fluticasone propionate, C,;H3,F;0-;S
50 uL. 79.0 to 97.0% of the stated amount.
SYSTEM SUITABILITS Content of salmeterol, C,;H3;NO,
> chromatogram obtained 75.5 to 92.5% of the stated amount.
with solution (3), the resolu tween salmeterol and IDENTIFICATION
Neer
fluticasone propionate is at A. The light absorption, Appendix II B, in the range 210 to
300 nm of solution (2) obtained in the test for Uniformity of
) at 239 nm; delivered dose closely resembles that of a solution containing
calculate the content of C,5H3,F30;S inl wader using 0.000025% w/v of salmeterol xinafoate BPCRS and an
appropriate concentration offluticasone propionate BPCRS,
propionate BPCRS. depending on the strength of the product, in a mixture of
methanol (70%).
In the chromatogram obtained with solution (2) using
fluorimetric detection; calculate the content of C.5H37 B. In the test for Uniformity of delivered dose, the
in the powder using the declared content of C.5;H37N chromatogram obtained with solution (1) shows a peak with
salmeterol xinafoate BPCRS. «game retention time as the peak due to fluticasone
LABELLING
e test for Uniformity of delivered dose, the
The quantity of Salmeterol Xinafoate is stated in terms of th
ogram obtained with solution (2) shows a peak with
equivalent amount of salmeterol.
IMPURITIES
monograph include:
A, C, D, E, F, G and H listed under Fluticasone Propionate;
A, B, C, E andG listed under Salmeterol Xinafoate; for Inhalation using the following
1. rac-1-hydroxy-4-{[2-hydroxy-5-(1-hydroxy-2- {6- method of analysis. Cart the method for liquid
LEN
(4-phenylbutoxy)hexyl]amino} ethyl)phenyl|methyl} chromatography, Appendi
naphthalene-2-carboxylic acid solutions.
=rit, methanol
% wily of
(2) Collect single doses of the preparation bein
using the procedure described under Pressurised Metered-
dose Preparations for Inhalation, Uniformity of delivered
wee
dose and dissolve the collected dose in sufficient methanol
(70%) to produce a solution containing the equivalent of
0.000025% w/v of salmeterol.
(3) 0.000125% w/v offluticasone propionate BPCRS and
0.000036% w/v of salmeterol xinafoate BPCRS in
methanol (70%).

with octadecylsilyl siica gel (5 um) (Hypersil BDS C18 is
suitable).
7 saa
ws aad
lheae
IWI-610 Fluticasone Preparations 2016
(b) Use isocratic elution and the mobile phase described (f) Inject 50 pL of each solution.
below. MOBILE PHASE
AN es
(c) Use a flow rate of 1.5 mL per minute. Mobile phase A 30 volumes of acetonitrile and 70 volumes of
(d) Use a column temperature of 40°. 0.05mM ammonium dihydrogen orthophosphate, previously
(e) Use a detection wavelength of 239 nm and a fluorimetric adjusted to pH 2.9 with 10% v/v of orthophosphoric acid.
detector with an excitation wavelength of 225 nm and an Mobile phase B22 volumes of 0.05m ammonium dihydrogen
emission wavelength of 305 nm. orthophosphate, previously adjusted to pH 2.9 with 10% v/v of
(f) Inject 200 wL of each solution. orthophosphoric acid and 78 volumes of acetonitrile.
MOBILE PHASE
30 volumes of acetonitrile, 30 volumes of methanol and Time Mobile phase A Mobile phase B Comment
60-61 0—100 100-0 linear gradient

4 minutes and f
about 9 minutes.
SYSTEM SUITABILITY When the chromatograms are recorded under the prescribed
conditions the retentions relative to fluticasone propionate
The test is not valid unl
(retention time about 37 minutes) are: salmeterol, about 0.41
fluticasone propionate impurity D, about 0.97 and
fluticasone propionate impurity G, about 1.1.
SYSTEM SUITABILITY
Calculate the content of fluticasone prépionate
The test 1s not valid unless, in the chromatogram obtained
C,5H3,F305S, per delivered dose using the | content
with solution (5), the resolution between fluticasone
of C.5H3)F305S, in fluticasone propionate BPG. 9 nm.
propionate impurity D and fluticasone propionate is at least
Calculate the content of salmeterol, C,5H37NO;; 1.5.
delivered dose using the declared content of C,5H3,
LIMITS
salmeterol xinafoate BPCRS using fluorimetric detection
Repeat the procedure as described under Pressurised For fluticasone propionate In the chromatogram obtained
Metered-dose Preparations for Inhalation, Uniformity of
delivered dose.
Related substances
Appendix III D, using the following solutions in solution A.
Solution A 0.5 volumes of orthophosphoric acid, 300 volumes
of water and 700 volumes of methanol.
(1) Dissolve with the aid of ultrasound, a quantity of the
suspension containing 0.05 mg of Fluticasone Propionate in
7 mL of 0.05% v/v of orthophosphoric acid in methanol.
Add 3 mL of water and mix for a further 5 minutes.
(2) Dissolve with the aid of ultrasound, a quantity of the
peak due to fluticasone in the:
suspension containing the equivalent of 0.025 mg of
salmeterol in 7 mL of 0.05% v/v of orthophosphoric acid in
methanol. Add 3 mL of water and mix for a further
5 minutes. solution (2):
(3) Dilute 2 volumes of solution (1) to 100 volumes with the area of any secondary peak is not greate area of
solution A. Further dilute 1 volume of the resulting solution the peak due to salmeterol in the chromatogre aed
to 10 volumes with solution A. with solution (4) (0.2%);
(4) Dilute 2 volumes of solution (2) to 100 volumes with the sum of the areas of any secondary peaks is not gtéater than
solution A. Further dilute 1 volume of the resulting solution 2.5 times the area of the peak due to salmeterol in the
to 10 volumes with solution A. chromatogram obtained with solution (4) (0.5%).
halk als
eae
(5) 0.005% w/v offluticasone propionate BPCRS and Disregard any peak with an area less than half the area of the
0.00002% w/v offluticasone S-methyl BPCRS (fluticasone peak due to salmeterol in the chromatogram obtained with
propionate impurity D) in methanol (70%). solution (4) (0.1%).
(a) Use a stainless steel column (25 cm x 4.6 mm) packed Use the average of the individual results obtained in the test
with octadecylsilyl silica gel (5 um) (Inertsil ODS2 is suitable). for Uniformity of delivered dose.
(b) Use gradient elution and the mobile phase described IMPURITIES
below. The impurities limited by the requirements of this
(c) Use a flow rate of 1.0 mL per minute. monograph include:
eA
bee
(d) Use a column temperature of 35°. A, C, D, E, F, G and H listed under Fluticasone Propionate
(©) Use a detection wavelength of 228 nm and A, B, C, E and G listed under Salmeterol Xinafoate.
SE Oe A EL
Bm OEno
Seng De ET
2016 Fluvoxamine Preparations III-611
LIMIT
Fluvoxamine Tablets
The amount of C,5H2,F3N2,02,C4H,O, released is not less
Action and use than 70% of the stated amount.
Selective serotonin reuptake inhibitor; antidepressant. Related substances
DEFINITION Appendix III D, using the following solutions.
Fluvoxamine Tablets contain Fluvoxamine Maleate.
The tablets comply with the requirements stated under Tablets and 0.25 g of Fluvoxamine Maleate with 125 mL of the mobile
with the following requirements. phase for 10 minutes, add sufficient mobile phase to produce
- Content of fluvoxamine maleate, C,;H,,F,N,0,,C,H,O, 250 mL, mix, centrifuge and use the supernatant liquid.
92.5 to 105.0% of the stated amount. (2) Dilute 1 volume of solution (1) to 100 volumes with the
mobile phase.
(3) Heat a 0.32% w/v solution offluvoxamine maleate
impurity standard BPCRS in 0.1M hydrochloric acid on a water
bath for 10 minutes (generation of impurity C).
with end-capped octylsilyl silica gel for chromatography (7 wm)
B. Carry out the method f (Zorbax C8 is suitable).
Appendix ITI A, using th (b) Use isocratic elution and the mobile phase described
below.
liquid.
maleate BI (d) Use a column temperature of 35°.
(2) 1.0% wiv offluvoxamine (e) Use a detection wavelength of 254 nm.
(a) Use as the coating silica gel HF 254 (Analtedh
MOBILE PHASE
suitable).
40 volumes of a solution containing 1.25% w/v of
diammonium hydrogen orthophosphate and 0.275% w/v of
(c) Apply 5 uL of each solution. odigm heptanesulfonate monohydrate and 60 volumes of
ultraviolet light (254 nm). e chromatograms are recorded under the prescribed
MOBILE PHASE scribed above, the retention time of fluvoxamine
5 volumes of 13.5mM ammonia and 95 volumes of ethanol
(96%).
CONFIRMATION

SYSTEM SUITABIE
solution (1) correspond to those in the chromatogram
The test is not vali
obtained with solution (2). |
TESTS
Dissolution
Comply with the requirements for Monographs of the British fluvoxamine and the Zisomer jis
LIMITS
Appendix XII Bl.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 50 revolutions with the reference material.
per minute. In the chromatogram obtained with solution (1):
(b) Use 900 mL of water, at a temperature of 37°, as the the area of any peak corresponding to impurity C is not
medium. greater than 3 times the area of the principal peak in the
PROCEDURE chromatogram obtained with solution (2) (3%);
After 20 minutes withdraw a 10 mL sample of the medium the area of any other secondary peak is not greater than half
and centrifuge. Measure the absorbance of the clear the area of the principal peak in the chromatogram obtained
supernatant liquid, suitably diluted with water if necessary, at with solution (2) (0.5%).
the maximum at 244 nm, Appendix IT B using water in the Disregard the peak corresponding to maleic acid (which
reference cell. elutes immediately after the solvent front) and any peak with
DETERMINATION OF CONTENT an area less than 0.05 times the area of the principal peak in
Calculate the total content of fluvoxamine maleate, the chromatogram obtained with solution (2) (0.05%).
C15H2)F3N202,C,H4O,, in the medium taking 270 as the
IWI-612 Folic Acid Preparations 2016
ASSAY CONFIRMATION
Weigh and powder 20 tablets. Carry out the method for The principal spot in the chromatogram obtained with
liquid chromatography, Appendix III D, using the following solution (1) is similar in position, fluorescence and size to
solutions. : that in the chromatogram obtained with solution (2).
(1) Shake a quantity of the powdered tablets containing B. In the Assay, the retention time of the principal peak in
0.25 g of Fluvoxamine Maleate with 125 mL of the mobile the chromatogram obtained with solution (1) corresponds to
phase for 10 minutes, add sufficient of the mobile phase to that of the principal peak in the chromatogram obtained with
produce 250 mL, mix, centrifuge and dilute 1 volume of the solution (2).
supernatant liquid to 10 volumes with the mobile phase.
TESTS
(2) 0.010% w/v offluvoxamine maleate BPCRS in the mobile Alkalinity
phase. pH, 8.0 to 11.0, Appendix V L.
Pe
Vw ava
| CHROMAs RAPHIC CONDITIONS Hydrolysis products
Leite 4
re| The chroma’ y conditions described under Related Carry out the method for liquid chromatography,
substances Appendix III D, using the following solutions protected from
DETERMINAT light.
Calculate the conter (1) Dilute a quantity of the injection with sufficient of the
tablets using the declare: mobile phase to produce a solution containing 0.01% w/v of
in fluvoxamine maleate B Folic Acid.
(2) 0.00005% w/v of 4-aminobenzoic acid and 0.0002% w/v of
STORAGE
N-(4-aminobenzoyl)-L-glutamic acid in the mobile phase.
~~ arse IMPURITIES
tee
The impurities limited by the requirertie
monograph include those listed under Fl
(Spherisorb ODS1 1s suitable).
below.
Folic Acid Injection d) Use an ambient column temperature.
NOTE: Folic Acid Injection is not currently licensed in the Unit > a detection wavelength of 269 nm.
Kingdom.
ject:20 uL of each solution.
Action and use matogram obtained with solution (2) the
Vitamin B component. elute in the following order: N-(4-aminobenzoyl)-
DEFINITION
Folic Acid Injection is a sterile solution of Folic Acid in a
suitable liquid.
Parenteral Preparations, the requirements stated under Unlicensed SYSTEM SUITABILI¥E%
Medicines and with the following requirements. The test is not valid uriless,.
Content of folic acid, Cy9H,9N7O;¢ with solution (2), the resolu
90.0 to 110.0% of the stated amount. principal peaks is at least 3.
LIMITS ae
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, In the chromatogram obtained with
(1) Dilute a quantity of the injection containing 15 mg of ninnobenzoic
Folic Acid with sufficient of a mixture of 1 volume of 5%)5
13.5mM ammonia and 9 volumes of methanol to produce
30 mL. glutamic acid is not greater than the area of the péak due to
(2) 0.05% w/v offolic acid BPCRS in a mixture of 2 volumes N-(4-aminobenzoyl)-L-glutamic acid in the chromatogram
of 13.5M ammonia and 9 volumes of methanol. obtained with solution (2) (2%).
ASSAY
ce
ee:a
was
sone
wae Ad
wie Nate
(a) Use as the coating silica gel G. Carry out the method for liquid chromatography,
(1) Dilute a volume of the injection containing 7.5 mg of
Folic Acid to 100 mL with a buffer solution prepared by
(d) Develop the plate to 15 cm. diluting 25 volumes of 0.1M anhydrous sodium dihydrogen
(e) After removal of the plate, dry in air and examine under orthophosphate, adjusted to pH 4.0 with 0.1m sodium
ultraviolet light (365 nm). hydroxide, to 250 volumes with water.
MOBILE PHASE (2) 0.0075% w/v offolic acid BPCRS in the buffer solution.
20 volumes of 13.5M ammonia, 20 volumes of propan-1-ol and
60 volumes of ethanol (96%).
wo
Ko eta,
|
2016 Folic Acid Preparations III-613
CHROMATOGRAPHIC CONDITIONS (1) Shake a quantity of the powdered tablets containing

"Nyaa (a) Use a stainless steel column (10 cm x 4.6 mm) packed 5.0 mg of Folic Acid with 50 mL of the mobile phase,
LS AS
wand with octadecylsilyl sihca gel for chromatography (5 wm) centrifuge and use the supernatant liquid.
(Lichrosorb RP-18 is suitable). (2) 0.5 pg of 4-aminobenzoic acid and 2.0 ug of
(b) Use isocratic elution and the mobile phase described N-(4-aminobenzoyl)-L-glutamic acid per mL in the mobile
below. phase.
(c) Use a flow rate of 1.2 mL per minute. CHROMATOGRAPHIC CONDITIONS
(d) Use an ambient column temperature. (a) Use a stainless steel column (20 cm x 4.6 mm) packed
(e) Use a detection wavelength of 280 nm. with octadecylsilyl sihca gel for chromatography (10 um)
below.
NAN te
Calculate the con | CioH N70, in the injection using
the declared content: N7O6g in folic acid BPCRS. In the chromatogram obtained with solution (2) the
substances elute in the following order: N-(4-aminobenzoyl)-
L-glutamic acid and 4-aminobenzoic acid.
MOBILE PHASE
0.05m potasstum dihydrogen orthophosphate, adjusted to pH 5.5

Folic Acid Tablets with 5m sodium hydroxide.
Action and use SYSTEM SUITABILITY
Vitamin B component. The test is not valid unless, in the chromatogram obtained
with solution (2), the resolution factor between the two peaks
DEFINITION
is at least 3.
Folic Acid Tablets contain Folic Acid.
LIMITS
The tablets comply with the requirements stated under Tablé
with the following requirements. In the chromatogram obtained with solution (1):
Content of folic acid, C;j)H;)>N/O;¢

areas of the peaks corresponding to 4-aminobenzoic acid
4-aminobenzoyl)-L-glutamic acid are not greater than
of the peaks corresponding to 4-aminobenzoic acid
IDENTIFICATION aminobenzoyl)-1-glutamic acidin the
(1) Extract a quantity of the powdered tablets containing
0.5 mg of Folic Acid with 1 mL of a mixture of 1 volume of
13.5mM ammonia and 9 volumes of methanol, centrifuge and
use the supernatant liquid.
(2) 0.05% w/v offolic acid BPCRS in a mixture of 2 volumes following solutions.—
of 13.5M ammonia and 9 volumes of methanol. (1) Shake one tablet wit

liquid.
2) Add 1 mL of0. 5M hydrochloric a
MOBILE PHASE with octadecylsilyl silica gel for chromatography (10 um)
20 volumes of 13.5M ammonia, 20 volumes of propan-1-ol and (Spherisorb ODS1 1s suitable).
60 volumes of ethanol (96%). (b) Use isocratic elution and the mobile phase described
CONFIRMATION below.
The principal spot in the chromatogram obtained with (c) Use a flow rate of 2 mL per minute.
solution (1) is similar in position, fluorescence and size to (d) Use an ambient column temperature.
that in the chromatogram obtained with solution (2). (e) Use a detection wavelength of 283 nm.
TESTS (f) Inject 20 uwL of each solution.
Hydrolysis products
MOBILE PHASE
7 volumes of acetonitrile and 93 volumes of 0.05m potassium
dihydrogen orthophosphate adjusted to pH 6.0 with 5m sodium
light.
hydroxide.
III-614 Foscarnet Preparations 2016
DETERMINATION OF CONTENT Phosphate and phosphite

Calculate the content of C;9>H;9N7O,¢ in each tablet using Carry out the method for liquid chromatography,
tale as
mente a
the declared content of CygH,9N7Og¢ in folic acid BPCRS. Appendix III D, using the following solutions. Prepare a
solution containing 0.04% w/v of sodium dihydrogen
ASSAY
orthophosphate monohydrate and 0.06% w/v of sodium phosphite
For tablets containing less than 2 mg and/or less than (solution A). For solution (1) add 6 mL of solution A to
2% w/w of Folic Acid 60 mg offoscarnet sodium BPCRS and dilute to 25 mL with
Use the average of the 10 individual results obtained in the water. For solution (2) dilute a volume of the infusion with
test for Uniformity of content. sufficient water to produce a solution containing 0.24% w/v
For tablets containing 2 mg or more and 2% w/w or of Foscarnet Sodium.
more of Folic Acid The chromatographic procedure may be carried out using
Weigh and powder 20 tablets. Carry out the method for (a) a stainless steel column (5 cm x 4.6 mm) packed with
an anion exchange resin (Waters IC PAK is suitable) at a
‘om light. temperature of 25°, (b) as the mobile phase with a flow rate
the powdered tablets containing of 1.4 mL per minute a solution prepared by dissolving
50 mL of 0.1m sodium hydroxide, 0.204 g of potassium hydrogen phthalate in water, adding 5 mL
me solvent, centrifuge and dilute of 1m mitric acid VS and sufficient water to produce 2000 mL
to 100 mL with the mobile and (c) a detection wavelength of 290 nm. Inject 20 pL of
phase. each solution.
(2) Dilute 5 mL of a 0.020 tion offolic Allow the column to stabilise by passing mobile phase
acid BPCRS in 0.1M sodium 100 mL with the through it for at least 2 hours before starting the
mobile phase. chromatography. The test is not valid unless, in the
sae asd
CHROMATOGRAPHIC CONDITI chromatogram obtained with solution (1), the peak due to
phosphate (which elutes first) shows baseline separation from
The chromatographic conditions describe
the peak due to phosphite.
of content may be used. :
DETERMINATION OF CONTENT e
any peak corresponding to phosphate is not greater than
Calculate the content of Cj>H 9N7Og in the tablets us 0.7 times the area of the corresponding peak in the
declared content of Cj9>9H 9N7Og¢ in folic acid BPCR: chromatogram obtained with solution (1) and the area of any
STORAGE peak corresponding to phosphite is not greater than half the
Folic Acid Tablets should be protected from light. irea of the corresponding peak in the chromatogram
ith solution (1) (2.0% of phosphate and 1.0% of
rs
fhe method for liguid chromatography,
Foscarnet Infusion
Foscarnet Intravenous Infusion
diluted to contain (1)
Action and use respectively of Fosgéa Sodium. Solution (3) contains
Antiviral (cytomegalovirus) 0.02% w/v offosca BPCRS and 0.02% w/v of
DEFINITION
y be carried out using
Foscarnet Infusion is a sterile solution containing Foscarnet
|
x 4.6 mm) packed with
Sodium. It is supplied as a ready-to-use solution.
Content of foscarnet sodium, CNa3;0,;P,6H,O
CHARACTERISTICS 0.1m sodium pyrophosphate and 3.22 g of sodt f
sufficient water to produce 1000 mL and (B) 6.8°g
acetate, 6 mL of 0.1m sodium pyrophosphate and 3.22 g of
IDENTIFICATION sodium sulfate in sufficient water to produce 1000 mL.
A. Dry a quantity containing 48 mg of Foscarnet Sodium Mix solution A and solution B to produce a solution of
ae ee over phosphorus pentoxide at a pressure not exceeding 0.7 kPa pH 4.4 and to 1000 mL of this solution add 0.25 g of
way 4
wet std
for 16 hours. The infrared absorption spectrum of the residue, tetrahexylammonium hydrogen sulfate and 100 mL of methanol.
Appendix IT A, is concordant with the reference spectrum of Inject 5 wL of each solution.
foscarnet sodium (RS 160). Disregard any peak occurring at The test is not valid unless, in the chromatogram obtained
902 cm™ or any shoulder at 1179 cm”. with solution (3), the resolution factor between the peaks due
B. In the Assay, the chromatogram obtained with solution to foscarnet sodium and foscarnet impurity B (disodium
(1) shows a peak with the same retention time as the (ethoxyoxydophosphany]l)formate) is at least 7.
principal peak in the chromatogram obtained with For solution (1) allow the chromatography to proceed for at
solution (2). least 2.5 times the retention time of the principal peak. In the
TESTS chromatogram obtained with solution (1) the area of any
secondary peak is not greater than the area of the principal
28 A
ae
=
Alkalinity
winter
AN aN,
pH, 7.2 to 7.6, Appendix V L. peak in the chromatogram obtained with solution (2) (0.2%)
we ee
a
ee a OT ry
LE
ee en en
Es OF
ne ae
Ee Oa ne AE ya
2016 Fosinopril Preparations II-615
and the sum of the areas of any such peaks is not greater PROCEDURE
ao than 2.5 times the area of the principal peak in the Carry out the method for liguid chromatography,
TANNA chromatogram obtained with solution (2) (0.5%). Appendix III D, using the following solutions.
vet Sy
Bacterial endotoxins (1) After 30 minutes withdraw a sample of the medium and
The endotoxin limit concentration is 2 IU per mL, filter. Use the filtered dissolution medium, diluted with water
Appendix XIV C. if necessary, to produce a solution expected to contain
0.0005% w/v of Fosinopril Sodium.
ASSAY
Carry out the method for liquid chromatography, (2) To 20 mg offosinopril sodium BPCRS add 6 mL of
Appendix III D, using the following solutions in the mobile methanol, dissolve with the aid of ultrasound and dilute to
phase containing (1) a solution of the infusion diluted to 100 mL with water. Dilute 1 volume of this solution to
contain 0.10% w/v of Foscarnet Sodium and (2) 0.10% w/v 40 volumes with water.
(3) 0.002% w/v each offosinopril sodium BPCRS and fosinopril
impurity 1 BPCRS in mobile phase.
but injecting 5 wL of each solution. CHROMATOGRAPHIC CONDITIONS
of CNa305P,6H.O in the infusion (a) Use a stainless steel column (15 cm x 4.6 mm) packed
using the decla with octadecylsilyl silica gel for chromatography (5 um)(Waters
sodium BPCRS. Nova-Pak is suitable).
STORAGE (b) Use isocratic elution and the mobile phase described
Foscarnet Infusion shou d below.
exceeding 30°. It should not (c) Use a flow rate of 3 mL per minute.
IMPURITIES (d) Use a column temperature of 40°.
The impurities limited by the requir (e) Use a detection wavelength of 215 nm.
monograph include impurities B, C an, li ed under (f) Inject 50 pL of each solution.
Foscarnet Sodium.
MOBILE PHASE
36 volumes of a 0.2% w/v solution of orthophosphoric acid and
64 volumes of acetonitrile R1.
SYSTEM SUITABILITY
Fosinopril Tablets The test is not valid unless, in the chromatogram obtained
Action and use 2.solution (3), the resolution factor between the peaks due
Angiotensin converting enzyme inhibitor. opril and fosinopril impurity 1 is at least 1.7.
INATION OF CONTENT
DEFINITION
late the total content of fosinopril sodium,
Fosinopril Tablets contain Fosinopril Sodium. P, in the medium from the chromatograms
Content of fosinopril sodium, C3,)H,;NNaO,7P LIMITS
90.0 to 105.0% of the stated amount. sodium released is not less than
The amount of fosir
IDENTIFICATION 80% (Q) of the stat
A. Shake a quantity of the powdered tablets containing Related substances
50 mg of Fosinopril Sodium with 40 mL of water and filter. Carry out the method for® d chromatography,
Centrifuge, adjust the pH of the supernatant to 3.0 with Appendix III D, using the folowimg Jutions in a mixture of
orthophosphoric acid and filter. Wash the filter with several 20 volumes of acetonitrile R1 and80 vo es of 0.2M urea
quantities of dichloromethane, collect the washings and (Solvent A).
evaporate to dryness under a stream of air and dry the
(1) Dissolve a quantity of the powderé
residue for 10 minutes at 60° under vacuum. The infrared
25 mg of Fosinopril Sodium with sufficier
absorption spectrum, Appendix II A, of the oily residue is
produce a solution containing 0.05% w/v of&
concordant with the reference spectrum of fosinopril sodium
Sodium.
(RS 472).
(3) 0.007% w/v offosinopril sodium BPCRS and 0.003% wiv
that of the principal peak in the chromatogram obtained with offosinopril impurity A BPCRS.
solution (2). (4) Dilute 1 volume of solution (2) to 10 volumes.
TESTS CHROMATOGRAPHIC CONDITIONS

Dissolution (a) Use a stainless steel column (30 cm x 3.9 mm) packed
Comply with the requirements in the dissolution test for tablets with octadecylsilyl silica gel for chromatography (10 um)
and capsules, Appendix XII B1. (Bondclone C18 or Hypersil ODS C18 are suitable).
TEST CONDITIONS (b) Use isocratic elution and the mobile phase described
below.
per minute. (c) Use a flow rate of 2.0 mL per minute.
-- ve
we

ON
ow Oe

medium. (e) Use a detection wavelength of 215 nm.
III-616 Furosemide Preparations 2016

Furosemide Injection
(g) Allow the chromatography to proceed for three times the
retention time of Fosinopril. Action and use
MOBILE PHASE Loop diuretic.
22 volumes of 0.2% v/v solution of orthophosphoric acid and DEFINITION
78 volumes of methanol R1. Furosemide Injection is a sterile solution of furosemide
When the chromatograms are recorded under the prescribed sodium, prepared by the interaction of Furosemide with
conditions, the relative retention with reference to fosinopril Sodium Hydroxide, in Water for Injections.
(retention time, about 7.6 minutes) of impurity A is about
0.5.
SYSTEM SUELABILITY
Content of furosemide, C,,H,,;CIN,O-;S
e resolution factor between the peaks due
CHARACTERISTICS
Hopril impurity A is at least 2.0.
LIMITS
IDENTIFICATION
In the chromatogr A. The light absorption, Appendix IT B, in the range 220 to
(3)) and multiply the area two maxima, at 228 nm and 271 nm.
of 0.8; B. In the test for Related substances, the chromatogram
the area of any peak correspon obtained with solution (2) shows a peak with the same
not greater than 5 times the ar retention time as that of the principal peak in the
chromatogram obtained with solution ¢ chromatogram obtained with solution (3).
the area of any other secondary peak is no han TESTS
0.2 times the area of the principal peak in Alkalinity
obtained with solution (2) (0.2%); pH, 8.0 to 9.3, Appendix V L.
the sum of the areas of any secondary peaks excluding:
Related substances
fosinopril impurity A is not greater than the area of pris
peak in the chromatogram obtained with solution (2) (1.
ppendix III D, using the following solutions. Prepare the
Disregard any peak with an area less than the area of the atzons immediately before use and protect from light.
(4) (0.1%). f the mobile phase to produce a solution
ASSAY 0.1% w/v of Furosemide. For solution (2) dilute
solutions in a mixture of 20 volumes of acetonitrile R1 and
80 volumes of 0.2m urea (Solvent B).
impurity A EPCRS§ in the mobile phase. Solution (5) contains
(1) To a quantity of the powdered tablets containing 50 mg
0.001% w/v of 4-chleg fi
of Fosinopril Sodium add 400 mL of solvent B, mix and add
the mobile phase.
sufficient solvent B to produce 500 mL. Centrifuge an
aliquot of the solution and use the supernatant liquid. The chromatographic proce :hay be carried out using
(a) a stainless steel column n x 4.6 mm) packed with
(2) 0.01% w/v offosinopril sodium BPCRS in solvent B.
(3) 0.007% w/v offosinoprol sodium BPCRS and 0.003% wiv
offosinopril impurity. A BPCRS in solvent B. per minute a mixture prepared in th
CHROMATOGRAPHIC CONDITIONS dissolve 0.2 g of potasstum dihydrogen ort.
The chromatographic conditions described under Related 0.25 g of cetrimide in 70 mL of water, adjust
substances may be used. with 6M ammonia and add 30 mL of propan-1-
SYSTEM SUITABILITY
Inject 100 pL of solution (4). Adjust the sensitivity of the
system so that the heights of the two peaks in the
chromatogram obtained are not less than 20% of the full-
to fosinopril and fosinopril impurity A is at least 2.0.
scale of the recorder. The test is not valid unless the resolution
DETERMINATION OF CONTENT factor between the first peak (furosemide impurity A) and the
Calculate the content of C3)H4;NNaO-P in the tablets using second peak (furosemide) is at least 4.
the declared content of C3)H,5;NNaO-,P in fosinopril Inject 100 uL of solution (1) and allow the chromatography
sodium BPCRS. to proceed for three times the retention time of the principal
IMPURITIES peak. The area of any peak corresponding to 4-chloro-5-
The impurities limited by the requirements of this sulfamoylanthranilic acid is not greater than the area of the
monograph include impurity A listed under Fosinopril peak in the chromatogram obtained with solution (5) (1%)
Sodium. and the sum of the areas of any other secondary peaks is not
greater than twice the area of the first peak in the
chromatogram obtained with solution (4) (0.5%). Disregard
any peak with an area less than 0.1 times the area of the first
2016 Fusidic Acid Preparations III-617
peak in the chromatogram obtained with solution (4) solutions immediately before use and protect from light.
(0.025%). For solution (1) dissolve a quantity of the powdered tablets
Bacterial endotoxins containing 20 mg of Furosemide in sufficient of the mobile
Carry out the test for bacterial endotoxins, Appendix XIV C. phase to produce 50 mL and mix with the aid of ultrasound
Dilute the injection with water BET, if necessary, to contain for 15 minutes. For solution (2) dilute 1 volume of solution
the equivalent of 10 mg of Furosemide per mL (solution A). (1) to 500 volumes with the mobile phase. Solution (3)
The endotoxin limit concentration of this solution is 35 IU of contains 0.00008% w/v offurosemide BPCRS in the mobile
endotoxin per mL. phase. Solution (4) contains 0.00008% w/v of each of
furosemide BPCRS and furosemide impurity A EPCRS in the
ASSAY mobile phase. Solution (5) contains 0.00032% w/v of
To a volume containing the equivalent of 20 mg of 4-chloro-5-sulfamoylanthranilic acid BPCRS in the mobile
Furosemide add sufficient water to produce 100 mL. Dilute phase.
Tete vat
octylsilyl silica gel for chromatography (5 um) (ChromSpher C8
is suitable), (b) as the mobile phase with a flow rate of 1 mL
per minute a mixture prepared in the following manner:
STORAGE dissolve 0.2 g of potassium dihydrogen orthophosphate and
Furosemide Injectio 0.25 g of cetrrmide in 70 mL of water, adjust the pH to 7.0
with 6M ammonia and add 30 mL of propan-1-ol and (c) a
LABELLING
The strength is stated in tet
Furosemide in a suitable do: Inject 100 uL of solution (4). Adjust the sensitivity of the
system so that the heights of the two peaks in the
chromatogram obtained are not less than 20% of the full-
scale of the recorder. The test is not valid unless the resolution
factor between the first peak (furosemide impurity A) and the
Furosemide Tablets second peak (furosemide) is at least 4.
Inject 100 uL of solution (1) and allow the chromatography
Action and use
to proceed for three times the retention time of the principal
Loop diuretic.
peak. In the chromatogram obtained with solution (1) the
DEFINITION areaa of any peak corresponding to 4-chloro-5-
“moylanthranilic acidis not greater than the area of the
Furosemide Tablets contain Furosemide.
the chromatogram obtained with solution (5) (0.8%)
sum of the areas of any other secondary peaks is not
an 2.5 times the area of the first peak in the
Content of furosemide, C;,H,,;CIN,O;S ? am obtained with solution (4) (0.5%). Disregard
IDENTIFICATION peak in tk ma ‘Ogram obtained with solution (4)
A. The light absorption, Appendix IIT B, in the range 220 to (0.02%).
two maxima, at 228 nm and 271 nm.
B. In the test for Related substances, the principal peak in semide with 300 mL of
~
the chromatogram obtained with solution (2) shows a peak minutes, add sufficient
with the same retention time as the principal peak in the
chromatogram obtained with solution (3). 5 mL to 250 mL with 0.1M so Odt
absorbance of the resulting solutiGa_a
TESTS
271 nm, Appendix II B. Calculate t of
Dissolution
C,2H,,;CIN2O;S taking 580 as the vali o, 1 cm) at
Tablets containing less than 100 mg of Furosemide comply
with the requirements for Monographs of the British
900 mL of phosphate buffer pH 5.8 and rotate the paddle at
50 revolutions per minute. Withdraw a sample of 10 mL of Fusidic Acid Cream
the medium, filter and dilute the filtrate with sufficient of the
dissolution medium to give a solution expected to contain Action and use
about 0.001% w/v of Furosemide. Measure the absorbance of Antibacterial.
this solution, Appendix IT B, at 277 nm using dissolution
medium in the reference cell. Calculate the total content of DEFINITION
furosemide, C,,H,,CIN.O;S, in the medium from the Fusidic Acid Cream contains Fusidic Acid in a suitable basis.
absorbance obtained from a 0.001% w/v solution of The cream complies with the requirements stated under Topical
furosemide BPCRS in the dissolution medium and using the Semi-solid Preparations and with the following requirements.
declared content of C,;,H,,;CIN2O5S in furosemide BPCRS.
Content of anhydrous fusidic acid, C3,H4s:0¢
Related substances 90.0 to 110.0% of the stated amount.
Carry out the method for lguid chromatography,
III-618 Fusidic Acid Preparations 2016
IDENTIFICATION in chromatogram obtained with solution (2), the column

ven te
A. Carry out the method for thin-layer chromatography, efficiency, determined on the peak due to fusidic acid, is at
Tee tes
Appendix III A, using the following solutions. least 2000 theoretical plates per metre;
(1) Disperse, with shaking, a quantity of the cream in the chromatogram obtained with solution (2), the
containing the equivalent of 40 mg of anhydrous fusidic acid symmetry factor of the principal peak is 2.0 or less;
in 10 mL of ethanol (96%), filter and use the filtrate. in the chromatogram obtained with solution (3), the principal
(2) 0.5% w/v of diethanolamine fusidate BPCRS in peak has a signal-to-noise ratio of at least 3.
ethanol (96%). If necessary, adjust the composition of the mobile phase.
(3) 0.05% w/v of potassium sorbate in water. LIMITS
CHROMATOGRAPHIC CONDITIONS In the chromatogram obtained with solution (1):
ilica gel F254 plate (Merck silica gel 60 Fasq4 the sum of the areas of any secondary peaks is not greater than
five times the area of the peak corresponding to fusidic acid
in the chromatogram obtained with solution (2) (5%).
op th epl ce principal peak in the chromatogram obtainedwith solution
(d)Devel
(3) (0.03%) and any peak with the same retention time as
(e) After removal of ‘th that of the principal peak in the chromatogram obtained with
solution (4).
ASSAY
10 volumes of cyclohexane and
CONFIRMATION (1) Disperse a quantity of the cream containing the
equivalent of 15 mg of anhydrous fusidic acid in 50 mL of
solution (1) is similar in position and size to f the mobile phase, heat until the cream has melted and shake
chromatogram obtained with solution (2) and’ vigorously for 15 minutes. Cool the mixture to below 10°,
separated from any spot corresponding to the spét 1 filter through a glass microfibre filter (Whatman GF/A is
chromatogram obtained with solution (3). suitable), discarding the first few mL of filtrate, and allow to
B. In the Assay, the chromatogram obtained with solutio warm to room temperature.
(1) shows a peak with the same retention time as the pea
due to fusidic acid in the chromatogram obtained with
solution (2).
TESTS
Acidity
pH, 4.5 to 6.0, determined directly on the cream,
Appendix V L.
Related substances
(1) Disperse a quantity of the cream containing the
equivalent of 15 mg of anhydrous fusidic acid in 25 mL of
te mee
the mobile phase, heat the mixture until the cream has
tyne melted and shake vigorously for 15 minutes. Cool the MOBILE PHASE
mixture to below 10°, filter through a glass microfibre filter 10 volumes of methanol, 40 volu
peed
(Whatman GF/A is suitable), discarding the first few mL of acid and 50 volumes of acetonitrile.
filtrate, and allow to warm to room temperature.
SYSTEM SUITABILITY
The Assay is not valid unless the column efficténc
mobile phase.
determined on the peak due to fusidic acid in th
(3) Dilute 30 pL of solution (1) to 100 mL with the mobile chromatogram obtained with solution (2), is at least’ 2000
phase. theoretical plates per metre and the symmetry factor of the
(4) 0.004% w/v of potassium sorbate in the mobile phase. principal peak is 2.0 or less.
The chromatographic conditions described under Assay may Calculate the content of C3;H4,O¢ in the cream using the
be used. declared content of C3;H4gO¢ in diethanolamine
For solution (1) allow the chromatography to proceed for fusidate BPCRS.
3.5 times the retention time of the principal peak. LABELLING
When the chromatograms are recorded under the prescribed The quantity of active ingredient is stated in terms of the
conditions, the retention time of fusidic acid is about equivalent amount of anhydrous fusidic acid.
5.1 minutes and the retention time of 3-ketofusidic acid
relative to that of fusidic acid is about 0.7.
SYSTEM SUITABILITY

oA
aA
Lape
eorety
2016 Fusidic Acid Preparations III-619
Fusidic Acid Eye Drops CHROMATOGRAPHIC CONDITIONS

AwAN
Action and use be used.
Antibacterial. For solution (1) allow the chromatography to proceed for
DEFINITION
Fusidic Acid Eye Drops are a sterile suspension of Fusidic conditions, the retention time of fusidic acid is about
Acid in a suitable vehicle. 5.1 minutes and the retention time of 3-ketofusidic acid
The eye drops comply with the requirements stated under Eye relative to that of fusidic acid is about 0.7.
SYSTEM SUITABILITY
Contentof anhydrous fusidic acid, C3;H4,0¢ The test is not valid unless:
90.0 ta, 110.0% of the stated amount.
in the chromatogram obtained with solution (2), the column
IDENII [ON efficiency, determined on the peak due to fusidic acid is at
A. Carry gt eaethod for thin-layer chromatography, least 2000 theoretical plates per metre;
Appendix I g the following solutions. in the chromatogram obtained with solution (2), the
symmetry factor of the principal peak is 2.0 or less;
containing the equiva in the chromatogram obtained with solution (3), the principal
in 10 mL of ethanol( peak has a signal-to-notse ratio of at least 3.
LIMITS
ethanol (70%).
ate eat
CHROMATOGRAPHIC CON
tara
(a) Use a TLC silica gel F254 plate (I four times the area of the peak corresponding to fusidic acid
plates are suitable). in the chromatogram obtained with solution (2) (4%).
(b) Use the mobile phase as described belo Disregard any peak with an area less than that of the
(c) Apply 10 uL of each solution. principal peak in the chromatogram obtained with solution
(d) Develop the plate to 12.5 cm. (3) (0.03%).
(e) After removal of the plate, dry in a current of aig ASSAY
examine under ultraviolet light (254 nm). Carry out the method for liguid chromatography,
MOBILE PHASE endix III D, using the following solutions.
2.5 volumes of methanol, 10 volumes of glacial acetic acid, ute the eye drops with a mixture of 10 volumes of
10 volumes of cyclohexane and 80 volumes of chloroform. l, 30 volumes of 1% w/v solution of glacial acetic acid
volumes of acetonitrile (solution A) to contain the
CONFIRMATION
solution (1) is similar in position and size to that in the minute. Filter through a glass microfibre
chromatogram obtained with solution (2). GP/A is suitable), discarding the first
B. In the Assay, the chromatogram obtained with solution dilute 10 volumes of the filtrate to
(1) shows a peak with the same retention time as the peak rthophosphoric acid.
due to fusidic acid in the chromatogram obtained with lamine fusidate BPCRS ina
ae a
solution (2). mixture of 40 volumes o
Nw aS
S
TESTS 0.05M orthophosphoric act
Acidity
Related substances with end-capped octadecylsilyl silica gel fe
Carry out the method for liquid chromatography, (5 um) (Lichrospher 100 RP-18 is suitab
Appendix III D, using the following solutions. (b) Use isocratic elution and the mobile
(1) Dilute the eye drops with a mixture of 10 volumes of below.
methanol, 30 volumes of 1% w/v solution of glacial acetic acid (c) Use a flow rate of 2.5 mL per minute.
and 60 volumes of acetonitrile to contain the equivalent of
0.075% w/v of anhydrous fusidic acid. Shake vigorously for
15 minutes, add 0.5 g of potassium nitrate and shake fora _ (e) Use a detection wavelength of 235 nm.
further minute. Filter through a glass microfibre filter paper (f) Inject 20 wL of each solution.
(Whatman GF/A is suitable), discarding the first few mL of MOBILE PHASE
filtrate, and dilute 10 volumes of the filtrate to 12.5 volumes
10 volumes of methanol, 40 volumes of 0.05m orthophosphoric
with 0.05m orthophosphoric acid.
acid and 50 volumes of acetonitrile.
(2) Dilute one volume of solution (1) to 100 volumes with
SYSTEM SUITABILITY
the mobile phase.
The Assay is not valid unless the column efficiency,
(3) Dilute 30 wL of solution (1) to 100 mL with the mobile
determined on the peak due to fusidic acid in the
phase.
chromatogram obtained with solution (2), is at least 2000
ee re el
waa theoretical plates per metre and the symmetry factor of the
eee
principal peak is 2.0 or less.
IWI-620 Fusidic Acid Preparations 2016
DETERMINATION OF CONTENT (g) For solution (1) allow the chromatography to proceed for
Calculate the content of C3;H 40, in the eye drops using the at least 3.5 times the retention time of the principal peak.
Ne
eee
declared content of C3;H4gO¢ in diethanolamine MOBILE PHASE
sete e
fusidate BPCRS.
10 volumes of methanol, 20 volumes of a 1% w/v solution of
LABELLING orthophosphoric acid, 20 volumes of water and 50 volumes of
The quantity of active ingredient is stated in terms of the acetonitrile.
equivalent amount of anhydrous fusidic acid. When the chromatograms are recorded under the prescribed
conditions, the retention time of fusidic acid is about
5.1 minutes and the retention time of 3-ketofusidic acid
relative to that of fusidic acid is about 0.7.
Fusidic.Acid Oral Suspension SYSTEM SUITABILITY

in chromatogram obtained with solution (2), the column
efficiency, determined on the peak due to fusidic acid, is at
least 14,000 theoretical plates per metre;
Fusidic Acid Oral Suspe¢ 31a9n 1s a suspension of Fusidic Acid in the chromatogram obtained with solution (3), the principal
in powder of suitablefin in a suitable flavoured vehicle. peak has a signal-to-noise ratio of at least 3.
It should not be diluted. If necessary, adjust the composition of the mobile phase.
LIMITS

ve Ne
Content of anhydrous fusidié’a the sum of the areas of any secondary peaks is not greater than
92.5 to 107.5% of the stated amount. ; three times the area of the peak corresponding to fusidic acid
IDENTIFICATION in the chromatogram obtained with solution (2) (3%).
of
A. To a quantity containing the equivalent Disregard any peak with an area less than that of the
anhydrous fusidic acid add 5 mL of water and principal peak in the chromatogram obtained with solution
(3) (0.02%).
extracts with two 10-mL quantities of water, dry with
ASSAY
anhydrous sodium sulfate, evaporate to dryness and dissolv
arry out the method for liquid chromatography,
the residue in 1 mL of chloroform IR. The infrared absorpti
ppendix II D, using the following solutions.
spectrum of the resulting solution, Appendix II A, is
concordant with the reference spectrum of fusidic acid ké. thoroughly a weighed quantity of the oral
(RS 166).
ith 25 mL of the mobile phase, dilute to 50 mL
ie phase, filter and use the clear filtrate.
due to fusidic acid in the chromatogram obtained with
solution (2).
TESTS
Acidity
Related substances
Carry out the method for liquid chromatography, (b) Use isocratic elution an
Appendix III D, using the following solutions. below.
(1) Extract a quantity of the oral suspension containing the
equivalent of 0.10 g of anhydrous fusidic acid with two (d) Use an ambient column temperatur
20-mL quantities of chloroform, evaporate the combined (e) Use a detection wavelength of 235 n
extracts to dryness and dissolve the residue in 20 mL of the (f) Inject 20 L of each solution.
mobile phase.
MOBILE PHASE
(2) Dilute 0.2 mL of solution (1) to 20 mL with the mobile
phase. 10 volumes of methanol, 30 volumes of a 1% v/v solution of
glacial acetic acid and 60 volumes of acetonitrile.
(3) Dilute 20 pL of solution (1) to 100 mL with the mobile
eenol phase. SYSTEM SUITABILITY
yen
* ays
The Assay is not valid unless the column efficiency,
determined using the principal peak in the chromatogram
(a) Use a stainless steel column (12.5 to 15 cm x 4 to
obtained with solution (2), is at least 14,000 theoretical plates
5 mm) packed with end-capped octadecylsilyl silica gel for
per metre.
chromatography (5 um) (Lichrospher 100 RP-18 is suitable).
below. Determine the weight per mL of the oral suspension,
Appendix V G, and calculate the content of C3,;H40¢,
weight in volume, using the declared content of C3;H4gQ,¢ in
(d) Use an ambient column temperature. diethanolamine fusidate BPCRS.
2016 Gemfibrozil Preparations III-621
STORAGE (1) Shake a quantity of the contents of the capsules

Fusidic Acid Oral Suspension should be protected from light. containing 0.4 g of Gemfibrozil with 100 mL of methanol and
reer
LABELLING filter
The quantity of active ingredient is stated in terms of the (2) Dilute 1 volume of solution (1) to 100 volumes with the
equivalent amount of anhydrous fusidic acid. mobile phase and further dilute 1 volume of this solution to
When Fusidic Acid Oral Suspension is prescribed or
demanded, no strength being stated, an Oral Suspension (3) 0.0004% w/v of gemfibrozil impurity E BPCRS in the
containing the equivalent of 250 mg of anhydrous fusidic mobile phase.
acid in 5 mL shall be dispensed or supplied. (4) 0.001% w/v of gemfibrozil methyl ester BPCRS and
0.0004% w/v of gemfibrozil impurity E BPCRS in solution (2).
The chromatographic procedure described under Assay may
be used. For solution (1) allow the chromatography to
Action and'use. SYSTEM SUITABILITY
Fibrate lipid-re The test is not valid unless, in the chromatogram obtained
DEFINITION
gemfibrozil and gemfibrozil methyl ester is at least 4.0 and
Gemfibrozil Capsules ¢
the resolution between the peaks due to gemfibrozil methyl
The capsules comply with ester and gemfibrozil impurity E is at least 1.2.
and with the following require
Nene,
LIMITS
Content of gemfibrozil, Cis 22
the area of any peak corresponding to gemfibrozil impurity E
IDENTIFICATION is not greater than the area of the principal peak in the
Shake a quantity of the contents of the c chromatogram obtained with solution (3) (0.1%);
water bath and then dry over silica gel at a pressure of%
for 2 hours or until a waxy solid 1s obtained. The infrarea the sum of the areas of any secondary peaks other than any
absorption spectrum of the residue, Appendix II A, is rresponding to gemfibrozil impurity E is not greater
concordant with the reference spectrum of gemfibrozil 5 times the area of the principal peak in the
(RS 167). gram obtained with solution (2) (0.5%).
TESTS
Dissolution ethod for liquid chromatography,
Comply with the requirements for Monographs of the British é sine the following solutions.
Pharmacopoeia in the dissolution test for tablets and capsules, (1) Add 50 thanol to a quantity of the mixed
Appendix XII Bl. contents of 20°capst s containing 0.15 g of Gemfibrozil,
shake on a mechani iker for 10 minutes, add 20 mL of
TEST CONDITIONS
water, 1 mL ofglaci c.acid and sufficient methanol to
(a) Use Apparatus 2, rotating the paddle at 50 revolutions produce 100 mL, m er (Whatman GF/C paper is
per minute. suitable), discarding the first<20 mL of filtrate. Dilute
(b) Use 900 mL of 0.2m phosphate buffer pH 7.5, ata 1 volume of the filtrate to 5 volun: ith the mobile phase.
temperature of 37°, as the medium. (2) Dissolve 30 mg of gemfibrozt.
PROCEDURE methanol, add 1 mL of glacial ac
(1) After 45 minutes withdraw a 10 mL sample of the 100 mL with water.
medium and measure the absorbance of the filtered sample, (3) 0.01% w/v of gemfibrozil methyl ester
suitably diluted with the dissolution medium if necessary, at prepared by diluting 1 volume of solution (1)
the maximum at 276 nm, Appendix II B using with the mobile phase.
0.2m phosphate buffer pH 7.5 in the reference cell. CHROMATOGRAPHIC CONDITIONS
(2) Measure the absorbance of a suitable solution of (a) Use a stainless steel column (10 cm x 4.6 mm) packed
- AR
gemfibrozil BPCRS, adding the minimum volume of with end-capped octadecylsilyl silica gel for chromatography
0.1M sodium hydroxide, if necessary, to complete dissolution, (3 um) (Spherisorb ODS 2 or Regis C18 are suitable).
and using 0.2m phosphate buffer pH 7.5 in the reference cell.
DETERMINATION OF CONTENT below.
Calculate the total content of gemfibrozil, C,;H».03, in the (c) Use a flow rate of 1 mL per minute.
declared content of C,5H22O03, in gemfibrozil BPCRS.
Related substances
IWI-622 Gemfibrozil Preparations 2016
MOBILE PHASE (1) Shake a quantity of the powdered tablets containing 0.6 g
1 volume of glacial acetic acid, 19 volumes of water and of Gemfibrozil with 70 mL of methanol for 15 minutes, add
80 volumes of methanol. sufficient methanol to produce 100 mL and filter.
SYSTEM SUITABILITY (2) Dilute 1 volume of solution (1) to 100 volumes with
mobile phase and further dilute 1 volume of this solution to
5 volumes with mobile phase.
gemfibrozil and gemfibrozil methyl ester is at least 4.0. (3) 0.0006% w/v of gemfibrozil impurity E BPCRS in mobile
phase.
(4) 0.001% w/v of gemfibrozil methyl ester BPCRS and
Calculate the content of C,;5H».O3 in the capsules from the
0.0004% w/v of gemfibrozil impurity E BPCRS in solution (2).
chromatograms obtained using the declared content of
C,5H2,03 emfpibrozil BPCRS.
The chromatographic procedure described under Assay may
be used. For solution (1) allow the chromatography to
Gemfibrozi SYSTEM SUITABILITY
Action and use with solution (4), the resolution between the peaks due to
Fibrate lipid-regulating gemfibrozil and gemfibrozil methyl ester is at least 4.0 and
the resolution between the peaks due to gemfibrozil methyl
DEFINITION
ester and gemfibrozil impurity E is at least 1.2.
Gemfibrozil Tablets contain &
LIMITS
tN ae The tablets comply with the requir
with the following requirements. In the chromatogram obtained with solution (1):
Content of gemfibrozil, C,;H,.03 the area of any peak corresponding to gemfibrozil impurity E
95.0 to 105.0% of the stated amount. is not greater than the area of the principal peak in the
IDENTIFICATION . |
Mix a quantity of the powdered tablets containing 0:3 ¢ area of the principal peak in the chromatogram obtained with
Gemfibrozil with 10 mL of 0.1m sodium hydroxide, filter solution (2) (0.2%);
(Whatman 541 paper is suitable), acidify with a few drops
the sum of the areas of any secondary peaks other than the
2M sulfuric acid, shake and centrifuge. Wash the precipitate
sponding to gemfibrozil impurity E is not greater
with water, allow to dry in air and dry over anhydrous silica gel ‘
mes the area of the principal peak in the
at a pressure of 2 kPa for 4 hours. The ifrared absorption
am obtained with solution (2) (0.5%).
spectrum of the dried residue, Appendix IT A, is concordant
with the reference spectrum of gemfibrozil (RS 167).
TESTS 20 tablets. Carry out the method for
Dissolution
Pharmacopoeia in the dissolution test for tablets and capsules, ty
Appendix XII Bl. 84 mg of Gemfibrozil’v
mechanical shaker for 1
TEST CONDITIONS
(80%) to produce 100 filter (Whatman 542
(a) Use Apparatus 2, rotating the paddle at 50 revolutions first 20 mL of filtrate.
per minute.
( ared by dissolving
(b) Use 900 mL of 0.2m phosphate buffer pH 7.5, at a the substance in the minimum volume o
temperature of 37°, as the medium. diluting with methanol (807%). <
PROCEDURE (3) 0.01% w/v of gemfibrozil methyl ester B,
(1) After 45 minutes withdraw a 10 mL sample of the prepared by diluting 1 volume of solution (1 (
medium and measure the absorbance of the filtered sample, with a mixture of 2 volumes of methanol and 3 yeh
suitably diluted with the dissolution medium if necessary, at mobile phase.
the maximum at 276 nm, Appendix II B using CHROMATOGRAPHIC CONDITIONS
0.2m phosphate buffer pH 7.5 in the reference cell.
(2) Measure the absorbance of a suitable solution of with end-capped octadecylsilyl silica gel for chromatography
rea wan
gemfibrozil BPCRS prepared by dissolving the substance in (3 um) (Spherisorb ODS 2 or Regis C18 are suitable).
the minimum volume of methanol and diluting with
0.2m phosphate buffer pH 7.5. and using 0.2m phosphate buffer
below.
pH 7.5 in the reference cell.
Calculate the total content of gemfibrozil, C;;H2.03, in the
declared content of C,;5H».03 in gemfibrozil BPCRS. (f) Inject 20 wL of each solution.
Related substances MOBILE PHASE
Carry out the method for liquid chromatography, 1 volume of glacial acetic acid, 19 volumes of water and
Appendix III D, using the following solutions. 80 volumes of methanol.
sar
Se es
wos
Re awe
2016 Gentamicin Preparations III-623
SYSTEM SUITABILITY Repeat the extraction with two 5 mL quantities of the

arate et
yee
The test is not valid unless, in the chromatogram obtained sodium tetraborate solution, dilute the combined aqueous
extracts to 25 mL with the same solution and filter.
Met et

gemfibrozil and gemfibrozil methyl ester is at least 4.0. To 10 mL of the clear filtrate add 5 mL of methanol, swirl,
add 4 mL of phthalaldehyde reagent, mix, add sufficient
methanol to produce 25 mL, heat in a water bath at 60° for
Calculate the content of C,;5H»2203 in the tablets from the 15 minutes and cool. If the solution is not used immediately,
chromatograms obtained using the declared content of cool to 0° and use within 4 hours.
C,5H.2203 in gemfibrozil BPCRS.
STORAGE 10 mL of a 0.065% w/v solution of gentamicin sulfate BPCRS
Gemfibrozil Tablets should be protected from light. in place of the preparation being examined and beginning at
the words “To 10 mL of the clear filtrate ...’.

(5 um) (Hypersil ODS and Kromasil C18 are suitable).
below.

Gentamicin Cream is a visce water emulsion (d) Use an ambient column temperature.
containing Gentamicin Sulf: (e) Use a detection wavelength of 330 nm.
phase. (f) Inject 20 wL of each solution.
MOBILE PHASE
0.025m sodium heptanesulfonate monohydrate in a mixture of
(1) Disperse a quantity of the cream containing the conditions the retention time of component C), is 10 to
equivalent of 7.5 mg of gentamicin in 20 mL of chloroft 20 minutes. The retention times relative to component C,
extract with 10 mL of water and use the aqueous layer. about 0.13 (reagent); about 0.27 (component C,); about
(2) A solution of gentamicin sulfate BPCRS in water component C,,); about 0.85 (component C,,).
containing the equivalent of 0.075% w/v of gentamicin. UITABILITY
CHROMATOGRAPHIC CONDITIONS ot valid unless, in the chromatogram obtained
(a) Usea silica gel precoated plate (Merck silica gel 60 plates 2 , the resolution factor between the peaks due
are suitable).
(d) Develop the plate to 15 cm. the percentage c of components C,, C;,, Cz and Cr,
in the cream by norn stttlev. | he proportions are within the
(e) After removal of the plate, allow it to dry in air, spray
following limits:
ve aye with ninhydrin solution R1 and heat at 105° for 2 minutes.
C,, 25.0 to 50.0%;
MOBILE PHASE
Ci) 10.0 to 35.0%;
The lower layer obtained by shaking together equal volumes
of 13.5m ammonia, chloroform and methanol and allowing to C, plus C,,, 25.0 to 55.0%.
separate.
CONFIRMATION Dissolve as completely as possible a quantify e cream
containing the equivalent of 3 mg of gentamigin 1
The three principal spots in the chromatogram obtained with
solution (1) correspond to the three principal spots in the
chloroform, shake vigorously with 75 mL of phosp
pH 8.0 and allow to separate. Dilute 10 mL of the aqueous
layer to 50 mL with phosphate buffer pH 8.0. Carry out the
B. In the test for Composition of gentamicin sulfate, the microbiological assay of antibiotics, Appendix XIV A.
retention times of the four principal peaks in the The precision of the assay is such that the fiducial limits of
chromatogram obtained with solution (1) correspond to error are not less than 95% and not more than 105% of the
those of the four principal peaks in the chromatogram estimated potency.
Calculate the content of gentamicin in the cream, taking each
TESTS 1000 IU found to be equivalent to 1 mg of gentamicin.
Composition of gentamicin sulfate The upper fiducial limit of error is not less than 90.0% and
Carry out the method for liquid chromatography, the lower fiducial limit of error is not more than 120.0% of
Appendix III D, using the following solutions. the stated content.
(1) Disperse a quantity of the cream containing the LABELLING
equivalent of 15 mg of gentamicin in 10 mL of chloroform, The quantity of active ingredient is stated in terms of the
add 10 mL of a 0.25% w/v solution of sodium tetraborate, equivalent amount of gentamicin.
shake vigorously, centrifuge and separate the aqueous layer.
IiI-624 Gentamicin Preparations 2016

Gentamicin Ear Drops
ZN) Action and use
Met ate
MOBILE PHASE
SS Aminoglycoside antibacterial.
0.025m sodium heptanesulfonate monohydrate in a mixture of
DEFINITION
Gentamicin Ear Drops are a solution of Gentamicin Sulfate
in Purified Water. When the chromatograms are recorded under the prescribed
conditions the retention time of component C, is 10 to
The ear drops comply with the requirements stated under Ear
20 minutes. The retention times relative to component C,
are: about 0.13 (reagent); about 0.27 (component C)); about
IDENTIFICATION 0.65 (component C,,); about 0.85 (component C,,).
SYSTEM SUITABILITY

to components C,, and Cz is at least 1.3.
(2) 0.5% wiv of genta

LIMITS
Using the chromatogram obtained with solution (1) calculate

CHROMATOGRAPHIC C( the percentage content of components C,, C,,, C, and Co,
(a) Use as the coating silica: in the ear drops by normalisation. The proportions are within
are suitable). the following limits:
(b) Use the mobile phase as dest C,, 25.0 to 50.0%;
(c) Apply 10 uwL of each solution. Cy.) 10.0 to 35.0%3
(d) Develop the plate to 15 cm. C, plus C,,, 25.0 to 55.0%.
(e) After removal of the plate, allow it to dry:i
ASSAY
with ninhydrin solution R1 and heat at 105° for
Dilute a volume of the ear drops containing the equivalent of
MOBILE PHASE 15 mg of gentamicin to 50 mL with sterile phosphate buffer
The lower layer obtained by shaking together equal vol pH 8.0 and dilute 10 mL of the resulting solution to 50 mL
of 13.5m ammonia, chloroform and methanol and allowing to ith the same solvent. Carry out the microbiological assay of
separate. Lyotics, Appendix XIV A. The precision of the assay is
the fiducial limits of error are not less than 95%
CONFIRMATION
re than 105% of the estimated potency.
The three principal spots in the chromatogram obtained with
he content of gentamicin in the ear drops, taking
found to be equivalent to 1 mg of gentamicin.
dueial limit of error is not less than 90.0% and
B. In the test for Composition of gentamicin sulfate, the fal imitgof error is not more than 120.0% of
retention times of the four principal peaks in the
chromatogram obtained with solution (1) correspond to
those of the four principal peaks in the chromatogram LABELLING
obtained with solution (2). The quantity of act redient is stated in terms of the
equivalent amount of géentaimue:
os TESTS
SIA Composition of gentamicin sulfate
° Carry out the method for liquid chromatography,
(1) Add 5 mL of methanol to 10 mL ofa solution prepared Gentamicin Eye Drops
by diluting a suitable volume of the ear drops with water to
contain the equivalent of 0.045% w/v of gentamicin. Swirl Action and use
and add 4 mL of phthalaldehyde reagent, mix and add Aminoglycoside antibacterial.
sufficient methanol to produce 25 mL, heat in a water bath at
DEFINITION
60° for 15 minutes and cool. If the solution is not used
Gentamicin Eye Drops are a sterile solution of Gentamicin
immediately, cool to 0° and use within 4 hours.
Sulfate in Purified Water.
ody (2) Prepare in the same manner as solution (1) but using
24 10 mL of a 0.065% w/v solution of gentamicin sulfate BPCRS The eye drops comply with the requirements stated under E’ye
in place of 10 mL of the preparation being examined. Preparations and with the following requirements.

(5 um) (Hypersil ODS and Kromasil C18 are suitable). (1) Dilute a volume of the eye drops, if necessary, with
sufficient water to produce a solution containing the
equivalent of 0.3% w/v of gentamicin.
below.
(2) 0.5% wiv of gentamicin sulfate BPCRS in water.
aan al
2016 Gentamicin Preparations III-625

(a) Use as the coating silica gel (Merck silica gel 60 plates Using the chromatogram obtained with solution (1) calculate
are suitable). the percentage content of components C,, C,,, C, and Co,
(b) Use the mobile phase as described below. in the eye drops by normalisation. The proportions are within
the following limits:
C1, 25.0 to 50.0%;
C14 10.0 to 35.0%;
(e) After removal of the plate, allow it to dry in air, spray
with ninhydrin solution R1 and heat at 105° for 2 minutes. C, plus Co,, 25.0 to 55.0%.
MOBILE PHASE ASSAY

Dilute a volume of the eye drops containing the equivalent of
15 mg of gentamicin to 50 mL with sterile phosphate buffer
pH 8.0 and dilute 10 mL of the resulting solution to 50 mL
with the same solvent. Carry out the microbiological assay of
antibiotcs, Appendix XIV A. The precision of the assay is
such that the fiducial limits of error are not less than 95%
and not more than 105% of the estimated potency.
Calculate the content of gentamicin in the eye drops, taking
each 1000 IU found to be equivalent to 1 mg of gentamicin.
The upper fiducial limit of error is not less than 90.0% and
the lower fiducial limit of error is not more than 120.0% of
those of the four principal pe the stated content.
obtained with solution (2). *
LABELLING
TESTS , The quantity of active ingredient is stated in terms of the
Composition of gentamicin sulfate : equivalent amount of gentamicin.
by diluting a suitable volume of the eye drops with {

contain the equivalent of 0.045% w/v of gentamicin. S¥ Gentamicin Injection
and add 4 mL of phthalaldehyde reagent, mix and add
and use
sufficient methanol to produce 25 mL, heatin a water bathat
ycoside antibacterial.
60° for 15 minutes and cool. If the solutionis not used
immediately, cool to 0° and use within 4 hours. TION
(2) Prepare in the same manner as solution (1) but using Injection is a sterile solution of Gentamicin
10 mL of a 0.065% w/v solution of gentamicin sulfate BPCRS
in place of 10 mL of the preparation being examined.

(5 um) (Hypersil ODS and Kromasil C18 are suitable).
below.
(c) Use a flow rate of 1.5 mL per minute. equivalent of 0.5% w/v of genta
(d) Use an ambient column temperature. (2) 0.8% wiv of gentamicin sulfate I
(e) Use a detection wavelength of 330 nm. CHROMATOGRAPHIC CONDITIONS
(f) Inject 20 uwL of each solution. (a) Use as the coating silica gel (Merck si
MOBILE PHASE are suitable).
0.025m sodium heptanesulfonate monohydrate in a mixture of (b) Use the mobile phase as described below.
5 volumes of glacial acetic acid, 25 volumes of water and (c) Apply 6 uwL of each solution.
70 volumes of methanol. (d) Develop the plate to 15 cm.
When the chromatograms are recorded under the prescribed (e) After removal of the plate, allow it to dry in air, spray
conditions the retention time of component C, is 10 to with ninhydrin solution R1 and heat at 105° for 2 minutes.
20 minutes. The retention times relative to component C,
MOBILE PHASE
are: about 0.13 (reagent); about 0.27 (component C,); about
0.65 (component C,,); about 0.85 (component C,,). The lower layer obtained by shaking together equal volumes
of 13.5m ammonia, chloroform and methanol and allowing to
SYSTEM SUITABILITY
separate.
with solution (2), the resolution factor between the peaks due CONFIRMATION
to components C,, and Cz is at least 1.3. The three principal spots in the chromatogram obtained with
IlI-626 Gentamicin Preparations 2016
B. In the test for Composition of gentamicin sulfate, the fiducial limits of error are not less than 95% and not more
retention times of the four principal peaks in the than 105% of the estimated potency.
SAN oe chromatogram obtained with solution (1) correspond to Calculate the content of gentamicin in the injection, taking
those of the four principal peaks in the chromatogram
ees
each 1000 IU found to be equivalent to 1 mg of gentamicin.

obtained with solution (2). The upper fiducial limit of error is not less than 97.0% and
TESTS the lower fiducial limit of error is not more than 110.0% of
Acidity the stated content.
pH, 3.0 to 5.5, Appendix V L. LABELLING
Composition of gentamicin sulfate The strength is stated in terms of the equivalent amount of
Carry out the method for liguid chromatography, gentamicin in a suitable dose-volume.
Appendix
olume of the injection with water to

i at of 0.045% w/v of gentamicin. Swirl
and add 4 mL ef phtbalaldehyde reagent, mix and add
Gentamicin Ointment
sufficient methanol t Action and use
60° for 15 minutes 2 Aminoglycoside antibacterial.
(2) Prepare in the same man DEFINITION

10 mL of a 0.065% w/v solutignofgen. Gentamicin Ointment is a dispersion of Gentamicin Sulfate
in place of 10 mL of the preparation b in microfine powder in White Soft Paraffin or other suitable
anhydrous greasy basis.
(5 um) (Hypersil ODS and Kromasil C18 are IDENTIFICATION
(b) Use isocratic elution and the mobile phase A. Carry out the method for thin-layer chromatography,
below. Appendix III A, using the following solutions.
(c) Use a flow rate of 1.5 mL per minute. (1) Disperse a quantity of the ointment containing the
(d) Use an ambient column temperature. quivalent of 7.5 mg of gentamicin in 20 mL of chloroform,
with 10 mL of water and use the aqueous layer.
tion of gentamicin sulfate BPCRS in water
the equivalent of 0.075% w/v of gentamicin.
MOBILE PHASE
OGRAPHIC CONDITIONS
0.025M sodium heptanesulfonate monohydrate in a mixture of
ita gel precoated plate (Merck silica gel 60 plates
conditions the retention time of component C, is 10 to (c) Apply 20 pL.
20 minutes. The retention times relative to component C, (d) Develop the pla
are: about 0.13 (reagent); about 0.27 (component C)); about (e) After removal of the
0.65 (component C,,); about 0.85 (component C,,). with ninhydrin solution R1 a
The test is not valid unless, in the chromatogram obtained The lower layer obtained by shaking to
to components C,, and Cz is at least 1.3. separate.
LIMITS CONFIRMATION
the percentage content of components C,, C,,, C2 and Co,
in the injection by normalisation. The proportions are within chromatogram obtained with solution (2).
the following limits: B. In the test for Composition of gentamicin sulfate, the
Cy, 25.0 to 50.0%; retention times of the four principal peaks in the
Ci,, 10.0 to 35.0%; chromatogram obtained with solution (1) correspond to
C, plus C2,, 25.0 to 55.0%. those of the four principal peaks in the chromatogram
Carry out the test for bacterial endotoxins, Appendix XIV C. TESTS
Dilute the injection, if necessary, with water BET to give a Composition of gentamicin sulfate
solution containing the equivalent of 10 mg of gentamicin Carry out the method for liguid chromatography,
per mL (solution A). The endotoxin limit concentration of Appendix III D, using the following solutions.
solution A is 7.1 IU per mL. (1) Disperse a quantity of the ointment containing the
ASSAY equivalent of 20 mg of gentamicin in 10 mL of chloroform,
add 20 mL of a 0.25% w/v solution of sodium tetraborate,
Carry out the microbiological assay of antibiotics,
Appendix XIV A. The precision of the assay is such that the shake vigorously, centrifuge and separate the aqueous layer.
2016 Gentamicin Preparations II-627
Filter and dilute to 50 mL with water. To 10 mL add 5 mL

of methanol, swirl, add 4 mL of phthalaldehyde reagent, mix,
Gentamicin and Hydrocortisone Acetate
add sufficient methanol to produce 25 mL, heat in a water Ear Drops
bath at 60° for 15 minutes and cool. If the solution is not to
be used immediately, cool to 0° and use within 4 hours Action and use
(2) Prepare in the same manner as solution (1) but using Aminoglycoside antibacterial (Gentamicin Sulfate);
10 mL of a 0.065% w/v solution of gentamicin sulfate BPCRS corticosteroid (Hydrocortisone Acetate).
in place of the preparation being examined and beginning at
DEFINITION
the words ‘To 10 mL add ...’.
Gentamicin and Hydrocortisone Acetate Ear Drops contain
CHROMATOGRAPHIC CONDITIONS Gentamicin Sulfate and Hydrocortisone Acetate suspended
(a) Use a.stainless steel column (12.5 cm x 4.6 mm) packed in a suitable vehicle.
adecylsilyl silica gel for chromatography The ear drops comply with the requirements stated under Ear
DS and Kromasil C18 are suitable). Preparations and with the following requirements.
elution and the mobile phase described Content of hydrocortisone acetate, C,3,H320,
L per minute.
IDENTIFICATION
t temperature. A. Carry out the method for thin-layer chromatography,
(e) Use a detection Ww Appendix III A, using the following solutions.
PAL A
(f) Inject 20 wL of each s (1) Dilute a volume of the ear drops, if necessary, with
MOBILE PHASE sufficient water to produce a solution containing the
equivalent of 0.3% w/v of gentamicin, filter and use the
0.025m sodium heptanesulfonate te In a mixture of
filtrate.
5 volumes of glacial acetic acid, 25 Vo es of water and
70 volumes of methanol. (2) 0.5% wiv of gentamicin sulfate BPCRS in water.
(a) Usea silica gel precoated plate (Merck silica gel 60 plates
are suitable).
0.655 (component C,,); about 0.85 (component C,,).
SYSTEM SUITABILITY
ENevelop the plate to 15 cm.
ter removal of the plate, allow it to dry in air, spray
drin solution R1 and heat at 105° for 2 minutes.
to components C,, and Cz is at least 1.3.
LIMITS
the percentage content of components C,, C,,, Cz and Co,
in the ointment by normalisation. The proportions are within
the following limits: CONFIRMATION
C,, 25.0 to 50.0%; The three princip ots. in the chromatogram obtained with
solution (1) are simi i | n, colour and size to those
C,,, 10.0 to 35.0%;
in the chromatogram obtained. ith solution (2).
C, plus C,,, 25.0 to 55.0%.
B. Comply with the test fo Comp ition of gentamicin
ASSAY sulfate.
Dissolve as completely as possible a quantity of the ointment C. Filter 20 mL of the well-mixe (Whatman No.
containing the equivalent of 4 mg of gentamicin in 50 mL of 1 filter paper is suitable), wash the residue: ith the minimum
chloroform, extract with three 20-mL quantities of phosphate
buffer pH 8.0 and dilute the combined extracts to 100 mL
with phosphate buffer pH 8.0. Dilute 10 mL of the resulting
solution to 50 mL with phosphate buffer pH 8.0. Carry out the fluorescence
microbiological assay of antibiotics, Appendix XIV A. whichis particularly intense when viewed under ultraviolet
The precision of the assay is such that the fiducial limits of light (365 nm). Add the solution to 10 mL of water and mix;
error are not less than 95% and not more than 105% of the the fluorescence under ultraviolet light (365 nm) does not
eA ee
estimated potency. disappear.
Calculate the content of gentamicin in the ointment, taking D. In the Assay for hydrocortisone acetate, the
each 1000 IU found to be equivalent to 1 mg of gentamicin. chromatogram obtained with solution (1) shows a peak with
The upper fiducial limit of error is not less than 90.0% and the same retention time as the principal peak in the
the lower fiducial limit of error is not more than 120.0% of chromatogram obtained with solution (2).
the stated content.
TESTS
LABELLING Acidity or alkalinity
The quantity of active ingredient is stated in terms of the pH, 6.0 to 7.0, Appendix V L.
equivalent amount of gentamicin.
Composition of gentamicin sulfate
IlI-628 Glibenclamide Preparations 2016
(1) Add 5 mL of methanol to 10 mL of a solution prepared sufficient methanol to produce 100 mL and dilute 10 mL of
by diluting a suitable volume of the ear drops with water to this solution to 50 mL with the mobile phase.
Nea
contain the equivalent of 0.045% w/v of gentamicin. Swirl (2) Dilute 10 mL of a 0.1% w/v solution of hydrocortisone
and add 4 mL of phthalaldehyde reagent, mix and add
te we 4
acetate BPCRS in methanol to 50 mL with the mobile phase.

sufficient methanol to produce 25 mL, heat in a water bath at
60° for 15 minutes and cool. If the solution is not used
immediately, cool to 0° and use within 4 hours. (a) Use a stainless steel column (12.5 cm x 4.6 mm) packed
10 mL of a 0.065% w/v solution of gentamicin sulfate BPCRS
in place of 10 mL of the preparation being examined. (b) Use isocratic elution and the mobile phase described
below.
(b) Use isocra (f) Inject 20 pL of each solution.
below. MOBILE PHASE

Calculate the content of C,3H3.0, in the ear drops using the

(f) Inject 5 wL of each solution declared content of C.3H320¢ in hydrocortisone
tN wl
MOBILE PHASE acetate BPCRS.
0.025M sodium heptanesulfonate monohyé STORAGE
5 volumes of glacial acetic acid, 25 volumes Gentamicin and Hydrocortisone Acetate Ear Drops should
70 volumes of methanol. not be allowed to freeze.
LABELLING
The quantity of Gentamicin Sulfate is stated in terms of the
equivalent amount of gentamicin.
are: about 0.13 (reagent); about 0.27 (component C));
0.65 (component C,,); about 0.85 (component C,,).
SYSTEM SUITABILITY
to components C,, and C, is at least 1.3.
LIMITS
the percentage content of components C,, C;,, Cz and Co,
DEFINITION <¢
in the ear drops by normalisation. The proportions are within
the following limits: Glibenclamide Tab
C,, 25.0 to 50.0%; PRODUCTION

C,,, 10.0 to 35.0%;
appropriate release of Glibenc
C, plus C,,, 25.0 to 55.0%.
the competent authority. a
ASSAY Prepare a mixture containing 0.813:
For gentamicin disodium hydrogen phosphate and 0.13509
Dilute a volume of the ear drops containing the equivalent of dihydrogen orthophosphate (solution A).
15 mg of gentamicin to 50 mL with sterile phosphate buffer
pH 8.0 and dilute 10 mL of the resulting solution to 50 mL
with the same solvent. Carry out the microbiological assay of
antibiotucs, Appendix XIV A. The precision of the assay is
solutions.
such that the fiducial limits of error are not less than
95% and not more than 105% of the estimated potency. TEST CONDITIONS
Calculate the content of gentamicin in the ear drops, taking (a) Use Apparatus 2 rotating the paddle at 100 revolutions
each 1000 IU found to be equivalent to 1 mg of gentamicin. per minute.
The upper fiducial limit of error is not less than 90.0% and (b) Use 900 mL of solution A at a temperature of 37° as the
the lower fiducial limit of error is not more than 120.0% of medium.
the stated content. PROCEDURE
For hydrocortisone acetate (1) Withdraw 10 mL of the medium, filter (Minisart GS
Carry out the method for liquid chromatography, 25mm filters are suitable) and use the filtrate, discarding the
Appendix III D, using the following solutions. first 5 mL of the filtrate.
(1) Shake a quantity of the ear drops containing 0.1 g of (2) Dissolve glibenclamide BPCRS in the minimum quantity
Hydrocortisone Acetate with 25 mL of methanol, add of methanol and dilute to an appropriate concentration with
swan d
Santee
solution A.
ve VET ee
2016 Glibenclamide Preparations JII-629
(a) Use a stainless steel column (25 cm x 4.6 mm) packed In the chromatogram obtained with solution (1);
with octadecylsilyl sihca gel for chromatography (5 um) any spots corresponding to 4-[2-(5-chloro-2-
(Spherisorb ODS is suitable). methoxybenzamido)ethyl]benzenesulfonamide and methyl
(b) Use isocratic elution using the mobile phase described N-4-[2-(5-chloro-2-
below. methoxybenzamido)ethyl]benzenesulfonylcarbamate are not
(c) Use a flow rate of 1.0 mL per minute. more intense than the spots in the chromatograms obtained
with solutions (2)(2.4%) and (3)(0.4%) respectively.
(e) Use a detection wavelength of 225 nm. Uniformity of content
Tablets containing 5 mg or less of Glibenclamide comply
with the requirements stated under Tablets using the
following method of analysis. Carry out the method for liguid
solutions.
(1) Powder one tablet, add a mixture of 2 mL of water and
20 mL of methanol, mix with the aid of ultrasound until fully
t of glibenclamide, dispersed and filter through a 0.2-um membrane filter
Calculate the total ¢
(Anatop LC is suitable).
C,3H»3sCIN305S, in th iim from the chromatograms
(2) Add 2 mL of water to 20 mL of a 0.025% w/v solution of
ghbenclamide BPCRS in methanol, mix with the aid of
ultrasound until fully dispersed and filter (0.2-um Anatop LC
is suitable).
Content of glibenclamide, C3H2gC [
95.0 to 105.0% of the stated amount. The chromatographic conditions described under Assay may
be used.
IDENTIFICATION
A. In the Assay, the principal peak in the chromates DETERMINATION OF CONTENT
obtained with solution (1) has the same retention timé Calculate the content of C23H»gCIN3O05S in each tablet
that of the principal peak in the chromatogram obtain using the declared content of C,3,H»sCIN30;S in
solution (2). glibenclamide BPCRS.
B. In the test for Related substances, the principal spot in
chromatogram obtained with solution (1) corresponds to that ; nd powder 20 tablets. Carry out the method for
in the chromatogram obtained with solution (4). matography, Appendix III D, using the following
TESTS
Related substances
Appendix III A, using the following solutions. ter and 20 mL of methanol until fully
(1) Extract a quantity of the powdered tablets containing dispersed an ough a 0.2-um membrane filter
20 mg of Glibenclamide with four 5-mL quantities of a (Anatop LC is suigab
mixture of 10 volumes of acetone and 20 volumes of (2) Dissolve 50 mg 6 mide BPCRS in 10 mL of
dichloromethane, evaporate the combined extracts to dryness methanol with the aid d for 20 minutes, add
at a temperature not exceeding 40° at a pressure of 2 kPa sufficient methanol to prod. 50 mL and dilute 1 volume of
and dissolve the residue in 4 mL of a mixture of equal this solution to 4 volumes with, l. To 20 mL of this
volumes of chloroform and methanol. solution add 2 mL of water and
(2) 0.012% w/y of 4-[2-(5-chloro-2- CHROMATOGRAPHIC CONDITIO
methoxybenzamido) ethyl]benzenesulfonamide BPCRS in a (a) Use a stainless steel column (10 c
mixture of equal volumes of chloroform and methanol. with octadecylsilyl silica gel for chromatograp
(3) 0.0020% w/v of methyl N-4-[2-(5-chloro-2- (Spherisorb ODS is suitable).
methoxybenzamido) ethyl]benzenesulfonylcarbamate BPCRS in a (b) Use isocratic elution using the mobile phase“below.
mixture of equal volumes of chloroform and methanol.
(4) 0.5% w/v of ghbenclamide BPCRS in a mixture of equal
volumes of chloroform and methanol.
(a) Use as the coating substance silica gel GF 254.
MOBILE PHASE
solution of potassium dihydrogen orthophosphate previously
(d) Develop the plate to 15 cm. adjusted to pH 3.0 with orthophosphoric acid.
(e) After removal the plate, dry in air and examine under
Calculate the content of C.3;H»gCIN30;S in the tablets using
MOBILE PHASE the declared content of C23H»sCIN305S in
et
5 volumes of ethanol (96%), 5 volumes of glacial acetic acid,

ter
glibenclamide BPCRS.
iccetrs
45 volumes of chloroform and 45 volumes of cyclohexane.

IiI-630 Gliclazide Preparations 2016
Gliclazide Tablets
ANS
Action and use with octylsilyl silica gel for chromatography (4 um) (Superspher
Inhibition of ATP-dependent potassium channels 60RP8 is suitable).
(sulfonylurea); treatment of diabetes mellitus. (b) Use isocratic elution and the mobile phase described
below.
Gliclazide Tablets contain Gliclazide.
Contentt of sliclazide, C,5H2,N303S
MOBILE PHASE
of Gliclazide { of dichloromethane, centrifuge and 0.1 volume of triethylamine, 0.1 volume of trifluoroacetic acid,
evaporate the sup iquid to dryness. The infrared 45 volumes of acetonitrile R1 and 55 volumes of water
absorption spectrum 0 ue, Appendix II A, 1S SYSTEM SUITABILITY
concordant with the refe The test is not valid unless, in the chromatogram obtained
TESTS with solution (3), the resolution factor between the peaks due
Dissolution to gliclazide and gliclazide impurityF 1s at least 1.8.
LIMITS

Appendix XII B1. the area of any peak corresponding to gliclazide impurityF is
TEST CONDITIONS not greater than the area of the principal peak in the
per minute. the area of any other secondary peak is not greater than the
(b) Use 900 mL of phosphate buffer pH 7.4, at a tempe tu area of the principal in the chromatogram obtained with
of 37°, as the medium. solution (2) (0.2%);
PROCEDURE m of the areas of any other secondary peaks is not
medium and measure the absorbance of the filtered sample, am obtained with solution (2) (0.4%).
suitably diluted with the dissolution medium if necessary, any peak with an area less than 0.25 times the area
expected to contain 0.00125% w/v of Gliclazide at 226 nm
and 290 nm, Appendix II B using phosphate buffer pH 7.4 in
the reference cell. Correct the absorbance obtained at
226 nm by subtracting the absorbance obtained at 290 nm. x20 tablets. Carry out the method for
(2) Measure the absorbance of a 0.00124% w/v solution of liquid chromatogrdiphy, j dix III D, using the following
ghclazide BPCRS using phosphate buffer pH 7.4 in the solutions.
reference cell. (1) Shake a quantity o lered tablets containing 0.8 g
DETERMINATION OF CONTENT of Gliclazide for 1 hour wi 200 mL of acetonitrile, filter and
ras
Calculate the total content of Gliclazide, C,5H2;N303S, in dilute 10 mL of the filtrate tex2i
the medium from the absorbances obtained and using the 2 volumes of acetonitrile and 3 vél
declared content of C,5H2,;N3038S, in gliclazide BPCRS. (2) Dissolve 40 mg of gliclazide BP
Related substances acetonitrile and dilute to 200 mL with a
Carry out the method for liquid chromatography, of acetonitrile and 3 volumes of water.
solutions immediately before use.
(1) Shake a quantity of the powdered tablets containing 0.8 g with water and dilute 1 volume of the resulting softition to
of Gliclazide for 1 hour with 200 mL of acetonitrile, filter and 20 volumes with a mixture of 45 volumes of acetonitrile and
dilute 10 mL of the filtrate to 50 mL with a mixture of 55 volumes of water.
1 volume of acetonitrile and 2 volumes of water. CHROMATOGRAPHIC CONDITIONS
PAL wey
(2) Dilute 1 volume of solution (1) to 500 volumes with a The chromatographic conditions described under Related
mixture of 45 volumes of acetonitrile and 55 volumes of water. substances may be used.
(3) Dissolve 5 mg of gliclazide BPCRS and 15 mg of ghiclazide SYSTEM SUITABILITY
impurity F BPCRS in 25 mL of acetonitrile, dilute to 50 mL The test is not valid unless, in the chromatogram obtained
with water and dilute 1 volume of the resulting solution to with solution (3), the resolution factor between the peaks due
20 volumes with a mixture of 45 volumes of acetonitrile and to gliclazide and gliclazide impurity F is at least 1.8.
(4) Dissolve 8 mg of gliclazide impurity F BPCRS in 25 mL
of acetonitrile, dilute to 50 mL with water and dilute 1 volume Calculate the content of C;;H2;N303S in the tablets using
the declared content of C,;5H2,N303S in gliclazide BPCRS.
Paw ad
of the resulting solution to 100 volumes with a mixture of

Bis
wea ey
2016 Glimepiride Preparations III-631
MOBILE PHASE
Glimepiride Tablets
Equal volumes of a 0.1% w/vsolution of sodium dihydrogen
Action and use phosphate dihydrate and acetonitrile R1, the pH adjusted to 2.5
Inhibition of ATP-dependent potassium channels with orthophosphonic acid.
(sulfonylurea); treatment of diabetes mellitus. SYSTEM SUITABILITY
DEFINITION
with solution (2), the retention time of glimepiride is about
Glimepiride Tablets contain Glimepiride.
8 minutes.
Calculate the total content of glimepiride, C.,H3,N,05S, in
Content,of glimepiride, w2aFlsdNaOs8
the medium from the chromatograms obtained and using the
declared content of C2,H3,N405S in glimepiride BPCRS.
LIMITS
The amount of glimepiride released is not less than 75% (Q)
ith 20 mL of acetonitrile, centrifuge
iquid, evaporate to dryness at a
30°. The infrared absorption Related substances
B. In the Assay, the retenticr 1 volume of water and 4 volumes of acetonitrile. Store the
the chromatogram obtained solutions at a temperature not exceeding 12° and use within
that of the principal peak in the 15 hours.
solution (2). (1) Shake a quantity of the powdered tablets containing 2 mg
of Glimepiride with 8 mL of a mixture of 1 volume of water
TESTS
and 4 volumes of acetonitrile. Dilute to 10 mL with the same
Dissolution
solvent, centrifuge and use the supernatant liquid.
(3) 0.04% w/v of ghmepinde for system suitability BPCRS.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 75 revoluti
per minute. OMATOGRAPHIC CONDITIONS
(b) Use 900 mL of a pH 7.8 buffer solution prepared by stainless steel column (25 cm x 4 mm) packed
mixing 14.5 g of potassium dihydrogen phosphate and 277.76 g capped octadecylsilyl silica gel for chromatography
of disodium hydrogen orthophosphate dihydrate with sufficient s upelco Superspher RP18isSuitable).
water to make 25 litres, adjusted to pH 7.8 with 10% v/v
orthophosphoric acid, at a temperature of 37°, as the medium.
PROCEDURE mL per minute.
Carry out the method for liquid chromatography, umn temperature.
Appendix III D, using the following solutions. Store the
solutions at a temperature not exceeding 12° and use within
15 hours.
filter. Use the filtrate, diluted with the dissolution medium, if
0.0001% w/v of Glimepiride. MOBILE PHASE
(2) Dilute 1 volume of a 0.001% w/v solution of Equal volumes of a 0.1% w/v solutionof sedis
ghmepiride BPCRS in acetonitrile to 10 volumes with the phosphate dihydrate and acetonitrile R1, the pFI adjusted to 2.5
dissolution medium. with orthophosphoric acid.
CHROMATOGRAPHIC CONDITIONS When the chromatograms are recorded under thy
conditions the retention time of glimepiride1s about
17 minutes. Retention times relative to glimepiride are:
impurity B, about 0.24; impurity C, about 0.3.
(Phenomenex Lichrospher RP 18 is suitable).
SYSTEM SUITABILITY
below. The test is not valid unless, in the chromatogram obtained
(c) Use a flow rate of 1 mL per minute. with solution (3), the resolution between the peaks due to
impurity B and impurity C is at least 4.0.
LIMITS
(e) Use an auto-sampler temperature of 12°.
Identify the peak due to impurity B in solution (1) using
(f) Use a detection wavelength of 228 nm.
solution (3) and multiply the peak area by the correction
(g) Inject 50 wL of each solution. factor of 0.7.
II-632 Glipizide Preparations 2016
the area of any peak corresponding to impurity B is not For tablets containing 2 mg or more, or 2% wiw or
we
a
greater than twice the area of the principal peak in the more of glimepiride
-awal
chromatogram obtained with solution (2) (2.0%); Weigh and powder 20 tablets. Carry«out the method for
the area of any other secondary peak is not greater than liquid chromatography, Appendix III D, using the following
0.2 times the area of the principal peak in the chromatogram solutions
obtained with solution (2) (0.2%); (1) To a quantity of powdered tablets containing 10 mg of
the sum of the areas of any other secondary peaks is not Glimepiride, add 80 mL of a solution containing 1 volume of
greater than the area of the principal peak in the water and 9 volumes of acetonitrile, mix with the aid of
chromatogram obtained with solution (2) (1.0%). ultrasound. Add sufficient of a mixture containing 1 volume
Disregard any peak with an area less than the area of the of water and 9 volumes of acetonitrile to produce 100 mL,
‘
peak due to glimepiride iin the chromatogram obtained with

Lo
(2) 0.01% wiv of ghmepinde BPCRS in a mixture of 1 volume

rae)
of water and 4 volumes of acetonitrile.

vo
a4
ess than 2 mg and/or 2% w/w of (3) 0.04% w/v of ghmepiride for system suitability BPCRS in a
,
ith the requirements stated under mixture of 1 volume of water and 4 volumes of acetonitrile.
method of analysis. CHROMATOGRAPHIC CONDITIONS
Carry out the methodic The chromatographic conditions described under Uniformity
eC.
Appendix III D, using ti of content may be used.

ee
ot
solutions at a temperature not |

Tee
te.
SYSTEM SUITABILITY
‘
15 hours. |
ta tL

Te
.
(1) To one tablet add 1 mLo

eee eo

OG
eso eS
impurity B and impurity C is at least 4.0.

water and 9 volumes of acetonitrile, mixX*wi
By
Ce
ultrasound for 15 minutes. Dilute to 10 : DETERMINATION OF CONTENT

a,
solvent, centrifuge and use the supernatant hig Calculate the content of C24H34N,05S in the tablets using
necessary with mobile phase to produce a solu the declared content of C.,H34N,05S in ghmepiride BPCRS.
to contain 0.01% w/v of Glimepiride. IMPURITIES
(2) 0.01% w/v of ghmepiride BPCRS in a mixture of The impurities limited by the requirements of this
of water and 4 volumes of acetonitrile. monograph include those listed under Glimepiride.
(3) 0.04% w/v of ghmepinde for system suitabihty BPCRS in
mixture of 1 volume of water and 4 volumes of acetonitrile.
(Phenomenex Lichrospher RP 18 is suitable).
below.
(e) Use an auto-sampler temperature of 12°. The tablets comply with the r
(f) Use a detection wavelength of 228 nm. with the following requirements:
(g) Inject 10 wL of each solution.
MOBILE PHASE
Equal volumes of a 0.1% w/v solution of sodium dihydrogen IDENTIFICATION
phosphate dihydrate and acetonitrile R1, the pH adjusted to 2.5 A. The light absorption, Appendix II B, in
with orthophosphoric acid. 320 nm of the final solution obtained in theA
SYSTEM SUITABILITY maxima at 226 nm and 274 nm.
The test is not valid unless, in the chromatogram obtained B. Shake a quantity of the powdered tablets containing
with solution (3), the resolution between the peaks due to 25 mg of Glipizide with 10 mL of dichloromethane for
impurity B and impurityC is at least 4.0. 5 minutes, filter, dry the filtrate with anhydrous sodium sulfate,
filter again and evaporate the filtrate to dryness. The infrared
Calculate the content of C,,4H34N,0O;S in each tablet using concordant with the reference spectrum of glipizide (RS 169).
the declared content of C24H34N,405S in glimepiride BPCRS.
TEST
ASSAY Related substances
For tablets containing less than 2 mg, or 2% wiw of Carry out the method for thin-layer chromatography,
glimepiride Appendix III A, using the following solutions.
(1) Extract a quantity of the powdered tablets containing
0.1 g of Glipizide with four 10-mL quantities of acetone,
evaporate the combined extracts to dryness under reduced
oan
ee ath
Se one
ta
pressure at a temperature not exceeding 30° and dissolve the

2016 Gliquidone Preparations III-633
residue in sufficient of a mixture of equal volumes of B. In the test for Related substances, the principal spot in the
dichloromethane and methanol to produce 5 mL. chromatogram obtained with solution-(1) corresponds to that
~ (2) Dilute 1 volume of solution (1) to 200 volumes with a in the chromatogram obtained with solution (2).
mixture of equal volumes of dichloromethane and methanol. TESTS
(3) Dilute 1 volume of solution (1) to 500 volumes with the Dissolution
same solvent mixture. Comply with the requirements for Monographs of the British
(4) 0.010% w/v of ghpizide impunity A EPCRS (5-methyl-N- Pharmacopoeia in the dissolution test for tablets and capsules,
[2-(4-sulfamoylphenyl) ethyl] pyrazine-2-carboxamide) in a Appendix XII B1, using Apparatus 2. Use as the medium
mixture of equal volumes of dichloromethane and methanol. 900 mL of a citro-phosphate buffer prepared by dissolving
35.6 g of disodium hydrogen orthophosphate dihydrate in
sufficient water to produce 1000 mL, adjusting the pH to 8.5
with citric acid, and rotate the paddle at 75 revolutions per
minute. Withdraw a sample of 50 mL of the medium and
filter (Whatman No. | filter paper is suitable), discarding the
first 15 mL of filtrate. Measure the absorbance of the filtered
15 cm. solution, Appendix II B, at the maximum at 314 nm using a
filtered solution of the dissolution medium in the reference
(e) After removal
cell. Measure the absorbance of a solution of
ultraviolet light (254
ghquidone BPCRS prepared in the following manner. Dissolve
MOBILE PHASE about 30 mg of ghgquidone BPCRS in 10 mL of
20 volumes of ethyl acetat dimethylformamide, add sufficient dissolution medium to
acid and 40 volumes of dich produce 100 mL and mix. Dilute 10 mL of this solution to
LIMITS 100 mL with dissolution medium, mix and filter (Whatman
No. 1 filter paper is suitable), discarding the first 15 mL of
filtrate. Calculate the total content of gliquidone,
any spot corresponding to glipizide impu ot more C.7H33N30¢S, in the medium from the absorbances
intense than the spot in the chromatogra obtained and from the declared content of C.7H33N30;S in
solution (4) (0.5%); ghquidone BPCRS.
any other secondary spot is not more intensethan r Related substances
the chromatogram obtained with solution (2) (0.5%) Carry out the method for thin-layer chromatography,
and not more than two such spots are more intense than ndix III A, using silica gel GF>54 as the coating
spot in the chromatogram obtained with solution (3) (0.2% ce and a mixture of 5 volumes of glacial acetic acid,
ASSAY es of ethanol (96%), 45 volumes of chloroform and
Weigh and powder 20 tablets. To a quantity of the powder es of cyclohexane as the mobile phase but allowing
containing 15 mg of Glipizide add 30 mL of methanol, heat olyent front to ascend 10 cm above the line of
gently on a water bath whilst shaking, cool and add sufficient
methanol to produce 50 mL. Filter and dilute 5 mL of the
filtrate to 50 mL with methanol. Measure the absorbance of
the resulting solution at the maximum at 274 nm, 50 volumes of dichloromethane and
Appendix II B, using methanol in the reference cell. Calculate ix with the aid of ultrasound for
the content of C,;H»7N50,S taking 237 as the value of 10 minutes, add suf -of the same solvent mixture to
A(1%, 1 cm) at the maximum at 274 nm. produce 10 mL, filters@ ne
suitable) and use the filtrate. Solution (2) contains 1.0% w/v
of gliquidone BPCRS in a tiixture of 50 volumes of
dichloromethane and 50 volumé
Gliquidone Tablets
Action and use
Inhibition of ATP-dependent potassium channels sulfonamide BPCRS in a mixture of 50 vol
(sulfonylurea); treatment of diabetes mellitus. dichloromethane and 50 volumes of methanol.
ution (4).
DEFINITION After removal of the plate, allow it to dry in air and examine
Gliquidone Tablets contain Gliquidone. under ultraviolet hght (254 nm). In the chromatogram
obtained with solution (1) any spot corresponding to
gliquidone sulfonamide is not more intense than the spot in
the chromatogram obtained with solution (4) (1%) and any
Content of gliquidone, C,7H33N3;0,S other secondary spot is not more intense than the spot in the
95.0 to 105.0% of the stated amount. chromatogram obtained with solution (3) (0.3%). The test is
IDENTIFICATION not valid unless the chromatogram obtained with solution (5)
A. Extract a quantity of the powdered tablets containing shows two clearly separated principal spots.
30 mg of Gliquidone in 10 mL of methanol with the aid of ASSAY
ultrasound, filter, evaporate the filtrate to dryness using a Weigh and powder 20 tablets. To a quantity of the powdered
rotary evaporator and dry the residue at a temperature of 50° tablets containing 0.1 g of Gliquidone add 50 mL of
at a pressure of 2 kPa for 1 hour. The infrared absorption
ee
methanol, mix with the aid of ultrasound for 10 minutes,

spectrum of the dried residue, Appendix II A, is concordant allow to cool, add sufficient methanol to produce 100 mL and
with the reference spectrum of gliquidone (RS 170).
IiI-634 Glucagon Preparations 2016
filter. Dilute 15 mL of the filtrate to 100 mL with methanol Dissolve 16.3 g of potasstum dihydrogen orthophosphate in
and measure the absorbance of the resulting solution at the 800 mL of water, adjust to pH 2.7 with orthophosphoric acid.
aN,
maximum at 310 nm, Appendix II B. Calculate the content Mobile phase B 400 volumes of acetomitrile for chromatography
of C.7H33N30¢S in the tablets from the absorbance of a and 600 volumes of water.
0.015% w/v solution of glhquidone BPCRS in methanol and
Use the following gradient elution.
using the declared content of C.7H33N30,S in
ghquidone BPCRS.
DEFINITION Note: The relative retention time with respect to glucagon

Human Glucagon is a sterile material consisting (retention time about 21 minutes) of deamidated glucagon 1
of freeze-dried Huma m (produced by recombinant is about 1.1. The end time of the isocratic elution may be
adjusted so that the gradient begins after elution of the peak
a sealed container. due to deamidated glucagon 4 (relative retention with
The contents of the sealed containé} reference to glucagon about 1.4).
for Powders for Injections stated u SYSTEM SUITABILITY
and with the following requirements. The test is not valid unless, in the chromatogram obtained
Content of glucagon, C,53H>.;N43049S with solution (3):
75.0 to 104.0% of the stated amount. the resolution factor between the peak due to glucagon and the
IDENTIFICATION following peak due to deamidated glucagon 1 is at least 1.5;
In the Assay, the retention time of the principal peak 4 the 4 peaks eluting after the principal peak, that correspond
chromatogram obtained with solution (1) is similar to th to the deamidated forms, are clearly visible;
the principal peak in the chromatogram obtained with d, in the chromatogram obtained with solution (2):
solution (2). metry factor of the peak due to glucagon is a
TESTS m, of 1.8;
Acidity
PH of a 0.1% w/v solution, 2.5 to 3.5, Appendix V L.
Related proteins and deamidated forms
Appendix III D, using the following solutions and the
(1) Dissolve the powder being examined in 0.01m hydrochloric
acid to obtain the equivalent of 0.05% w/v of human
glucagon. Maintain the solution at 2° to 8°.
(2) Dissolve the contents of a vial of human glucagon EPCRS
in 0.01m hydrochloric acid to obtain a concentration of
(containing 1 mg of the powde
0.05 % why. Maintain the solution at 2° to 8°.
(3) Dissolve the powder being examined in 0.01m hydrochloric
acid to obtain a concentration of about 0.05% w/v human Carry out the test for bacterial endotox
Dissolve the contents of the sealed conta
glucagon. Heat at 50° for 48 hours (generation of all 4
deamidated forms of glucagon at a total concentration of not
less than 7%).
is 10 IU of endotoxin per mL.
ASSAY
with octadecylsilyl sihca gel for chromatography (3 um) (ACE 3
Appendix III D, using the method described under Related
C18 is suitable).
proteins and deamidated forms, injecting solutions (1)
(b) Use gradient elution and the mobile phase described and (2).
below.
Calculate the content of human glucagon
(C153H225N43040S) from the chromatograms obtained and
(e) Use a detection wavelength of 214 nm. using the declared content of C,53H225N43049S in human
(f) Inject 15 wL of each solution. glucagon EPCRS.
MOBILE PHASE STORAGE
Mobile phase A 200 volumes of acetonitrile for chromatography Human Glucagon for Injection should be protected from
and 800 volumes of the solution prepared as described light and stored strictly in accordance with the
below. manufacturer’s instructions.
2016 Glucose Preparations III-635
Glucose Infusion Compound Glucose, Sodium Chloride

Glucose Injection and Sodium Citrate Oral Solution
Glucose Intravenous Infusion St. Marks Solution
DEFINITION NOTE: Compound Glucose, Sodium Chloride and Sodium Citrate
Glucose Infusion is a sterile solution containing Anhydrous Oral Solution 1s not currently licensed in the United Kingdom.
Glucose or Glucose. It is supplied as a ready-to-use solution.
The infusion complies with the requirements stated under Action and use
Parenteral Preparations and with the following requirements. Prevention and treatment of dehydration.
Content of glucose, C,H,;,0¢ DEFINITION

95.0 to 105.0% of the stated amount. Compound Glucose, Sodium Chloride and Sodium Citrate
TERISTICS Oral Solution contains Anhydrous Glucose, Sodium Chloride
solution. Solutions containing the equivalent of and Sodium Citrate. It is prepared by dissolving the dry
ingredients in the specified volume of Water just before issue
for use.
The following formula and directions apply.
A. Heat with cupri-t
Anhydrous Glucose 20 g
produced.
Sodium Chloride 3.5 ¢g
B. The solution prepare Sodium Citrate 2.5 g
dextrorotatory. Water Sufficient to produce 1000 mL
TESTS Dissolve the dry ingredients in Water and add sufficient
Acidity ' Water to produce 1000 mL.
pH, 3.5 to 6.5, Appendix V L, when det
solution diluted, if necessary, with water joy
Liquids, the requirements stated under Unlicensed Medicines and
contain not more than the equivalent of 5%
potassium chloride has been added for each 100 m Qt Content of glucose, Cs5H,,0¢
solution. 1.9 to 2.1% wiv.
5-Hydroxymethylfurfural and related substances Content of sodium chloride, NaCl

Dilute a volume containing the equivalent of 1.0 g of 0.37% wiv.
glucose, CgH,20¢, to 250 mL with water. The absorbance of : t of sodium citrate, CsH;Na3;0/,2H,O
the resulting solution at the maximum at 284 nm is not more 26% wiv.
than 0.25, Appendix IT B.
CATION
Bacterial endotoxins | with cupri-tartaric solution R1. A red
The endotoxin limit concentration is 0.25 IU per mL, pre pitat
Appendix XIV C. Dilute infusions containing more than
B. Yields re haracteristic of sodium salts, reaction A
5% wy of Glucose with water BET to contain 5% w/v.
characteristic es and the reactions characteristic of
ASSAY
To a volume containing the equivalent of 2 g to 5 g of C. The solution prep red asdirected in the Assay for glucose
glucose, Cg5H)2.0O.,, add 0.2 mL of 5M ammonia and sufficient is dextrorotatory.
water to produce 100 mL. Mix well, allow to stand for
TESTS
30 minutes and determine the optical rotation in a 2-dm tube,
Appendix V F. The observed rotation in degrees multiplied Acidity or alkalinity
by 0.9477 represents the weight in g of glucose, CgH,20O¢, in
the volume taken for assay. ASSAY
LABELLING For glucose
The strength is stated as the equivalent number of grams of To 100 mL of the solution add 0.2 mL of 5)
glucose, CgH)20,, per litre.
mix well. Allow to stand for 30 minutes and detérmine the
optical rotation in a 2-dm tube, Appendix V F. Multiply the
When Glucose Infusion is required as a diluent for Injections
observed rotation in degrees by 0.9477, then by 1.002 and
or Infusions of the Pharmacopoeia, Glucose Infusion (50 g
then by 10 to calculate the weight in grams of glucose,
per litre) shall be used.
C.6H,,0¢, in the original powder.
For sodium chloride
Titrate 20 mL of the solution with 0.1M silver nitrate VS using
potassium chromate solution as indicator. Each mL of silver
nitrate VS is equivalent to 5.844 mg of NaCl.
For sodium citrate
Evaporate 25 mL of the solution almost to dryness on a
rotary evaporator, add 10 mL of acetone and evaporate to
dryness. Add 10 mL of acetone, 10 mL of acetic anhydride and
20 mL of anhydrous acetic acid to the residue and warm to
about 60° until dissolution is complete. Allow to cool and
III-636 Glutaraldehyde Preparations 2016
carry out Method I for non-aqueous titration, IDENTIFICATION

Appendix VIII A, using 0.25 mL of crystal violet solution as Mix 1 mL of the eye drops with 0.5 mL of mitric acid and
indicator, titrating to a blue end point. Each mL of superimpose 0.5 mL of potassium dichromate solution. A blue
0.1m perchloric acid VS is equivalent to 9.803 mg of ring develops at the interface of the liquids, which does not
C.6H5Na307,2H.,O. diffuse into the lower layer within 10 minutes.
STORAGE TESTS
Compound Glucose, Sodium Chloride and Sodium Citrate Acidity or alkalinity
Oral Solution should be stored at a temperature of 2° to 8°. pH, 4.5 to 7.5, Appendix V L.
LABELLING ASSAY
The label states that any portion of the oral solution that Dilute a suitable volume of the eye drops with sufficient
24 hours after preparation should be water to produce a solution containing 3% w/v of Glycerol.
To 5 mL add 150 mL of water and neutralise with
0.1M sodium hydroxide VS, using bromocresol purple solution as
indicator. Add 1.6 g of sodium periodate and allow to stand
protected from light for 15 minutes. Add 3 mL of propan-
1,2-diol, shake, allow to stand protected from light for
Glutaraldehyc 5 minutes and titrate with 0.1m sodium hydroxide VS. Each
DEFINITION mL of 0.1m sodium hydroxide VS is equivalent to 9.21 mg of
Glutaraldehyde Solution 1 . of Strong C3HgO3,
Glutaraldehyde Solution in yf Purified Water and STORAGE
Ethanol (96 per cent). Glycerol Eye Drops should be protected from light.
In making Glutaraldehyde Soluti Strengths available
may be replaced by Industrial Methylat
Eye Drops containing 10, 20, 30 and 50% w/v of glycerol are
Content of glutaraldehyde, C;H,;O, available.
9.2 to 10.5% w/v.
IDENTIFICATION :
A. Heat 5 mL with 10 mL of a solution containing ?'g
hydroxylamine hydrochloride and 2 g of sodium acetate o
water bath for 10 minutes, allow to cool and filter. The
Glycerol Suppositories
lycerin Suppositories
melting point of the residue, after washing with water and
drying at 105°, is about 178°, Appendix V A.
B. To 1 mL add 2 mL of ammoniacal silver nitrate solution l4g
and mix gently for a few minutes. Silver is deposited. 70 g
A sufficient quantity
TESTS
Ethanol content ibtropical countries the quantity of Gelatin
50.0 to 60.0% v/v, Appendix VIII F. k amount not exceeding 18 g.
ASSAY
Mix 10 mL with 100 mL of a 7% w/v solution of
hydroxylamine hydrochloride previously neutralised to
bromophenol blue solution with 1m sodium hydroxide VS and nearly to boiling, then ade
allow to stand for 30 minutes. Add 20 mL of petroleum spirit 100° and heat the mixture
(boiling range, 40° to 60°) and titrate with 1m sodium hydroxide until solution is complete. Ad
VS until the colour of the aqueous phase matches that of a to 100 g by the addition of hot Pti ‘ater or by
7% w/v solution of hydroxylamine hydrochloride previously evaporation on a water bath and po itable moulds.
neutralised to bromophenol blue solution with 1M sodium The suppositories comply with the requirements stated under Rectal
hydroxide VS. Each mL of 1m sodium hydroxide VS is Preparations and with the following requiremé?it
equivalent to 50.05 mg of C5HgQO>. Content of glycerol, C;H;QO3
66.5 to 73.5% w/w.
'The law and the statutory regulations governing the use of Industrial
Methylated Spirit must be observed. Disintegration
Maximum time, 1 hour, Appendix XII A2.
Te ot ASSAY
Dissolve a number of suppositories containing 8 g of
Glycerol in 50 mL of water and add sufficient water to
Glycerol Eye Drops produce 250 mL. To 5 mL add 150 mL of water and
DEFINITION 0.25 mL of bromocresol purple solution and neutralise with
Glycerol Eye Drops area sterile solution of Glycerol in 0.1M sodium hydroxide VS to the blue colour of the indicator.
Purified Water. Add 1.6 g of sodium periodate and allow to stand for
The eye drops comply with the requirements stated under Eye 15 minutes. Add 3 mL of propan-1,2-diol, shake, allow to
Preparations and with the following requirements. stand for 5 minutes and titrate with 0.1m sodium hydroxide VS
to the same blue colour. Each mL of 0.1m sodium hydroxide
Content of glycerol, C;H;0;3
VS is equivalent to 9.210 mg of C3HgQ3.
95.0 to 105.0% of the stated amount
2016 Glyceryl Trinitrate Preparations III-637
Glyceryl Trinitrate Ointment reaction vial at 100° for 30 minutes (production of the
dinitrate impurities).
Action and use (4) Dilute 1 volume of solution (2) to 10 volumes with
Vasodilator. methanol.
DEFINITION
Glyceryl Trinitrate Ointment contains Glyceryl Trinitrate in a
with octadecylsilyl silica gel for chromatography (5 yum)
suitable basis.
(Nucleosil C18is suitable).
below.
f glyceryl trinitrate, C;H;N3;0,
0% of the stated amount.
method for thin-layer chromatography,
=the following solutions.
for three times the retention time of the principal peak.
MOBILE PHASE
50 volumes of acetonitrile R1 and 50 volumes of water.

(2) Dilute a quantity of glyceé When the chromatograms are recorded under the prescribed
sufficient methanol to product conditions the retention times relative to glyceryl trinitrate
approximately 0.01% w/v of (retention time, about 11 minutes) are: glyceryl mononitrate,
(3) Equal volumes of solutions (1) and ¢2). about 0.23; 1,3-glyceryl dinitrate, about 0.42; 1,2-glyceryl
dinitrate, about 0.45.
CHROMATOGRAPHIC CONDITIONS |
(a) Use a silica gel plate (Merck silica gel 60) SYSTEM SUITABILITY
suitable). | The test is not valid unless the chromatogram obtained with
(b) Use the mobile phase as described below. solution (3) resembles the reference chromatogram supplied
with glyceryl trinitrate solution BPCRS, in that it shows a
principal peak due to glyceryl trinitrate and two clearly
(d) Develop the plate to 15 cm. ted peaks due to the dinitrate impurities.
(e) After removal of the plate, dry in a current of cool air,
spray with freshly prepared potasstum todide and starch solution
Expose the plate to ultraviolet hght (254 nm) for 15 minutes romatogram obtained with solution (1):
and examine in daylight. . ALE, of anypeak due to glyceryl mononitrate, 1,3-glyceryl
MOBILE PHASE
20 volumes of ethyl acetate and 80 volumes of toluene.

SYSTEM SUITABILITY
CONFIRMATION
obtained with solution (2). Disregard any peak with an area
a
B. In the Assay, the chromatogram obtained with solution principal peak in the chromatogr
(1) shows a peak with the same retention time as the solution (4) (0.1%).
principal peak in the chromatogram obtained with ASSAY
solution (2). Carry out the method for liquid chromatograph
TESTS Appendix III D, using the following solutions.
Related substances (1) To a quantity of the ointment containing 40 mg of
Carry out the method for liguid chromatography, Glyceryl Trinitrate add 70 mL of methanol and, completely
Appendix III D, using the following solutions. disperse with the aid of ultrasound. Cool the contents in ice
for 30 minutes, allow to attain room temperature, add
(1) To a quantity of the ointment containing 50 mg of
sufficient methanol to produce 100 mL and centrifuge.
Glyceryl Trinitrate add 70 mL of methanol and completely
disperse with the aid of ultrasound. Cool the contents in ice (2) Dilute a quantity of glyceryl trinitrate solution BPCRS with
for 30 minutes, allow to attain room temperature, add sufficient methanol to produce a solution containing
sufficient methanol to produce 100 mL and centrifuge. 0.04% w/v of Glyceryl Trinitrate.
(2) Dilute 1 volume of solution (1) to 100 volumes with (3) Dilute a quantity of glyceryl trimtrate solution BPCRS with
methanol. sufficient 1m hydrochloric acid to produce a solution
(3) Dilute a quantity of glyceryl trinitrate solution BPCRS with containing 0.05% w/v of Glyceryl Trinitrate and heat in a
sufficient 1m hydrochloric acid to produce a solution reaction vial at 100° for 30 minutes.
containing 0.05% w/v of Glyceryl Trinitrate and heat in a
IWI-638 Glyceryl Trinitrate Preparations 2016
CHROMATOGRAPHIC CONDITIONS chromatogram obtained with solution (2). The principal spot
(a) Use a stainless steel column (25 cm x 4.6 mm) packed in the chromatogram obtained with solution (3) appears as a
with octadecylsilyl silica gel for chromatography (5 um) single compact spot.
(Nucleosil C18 is suitable). B. In the Assay, the chromatogram obtained with solution
(b) Use isocratic elution and the mobile phase described (1) shows a peak with the same retention time as the
below. principal peak in the chromatogram obtained with
(c) Use a flow rate of 1.3 mL per minute. solution (2).
(d) Use an ambient column temperature. TESTS

(e) Use a detection wavelength of 225 nm. Related substances
(1) expel a number of metered doses containing the
mol and 50 volumes of water. equivalent of about 5 mg of glyceryl trinitrate into a beaker,
grams are recorded under the prescribed dilute to 5 mL with methanol, mix well and add sufficient
water to produce 10 mL. For solution (2) dilute 1 volume of
solution (1) to 100 volumes with methanol (50%). For
about 0.4; 1,2-glyceryt solution (3) dilute a quantity of glyceryl trinitrate
dinitrate, about 0.7. solution BPCRS with sufficient 1M hydrochloric acid to produce
a solution containing 0.05% w/v of glyceryl trinitrate and
SYSTEM SUITABILITY
heat in a reaction vial at 100° for 30 minutes.
The test is not valid unless, in
- with solution (3), the peak to v ween
1,3-glyceryl dinitrate and 1,2-glyce fe is at least 5.
octadecylsilyl silica gel for chromatography (5 um) (Nucleosil
DETERMINATION OF CONTENT C18 is suitable), (b) as the mobile phase with a flow rate of
Calculate the content of C;3H5N3QOo in the m 1.0 mL per minute a mixture of 50 volumes of acetonitrile
the declared content of C;H5N3O¢ in glycery and 50 volumes of water and (c) a detection wavelength of
solution BPCRS. 210 nm.
solution (3) resembles the reference chromatogram supplied
ith glyceryl trinitrate solution BPCRSin that it shows a
carerpal peak due to glyceryl trinitrate and two clearly
Glyceryl Trinitrate Sublingual Spray “peaks due to the dinitrate impurities with retention
DEFINITION ve to glyceryl trinitrate of approximately 0.5.
Glyceryl Trinitrate Sublingual Spray contains Glyceryl inatogram obtained with solution (1) the area of
Trinitrate Solution in a suitable vehicle either in a suitable peakis not greater than the area of the
pressurised container or in a container fitted with a spray pal p itithe chromatogram obtained with solution
device. (2) (1%) an im.@f areas of any secondary peaksis not
PRODUCTION greater than t [ e area of the principal peakin the
chromatogram obtai ith solution (2) (3%). Disregard
A suitable test is carried out to demonstrate the uniformity of
any peak with an ar n 0.1 times the area of the
dose.
principal peak in the métogram obtained with solution
The oromucosal spray complies with the requirements stated under (2) (0.1%).
ASSAY
Content of glyceryl trinitrate, C;,H;N30,5
Carry out the method for liquid chro
80.0 to 120.0% of the amount stated to be delivered per
metered dose.
(1) collect 10 metered doses in a vessel
IDENTIFICATION material, dissolve the expelled material 1
plates are suitable) and a mixture of 20 volumes of ethyl (2) dilute a quantity of glyceryl trinitrate solution B i
acetate and 80 volumes of toluene as the mobile phase. Apply sufficient methanol (50%) to produce a solution containing
separately to the plate 5 wL of each of the following 0.04% w/v of glyceryl trinitrate.
solutions. For solution (1) expel a number of metered doses The chromatographic procedure may be carried out using
containing the equivalent of about 4 mg of glyceryl trinitrate (a) a stainless steel column (25 cm x 4.6 mm) packed with
into a beaker, add 5 mL of acetone, transfer to a graduated octadecylsilyl silica gel for chromatography (5 ym) (Nucleosil
flask and add sufficient acetone to produce 10 mL. C18 is suitable), (b) as the mobile phase with a flow rate of
For solution (2) dilute a quantity of glyceryl trinitrate 1.3 mL per minute a mixture of 50 volumes of methanol and
solution BPCRS with methanol (50%) to produce a solution 50 volumes of water and (c) a detection wavelength of
containing 0.04% w/v of glyceryl trinitrate. Solution (3) is a 225 nm.
mixture of equal volumes of solutions (1) and (2). After
Calculate the content of C3H;N3O, per metered dose using
removal of the plate, allow it to dry in air and spray with
the declared content of C3H5N3O¢ in glyceryl trinitrate
freshly prepared potassium todide and starch solution. Expose
solution BPCRS.
the plate to ultraviolet ight (254 nm) for 15 minutes and
examine in daylight. The principal spot in the chromatogram
obtained with solution (1) corresponds to that in the
2016 Glyceryl Trinitrate Preparations III-639
Glyceryl Trinitrate Tablets CHROMATOGRAPHIC CONDITIONS

Glyceryl Trinitrate Sublingual Tablets; Trinitrin Tablets;
with with octadecylsilyl silica gel for chromatography (5 um)
Nitroglycerin Tablets
(Nucleosil ODS is suitable).
DEFINITION (b) Use isocratic elution and the mobile phase described
Glyceryl Trinitrate Tablets are sublingual tablets made with below.
Mannitol as the basis and may be prepared by adding (c) Use a flow rate of 1.0 mL per minute.
Glyceryl Trinitrate Solution of an appropriate concentration
to dried granules of Mannitol, mixing intimately, drying at a
temperature not exceeding 50° or without heating for not (e) Use a detection wavelength of 210 nm.
more than 4 hours and compressing. (f) Inject 50 wL of each solution.
for three times the retention time of the principal peak.
MOBILE PHASE

SYSTEM SUITABILITY
IDENTIFICATION with glyceryl trinitrate solution BPCRS in that it shows a
A. Carry out the method for. principal peak due to glyceryl trinitrate and two clearly
Appendix II A, using the fol separated peaks due to the dinitrate impurities with retention
(1) Extract a quantity of the D times relative to glyceryl trinitrate of approximately 0.5.
0.5 mg of glyceryl trinitrate with 1 mL LIMITS
centrifuge. In the chromatogram obtained with solution (1):
(2) Dilute a quantity of glyceryl trimtrate solitt
sufficient water to produce a solution containi the principal peak in the chromatogram obtained with
of glyceryl trinitrate. solution (2) (1%);
CHROMATOGRAPHIC CONDITIONS the sum of the areas of any such peaks is not greater than
(a) Use as the coating silica gel G. three times the area of the principal peak in the
(b) Use the mobile phase as described below. matogram obtained with solution (2) (3%).
(c) Apply 20 pwL of each solution. any peak with an area less than 0.1 times the area
(d) Develop the plate to 15 cm. ncipal peak in the chromatogram obtained with
(e) After removal of the plate, dry in a stream of air, spray

with diphenylamine solution R1 and irradiate for 15 minutes
with ultraviolet hght (365 nm). Examine the plate in daylight.
MOBILE PHASE
toluene.
CONFIRMATION
The principal spot in the chromatogram obtained with e tablet, mix with the aid of
solution (1) corresponds in position and colour to that in the rough a 4-um filter and
chromatogram obtained with solution (2). qual volume of water.
3 mg of glyceryl trinitrate with 5 mL of ether and filter.
Evaporate the ether and dissolve the residue in 0.2 mL of
sulfuric acid containing a trace of diphenylamine. An intense (3) Dilute a quantity of glyceryl trinitrate s ation PCRS with
blue colour is produced. sufficient 1m hydrochloric acid to produce a sol /
TESTS containing 0.05% w/v of glyceryl trinitrate and h tina
reaction vial at 100° for 30 minutes.
Related substances
Appendix III D, using the following solutions. The chromatographic conditions described under Related
(1) Mix a quantity of the powdered tablets containing 2.5 mg substances may be used, with the exception of the run time.
of glyceryl trinitrate with 10 mL of acetonitrile with the aid of SYSTEM SUITABILITY
ultrasound, filter through a 4-um filter and dilute one volume
of the filtrate with an equal volume of water.
(2) Dilute 1 volume of solution (1) to 100 volumes with the with glyceryl trinitrate solution BPCRS in that it shows a
mobile phase. principal peak due to glyceryl trinitrate and two clearly
(3) Dilute a quantity of glyceryl trinitrate solution BPCRS with separated peaks due to the dinitrate impurities with retention
sufficient 1M hydrochloric acid to produce a solution times relative to glyceryl trinitrate of approximately 0.5.
containing 0.05% w/v of glyceryl trinitrate and heat in a
reaction vial at 100° for 30 minutes.
IlI-640 Glyceryl Trinitrate Preparations 2016
DETERMINATION OF CONTENT B. In the test for Uniformity of content, the chromatogram

Calculate the content of C;3H;N30, in each tablet from the obtained with solution (1) shows a peak with the same
chromatograms obtained and using the declared content of retention time as the principal peak in the chromatogram
C3H5N3QOo in glyceryl trinitrate solution BPCRS. obtained with solution (2).
ASSAY TESTS
Use the average of the 10 individual results obtained in the Related substances
test for Uniformity of content. Carry out the method for liguid chromatography,
STORAGE
(1) Clean the outer surface of five patches using a lint-free
Glyceryl Trinitrate Tablets should be protected from light
cloth moistened with methanol. Remove the release liners and
and stored in a glass container closed by means of a screw
score the exposed surfaces. Place the patches in a flask
closure lined:with aluminium or tin foil; additional packing
containing sufficient methanol to produce a solution
containing 0.1% w/v of glyceryl trinitrate, mix with the aid of
ultrasound in a water bath at 40° for 15 minutes and then
shake mechanically at room temperature for 3 hours. Dilute
the methanolic extract with sufficient water to produce a final
concentration of 0.05% w/v of glyceryl trinitrate.
methanol (50%).
DEFINITION (3) Dilute a quantity of glyceryl trinitrate solution BPCRS with
Glyceryl Trinitrate Transderma sufficient 1M hydrochloric acid to produce a solution
trinitrate in a suitable matrix or containing 0.05% w/v of glyceryl trinitrate and heat in a
are prepared from Glyceryl Trinitrate§ reaction vial at 100° for 30 minutes.
PRODUCTION !
A suitable dissolution test 1s carried out to d C. (a) Use a stainless steel column (25 cm x 4.6 mm) packed
appropriate release of glyceryl trinitrate. with octadecylsilyl silica gel for chromatography (5 um)
The transdermal patches comply with the requirements si
under Transdermal Patches and with the following require (b) Use isocratic elution and the mobile phase described
ebelow.
Content of glyceryl trinitrate, C;,H;N30,
90.0 to 115.0% of the stated amount. se.a flow rate of 1.0 mL per minute.
ambient column temperature.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, etection wavelength of 210 nm.
Appendix ITI A, using the following solutions. ) ul, of each solution.
(1) Clean the outer surface of a patch using a lint-free cloth
moistened with methanol. Remove the release liner and score
the exposed surface. Place the patch in a flask containing
sufficient methanol to produce a solution containing 0.1% w/v
of glyceryl trinitrate, mix with the aid of ultrasound in a
water bath at 40° for 15 minutes and then shake solution (3) closely resembl
mechanically at room temperature for 3 hours. Dilute the supplied with glyceryl trimwtate:
methanolic extract with sufficient water to producea final a principal peak due to glyc
concentration of 0.05% w/v of glyceryl trinitrate.
(2) Dilute a quantity of glyceryl trinitrate solution BPCRS with
methanol (50%) to produce a solution containing 0.05% w/v
of glyceryl trinitrate.
CHROMATOGRAPHIC CONDITIONS the area of any secondary peak is not greater thi
(a) Use as the coating silica gel (Merck silica gel plates are the principal peak in the chromatogram obtained
suitable). solution (2) (1%);
(b) Use the mobile phase as described below. the sum of the areas of any secondary peaks is not greater than
three times the area of the principal peak in the
(e) After removal of the plate, dry in air, spray with freshly of the principal peak in the chromatogram obtained with
prepared potassium todide and starch solution. Expose the plate solution (2) (0.1%).
to ultraviolet ight (254 nm) for 15 minutes and examine in
daylight.
Comply with the requirements stated under uniformity of
MOBILE PHASE content, Appendix XII C3, Test C, with respect to the
20 volumes of ethyl acetate and 80 volumes of toluene. individual content of each dosage unit and using the
CONFIRMATION following method of analysis. Carry out the method for liquid
solutions.
2016 Glycopyrronium Bromide Preparations III-641
(1) Clean the outer surface of a patch using a lint-free cloth CONFIRMATION
moistened with methanol. Remove the release liner and score The principal spot in the chromatogram obtained with
the exposed surface. Place the patch in a flask containing solution (1) corresponds in position and colour to that in the
hm sufficient methanol to produce a solution containing 0.1% w/v chromatogram obtained with solution (2).
of glyceryl trinitrate, mix with the aid of ultrasound in a
TESTS
water bath at 40° for 15 minutes, shake mechanically at
Acidity
room temperature and dilute a volume of the solution with
an equal volume of water.
(2) Dilute a quantity of glyceryl trinitrate solution BPCRS with Ammonium compounds
sufficient methanol (50%) to produce a solution containing Dilute a volume containing 0.2 g of Glycine to 70 mL with
0.05% w/v of glyceryl trinitrate. water in an ammonia-distillation apparatus, add 25 mL of a
solution prepared by boiling 25 mL of 5m sodium hydroxide
RAPHIC CONDITIONS
with 50 mL of water and 50 mg of aluminium until the
volume is reduced to 25 mL and distil into 2 mL of a
saturated solution of boric acid until 50 mL is obtained.
Add 2 mL of a solution prepared by boiling 25 mL of
5m sodium hydroxide with 50 mL of water until the volume is
using the declaredieé: reduced to 25 mL and 2 mL of alkaline potassium
tetraiodomercurate solution. Any colour produced is not more
solution BPCRS.
intense than that obtained by treating 70 mL of water
ASSAY containing 4 mL of ammonia standard solution (10 ppm NH4)
Use the average of the 10 régul OE ined in the test for in the same manner, beginning at the words ‘add 25 mL
Uniformity of content. of...’ (200 ppm, calculated with reference to the content of
IMPURITIES glycine).
A. Glyceryl-1,2-dinitrate, ASSAY
B. Glyceryl-1,3-dinitrate. Dilute a volume containing 0.15 g of Glycine to 25 mL with
water and add 10 mL offormaldehyde solution previously
adjusted to pH 9.0 and 0.25 mL of a mixed indicator
solution prepared by dissolving 75 mg of phenolphthalein and
25 mg of thymol blue in 100 mL of ethanol (50%). Titrate
Glycine Irrigation Solution with 0.1M sodium hydroxide VS until the yellow colour
DEFINITION appears and a faint violet colour is produced. Each mL of
Glycine Irrigation Solution is a sterile solution of Glycine in
Water for Irrigation.
The irrigation solution complies with the requirements stated under
Preparations for Irrigation and with the following requirements.
Content of glycine, C,H;NO,
yrent
CHARACTERISTICS note: Glycop romide Oral Solution 1s not currently
.
licensed 1n the Unité 5

ngdom.
et .
.
.
IDENTIFICATION
:
Action and use

ty
A. Evaporate 5 mL to dryness on a water bath and dry at Anticholinergic.

Ce were
Blots
105° for 1 hour. The infrared absorption spectrum,

neta
Appendix II A, is concordant with the reference spectrum of DEFINITION &

— ta.
>
.*
.
glycine (RS 171). Glycopyrronium Bromide Oral S s.a solution of

Appendix III A, using the following solutions. The oral solution complies with the requiré®meénits.sttited under Oral
(1) Dilute the irrigation solution with water to contain Liquids, the requirements stated under Unlicerise d cines and
0.25% w/v of Glycine. with the following requirements.
(2) 0.25% w/v of glycine in water. Content of glycopyrronium bromide, C, ,H;,;BrNO;
(a) Use as the coating silica gel GF 254. IDENTIFICATION

Appendix III A, using the following solutions in water.
(1) Dilute a volume of the oral solution, if necessary, to
(d) Develop the plate to 15 cm. produce a solution containing 0.01% w/v of Glycopyrronium
(e) After removal of the plate, dry it at 100° to 105° for Bromide.
10 minutes, spray with ninhydrin solution and heat at 100° to (2) 0.01% w/v of glycopyrronium bromide BPCRS.
105° for 2 minutes.
MOBILE PHASE
30 volumes of 13.5M ammonia and 70 volumes of
propan-1-ol.
Ill-642 Goserelin Preparations 2016

Goserelin Implants
(e) After removal of the plate, dry in air, spray with a
solution of 10 volumes of potassium iodide solution, Action and use
10 volumes of potassium todobismuthate solution, 12 volumes of Gonadotrophin-releasing hormone, gonadorelin analogue;
glacial acetic acid and 67 volumes of water. treatment of prostate cancer.
MOBILE PHASE
DEFINITION
Goserelin Implants are biodegradable and biocompatible
60 volumes of butan-1-ol.
cylinders for subcutaneous injection containing Goserelin, as
CONFIRMATION acetate, dispersed in a polymeric matrix. They are formulated
The principal spot in the chromatogram obtained with so that the medicament is released over a period of weeks.
J«corresponds in position and colour to that in the The implants comply with the requirements stated under Parenteral
retention time of the principal peak in Content of goserelin, C59Hs4,N;30,4
tained with solution (1) is similar to 90.0 to 110.0% of the stated amount of the peptide.
solution (2). IDENTIFICATION

In test B for Related substances, the retention time of the
ASSAY principal peak in the chromatogram obtained with solution
Carry out the method fo (1) is similar to that of the principal peak in the
Appendix III D, using the f chromatogram obtained with solution (2).
phase.
TESTS
(1) Dilute a weighed quantity of
Drug release
NOTE: Suitable procedures should be employed to minimise the
presence of bacteria on glassware immediately prior to the
dissolution tests.
(3) Dissolve 2 mg of benzaldehyde EPCRS in S For 3.6 mg implants
dilute to 100 mL with solution (2).
PROCEDURE
Perform the test in a 120-mL flat-bottomed glass jar with a
(a) Use either a stainless steel column (25 cm x 4.6 mm) ap, incubated at 39° + 0.5°. Use as the medium 50 mL of
packed with mitrile silica gel for chromatography (5 um) %4 buffer solution prepared by dissolving 25.8 g of
(Phenomenex PhenoSphere CN is suitable) or a stainless rou’. disodium hydrogen orthophosphate, 1.92 g of citric
steel column (25 cm x 4.6 mm) packed with spherical base- t 0.2 g of sodium azide in sufficient distilled water to
deactivated, end-capped octadecylsilyl silica gel for chromatography 100 mL. Adjust the pH of the resulting solution to
(5 um) (Restek Pinnacle DB C18 is suitable).
(b) Use isocratic elution and the mobile phase described nd filter througha sterile filter with a
below. iot.greater than 0.2 um intoa sterile
(c) Use a flow rate of 2 mL per minute. nplants into the glass vessel, add 50 mL
(d) Use an ambient column temperature. in the incubator. At the times
(f) Inject 20 nL of each solution.
MOBILE PHASE
3 volumes of 0.5m sulfuric acid, 25 volumes of acetonitrile, measure the average of the in
150 volumes of methanol and 615 volumes of a solution obtained at 1 nm intervals between. m and 285 nm,
containing 0.16% w/v of sodium pentanesulfonate and Appendix II B, using the dissolutio Hin the reference
0.032% w/v of sodium sulfate.
replace the volume removed and return th
SYSTEM SUITABILITY
incubator. At least three replicate analyses s
The test is not valid unless, in the chromatogram obtained performed.
to benzaldehyde and glycopyrronium bromide is at least 3.0.
Table |
Determine the weight per mL of the oral solution, Test Duration Amount dissolved
Appendix V G, and calculate the content of C;>)H23BrNOs;, Hours (days) (each replicate)
Ci9H2gBrNO3 in glycopyrronium bromide BPCRS. 168 (7) 2 to 20%
STORAGE 336 (14) 25 to 55%
Glycopyrronium Bromide Oral Solution should be protected
from light. 408 (17) 35 to 75%
504 (21) 65 to 90%
672 (28) 85 to 105%
2016 Goserelin Preparations III-643
DETERMINATION OF CONTENT (3) 0.002% w/v each of + -Ser-goserelin EPCRS and

Calculate the content of C597Hg4N 0,4 dissolved in the goserelin EPCRSin water.
portions of the medium from the absorbance obtained from a CHROMATOGRAPHIC CONDITIONS
solution prepared by diluting a suitable amount of
goserelin EPCRS in the dissolution medium and using the
declared content of C597Hg4N sO14 in goserelin EPCRS; at the
(Spherisorb ODS is suitable).
times specified in Table I the cumulative percentages comply
with the criteria given.
below.
For 10.8 mg implants
PROCEDURE
MOBILE PHASE
f anhydrous disodium hydrogen 0.272% wiv of potassium dihydrogen orthophosphate in a
of sodium azide in 1000 mL of mixture of 27 volumes of acetonitrile and 73 volumes of water.
Adjust the pH to 3.0 with orthophosphoric acid.
ize not greater than 0.2 um
conditions, the relative retention with reference to goserelin
mL of medium to a
(retention time about 30 minutes) of 4-p-Ser-goserelin is
about 0.84.
SYSTEM SUITABILITY
504, 672, 840, 1008, 1176, 1344, 15 The test is not valid unless, in the chromatogram obtained
2016 hours (14, 21, 28, 35, 42, 49, 5 with solution (3):
84 days) following gentle swirling to ensur the resolution between the peaks due to 4-p-Ser-goserelin and
solution. Replace the volume removed with thé’equi goserelin is at least 4.5;
amount of warmed medium. Filter the aliquot, ifstie
the symmetry factor of the peak due to goserelin is less than
and measure the average of the individual absorbang
2.0.
obtained at 1 nm intervals between 275 nm and 285 ng
Appendix IT B, using the dissolution medium in the refe LIMITS
cell. At least six replicate analyses should be performed. 1@,chromatogram obtained with solution (1):
2A of any secondary peak is not greater than the area of
Table I!
cipal peak in the chromatogram obtained with
Test Duration Amount dissolved
Hours (days) (each replicate)
72 (3) 5 to 30% 1ed with solution (2) (4%).

Disregard any Z h an area less than 0.1 times the area
336 (14) 10 to 45% of the principal
840 (35) 15 to 60% solution (2) (0.1%).
1,344 (56) 55 to 90% Appendix III C, using the'fe!

(1) Weigh and dissolve 10 implant
2,016 (84) Not less than 70%
85 volumes of acetonitrile to obtain a on containing

0.2% wv of Goserelin.
Calculate the content of C59Hg4N 0,4 dissolved in the
portions of the medium from the absorbance obtained from a
solution prepared by diluting a suitable amount of
goserelin EPCRS in the dissolution medium and using the
declared content of C597Hg4N 180}, in goserein EPCRS. At all mixture of 15 volumes of water and 85 volumes of acetonitrile.
time points calculate the cumulative percentage of the (4) 0.002% w/v each of 4-p-Ser-goserelin EPCRS and
whe ee
oe
labelled amount of C59Hg4N1;.Q0j,,4 dissolved; at the times goserelin EPCRS in a mixture of 20 volumes of water and
specified in Table II the cumulative percentages comply with 80 volumes of acetonitrile.
the criteria given. CHROMATOGRAPHIC CONDITIONS
Related substances (a) Use a stainless steel column (30 cm x 7.8 mm) packed
A. Carry out the method for liquid chromatography, with hydrophilic silica gel for chromatography (5 um) with a
Appendix III D, using the following solutions. fractionation range for proteins with a relative molecular
(1) Weigh and dissolve 10 implants, with the aid of mass of approximately 4000 to 500 000 (TSK-GEL-G2000
ultrasound, in a mixture of 15 volumes of water and SWXL is suitable).
85 volumes of acetonitrile to obtain a solution containing (b) Use isocratic elution and the mobile phase described
0.2% wv of Goserelin. below.
(2) Dilute 1 volume of solution (1) to 100 volumes using a
mixture of 15 volumes of water and 85 volumes of acetonitrile.
IlI-644 Goserelin Preparations 2016
(d) Use an ambient column temperature. Add 167.5 g of a 60% w/v solution of perchloric acid to a
(e) Use a detection wavelength of 280 nm. 1000 mL volumetric flask, cool in ice and dilute to volume
with 1m sodium hydroxide. To 100 mL of this solution add
sufficient water to produce 1000 mL and adjust the pH of
MOBILE PHASE
the solution to 2.1 with 5m sodium hydroxide.
8 volumes of a solution prepared as described below and When the chromatograms are recorded under the prescribed
92 volumes of acetonitrile. conditions the retention time relative to des-z-butyl-goserelin
To prepare the solution add 167.5 g of a 60% w/v solution (retention time about 20 minutes) of impurity 13 is
of perchloric acid to a 1000 mL volumetric flask, cool in ice about 1.1.
and dilute to volume with 1M sodium hydroxide. To 100 mL
SYSTEM SUITABILITY
of this solution add sufficient water to produce 1000 mL and
adjust the pH of the solution to 2.1 with 5m sodium hydroxide. The test is not valid unless, in the chromatogram obtained
with solution (4), the retention time of des-z-butyl-goserelin
is between 19 and 22 minutes.
LIMITS
the peak corresponding to impurity 13 is not greater than the
solution (2) (1%).
, en the peaks due to 4-p-
Ser-goserelin and goserelin 1 i Disregard any peak with an area less than that of the
LIMITS
(3) (0.05%).
The sum of impurities obtained in tests B and C is not more
the area of any peak corresponding to dm than 10%.
greater than twice the area of the princip
Acetic acid
Appendix III B, using a 2% v/v solution of n-hexadecane
polymer envelope is not greater than 5.5 times thear
(internal standard) in dimethylformamide (solution B) and the
principal peak in the chromatogram obtained with sol
(2) (5.5%).
1) Dissolve a quantity of the implant and a quantity of
akstren B and dilute with sufficient dimethylformamide to
aim.a Solution containing about 2.8% w/v of Goserelin
(3) (0.05%).
d 0.1% viv of n-hexadecane.
C. Carry out the method for size-exclusion chromatography,
Appendix III C, using the following solutions.
(1) Weigh and dissolve 10 implants, with the aid of
ultrasound, in a mixture of 15 volumes of water and
85 volumes of acetonitrile to obtain a solution containing
0.2% w/v of Goserelin.
(FFAP CB is suitable).
(b) Use helium as the carrie
minute with a flow rate of the nake up.gas of 30 mL per
(4) To 4 mg of goserelin EPCRS add 250 uL of trifluoroacetic minute.
acid and leave to stand for 24 hours. Dissolve the product in
20 mL of a mixture of 15 volumes of water and 85 volumes
of acetonitrile to obtain a solution containing des-t-butyl-
goserelin. (d) Use a flame ionisation detector at a te
CHROMATOGRAPHIC CONDITIONS (e) Inject 1 pL of each solution.
(a) Use a stainless steel column (30 cm x 7.8 mm) packed (f) Use a split ratio of 30:100.
with hydrophilic silica gel for chromatography (5 um) with a
fractionation range for proteins with a relative molecular
mass of approximately 4000 to 500 000 (TSK-GEL-G2000 Time Temperature Comment
SWXL is suitable).
ate ret
(Minutes)
below. 0-1 50° isothermal
(c) Use a flow rate of 2 mL per minute. 16 50°—200° linear gradient
6-9 200° isothermal
(f) Inject 50 pL of each solution. 9-10 200°-—>50° linear gradient
MOBILE PHASE 10-15 50° re-equilibration
12.5 volumes of a solution prepared as described below and
87.5 volumes of acetonitrile.
2016 Goserelin Preparations III-645
SYSTEM SUITABILITY ASSAY

The test is not valid unless, in the chromatogram obtained Carry out the method for size-exclusion chromatography,
with solution (2): Appendix II C, using the following solutions.
the resolution between the peaks due to acetic acid and n- (1) Weigh and dissolve 10 implants, with the aid of
hexadecane is at least 15; ultrasound, in a mixture of 15 volumes of water and |
the symmetry factor of the peak due to acetic acid is less than 85 volumes of acetonitrile to obtain a solution containing
2.0. 0.2% w/v of Goserelin.
LIMITS
(2) 0.2% wiv of goserelin EPCRS in a mixture of 15 volumes
In the chromatogram obtained with solution (1) the ratio of
(3) 0.002% w/v each of 4-p-Ser-goserelin EPCRS and
the area of any peak corresponding to acetic acid to the area
goserelin EPCRS in a mixture of 20 volumes of water and
of the peak due to the internal standardis not greater than
ratio in the chromatogram obtained with

substances test B, may be used.
issolving approximately 110 mg of SYSTEM SUITABILITY
y.dimethylformamide. The test is not valid unless, in the chromatogram obtained
4-p-Ser-goserelin and goserelin is at least 4.0.
Dissolve the copolymer usitig, 2 mil ‘of acetonitrile per implant
and dilute to a suitable conc : water BET
(solution A). The endotoxin limi ation of solution A Calculate the content of goserelin, C597Hg,N;.0},,4, from the
is 350 IU of endotoxin per implant. chromatograms obtained and using the declared content of
C59Hg4N 18014 in goserelin EPCRS.
The implants comply with the limits descritt STORAGE
uniformity of content, Appendix XII C, using the Goserelin Implants should be stored in a sealed container,
method of analysis. protected from light and moisture, at a temperature not
Carry out the method for liguid chromatography, exceeding 25°.
Appendix III D, using the following solutions. LABELLING
(1) Dissolve with the aid of ultrasound, 1 implant in a | bel states the equivalent amount of the peptidein mg
mixture of 15 volumes of water and 85 volumes of acetonitrile
to obtain a solution containing 0.02% w/v of Goserelin.
(2) 0.02% w/v of goserelin EPCRS in a mixture of 15 volumes ~
(3) 0.02% wiv each of goserelin hexapeptide BPCRS and
goserelin EPCRS in a mixture of 4 volumes of water and O. ~NH>
Ch3 y
1 volume of acetonitrile. H3C CH
o nA ° NH
O /
(a) Use a stainless steel column (25 cm x 4.6 mm) packed er-X7/-Arg-X
(Spherisorb ODS is suitable).
(b) Use isocratic elution and the mobile phase described © 1. X2 = L-His, X4 = p-Ser,
below. X9 = L-Pro: 4(p-serine)-goserelit
(c) Use a flow rate of 1.8 mL per minute. impurity A),
(d) Use a column temperature of 35°. 6. X2 = L-His, X4 = L-Ser, X5 = D-TF
(e) Use a detection wavelength of 220 nm. X9 = 1-Pro: 5(p-tyrosine)-goserelin (equiv
impurity FP),
12. X2 = 1-His, X4 = 1-Ser, X5 = t-Tyr, X7 = p-Leu,
MOBILE PHASE
X9 = L-Pro: 7(p-leucine)-goserelin (equivalent to Ph. Eur.
0.272% wiv of potassium dihydrogen orthophosphate in a impurity L),
Adjust the pH to 3.0 with orthophosphonic acid.
SYSTEM SUITABILITY CH, O. ~Nh>
The test is not valid unless, in the chromatogram obtained ENE Y
NH
with solution (3), the resolution between the peaks due to O /
goserelin hexapeptide and goserelin is not less than 4.0. His-Trp-Ser-Tyr-L-Ser-Leu-Arg-Pro—NH
Calculate the total content of goserelin, C59Hg4N 80,4, from
2. 6-[O-(1,1-dimethylethyl)-L-serine]-goserelin (equivalent to
the chromatograms obtained and using the declared content
Ph, Eur. impurity B),
of C597Hg4N;80j4 in goserelin EPCRS.
aoe
‘ tee
ta al
Sw on”
III-646 Griseofulvin Preparations 2016
O Dilute 2 mL of the filtrate to 100 mL with ethanol (96%).

CH; "\7 NH.
The light absorption of the resulting solution, Appendix IT B,
NH Y H3C CH;
| NH in the range 240 to 400 nm, exhibits two maxima at 291 nm
O O / and 325 nm and a shoulder at 250 nm.
H t— His-Trp-X4-Tyr-L-Ser-Leu-Arg-Pro—NH
C. Dissolve 5 mg of the powdered tablets in 1 mL of sulfuric
O
acid and add 5 mg of powdered potassium dichromate. A red
colour is produced.
3. X4 = 1-Ser, Y = Acetyl: 4-(acetyl-L-serine)-goserelin,
4, X4 = p-Ser, Y = Acetyl: 4-(acetyl-p-serine)-goserelin, TESTS
Dissolution
5. X4 = L-Ser, Y = Lactyl: 4-(lactyl-L-serine)-goserelin,
11. X4 = 1-Ser, Y = Glycolyl: 4-(glycolyl-L-serine)-goserelin,
Appendix XII B1.
TEST CONDITIONS
On per minute.
H Tt His-Trp-Ser-Ty
PROCEDURE
O
After 45 minutes withdraw a 10 ml sample of the medium
and filter. Measure the absorbance of the filtrate, suitably
diluted if necessary with methanol (80%), at the maximum at
291 nm, Appendix II B, using a 1.5% w/v solution of sodium
CH3 dodecyl sulfate in the reference cell.
oS Cr DETERMINATION OF CONTENT
O Calculate the total content of griseofulvin, C;7H,7ClOg, in
Tyr-L-Ser-Leu-Arg-Pro—NH the medium taking 725 as the value of A(1%, 1 cm) at the
maximum at 291 nm.
9. Hexapeptide,
Related substances
t the method for gas chromatography,
O
II B, using the following solutions. Dissolve
oe Y NH
,10-diphenylanthracene (internal standard) in
roform to produce 50 mL (solution A).
3 /
H Tt His-Trp-Ser-Tyr-D-Ser-Leu-Arg-Pro—NH L, of chloroform to a quantity of the powdered
O 0 mg of Griseofulvin, heat at 60° with
ates,:cool and dilute to 100 mL with
10. 6-(des-t-butyl-p-serine)-goserelin,
13. The structure of this peak has not been identified.
Griseofulvin Tablets to produce

about 1 mL.
Action and use
Antifungal.
DEFINITION washed, silanised diatomaceous support (100 to A

Griseofulvin Tablets contain Griseofulvin. coated with 1% w/w of cyanopropylmethyl phenyi
The tablets comply with the requirements stated under Tablets and silicone fluid (OV 225 is suitable).
with the following requirements. (b) Use nitrogen as the carrier gas at a flow rate of 50 to
Content of griseofulvin, C,,H,7ClO, 60 mL per minute.
wl ete
95.0 to 105.0% of the stated amount. (c) Use isothermal conditions maintained at 250°.
IDENTIFICATION -(d) Use an inlet temperature of 270°.
A. Extract a quantity of the powdered tablets containing (e) Use a flame ionisation detector at a temperature of 300°.
0.125 g of Griseofulvin with 20 mL of chloroform, add 1 g of (f) Inject a suitable volume of each solution.
anhydrous sodium sulfate, shake and filter. Evaporate the
filtrate to dryness and dry at a pressure not exceeding
for 3 times the retention time of griseofulvin.
0.7 kPa for 1 hour. The infrared absorption spectrum of the
conditions the retention time of griseofulvin is about
spectrum of griseofulvin (RS 172).
11 minutes. The retention times relative to griseofulvin are:
dechlorogriseofulvin, about 0.6; dehydrogriseofulvin,
80 mg of Griseofulvin with 150 mL of ethanol (96%) for
about 1.4.
20 minutes. Dilute to 200 mL with ethanol (96%) and filter
2016 Haemodialysis Solutions III-647
LIMITS 520 nm, Appendix II B, using in the reference cell a solution

Using the chromatogram obtained with solution (3), calculate prepared by treating 5 mL of water in the same manner,
the ratio (R) of the area of the peak due to griseofulvin to the beginning at the words ‘add 10 mL ofa solution...’. Repeat
the operation using 5 mL of a 0.03% w/v solution of
PNA
area of the peak due to the internal standard.

Alte al
In the chromatogram obtained with solution (2): guanethidine monosulfate BPCRS beginning at the words ‘add
10 mL of a solution ...’. Calculate the content of
the ratio of the area of any peak due to dechlorogriseofulvin
Ci0H22N4,H2SO, in the tablets from the absorbances
to the area of the peak due to the internal standard is not
obtained using the declared content of Cj9H22N4,H2SO, in
greater than 0.6R (3%);
guanethidine monosulfate BPCRS.
the ratio of the area of any peak due to dehydrogriseofulvin
to the area of the peak due to the internal standard is not STORAGE
greater than 0.15R (0.75%). Guanethidine Tablets should be protected from light.
nd jer 20 tablets. To a quantity of the powder

containing g.of Griseofulvin add 60 mL of ethyl acetate, KK
Haemodialysis Solutions
+4
+4
cool and dilut Ky
transfer two 5 (Solunions for Haemodialysis, Ph. Eur. monograph
0128)
Ph Eur
DEFINITION
Solutions of electrolytes with a concentration close to the
electrolytic composition of plasma. Glucose may be included
in the formulation.
Because of the large volumes used, haemodialysis solutions
are usually prepared by diluting a concentrated solution with
water of suitable quality (see the monograph Haemodialysis
solutions, concentrated, water for diluting (1167)), using for
difference obtained by repeating the operation using”35 example an automatic dosing device.
of griseofuluin BPCRS in place of the powdered tablet
from the declared content of C,;7H,7ClO¢ in QNCENTRATED SOLUTIONS FOR
griseofuluin BPCRS. ZTARMODIALYSIS
ated haemodialysis solutions are prepared and
ng materials and methods designed to produce
Guanethidine Tablets
Action and use
Adrenergic neuron blocker.
DEFINITION
Guanethidine Tablets contain Guanethidine Monosulfate.
Content of guanethidine monosulfate, C,~H..N,,H,SO,
IDENTIFICATION
Extract a quantity of the powdered tablets containing 50 mg
of Guanethidine Monosulfate with a mixture of 5 mL of
hydrochloric acid and 45 mL of water, filter, neutralise 25 mL concentrations of the components per litre are.
of the filtrate with 5m sodium hydroxide and add 20 mL of following ranges (see Table 0128.-1):
picric acid solution R1. The melting point of the precipitate,
after washing with water, is about 153°, Appendix V A. Table 0128.-1.
ASSAY
Concentration Concentration
Weigh and powder 20 tablets. Shake a quantity of the in mmol/L in mEq/L
powder containing 30 mg of Guanethidine Monosulfate for Sodium 130 - 145 130 - 145
15 minutes with 50 mL of water, dilute to 100 mL with water
Potassium 0 - 3.0 0 - 3.0
and filter. To 5 mL of the filtrate add 10 mL of a solution
prepared by dissolving 1 g of sodium nitroprusside and 1 g of Calcium 0 - 2.0 0 - 4.0
potassium hexacyanoferrate(ID in 50 mL of a 0.5% w/v Magnesium 0- 1.2 0 - 2.4
solution of sodium hydroxide, adding 5 mL of hydrogen
Acetate or lactate 32 - 45 32 - 45
peroxide solution (100 vol), swirling gently and diluting to
100 mL with the solution of sodium hydroxide. Mix, allow to Chloride 90 - 120 90 - 120
stand for 20 minutes, add sufficient water to produce 25 mL Glucose 0 - 12.0
and measure the absorbance of the resulting solution at
IlI-648 Haemodialysis Solutions 2016
Concentrated solutions with acetate or lactate are diluted — if the solution is free from glucose, use reaction (b);
before use. — if the solution contains glucose, use the following
2. Concentrated acid solutions method: to 5 mL of the solution to be examined add
Several formulations of concentrated solutions are used. 1 mL of hydrochloric acid R in a test-tube fitted with a
The concentrations of the components in the solutions are stopper and a bent tube, heat and collect a few
such that, after dilution to the stated volume and before millilitres of distillate; carry out reaction (b) of acetates
neutralisation with sodium hydrogen carbonate, the on the distillate;
concentrations of the components per litre are usually in the — magnesium: to 0.1 mL of titan yellow solution R add
following ranges (see Table 0128.-2): 10 mL of water R, 2 mL of the solution to be examined
and 1 mL ofa 4.2 g/L solution of sodium hydroxide R;
a pink colour is produced;
Table 0128.-2.
— glucose: to 5 mL of the solution to be examined add
2 mL of dilute sodium hydroxide solution R and 0.05 mL of
in mmol/L in mEq/L
copper sulfate solution R; the solution is blue and clear; heat
Sodium 80 - 110 80 - 110
to boiling; an abundant red precipitate is formed.
Potassium 0 - 3.0
TESTS
Calcium 0 - 4.0 Appearance of solution
Magnesium 0 - 2.4 The solution to be examined is clear (2.2.1). If it does not
contain glucose, it is colourless (2.2.2, Method J). If it
Acetic acid 2.5 - 10
contains glucose, it is not more intensely coloured than
Chloride 90 - 120 reference solution Y, (2.2.2, Method D.
Glucose Aluminium (2. 4. 17)
Maximum 0.1 mg/L.
Sodium hydrogen carbonate must be adde mrifediately Prescribed solution Take 20 mL of the solution to be
before use to a final concentration of not m examined, adjust to pH 6.0 using 0.1 M hydrochloric acid or
45 mmol/L. The concentrated solution of sod 0.1 M sodium hydroxide and add 10 mL of acetate buffer
carbonate is supplied in a separate container. solution pH 6.0 R.
The concentrated acid solutions and the concentrated Reference solution Mix 1 mL of aluminium standard solution
solutions of sodium hydrogen carbonate are diluted and (2 ppm Al) R, 10 mL of acetate buffer solution pH 6.0 R and
mixed immediately before use using a suitable device. QO mL of water R.
Alternatively, sodium hydrogen carbonate in powder form anksolution Mix 10 mL of acetate buffer solution pH 6.0 R
may be used to prepare the solution. . of water R.
3. Concentrated solutions without buffer volume (2.9. 17)
Several formulations of concentrated solutions without buffer smeasured is not less than the nominal volume
are used. The concentrations of the components in the
solutions are such that, after dilution to the stated volume,
the concentrations of the components per litre are usually in
the following ranges (see Table 0128.-3):
If the label states that

Table 0128.-3. solution is sterile, it co
in mmol/L in mEq/L
Bacterial endotoxins (2:6:
Less than 0.25 IU/mL in th
Sodium 130 - 145 130 - 145
Potassium 0 - 3.0 0 - 3.0

Pyrogens (2.6.8) 6
Solutions for which a validated test fi
Calcium 0 - 2.0 0 - 4.0 cannot be carried out comply with th
Magnesium 0-12 0 -2.4 Dilute the solution to be examined with w or.avjections R
to the concentration prescribed for use. Inject J :
Chloride 130 - 155 130 - 155
solution per kilogram of the rabbit’s mass.
Glucose 0 - 12.0
ASSAY
Determine the density (2.2.5) of the concentrated solution and
Concentrated solutions without buffer are used together with calculate the content in grams per litre and in millimoles per litre.
parenteral administration of suitable hydrogen carbonate Sodium
solutions. 97.5 per cent to 102.5 per cent of the content of
IDENTIFICATION sodium (Na) stated on the label.
According to the stated composition, the solution to be Atomic emission spectrometry (2.2.22, Method I).
examined gives the following identification reactions (2.3. 1): Test solution If necessary, dilute the solution to be examined
— potassium: reaction (b); with water R to a concentration suitable for the instrument to
— calcium: reaction (a); be used.
— sodium: reaction (b); Reference solutions Prepare the reference solutions using sodium
— chlorides: reaction (a); standard soluron (200 ppm Na) R.
— lactates;
Wavelengths 589.0 nm or 589.6 nm (sodium emits as a
— carbonates and hydrogen carbonates;
doublet).
— acetates:
ee ee ee
2016 Haemodialysis Solutions III-649
Potassium To a volume of the solution to be examined, corresponding

95.0 per cent to 105.0 per cent of the content of to about 0.7 mmol of acetate, add 10.0 mL of 0.1 M
potassium (K) stated on the label. hydrochloric acid. Carry out a potentiometric titration (2.2.20),
Atomic absorption spectrometry (2.2.23, Method I). using 0.1 M sodium hydroxide. Read the volume added
between the 2 points of inflexion.
Test solution Dilute with water R an accurately weighed
quantity of the solution to be examined to a concentration 1 mL of 0.1 M sodium hydroxide is equivalent to 0.1 mmol of
suitable for the instrument to be used. To 100 mL of this acetate.
solution add 10 mL of a 22 g/L solution of sodium chloride R. Lactate
Reference solutions Prepare the reference solutions using 95.0 per cent to 105.0 per cent of the content of lactate
potassium standard solution (100 ppm K) R. To 100 mL of stated on the label.
each reference solution add 10 mL of a 22 g/L solution of To a volume of the solution to be examined, corresponding
sodium chloride R. to about 0.7 mmol of lactate, add 10.0 mL of 0.1 M
hydrochloric acid. Then add 50 mL of acetonitrile R. Carry out
a potentiometric titration (2.2.20), using 0.1 M sodium
hydroxide. Read the volume added between the 2 points of
inflexion.
Calcium 1 mL of 0.1 M sodium hydroxide is equivalent to 0.1 mmol of
95.0 per cent to*h,
lactate.
Sodium hydrogen carbonate
Atomic absorption spectt
95.0 per cent to 105.0 per cent of the content of sodium
Test solution Dilute 5.0 m hydrogen carbonate stated on the label.
Titrate with 0.1 M hydrochloric acid a volume of the solution
to be examined corresponding to about 0.1 g of sodium
with water R.
hydrogen carbonate, determining the end-point
Reference solutions Into 4 identical vol potentiometrically (2.2.20).
1 mL of 0.1 M hydrochloric acid is equivalent to 8.40 mg of
respectively 2.5 mL, 5.0 mL, 7.0 mL and Iv.Q@:
NaHCO3.
standard solution (10 ppm Ca) R and dilute to 50.Q:mL with
water R. Reducing sugars
(expressed as anhydrous glucose): 95.0 per cent to
Source Calcium hollow-cathode lamp.
105.0 per cent of the content of glucose stated on the label.
Wavelength 422.7 nm.
asfer a volume of the solution to be examined containing
Atomisation device Air-acetylene flame. equivalent of 25 mg of glucose to a 250 mL conical flask
Magnesium ound-glass neck and add 25.0 mL of cupri-citric
95.0 per cent to 105.0 per cent of the content of
magnesium (Mg) stated on the label.
Atomic absorption spectrometry (2.2.23, Method I). in. Cool and add 3 g of potassium iodide R
Test solution Dilute 5.0 mL of the solution to be examined to L sf water R. Carefully add, in small
100.0 mL with water R. To 2.0 mL of this solution add
5 mL of lanthanum chloride solution R and dilute to 50.0 mL acid R. Titraté*wi
with water R. solution R, added
indicator. Carry out.
Reference solutions Into 4 identical volumetric flasks each
Nene
water R.
rawr Al
containing 5 mL of lanthanum chloride solution R, introduce
Vee eel
respectively 1.0 mL, 2.0 mL, 3.0 mL and 4.0 mL of Calculate the content of réd
anhydrous glucose (CgH 20635
magnesium standard solution (10 ppm Mg) R and dilute to
50.0 mL with water R.
Source Magnesium hollow-cathode lamp.
Wavelength 285.2 nm. Volume of 0.1 M sodium thiosulfate
in mL
Atomisation device Air-acetylene flame. 8
Total chloride
9
chloride (Cl) stated on the label. 10 25.0
Ae
Ste eet
tN Dilute to 50 mL with water R an accurately measured 11 27.6
wn ete
volume of the solution to be examined containing the 12 30.3
equivalent of about 60 mg of chloride. Add 5 mL of dilute
13 33.0
nitric acid R, 25.0 mL of 0.1 M silver nitrate and 2 mL of
dibutyl phthalate R. Shake. Using 2 mL of ferric ammonium 14 35.7
sulfate solution R2 as indicator, titrate with 0.1 M ammonium 15 38.5
thiocyanate until a reddish-yellow colour is obtained.
16 41.3
1 mL of 0.1 M silver nitrate is equivalent to 3.545 mg of Cl.
Acetate
95.0 per cent to 105.0 per cent of the content of acetate STORAGE
stated on the label. At a temperature not lower than 4 °C.
IWl-650 Water 2016
LABELLING Oxidisable substances

The label states: To 100 mL of the water to be examined add 10 mL of dilute
— the formula of the concentrated solution for haemodialysis sulfuric acid R and 0.1 mL of 0.02 M_ potassium permanganate
expressed in grams per litre and in millimoles per litre; and boil for 5 min. The solution remains faintly pink. |
— the nominal volume of the solution in the container; Total available chlorine
— where applicable, that the concentrated solution is sterile; Maximum 0.1 ppm.
— the storage conditions;
In a 125 mL test-tube (A), place successively 5 mL of buffer
— that the concentrated solution 1s to be diluted
solution pH 6.5 R, 5 mL of diethylphenylenediamine sulfate
immediately before use;
solution R and 1 g of potassium todide R. In a second 125 mL
— the dilution to be made;
test-tube (B), place successively 5 mL of buffer solution
— that the volume taken for use is to be measured
pH 6.5 Rand 5 mL of diethylphenylenediamine sulfate
solution R. Add as simultaneously as possible to tube A
100 mL of the water to be examined and to tube B a
reference solution prepared as follows: to 1 mL of a 10 mg/L
portion of solution is to be discarded;
solution of potassium 1odate R, add 1 g of potassium todide R
y cable; that sodium hydrogen carbonate is to
and 1 mL of dilute sulfuric acid R; allow to stand for 1 min,
be added béfore:
add 1 mL of dilute sodium hydroxide solution R and dilute to
Ph Eur 100 mL with water R. Any colour in the mixture obtained
with the water to be examined is not more intense than that
in the mixture obtained with the reference solution.
Chlorides (2.4.4)
Water for Diluting Concen po
: ' *
Maximum 50 ppm.
Dilute 1 mL of the water to be examined to 15 mL with
Haemodialysis Solutions . Xe water R.
(Haemodialysis Solutions, Concentrated, Wat Fluorides
Diluting, Ph Eur monograph 1167) Maximum 0.2 ppm.
Ph Eur Potentiometry (2.2.36, Method I): use as indicator electrode a
The following monograph is given for information. fluoride-selective solid-membrane electrode and as reference
The analytical methods described and the limits proposed at electrode a silver-silver chloride electrode.
intended to be used for validating the procedure for obtaining th Test solution The water to be examined.
water. Referexce solutions Dilute 2.0 mL, 4.0 mL and 10.0 mL of
DEFINITION evtde Standard solution (1 ppm F) R respectively to 20.0 mL
Water for diluting concentrated haemodialysis solutions is al-tonic-strength-adjustment buffer R1.
obtained from potable water by distillation, by reverse
osmosis, by ion exchange or by any other suitable method.
The conditions of preparation, transfer and storage are
Maxinrtim
designed to minimise the risk of chemical and microbial
Dilute 2 mL
contamination.
When water obtained by one of the methods described above
is not available, potable water may be used for home dialysis. L of diphenylamine solution R
Because the chemical composition of potable water varies se zing, 5 mL of sulfuric acid R.
considerably from one locality to another, consideration must
Ven be given to its chemical composition to enable adjustments to for 15 min. Any blue colour ifi* ion is not more
be made to the content of ions so that the concentrations in intense than that in a standard pfepgred‘at the same time
the diluted solution correspond to the intended use. and in the same manner using a mi Q.1 mL of nitrate
Attention has also to be paid to the possible presence of standard solution (2 ppm NO3) R and 4.9 mL of nitrate-free
residues from water treatment (for example, chloramines) water R,
and volatile halogenated hydrocarbons. Sulfates (2. 4. 13)
For the surveillance of the quality of water for diluting Maximum 50 ppm.
concentrated haemodialysis solutions, the following methods Dilute 3 mL of the water to be examined to 15 mL with
may be used to determine the chemical composition and/or distilled water R.
to detect the presence of possible contaminants together with
Aluminium (2.4.17)
aS te, A suggested limits to be obtained.
ees
Awan Maximum 10 pg/L.
CHARACTERS
aN nl
vw
Prescribed solution To 400 mL of the water to be examined

Clear, colourless, liquid. add 10 mL of acetate buffer solution pH 6.0 R and 100 mL of
TESTS water R.
Acidity or alkalinity Reference solution Mix 2 mL of aluminium standard solution
To 10 mL of the water to be examined, freshly boiled and (2 ppm Al) R, 10 mL of acetate buffer solution pH 6.0 R and
cooled in a borosilicate glass flask, add 0.05 mL of methyl red 98 mL of water R.
solution R. The solution is not red. To 10 mL of the water to Blank solution Mix 10 mL of acetate buffer solution pH 6.0 R
be examined add 0.1 mL of bromothymol blue solution R1. and 100 mL of water R.
ein wre |
ae
The solution is not blue.
~~
nde
ei
ON
2016 Water III-651
Ammonium using this solution. If the potassium content is more than

oN wt
Maximum 0.2 ppm. 0.75 mg/L, further dilute the water to be examined with
To 20 mL of the water to be examined in a flat-bottomed distilled water R.
and transparent tube, add 1 mL of alkaline potassium Test solution (6) Take 50.0 mL of the water to be examined
tetraiodomercurate solution R. Allow to stand for 5 min. or, if necessary, the water to be examined diluted as
The solution is not more intensely coloured than a standard described in the preparation of test solution (a).
prepared at the same time and in the same manner using a Add 1.25 mL of potasstum standard solution (20 ppm K) R
mixture of 4 mL of ammonium standard solution and dilute to 100.0 mL with distilled water R.
(1 ppm NH) R and 16 mL of ammonium-free water R. Reference solutions Prepare reference solutions (0 ppm;
Examine the solutions along the vertical axis of the tube. 0.25 ppm; 0.50 ppm; 0.75 ppm; 1 ppm) using potassium
Calcium standard solution (20 ppm K) R.
Maximum, 2 ppm. Wavelength 766.5 nm.
mn spectrometry (2.2.23, Method D. Calculate the potasstum content of the water to be examined
in parts per million from the expression:
px ny, X 0.5
Ng —- Ny
Dp = dilution factor used for the preparation of test

|
Atomisation device Oxidist
solution (a);
Magnesium ny = measured value of test solution (a);
Maximum 2 ppm. No = measured value of test solution (b).
Sodium
Test solution Dilute 10 mL of thewate Maximum 50 ppm.
100 mL with disulled water R.
Atomic emission spectrometry (2.2.22, Method D.
Test solution The water to be examined. If the sodium content
is more than 10 mg/L, dilute with distilled water R to obtain a
Source Magnesium hollow-cathode lamp. concentration suitable for the apparatus used.
Wavelength 285.2 nm. Reference solutions Prepare reference solutions (0 ppm;
Atomisation device Oxidising air-acetylene flame. .ppm; 5.0 ppm; 7.5 ppm; 10 ppm) using sodium standard
Mercury solution (200 ppm Na) R.
Maximum 0.001 ppm.
Atomic absorption spectrometry (2.2.23, Method I).
Test solution Add 5 mL of nitric acid R per litre of the water
to be examined. In a 50 mL borosilicate glass flask with a
ground-glass-stopper, place 20 mL of the water to be
examined and add 1 mL of dilute nitric acid R and shake.
Add 0.3 mL of bromine water R1. Stopper the flask, shake
and heat the stoppered flask at 45 °C for 4 h. Allow to cool.
If the solution does not become yellow, add 0.3 mL of
0.15 ppm) using zin
bromine water R1 and re-heat at 45 °C for 4 h. Add 0.5 mL
of a freshly prepared 10 g/L solution of hydroxylamine Source Zinc hollow-catho
hydrochloride R. Shake. Allow to stand for 20 min. Wavelength 213.9 nm.
Reference solutions Use freshly prepared reference solutions
(0.0005 ppm to 0.002 ppm) obtained by diluting mercury Heavy metals (2.4.8)
standard solution (1000 ppm Hg) R with a5 per cent V/V Maximum 0.1 ppm.
solution of dilute nitric acid R and treat as described for the
test solution.
To a volume of solution suitable for the instrument to be
used, add stannous chloride solution R2 equal to 1/5 of this Preparethe reference solution using lead standard solution
volume. Fit immediately the device for the entrainment of (1 ppm Pb) R.
the mercury vapour. Wait 20 s and pass through the device a
Le end
Nene tet Microbial contamination

stream of nitrogen R as the carrier gas.
eausy
Ven v4
TAMC: acceptance criterion 10? CFU/g (2.6.12).

Source Mercury hollow-cathode tube or a discharge lamp.
Bacterial endotoxins (2.6. 14)
Wavelength 253.7 nm. Less than 0.25 IU/mL.
Atomisation device Flameless system whereby the mercury can
Ph Eur
be entrained in the form of cold vapour.
Potassium
Maximum 2 ppm.
Atomic emission spectrometry (2.2.22, Method I).
Test solution (a) Dilute 50.0 mL of the water to be examined
Ste Be
ab AN,
to 100 mL with distilled water R. Carry out a determination
Be er et
IlI-652 Haemofiltration Solutions 2016
KK
& — sodium: reaction (b);
Haemofiltration and
4>t
— chlorides: reaction (a);
>
Haemodiafiltration Solutions eam — acetates:
eA ee
(Solutions for Haemofiltration and Haemodiafiltration, — if the solution is free from glucose, use reaction (b);
Ph Eur monograph 0861) — if the solution contains glucose, use the following
method: to 5 mL of the solution to be examined add
When the Solution is intended for haemofiltration only, the
1 mL of hydrochloric acid R in a test-tube fitted with a
title Haemofiltration Solutions may be used
stopper and a bent tube, heat and collect a few
Ph Eur millilitres of distillate; carry out reaction (b) of acetates
DEFINITION on the distillate;
Preparations for parenteral administration containing — lactates;
electrolytes with a concentration close to the electrolytic — carbonates and hydrogen carbonates;
itt lasma. Glucose may be included in the — magnesium: to 0.1 mL of titan yellow solution R add
stem
aN A
10 mL of water R, 2 mL of the solution to be examined
and 1 mL of 1 M sodium hydroxide; a pink colour is
produced;
— glucose: to 5 mL of the solution to be examined, add
2 mL of dilute sodium hydroxide solution R and 0.05 mL of
copper sulfate solution R; the solution is blue and clear; heat
envelopes;
to boiling; an abundant red precipitate is formed.
— glass containers.
The containers and closures the requirements TESTS
for containers for preparations dministration Appearance of solution
ts NAS
(3.2). The solution is clear (2.2.1). If it does not contain glucose, it
Pee
In haemofiltration and haemodiafiltrati is colourless (2.2.2, Method I). If it contains glucose, it is not
more intensely coloured than reference solution Y7 (2.2.2,
Method I).
Table 0861.-1): pH (2.2.3)
5.0 to 7.5. If the solution contains glucose, the pH
Table 0861.-1. is 4.5 to 6.5. If the solution contains hydrogen carbonate, the
PH is 7.0 to 8.5.
Concentration Concentratio
in mmol/L in mEq/L Hy droxymethylfurfural
Sodium 125 - 150 125 - 150 . the test only if glucose is added to the preparation.
Potassium 0-4.5 0-45
me of the solution to be examined containing the
Calcium 1.0 - 2.5 2.0 - 5.0

-toluidine R in 2-propanol R containing
Magnesium 0.25 - 1.5 0.50 - 3.0 IV of glacial acetic acid R, then add 1.0 mL of a
Acetate and/or lactate and/or 30 - 60 30 - 60
hydrogen carbonate fter allowing the mixture to stand for
Chloride 90 - 120 90 - 120 han that of a standard prepared at
Glucose 0-25
When hydrogen carbonate is present, the solution of sodium

hydrogen carbonate is supplied in a container or a separate
compartment and is added to the electrolyte solution
immediately before use. (800 ppm expressed with reference '
In haemofiltration and haemodiafiltration, the following concentration).
formulations may also be used (see Table 0861.-2): Aluminium (2. 4. 17)
Maximum 10 pg/L.
Table 0861.2. Prescribed solution ‘Take 200 mL of the solution to b
Concentration Concentration examined, adjust to pH 6.0 using 0.1 M hydrochloric acid or
in mmol/L in mEq/L 0.1 M sodium hydroxide and add 10 mL of acetate
Sodium 130 - 167 130 - 167 buffer solution pH 6.0 R.
Potassium 0 - 4.0 0-4.0
Reference solution Mix 1 mL of aluminium standard solution
(2 ppm Al) R, 10 mL of acetate buffer solution pH 6.0 R and
Hydrogen carbonate 20 - 167 20 - 167
9 mL of water R.
Chloride 0 - 147 0 - 147 Blank solution Mix 10 mL of acetate buffer solution pH 6.0 R
and 10 mL of water R.
Antioxidants are not added to the solutions. Particulate contamination (2.9.19, Method I
Use 50 mL of the solution to be examined.
IDENTIFICATION
Extractable volume (2.9. /7)
According to the stated composition, the solution to be
The solution complies with the test prescribed for parenteral
examined gives the following identification reactions (2.3.1):
infusions.
— potassium: reaction (b);
— calcium: reaction (a);
a
Haemofiltration Solutions ILI-653
Sterility (2.6.1) Total chloride

The solution complies with the test. 95.0 per cent to 105.0 per cent of the content of chloride
Bacterial endotoxins (2.6. 14) (Cl) stated on the label.
aNew A,
Less than 0.05 IU/mL. Dilute to 50 mL with water R an accurately

measured volume of the solution to be examined containing
Pyrogens (2.6.8)
the equivalent of about 60 mg of chloride. Add 5 mL of
Solutions for which a validated test for bacterial endotoxins
dilute nitric acid R, 25.0 mL of 0.1 M silver nitrate and 2 mL
cannot be carried out comply with the test for pyrogens.
of dibutyl phthalate R. Shake. Using 2 mL offerric ammonium
Inject per kilogram of the rabbit’s mass 10 mL of the
sulfate solution R2 as indicator, titrate with 0.1 M ammonium
solution.
thiocyanate until a reddish-yellow colour is obtained.
1 mL of 0.1 M silver nitrate is equivalent to 3.545 mg of Cl.
Acetate
95.0 per cent to 105.0 per cent of the content of acetate
stated on the label.
To a volume of the solution to be examined, corresponding
Test solution
to about 0.7 mmol of acetate, add 10.0 mL of 0.1 M
with water R to:
hydrochloric acid. Carry out a potentiometric titration (2.2.20),
be used.
using 0.1 M sodium hydroxide. Read the volume added
Reference solutions Prep between the 2 points of inflexion.
standard solution (200 pp
1 mL of 0.1 M sodium hydroxide is equivalent to 0.1 mmol of
Wavelengths 589.0 nm or 589.Qtim ‘(sodium emits as a acetate.
doublet).
Lactate
Potassium : 95.0 per cent to 105.0 per cent of the content of lactate
95.0 per cent to 105.0 per cent of the, of potassium stated on the label.
(K) stated on the label.
To a volume of the solution to be examined, corresponding
Atomic absorption spectrometry (2.2.23, to about 0.7 mmol of lactate, add 10.0 mL of 0.1 M
Test solution If necessary, dilute the solution to b hydrochloric acid. Add 50 mL of acetonitrile R. Carry out a
with water R to a concentration suitable for the instrzé potentiometric titration (2.2.20), using 0.1 M sodium
be used. To 100 mL of the solution add 10 mL of a 22g hydroxide. Read the volume added between the 2 points of
solution of sodium chloride R. inflexion.
Reference solutions Prepare the reference solutions using of 0.1 M sodium hydroxide is equivalent to 0.1 mmol of
potassium standard solution (100 ppm K) R. To 100 mL of
each reference solution add 10 mL of a 22 g/L solution of . hydrogen carbonate
sodium chloride R. t to 105.0 per cent of the content of sodium
Source Potassium hollow-cathode lamp.
Wavelength 766.5 nm.
Atomisation device Air-propane or air-acetylene flame.
Calcium
hydrogen carbs :
potentiometrically(2
calcium (Ca) stated on the label. 1 mL of 0.1 M hyd
Atomic absorption spectrometry (2.2.23, Method I).
NaHCoOs.
Test solution If necessary, dilute the solution to be examined Lactate and hydrogen ¢:
with water R to a concentration suitable for the instrument to 95.0 per cent to 105.0 per cent : content of lactates and
be used. hydrogen carbonates stated on 1

Reference solutions Prepare the reference solutions using Liquid chromatography (2.2.29).
calctum standard solution (400 ppm Ca) R. Test solution The solution to be exam
Source Calcium hollow-cathode lamp. Reference solution Dissolve in 100 mL of water.for
Wavelength 422.7 nm. chromatography R quantities of lactates and h
carbonates, accurately weighed, in order to obtain solutions
Atomisation device Air-propane or air-acetylene flame.
having concentrations representing about 90 per cent,
Magnesium 100 per cent and 110 per cent of the concentrations stated
fete ate
95.0 per cent to 105.0 per cent of the content of on the label.
magnesium (Mg) stated on the label. Column:
Atomic absorption spectrometry (2.2.23, Method I). — size. ] = 0.30 m, O = 7.8 mm;
Test solution If necessary, dilute the solution to be examined — stationary phase: cation-exchange resin R (9 um);
with water R to a concentration suitable for the instrument to — temperature: 60 °C.
be used. Mobile phase 0.005 M sulfuric acid previously degassed with
Reference solutions Prepare the reference solutions using helium for chromatography R.
magnesium standard solution (100 ppm Mg) R. Flow rate 0.6 mL/min.
Source Magnesium hollow-cathode lamp. Detection Differential refractometer.
Wavelength 285.2 nm. Injection 20 uwL, twice.
Atomisation device Air-propane or air-acetylene flame. Order of elution Lactates, hydrogen carbonates.
IlI-654 Haloperidol Preparations 2016
Determine the concentration of lactates and hydrogen The capsules comply with the requirements stated under Capsules
carbonates in the test solution by interpolating the peak area and with the following requirements. -
for lactate and the peak height for hydrogen carbonate from Content of haloperidol, C,,H,3;CIFNO,
the linear regression curve obtained with the reference 95.0 to 105.0% of the stated amount.
solutions.
IDENTIFICATION
Reducing sugars
A. To a quantity of the contents of the capsules containing
(expressed as anhydrous glucose): 95.0 per cent to
10 mg of Haloperidol add 10 mL of water and 1 mL of
105.0 per cent of the content of glucose stated on the label.
1M sodium hydroxide and extract with 10 mL of ether. Filter
Transfer a volume of the solution to be examined containing the ether extract through absorbent cotton, evaporate the
the equivalent of 25 mg of glucose to a 250 mL conical flask filtrate to dryness and dry the residue at 60° at a pressure not
with a ground-glass neck and add 25.0 mL of cupni-citric exceeding 0.7 kPa. The infrared absorption spectrum of the
solution R. Aéd a few grains of pumice, fit a reflux condenser, residue, Appendix II A, is concordant with the reference
‘ben curs within 2 min and boil for exactly spectrum of haloperidol (RS 173).
solution (2).
TESTS
Related substances
Volume of 0.1 M sodium thiosulfate
containing 10 mg of Haloperidol with 30 mL of chloroform,
disperse with the aid of ultrasound for 15 minutes, filter,
inmi_
8 evaporate the filtrate to dryness and dissolve the residue in
1 mL of chloroform.
9
10 chloroform.
ll 27.6 CHROMATOGRAPHIC CONDITIONS
12 30.3 as the coating a suitable silanised silica gel containing
13 33.0 t indicator with an optimal intensity at 254 nm
14 35.7
mobile phase as described below.
15 38.5
iL of each solution.
16 41.3
STORAGE for 15 minutes

At a temperature not below 4 °C. MOBILE PHASE
LABELLING
The label states:
— the formula of the solution for haemofiltration or 1,4-dioxan.
haemodiafiltration, expressed in grams per litre and in SYSTEM SUITABILITY
millimoles per litre;
— the calculated osmolarity, expressed in milliosmoles per
litre;
LIMITS
— the nominal volume of the solution for haemofiltration or
haemodiafiltration in the container; Any secondary spot in the chromatogram obtaine,
— that the solution is free from bacterial endotoxins, or solution (1) is not more intense than the spotin the’
where applicable, that it is apyrogenic; chromatogram obtained with solution (2) (0.5%).
— the storage conditions; Uniformity of content
— that any unused portion of solution is to be discarded. Capsules containing less than 2 mg and/or less than 2% w/w
Ph Eur of Haloperidol comply with the requirements stated under
Capsules using the following method of analysis. Carry out
the following solutions.
(1) Add sufficient of the mobile phase to the contents of one
Haloperidol Capsules capsule to producea solution containing 0.005% w/v of
Haloperidol, disperse with the aid of ultrasound for
Action and use 2 minutes, centrifuge and use the supernatant solution.
(2) 0.005% w/v of haloperidol BPCRS in the mobile phase.
DEFINITION
Haloperidol Capsules contain Haloperidol.
2016 Haloperidol Preparations III-655
CHROMATOGRAPHIC CONDITIONS spray with dilute potassium todobismuthate solution. Any

(a) Use a stainless steel column (15 cm x 5 mm) packed secondary spot in the chromatogram obtained with solution (1)
with end-capped octadecylsilyl silica gel for chromatography is Not more intense than the spot in the chromatogram
(5 um) (Hypersil ODS is suitable). obtained with solution (2) and not more than one such spot
(b) Use isocratic elution and the mobile phase described is more intense than the spot in the chromatogram obtained
below. with solution (3).
(c) Use a flow rate of 2 mL per minute. ASSAY

(d) Use an ambient column temperature. To a quantity containing 10 mg of Haloperidol add 8 mL of
water and 10 mL of 1m hydrochloric acid. Extract with
successive quantities of 25, 25, 10 and 10 mL of ether. Wash
(f) Inject 20 wL of each solution. the combined ether extracts with 10 mL of water, combine
the aqueous layers and remove the ether using a rotary
evaporator. Add sufficient water to produce 100 mL and
dilute 10 mL to 100 mL with methanol. Measure the
f C3,;H.3CIFNO, in each capsule C,,H23;CIFNO, taking 346 as the value of A(1%, 1 cm) at
using the declares of C,,H23CIFNO, in the maximum at 245 nm.
haloperidol BPCRS.
STORAGE
ASSAY “ Haloperidol Injection should be protected from light.
Use the average of the 10°indivi
test for Uniformity of conte
Haloperidol Oral Solution

Haloperidol Oral Drops
Haloperidol Injection
Action and use
Action and use Dopamine receptor antagonist; neuroleptic.
DEFINITION
DEFINITION peridol Oral Solution is an aqueous solution containing
Haloperidol Injection is a sterile solution of Haloperidol in: re than 0.2% w/v of Haloperidol.
Lactic Acid diluted with Water for Injections.
l solution complies with the requirements stated under Oral
The injection complies with the requirements stated under nd with the following requirements.
. £ haloperidol, C,,H,3;CIFNO,
Content of haloperidol, C,,H,,CIFNO,
IDENTIFICATION
A. To a volume containing 20 mg of Haloperidol add 5 mL
of water and 1 mL of 1m sodium hydroxide and extract with
10 mL of chloroform. Filter the chloroform extract through
absorbent cotton, evaporate the filtrate to dryness and dry with 10 mL of chloroform,
the residue at 60° at a pressure not exceeding 0.7 kPa. The to dryness. The infrared
infrared absorption spectrum of the residue, Appendix II A, is endix II A, is
concordant with the reference spectrum of haloperidol
(RS 173). (RS 173).
B. The light absorption, Appendix II B, in the range 230 to B. The light absorption, Appendix II B, 1
350 nm of the final solution obtained in the Assay exhibits a 350 nm of the final solution obtained 1n the
maximum only at 245 nm. maximum only at 245 nm. :
TESTS TESTS
Acidity Acidity
pH, 2.8 to 3.6, Appendix V L. pH, 2.5 to 3.5, Appendix V L.
Related substances Related substances

Carry out the method for thin-layer chromatography, Carry out the method for thin-layer chromatography,
Appendix III A, using a silica gel precoated plate (Merck Appendix III A, using the following solutions in methanol.
silica gel 60 plates are suitable) and a mixture of 92 volumes (1) Dilute the oral solution, if necessary, to contain 0.1% w/v
of chloroform, 8 volumes of methanol and 1 volume of of Haloperidol.
13.5M ammonia as the mobile phase. Apply separately to the (2) Dilute 1 volume of solution (1) to 100 volumes.
plate (1) a volume of the injection containing 0.1 mg of (3) Dilute 1 volume of solution (1) to 200 volumes.
Haloperidol, (2) the same volume of a solution prepared by
diluting 1 volume of the injection to 100 volumes with
methanol and (3) the same volume of a solution prepared by (a) Usea silica gel precoated plate (Merck silica gel 60 plates
diluting 1 volume of the injection to 200 volumes with are suitable).
methanol. After removal of the plate, allow it to dry in air and (b) Use the mobile phase as described below.
IlI-656 Haloperidol Preparations 2016
(c) Apply 50 uL of each solution. Related substances

(d) Develop the plate to 15 cm. Carry out the method for thin-layer chromatography,
(e) After removal of the plate, dry in air, spray with dilute
silica gel 60 plates are suitable) and a mixture of 92 volumes
potassium todobismuthate solution.
of dichloromethane, 8 volumes of methanol and 1 volume of
MOBILE PHASE 13.5M ammonia as the mobile phase. Apply separately to the
1 volume of 13.5mM ammonia, 8 volumes of methanol and plate 5 uL of each of the following solutions. Solution (1) is
92 volumes of dichloromethane. the preparation being examined. For solution (2) dilute
LIMITS 1 volume of solution (1) to 100 volumes with water.
200 volumes with water. After removal of the plate, allow it
to dry in air and spray with dilute potassium todobismuthate
obtained with solution (2) and not more than
solution. Any secondary spot in the chromatogram obtained
more intense than the spot in the
chromatogram obtained with solution (2) and not more than
one such spot is more intense than the spot in the
ASSAY
To 1 mL add 10 mL of water and 10 mL of 1m hydrochloric
acid and extract with two 10 mL quantities of ether. Wash the
combined ether extracts with 10 mL of water, combine the
aqueous solutions and remove the ether using a rotary
ting solution at
evaporator. Add sufficient water to produce 100 mL and
ulate the
dilute 10 mL to 100 mL with methanol. Measure the
) of
A(1%, 1 cm) at the maximum at 245 nm: 245 nm, Appendix IJ B. Calculate the content of
STORAGE C,,H.3CIFNO, taking 346 as the value of A(1%, 1 cm) at
Haloperidol Oral Solution should be protected fré the maximum at 245 nm.
It should not be refrigerated.
STORAGE
When Haloperidol Oral Solution or HaloperidolOral Strong Haloperidol Oral Solution should be protected from
is prescribed or demanded and no strengthis stated, an Or ight. It should not be refrigerated.
Solution containing 0.2% w/v of Haloperidol shall be
Strong Haloperidol Oral Solution

Strong Haloperidol Oral Drops
Action and use

DEFINITION
Strong Haloperidol Oral Solution is an aqueous solution
containing 1% w/v of Haloperidol. It is intended to be
diluted before use.
The oral solution complies with the requirements stated under Oral IDENTIFICATION
Liquids and with the following requirements. To a quantity of the powdered tablets c
Content of haloperidol, C,,;H,,;CIFNO,
0.95 to 1.05% ww.
extract through absorbent cotton, evaporate the filtrd
CHARACTERISTICS dryness and dry the residue at 60° at a pressure not
A clear, colourless solution. exceeding 0.7 kPa. The infrared absorption spectrum of the
IDENTIFICATION residue, Appendix II A, is concordant with the reference
ad
yee
A. To 2 mL add 10 mL of water and 1 mL of 1m sodium spectrum of haloperidol (RS 173).
hydroxide, extract with 10 mL of chloroform, filter and TESTS
evaporate the filtrate to dryness. The imfrared absorption Related substances
spectrum of the residue, Appendix IT A, is concordant with Carry out the method for thin-layer chromatography,
the reference spectrum of haloperidol (RS 173). Appendix III A, using the following solutions.
B. The light absorption, Appendix II B, in the range 230 to (1) Shake a quantity of the powdered tablets containing
350 nm of the final solution obtained in the Assay exhibits a 10 mg of Haloperidol with 10 mL of chloroform, filter,
maximum only at 245 nm. evaporate the filtrate to dryness and dissolve the residue in
TESTS 1 mL of chloroform.
Acidity (2) Dilute 1 volume of solution (1) to 200 volumes with
pH, 3.5 to 4.5, Appendix V L. chloroform.
2016 Heparin Preparations III-657
CHROMATOGRAPHIC CONDITIONS with the aid of ultrasound for 2 minutes, add sufficient
(a) Use as the coating a suitable silanised silica gel containing mobile phase to produce 100 mL; mix and filter.
a fluorescent indicator with an optimal intensity at 254 nm (2) 0.020% w/v of haloperidol BPCRS in the mobile phase.
(Merck silanised silica gel 60 F.5,4 plates are suitable).
The chromatographic procedure described under Uniformity
(c) Apply 10 uL of each solution. of content may be used.
(d) Develop the plate to 15 cm. DETERMINATION OF CONTENT
(e) After removal of the plate, dry in a current of warm air Calculate the content of C,;H23;CIFNO, using the declared
for 15 minutes and examine under ultraviolet hght (254 nm). content of Cz;H.3CIFNO>, in haloperidol BPCRS.
MOBILE PHASE
Heparin Injection
The test is not va Action and use
solution (2) show Anticoagulant.
LIMITS
DEFINITION
Any secondary spot in the « Heparin Injection is a sterile solution of Heparin Calcium or
solution (1) is not more int Heparin Sodium in Water for Injections. The pH of the
chromatogram obtained wi solution may be adjusted by the addition of a suitable alkali.
Uniformity of content PRODUCTION
Tablets containing less than 2 mg and The final product is produced from the drug substance
of Haloperidol comply with the requireme where the methods of manufacturing are designed to ensure
Tablets using the following method of ana ys freedom from contamination by over-sulfated
method for liquid chromatography, Appendix IIt glycosaminoglycans.
(1) Place one tablet in 10 mL of the mobile phase, Parenteral Preparations and with the following requirements.
with the aid of ultrasound for 2 minutes and centrifug
If necessary, dilute the supernatant liquid with the mobile
phase to produce a solution containing 0.005% w/v of se €Stimated potency is not less than 90% and not more
Haloperidol. 111% of the stated potency.
(2) 0.005% w/v of haloperidol BPCRS in the mobile phase.
(b) Use isocratic elution and the mobile phase described B. Carry outthe @
below. Appendix XIV J B2
ee

ne eh te tee

eee
(f) Inject 20 wL of each solution. supporting medium. To oquilibra

ea
MOBILE PHASE electrolyte solution use amixture of

elt

bo
e
solution of ammonium acetate.

Te
following solutions. For solution (1) dilute a volume of the
te
Calculate the content of C2;H23CIFNO>, using the declared

ery Gey Le
cyt
injection with water to give a solution containing 375 IU per

content of C,,;H»3;CIFNO, in haloperidol BPCRS. mL. For solution (2), dilute heparin sodium EPBRP with an
enka ty:
ASSAY equal volume of water. Pass a current of 1 mA to 2 mA

For tablets containing less than 2 mg and/or less than per centimetre of strip width at a potential difference of
2% w/w of Haloperidol 300 volts for about 10 minutes. Stain the strips using a
Use the average of the 10 individual results obtained in the 0.1% w/v solution of toluidine blue and remove the excess by
test for Uniformity of content. washing. The ratio of the distance migrated by the principal
band or bands in the gel obtained with solution (1) to the
distance migrated by the principal band in the gel obtained
more of Haloperidol
with solution (2) is 0.9 to 1.1.
D. When the injection contains Heparin Calcium, it yields
solutions. reactions A andB characteristic of calcium salts, Appendix VI.
When the injection contains Heparin Sodium, it yields
(1) Add 60 mL of the mobile phase to a quantity of the
reaction A characteristic of sodium salts, Appendix VI.
powdered tablets containing 20 mg of Haloperidol, disperse
IlI-658 Hexachlorophene Preparations 2016
TESTS B. Shake a quantity of the powder containing 30 mg of Zinc

Acidity or alkalinity Oxide with 10 mL of 2m hydrochloric acid for 15 minutes and
pH, 5.5 to 8.0, Appendix V L. filter. 5 mL of the filtrate yields the reaction characteristic
Bacterial endotoxins zinc salts, Appendix VI.
Carry out the test for bacterial endotoxins, Appendix XIV C. ASSAY
For a preparation supplied in a container with a nominal For hexachlorophene
content of less than 100 mL, dilute the injection if necessary Shake a quantity of the powder containing 15 mg of
with water BET to give a solution containing 1000 IU of Hexachlorophene with 50 mL of methanolic
heparin activity per mL (solution A). The endotoxin limit tris(hydroxymethyl) methylamine solution for 10 minutes, filter
concentration of solution A is 10 IU of endotoxin per mL. through a sintered-glass crucible ISO 4793, porosity grade
Carry out the test using a lysate with a declared sensitivity 3, is suitable), wash the filter with two 10 mL quantities of
than 0.0625 IU of endotoxin per mL. the tris(hydroxymethyl)methylamine solution and dilute the
For a prep yplied in a container with a nominal combined filtrate and washings to 100 mL with the same
content of 10@ more, the endotoxin limit solution. Dilute 10 mL of the resulting solution to 50 mL
concentration is¢ of endotoxin per mL. with methanolic tris(hydroxymethyl) methylamine solution and
measure the absorbance at the maximum at 312 nm,
For Heparin Injection p ed from Heparin Calcium it
Appendix II B, using in the reference cell a solution prepared
may be necessary to ¢ t cations in order to achieve
by diluting a further 10 mL of the solution to 50 mL with
the validation criteria.
acidified methanol. An absorbance of 0.432 is equivalent to
ASSAY 15 mg of C,3H,Cl,O, in the weight of powder taken.
Carry out the assay of anti-facts For zinc oxide
Appendix XIV J B2. The fiduci: To a quantity of the powder containing 90 mg of Zinc Oxide
than 80% and not more than 125% 6 stated potency. add 10 mL of 2m mutric acid and 20 mL of water, boil for
STORAGE ‘ 2 minutes, cool, filter and wash the filter with two 25 mL
Heparin Injection should preferably be kept: quantities of water. To the combined filtrate and washings
sealed by fusion of the glass. add 3 g of hexamine and titrate with 0.05mM disodium edetate
VS using 2 mL of xylenol orange solution as indicator. Each
LABELLING é
The strength is stated as the number of IU (Units) in
suitable dose-volume except that for multi-dose containe
the strength is stated as the number of IU (Units) per mL.
The label states (1) whether the material is the calcium or tates that the preparation should not be applied to
sodium salt; (2) when no antimicrobial preservative is present o large areas of skin except in accordance with
that the preparation contains no antimicrobial preservative
and that any portion of the contents not used at once should
be discarded.
Action and use

Hexachlorophene Dusting Powder Anticholinergic.
Hexachlorophene Cutaneous Powder; Zinc and
Hexachlorophene Dusting Powder DEFINITION
Homatropine Eye Drops ar rile solution of
Action and use Homatropine Hydrobromide in Purified
P:
Antiseptic. The eye drops comply with the requirementsSt under Eye
Preparations and with the following require
DEFINITION
Hexachlorophene Dusting Powder is a cutaneous powder. It is Content of homatropine hydrobromide,
a mixture of Hexachlorophene and Zinc Oxide with a C,¢6H2,NO3,HBr
suitable inert diluent. 90.0 to 110.0% of the stated amount.

The dusting powder complies with the requirements stated under IDENTIFICATION
Topical Powders and with the following requirements. A. To a volume containing 60 mg of Homatropine
Content of hexachlorophene, C,;H,;Cl,O2 Hydrobromide add 3 mL of 5m ammonia, extract with
90.0 to 110.0% of the stated amount. 15 mL of chloroform, dry the chloroform over anhydrous
sodium sulfate, filter and evaporate the filtrate to dryness. The
Content of zinc oxide, ZnO
infrared absorption spectrum of the residue, Appendix II A, 1s
concordant with the reference spectrum of homatropine
IDENTIFICATION : (RS 175).
A. Shake a quantity of the powder containing 30 mg of B. In the Assay, the chromatogram obtained with solution
Hexachlorophene with 25 mL of ether for 15 minutes, filter, (2) shows a peak with the same retention time as the peak
wash the filtrate with 10 mL of water, dry the ether layer over derived from homatropine hydrobromide in the
anhydrous sodium sulfate, filter and evaporate to dryness. The chromatogram obtained with solution (3).
C. To 1 mL of the eye drops, diluted with water if necessary
concordant with the reference spectrum of hexachlorophene
to give a solution containing 1% w/v of Homatropine
(RS 174).
Hydrobromide, add 1 mL of 5m ammonia, shake with
2016 Hyaluronidase Preparations III-659
chloroform and evaporate the chloroform solution to dryness DETERMINATION OF CONTENT

on a water bath. To the residue add 1.5 mL of a 2% w/v Calculate the content of C;gH2;NO3,HBr using the ratios of
solution of mercury(I] chloride in ethanol (60%). A yellow the peaks and the declared content of C;gH2,;NO3,HBr in
colour is produced which becomes red on gentle warming homatropine hydrobromide BPCRS.
(distinction from most other alkaloids except atropine and
hyoscyamine).
TESTS
Tropine
Hyaluronidase Injection
Appendix III A, usingthe rouowing solutions. Action and use
Used to promote absorption of fluid into tissues.
DEFINITION
Hyaluronidase Injection is a sterile solution of Hyaluronidase
in Water for Injections. It is prepared by dissolving
Hyaluronidase for Injection in the requisite amount of Water
for Injections immediately before use.
STORAGE
Hyaluronidase Injection should be used immediately after
preparation.
MOBILE PHASE
33 volumes of anhydrous formic acid, 3 HYALURONIDASE FOR INJECTION
DEFINITION
LIMITS Hyaluronidase for Injection is a sterile material consisting of
Hyaluronidase with or without excipients. It 1s supplied in a
obtained with solution (1) is not more intense than ‘the.g sealed container.
in the chromatogram obtained withsolution (2) (0.5% The contents of the sealed container comply with the requirements
ASSAY 2auders for Injections or Infusions stated under Parenteral
Carry out the method for gas chromatography, ‘ations and with the following requirements.
Appendix III B. Prepare a 2% w/v solution of atropine
sulfate BPCRS (internal standard) in methanol (solution A).
(1) Add 1 mL of solution A and 1 mL of 5M ammonia to a
volume of the eye drops containing 20 mg of Homatropine
Hydrobromide, diluted if necessary to 5 mL with water. sing 100 IU in 1 mL of a 0.9% w/y solution
Extract with two 5-mL quantities of chloroform, shake the 24 lymerises an equal volume of a 1% wiv
combined extracts with 1 g of anhydrous sodium sulfate, filter
and evaporate the filtrate to dryness. Dissolve the residue in
10 mL of dichloromethane. To 1 mL of this solution add destroyed by heating
wea
wir
0.2 mL of a mixture of 4 volumes of 30 minutes.
N,O-bis(trimethylsilyl) acetamide and 1 volume of
TESTS &
trimethylchlorosilane, mix and allow to stand for 30 minutes.
(2) Prepare in the same manner as solution (1) but omitting
DH of a 0.3% w/v solution in carbon
the addition of solution A.
7.5, Appendix V L.
(3) Add 1 mL of solution A and 1 mL of 5m ammonia to
5 mL of a 0.4% w/v solution of homatropine
A 1.0% w/v solution in carbon dioxide-free wai
hydrobromide BPCRS. Complete the procedure described
Appendix IV A, and not more than faintly yellow.
under solution (1), beginning at the words ‘Extract with two
5-mL quantities of chloroform...’. Bacterial endotoxins
we we
(a) Use a glass column (1.5 m x 4 mm) packed with acid-

ean
a
give a solution containing 150 IU of Hyaluronidase per mL

washed, silanised diatomaceous support (80 to 100 mesh) coated (solution A). The endotoxin limit concentration of solution A
with 3% w/w of phenyl methyl silicone fluid (50% phenyl) is 30 IU per mL.
ve ea
“4 ‘
(OV-17 is suitable).
ASSAY
(b) Use helium as the carrier gas at 1.7 mL per minute.
Carry out the Assay described under Hyaluronidase.
(d) Use an inlet temperature of 220°. LABELLING
The label of the sealed container states the total number
of IU (Units) contained in it.
III-660 Hydralazine Preparations 2016
Hydralazine Injection (a) Use as the coating silica gel (Merck silica gel 60 plates are
aA
FAN PLN
wea
Action and use suitable).
Vasodilator; treatment of hypertension. (b) Use the mobile phase as described below.
DEFINITION
Hydralazine Injection is a sterile solution of Hydralazine
Hydrochloride in Water for Injections. It is prepared by (e) After removal of the plate, dry in air and spray with
dissolving Hydralazine Hydrochloride for Injection in the dimethylaminobenzaldehyde solution R1.
requisite amount of Water for Injections immediately before MOBILE PHASE
use. For intravenous infusion, the Hydralazine Hydrochloride The upper layer of the mixture obtained by shaking together
hould be dissolved in, and then diluted with, 20 volumes of 13.5M ammonia, 20 volumes of ethyl acetate
and 80 volumes of hexane and allow to stand.
LIMITS
Any spot corresponding to hydrazine in the chromatogram
STORAGE obtained with solution (1) is not more intense than the spot
Hydralazine Injecticg in the chromatogram obtained with solution (2).
used immediately after
Sealed containers each containing 20 mg or less of
HYDRALAZINE HYD Hydralazine Hydrochloride comply with the requirements
INJECTION stated under Parenteral Preparations, Powders for Injections
or Infusions using the following method of analysis. Dissolve
DEFINITION the contents of a sealed container in sufficient water to
Hydralazine Hydrochloride for Injection is produce 100 mL and dilute a volume containing 1 mg of
consisting of Hydralazine Hydrochloride wit Hydralazine Hydrochloride to 100 mL with water. Measure
excipients. It is supplied in a sealed contain the absorbance of the resulting solution at the maximum at
The contents of the sealed container comply with the ‘require? 260 nm, Appendix II B. Calculate the content of
for Powders for Injections or Infusions stated under Pare? CgHgN,,HCl taking 535 as the value of A(1%, 1 cm) at the
Preparations and with the following requirements. maximum at 260 nm.
Content of hydralazine hydrochloride, CgH3sN,,HC1
98.0 to 114.0% of the stated amount. the weight of the contents of 10 containers
IDENTIFICATION n the test for uniformity of weight,
concordant with the reference spectrum of hydralazine
350 nm of a 0.002% w/v solution exhibits four maxima, at
240, 260, 305 and 315 nm. eference electrode. Each mL of
is equivalent to 4.916 mg of
C. Yield the reactions characteristic of chlorides, Appendix VI.
ontent of CgHgN,,HCl in a
TESTS container of average coriteti
Acidity
STORAGE
pH of a 2% w/v solution, 3.5 to 4.2, Appendix V L.
Clarity of solution
A 2.0% w/v solution is not more opalescent than reference
suspension IT, Appendix IV A.
Colour of solution
A 2.0% w/v solution in 0.01mM hydrochloric acid is not more Hydralazine Tablets
intensely coloured than reference solution GY.s, Appendix IV B,
Action and use
Method II.
Vasodilator; treatment of hypertension.
Hydrazine
Carry out the method for thin-layer chromatography, DEFINITION
Appendix III A, using the following solutions. Hydralazine Tablets contain Hydralazine Hydrochloride.
(1) Dissolve the contents of a sealed container in sufficient The tablets comply with the requirements stated under Tablets and
0.1M methanolic hydrochloric acid to produce a solution with the following requirements.
containing 0.5% w/v of Hydralazine Hydrochloride. To 2 mL
Content of hydralazine hydrochloride, CgHsN,,HCl
add 1 mL of a 2% w/v solution of salicylaldehyde in methanol
and 0.1 mL of hydrochloric acid, centrifuge and decant the
supernatant liquid. IDENTIFICATION
(2) Prepare in the same manner as solution (1), but use A. Dissolve a quantity of the powdered tablets containing
2 mL of a 0.00025% w/v solution of hydrazine sulfate in 0.1 g of Hydralazine Hydrochloride in 10 mL of water, make
0.1M methanolic hydrochloric acid in place of the solution of alkaline with 2 mL of 5mM:ammonia and extract with two
the material being examined. 10-mL quantities of chloroform. Combine the chloroform
extracts and evaporate to dryness. The infrared absorption
2016 Hydrochlorothiazide Preparations III-661
spectrum of the residue, Appendix II A, is concordant with IDENTIFICATION

the reference spectrum of hydralazine (RS 176). Carry out the method for thin-layer chromatography,
B. Shake a quantity of the powdered tablets containing Appendix III A, using the following solutions.
25 mg of Hydralazine Hydrochloride with 30 mL of methanol (1) Triturate a quantity of the powdered tablets containing
for 15 minutes, add sufficient methanol to produce 50 mL 10 mg of Hydrochlorothiazide with 10 mL of acetone and
and filter. Dilute 1 volume of the filtrate to 50 volumes with filter.
water. The light absorption of the resulting solution, (2) 0.1% wy of hydrochlorothiazide BPCRS in acetone.
Appendix II B, in the range 230 to 350 nm exhibits four
maxima, at 240, 260, 305 and 315 nm.
C. Extract a quantity of the powdered tablets containing (a) Use as the coating seca gel GF 254.
O.l g of Hydralazine Hydrochloride with two 25-mL (b) Use the mobile phase as described below.
methanol, filter the combined extracts and (c) Apply 5 uL of each solution.
fiess. To 5 mL of a 1% w/v solution of the (d) Develop the plate to 15 cm.
ladd 5 mL of a 2% w/v solution of
(e) After removal of the plate, dry in a current of air,
2-nitrobenzéa ethanol (96%). An orange precipitate is
examine under ultraviolet light (254 nm) and then treat the
produced.
plate by Method I and examine again.
TEST MOBILE PHASE
Hydrazine
ethyl acetate.
Carry out the metho chromatography,
Appendix III A, using a sif ' CONFIRMATION
silica gel 60 plates are suita By each method of visualisation the principal spot in the
upper layer obtained by sha t chromatogram obtained with solution (1) corresponds in
13.5M ammonia, 20 volumes of ethy g@cetateand 80 volumes colour and intensity to that in the chromatogram obtained
of hexane and allowing to separate. App with solution (2).
TESTS
(1) extract a quantity of the powdered tab
Related substances
50 mg of Hydralazine Hydrochloride with 10
0.1m methanolic hydrochloric acid; to 2 mL add 1 mL o:
2% wy solution of salicylaldehyde in methanol and 0.4m
hydrochloric acid, centrifuge and use the supernatant liqu (1) Shake a quantity of the powdered tablets containing
Prepare solution (2) in the same manner, but using 2 m 50 of Hydrochlorothiazide with 25 mL of a mixture of
a 0.00025% w/v solution of hydrazine sulfate in lumes of acetonitrile and methanol and dilute to
0.1m methanolic hydrochloric acid in place of the solution of with phosphate buffer solution pH 3.2 R1. Filter
the substance being examined. After removal of the plate, glass-fibre filter (Whatman 0.45 GD/X is
allow it to dry in air and spray with
dimethylaminobenzaldehyde solution R1. Any spot lume of solution (1) to 100 volumes with a
corresponding to hydrazine in the chromatogram obtained mixture cq 1g Levolume of methanol, 1 volume of
with solution (1) is not more intense than the spot in the acetonitrile an volumes of phosphate buffer solution
chromatogram obtained with solution (2) (0.05%). oH 3.2 R1.
ASSAY (3) Dissolve, with.¢he f ultrasound, 15 mg each of
Weigh and powder 20 tablets. To a quantity of the powder hydrochlorothiazide BI and chlorothiazide BPCRSin
containing 50 mg of Hydralazine Hydrochloride add 50 mL 25 mL of a mixture of mes of acetonitrile and
of water and shake for 20 minutes. Add 60 mL of hydrochloric methanol and dilute to 100.m with phosphate buffer solution
acid and titrate with 0.025m potassium todate VS determining
the end point potentiometrically using platinum and calomel with the same solvent mixture.”
electrodes. Each mL of 0.025m potassium iodate VS is CHROMATOGRAPHIC CONDITIO
equivalent to 4.916 mg of CgHgN,,HCl. (a) Use a stainless steel column (10 c
STORAGE
Hydralazine Tablets should be protected from light.
(b) Use gradient elution and the mobile phases
below.
Hydrochlorothiazide Tablets (d) Use an ambient column temperature.

Action and use (f) Inject 20 wL of each solution.
Thiazide diuretic.
MOBILE PHASE A
DEFINITION 10 volumes of tetrahydrofuran, 60 volumes of methanol and

Hydrochlorothiazide Tablets contain Hydrochlorothiazide. 940 volumes of phosphate buffer solution pH 3.2 R1.
The tablets comply with the requirements stated under Tablets and MOBILE PHASE B
with the following requirements. 50 volumes of tetrahydrofuran, 500 volumes of methanol and
Content of hydrochlorothiazide, C;HgCIN30,S, 500 volumes of phosphate buffer solution pH 3.2 R1.
92.5 to 107.5% of the stated amount. Equilibrate the column for at least 20 minutes with mobile
phase A.
rans
tT
srr e
ts.
oe
aw Le
IlI-662 Hydrocortisone Preparations 2016
Time Mobile phaseA Mobile phase Bo Comment For creams containing 0.5% w/w or less of Hydrocortisone:
Gnin} (percent VP) (per cent V/V) (1) Prepare in the same manner as solution (1) above but use
O-17 100-553 0-45 Linear gradient a quantity containing 5 mg of Hydrocortisone.
17-3035 43 lsocratic (2) 0.05% w/v of hydrocortisone BPCRS in methanol.
30-33 55»100 45-0 Linear gradient (3) A mixture of equal volumes of solutions (1) and (2).
35-30 = 100 0 Isocratic CHROMATOGRAPHIC CONDITIONS
500 100 i) Return to initial (a) Use as the coating sihca gel G.
eluent
COM POSITION (b) Use the mobile phase as described below.
(e) After removal of the plate, dry in air, spray with alkaline
L.unless, in the chromatogram obtained
tetrazolium blue solution and examine in white light.
ie resolution between the peaks
MOBILE PHASE
least 2.5. 1.2 volumes of water, 8 volumes of methanol, 15 volumes of
LIMITS ether and 77 volumes of dichloromethane.
In the chromatogram obtained with solution (1): CONFIRMATION
the area of any secondary pe greater than the area of The principal spot in the chromatogram obtained with
the principal peak in the chromatog: m obtained with solution (1) corresponds to that in the chromatogram
solution (2) (1%); obtained with solution (2); if it does not, the principal spot in
the sum of the areas of any second s not greater than the chromatogram obtained with solution (3) appears as a
2.5 times the area of the principal peak i fre chromatogram single, compact spot.
obtained with solution (2) (2.5%). B. In the Assay, the chromatogram obtained with solution
Disregard any peak with an area less than 04 (2) shows a peak with the same retention time as the peak
of the principal peak in the chromatogram obtaige due to hydrocortisone in the chromatogram obtained with
solution (2) (0.1%). solution (3).
ASSAY ASSAY
Weigh and powder 20 tablets. To a quantity of the powdé Carry out the method for liguid chromatography,
containing 30 mg of Hydrochlorothiazide add 50 mL of dix III D, using the following solutions.
0.1M sodium hydroxide, shake for 20 minutes and dilute to xs containing more than 0.5% w/w of Hydrocortisone:
100 mL with 0.1m sodium hydroxide. Mix, filter, dilute 5 mL 0.5% w/v solution of betamethasone (internal
of the filtrate to 100 mL with water and measure the
C7HgCIN30,S, taking 520 as the value of A(1%, 1 cm) at
the maximum at 273 nm. : 60 mL of hot hexane, shake and
eat the extraction using a further
Hydrocortisone Cream
Action and use suitable). —
Corticosteroid. (2) Preparein the same manner as:
5 mL of methanolin place of the 5 m
DEFINITION
(3) Dissolve 25 mg of hydrocortisone BPCR§
Hydrocortisone Cream contains Hydrocortisone in a suitable
methanol, add 5 mL of solution A and add
basis.
produce 100 mL.
For creams containing 0.5% wi/w or less ofHydrocortifone:
Prepare a 0.110% w/v solution of betamethasone (internal
Content of hydrocortisone, C,,H3,)0;
standard) in methanol (solution B).
7
cote 90.0 to 110.0% of the stated amount.
(1) Disperse, by shaking, a quantity of the cream containing
IDENTIFICATION 5 mg of Hydrocortisone in 40 mL of a mixture of 3 volumes
v*

'oy
of methanol and 1 volume of a 15% w/v solution of sodium

Oe
chloride. Add 50 mL of hot hexane, shake and separate the

ea Oe ae
For creams containing more than 0.5% wiw of Hydrocortisone: lower layer. Repeat the extraction using a further two 10-mL
Pulley
”
(1) Mix a quantity containing 25 mg of Hydrocortisone with quantities of the methanolic sodium chloride solution. To the
.
10 mL of methanol (90%), add 50 mL of hot hexane and combined extracts add 5 mL of solution B and sufficient
roe
.
water to produce 100 mL, mix and filter through a glass

pea
shake. Separate the lower layer, add 5 g of anhydrous sodium

sulfate, mix and filter through a glass microfibre filter microfibre paper (Whatman GF/C is suitable).
One
ee a
(Whatman GF/C is suitable). (2) Prepare in the same manner as solution (1), but add
» BPG e
Chl
(2) 0.25% w/v of hydrocortisone BPCRS in methanol. 5 mL of methanol in place of the 5 mL of solution B.
SPA
te

2016 Hydrocortisone Preparations III-663
(3) Dissolve 5 mg of hydrocortisone BPCRS in 45 mL of the same manner as solution (2) above but use a quantity
methanol and add 5 mL of solution B and sufficient water to containing 5 mg of Hydrocortisone. -
produce 100 mL.
STORAGE
CHROMATOGRAPHIC CONDITIONS Hydrocortisone Ointment should be protected from light.
(b) Use isocratic elution and the mobile phase described Hydrocortisone Oromucosal Tablets
below.
Action and use
(c) Use a flow rate of 2 mL per minute. Corticosteroid.
(d) Use —
bient column temperature.
DEFINITION
Hydrocortisone Oromucosal Tablets are mucoadhesive
buccal tablets containing hydrocortisone sodium succinate
prepared by buffering Hydrocortisone Hydrogen Succinate.
methanol (50%). The tablets comply with the requirements stated under Oromucosal
DETERMINATION O Preparations and with the following requirements.
Calculate the content of in the cream using the Content of hydrocortisone, C,,;H3 90;
ratios of the peaks and the gontent of C,;H3 905 in 90.0 to 110.0% of the stated amount.
hydrocortisone BPCRS.
IDENTIFICATION
Hydrocortisone Ointment 60 F454 plates are suitable) and a mixture of 20 volumes of
acetic anhydride, 20 volumes of water and 60 volumes of
Action and use butan-1-ol as the mobile phase. Apply separately to the plate
Corticosteroid. 5 pL of each of the following solutions. For solution (1)
shake a quantity of the tablets containing the equivalent of
DEFINITION 25 mg of hydrocortisone with 10 mL of methanol, filter and
Hydrocortisone Ointment contains Hydrocortisone in a use the filtrate. For solution (2) dissolve 50 mg of
suitable basis. ayarSeertisone acetate BPCRS in sufficient methanol to produce
The ointment complies with the requirements stated under Topical if. Solution (3) contains equal volumes of solutions (1)
Semi-solid Preparations and with the following requirements. fter removal of the plate, allow it to dry in air,
ethanolic sulfuric acid (20%), heat at 120° for
Content of hydrocortisone, C,,H3 0;
IDENTIFICATION 1)..corresponds to that in the chromatogram
A. Complies with test A for Identification described under utiore(2). The test is not valid unless the
Hydrocortisone Cream but preparing solution (1) in the ith solution (3) shows a single
following manner. For ointments containing more than 0.5% compact spot.
w/w of Hydrocortisone; disperse a quantity containing 25 mg TESTS
of Hydrocortisone in 5 mL of hot hexane, cool, extract with
Disintegration
10 mL of methanol (90%) and filter. For ointments The tablets disintegrate in nottéss th 10 minutes when
containing 0.5% w/w or less of Hydrocortisone, disperse a
examined by the disintegrationtestfor: lets and capsules,
quantity containing 5 mg of Hydrocortisone in 50 mL of hot
hexane, cool, extract with 10 mL of methanol (90%) and
filter.
due to hydrocortisone in the chromatogram obtained with
containing the equivalent of 7.5 mg of hydrocortiséne in
solution (1).
15 mL of a phosphate buffer prepared by dissolving 5.8 g of
ASSAY anhydrous disodium hydrogen orthophosphate and 1.6 g of
Carry out the Assay described under Hydrocortisone Cream sodium dihydrogen orthophosphate in 1000 mL of water and
but prepare solution (2) in the following manner. adjusting the pH to 7.4, if necessary, by adding 10 mg
For ointments containing more than 0.5% w/w of quantities of either anhydrous disodium hydrogen orthophosphate
Hydrocortisone, disperse a quantity containing 25 mg of or sodium dihydrogen orthophosphate. Shake and extract with
Hydrocortisone in 100 mL of hot hexane, cool and extract three 25-mL quantities of chloroform, combine the extracts in
with 20 mL of a solution prepared by mixing 3 volumes of a second separating funnel, wash the combined extracts with
methanol with 1 volume of a 15% w/v solution of sodium 2 mL of water, filter the chloroform layer through a plug of
chloride. Repeat the extraction using a further two 10 mL absorbent cotton, previously moistened with chloroform, into a
quantities of the methanolic sodium chloride solution. To the 250-mL round-bottomed flask, wash the funnel and
combined extracts add 5 mL of methanol and sufficient water absorbent cotton plug with two 10-mL quantities of
to produce 100 mL, mix and filter through a glass microfibre chloroform and add the washings to the flask; evaporate to
filter (Whatman GF/C is suitable). For ointments containing dryness using a rotary evaporator, allow to cool and dissolve
0.5% w/w or less of Hydrocortisone, prepare solution (2) in the residue in 50 mL of aldehyde-free ethanol (96%). Solution
(2) contains 0.00225% w/v of hydrocortisone BPCRS in (1) described above but using a quantity of the cream
aldehyde-free ethanol (96%). containing 5 mg of Hydrocortisone Acetate. Solution (2) is a
Protect all the solutions from light. Transfer 10 mL of mixture of equal volumes of solution (1) and a 0.05% w/v
solution (1) into a stoppered test-tube and repeat for solution solution of hydrocortisone acetate BPCRS in methanol.
(2). Place in a water bath at 35° for 10 minutes, add 1 mL of After removal of the plate, allow it to dry in air and spray
triphenyltetrazolium chloride solution and 1 mL of dilute with alkaline tetrazolium blue solution. The principal spot in
tetramethylammonium hydroxide solution to each tube, stopper the chromatogram obtained with solution (1) corresponds to
and mix well; allow the tubes to stand in the water bath at that in the chromatogram obtained with solution (2), which
35° for a further 25 minutes, remove from the water bath appears as a single, compact spot.
and allow to stand in water for 5 minutes at room B. In the Assay, the chromatogram obtained with solution
temperature. Measure the absorbance of the resulting (2) shows a peak with the same retention time as the peak
solutions 1n a stoppered cell at the maximum at 485 nm, due to hydrocortisone acetate in the chromatogram obtained
, » using in the reference cell a solution prepared with solution (1).
4edind in the same manner using 10 mL of
ASSAY
Calculate
ASSAY For creams containing more than 0.5% w/w of
Hydrocortisone Acetate, prepare solutions (1) and (2) in the
following manner. For solution (1) dissolve 25 mg of
hydrocortisone with 50 mi hydrocortisone acetate BPC'RS in 45 mL of methanol, add 5 mL
100 mL with water, filter a of a 0.5% w/v solution of betamethasone (internal standard) in
methanol and add sufficient water to produce 100 mL.
For solution (2) disperse, by shaking, a quantity containing
maximum at 248 nm using water in thé reference cell. 25 mg of Hydrocortisone Acetate in 40 mL of a solution
Calculate the content of hydrocortisone,°2,F prepared by mixing 75 mL of methanol with 25 mL of a
15% w/v solution of sodium chloride. Add 50 mL of hot
maximum at 248 nm. hexane, shake and separate the lower layer. Repeat the
LABELLING extraction using two 10 mL quantities of the methanolic
The quantity of active ingredient is stated in terms sodium chloride solution. Add 5 mL of methanol to the
equivalent amount of hydrocortisone. combined extracts and sufficient water to produce 100 mL,
mix and filter through a glass microfibre filter paper
Whatman GE/C is suitable).
reaims containing 0.5% w/w or less of Hydrocortisone
pare solutions (1) and (2) in the following
Hydrocortisone Acetate Cream r solution (1) dissolve 5 mg of hydrocortisone
Action and use
WAS in 45 mL of methanol and add 5 mL ofa
Corticosteroid.
methanol anid suffici
DEFINITION
Hydrocortisone Acetate Cream contains Hydrocortisone
Acetate in a suitable basis. on (3) in the same manner as
The cream complies with the requirements stated under Topical solution (2) but addin € appropriate internal
Semi-solid Preparations and with the following requirements. standard solution in place . 5) mL of methanol before
diluting to volume.
Content of hydrocortisone acetate, C,3H3,0,
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, ODS1is suitable), (b) methanol (50%) ‘ase
Appendix III A, using silica gel G as the coating substance with a flow rate of 2 mL per minute and (
and a mixture of 77 volumes of dichloromethane, 15 volumes wavelength of 240 nm.
of ether, 8 volumes of methanol and 1.2 volumes of water as Calculate the content of C,3H3 20, in the preparation being
the mobile phase. Apply separately to the plate 5 uL of each examined using the declared content of C,3H3,0.¢ in
of the following solutions. hydrocortisone acetate BPCRS.
For creams containing morethan 0.5% w/w of
Hydrocortisone Acetate, prepare two solutions in the
following manner. For solution (1) mix a quantity of the
cream containing 25 mg of Hydrocortisone Acetate with
10 mL of methanol (90%), add 50 mL of hot hexane and
Hydrocortisone Acetate Injection
shake. Discard the upper layer, add 5 g of anhydrous sodium Action and use
sulfate to the lower layer, mix and filter through a glass Corticosteroid.
microfibre filter (Whatman GEF/C is suitable). Solution (2) is
a mixture of equal volumes of solution (1) and a 0.25% w/v DEFINITION
solution of hydrocortisone acetate BPCRS in methanol. Hydrocortisone Acetate Injection is a sterile suspension of
For creams containing 0.5% w/w or less of Hydrocortisone Hydrocortisone Acetate in Water for Injections. It is prepared
Acetate, prepare solution (1) in the same manner as solution using aseptic technique.

Hydrocortisone Acetate Ointment
LAN
were ed Content of hydrocortisone acetate, C,3;H3,0,¢ Action and use
AS a
95.0 to 105.0% of the stated amount. Corticosteroid.
IDENTIFICATION
DEFINITION
Filter a volume containing 50 mg of Hydrocortisone Acetate
Hydrocortisone Acetate Ointment contains Hydrocortisone
through a sintered-glass filter, wash the residue with four
Acetate in a suitable basis.
5-mL quantities of water, dissolve in 20 mL of chloroform,
wash the chloroform solution with four 10-mL quantities of The omtment complies with the requirements stated under Topical
water, discard the washings, filter the chloroform solution Semi-solid Preparations and with the following requirements.
through absorbent cotton and evaporate the filtrate to Content of hydrocortisone acetate, C,3H3,0,
IDENTIFICATION
Appendix III A using the following solutions.
For ointments containing more than 0.5% w/w of
Hydrocortisone Acetate
(1) Disperse a quantity containing 25 mg of Hydrocortisone
Acetate in 5 mL of hot hexane, cool, extract with 10 mL of
Appendix VI. methanol (90%) and filter.
ASSAY (2) Equal volumes of solution (1) and a 0.25% w/v solution
of hydrocortisone acetate BPCRS in methanol.
Appendix HI D, using thefollowing : : For ointments containing 0.5% w/w or less of
(1) To a volume of the injection contaiz Hydrocortisone Acetate
| Hydrocortisone Acetate, add 70 mL of me (1) Disperse a quantity containing 5 mg of Hydrocortisone
ON
produce a clear solution and dilute to 100° Acetate in 5 mL of hot hexane, cool, extract with 10 mL of
methanol (90%) and filter.
_ (2) Equal volumes of solution (1) and a 0.05% w/v solution
oo of methanol and add sufficient water to produce 10 of hydrocortisone acetate BPCRS in methanol.
CHROMATOGRAPHIC CONDITIONS CHROMATOGRAPHIC CONDITIONS
the mobile phase as described below.
¥ 5 uL of each solution.
below.
ether and 77 volu 4 ‘uchloromethane.
CONFIRMATION
MOBILE PHASE
The principal spot in the:chromjatogram obtained with
50 volumes of methanol and 50 volumes of water. solution (1) corresponds sat in the chromatogram
DETERMINATION OF CONTENT obtained with solution (2) whigh appéars as a single,
Calculate the content of C.3H3.0¢ in the injection from the compact spot. :
chromatograms obtained using the declared content of B. In the Assay, the chromatogram obtained with solution
C33H3206¢ in hydrocortisone acetate BPCRS. (2) shows a peak with the same reten imé.as the peak
due to hydrocortisone acetate in the chro btained
STORAGE
with solution (1).
Hydrocortisone Acetate Injection should be protected from
light. ASSAY
LABELLING
Appendix III D using the following solutions.
The label states (1) that it is intended for local action;
(2) that the container should be gently shaken before a dose For ointments containing more than 0.5% w/w of
is Withdrawn. Hydrocortisone Acetate
(1) Disperse a quantity of the ointment containing 25 mg of
Hydrocortisone Acetate in 100 mL of hot hexane, cool and
extract with 20 mL of a solution prepared by mixing
3 volumes of methanol and 1 volume of a 15% w/v solution
of sodium chloride. Repeat the extraction using two 10-mL
quantities of the methanolic sodium chloride solution.
Add 5 mL of methanol to the combined extracts and
an 8s,
sufficient water to produce 100 mL, mix and filter through a
Wee
1APete Se)
glass microfibre filter (Whatman GF/C is suitable).
(2) Dissolve 25 mg of hydrocortisone acetate BPCRS in 45 mL The oral suspension should be shaken vigorously before carrying
of methanol, add 5 mL of a 0.5% w/v solution of out the following tests.
betamethasone (internal standard) in methanol and sufficient IDENTIFICATION
A. Filter a volume of the oral suspension containing the
(3) Prepare in the same manner as solution (1) but add equivalent of 50 mg of hydrocortisone through a sintered-
5 mL of the internal standard solution in place of the 5 mL glass filter, wash the residue with four 5-mL quantities of
of methanol before diluting to volume. water, dissolve in 20 mL of dichloromethane, wash the
For ointments containing 0.5% w/w or less of dichloromethane solution with four 10-mL quantities of
Hydrocortisone Acetate water, discard the washings, filter the dichloromethane
(1) Disperse a quantity of the ointment containing 5 mg of solution through absorbent cotton and evaporate the filtrate
Hydrocortisone Acetate in 100 mL of hot hexane, cool and to dryness. The residue complies with the test for
20.mL of a solution prepared by mixing identification of steroids, Appendix III A, using impregnating
!and 1 volume of a 15% w/v solution solvent I and mobile phase B.
at the extraction using two 10-mL B. In the Assay, the retention time of the principal peak in
olic sodium chloride solution. the chromatogram obtained with solution (1) corresponds to
the combined extracts and that of the principal peak in the chromatogram obtained with
solution (2).
(¥ ,
glass microfibre filter C. The residue obtained in test A yields the reaction
mg of hydri characteristic of acetyl groups, Appendix VI.
(2) Dissolve 5
TESTS
betamethasone (internal standard):.
Dissolution
sufficient water to produce 100
Medicines, Oral Suspensions. Use a volume of the oral
of methanol before diluting to volume.
ASSAY
(a) Use a stainless steel column 10 cm x 5 mm) fac Appendix III D, using the following solutions.
equivalent of 10 mg of hydrocortisone add 50 mL of
(b) Use isocratic elution and the mobile phase described thanol, mix with the aid of ultrasound, dilute to 100 mL
below. tanol and filter (Whatman No. 1 paper is suitable).
(c) Use a flow rate of 2 mL per minute. v of hydrocortisone BPCRS in methanol.
(d) Use an ambient column temperature. SRAPHIC CONDITIONS
(f) Inject 20 wL of each solution. iiSilica gel for chromatography (5 um)
MOBILE PHASE table).
Calculate the content of C3H3 0, in the ointment using the
declared content of C.3H3.0¢ in hydrocortisone (d) Use an ambient colur
acetate BPCRS. (e) Use a detection wavelen
STORAGE (f) Inject 10 pL of each solution. ,
Hydrocortisone Acetate Ointment should be protected from MOBILE PHASE
light. 4 volumes of a 1% w/v solution of acetic agid in, water and
Hydrocortisone Acetate Oral Suspension Determine the weight per mL of the oral suspension,
NOTE: Hydrocortisone Acetate Oral Suspension 1s not currently Appendix V G, and calculate the content of C2;H3 05,
licensed in the United Kingdom. weight in volume, using the declared content of C2;H3 0s in
hydrocorusone BPCRS.
Action and use
LABELLING
Corticosteroid.
DEFINITION equivalent amount of hydrocortisone.
Hydrocortisone Acetate Oral Suspension is a suspension of
Hydrocortisone Acetate in a suitable flavoured aqueous |
vehicle.
Oral Liquids, the requirements stated under Unlicensed Medicines
Content of hydrocortisone, C,,H3 0;
20 mL of methanol (80%), combine the aqueous methanolic

Hydrocortisone and Clioquinol Cream layers, cool to about 20° and dilute to. 100 mL with the same
Action and use
solvent.
Corticosteroid. (2) Dissolve 5 mg of hydrocortisone BPCRS in 5 mL of a
4% v/v solution of bromobenzene (internal standard) in
DEFINITION methanol and dilute to 50 mL with methanol (80%).
Hydrocortisone and Clioquinol Cream contains (3) Prepare in the same manner as solution (1) but adding
Hydrocortisone and Clioquinol, the latter in very fine powder, 10 mL of a 4% v/v solution of bromobenzene in methanol to
in a suitable basis. the cooled methanolic extract.
The cream complies with the requirements stated under Topical CHROMATOGRAPHIC CONDITIONS
below.
(1) Disperse, by warmin (f) Inject 20 wL of each solution.
cream containing 2.5 go
MOBILE PHASE
ethanol (96%), cool, allow
and use the filtrate. methanol (65%).
(3) Dissolve 12.5 mg of hydrocortisone Calculate the content of C,,;H3 )05 in the cream using the
solution (1). declared content of C,;H3 905 in hydrocortisone BPCRS.
CHROMATOGRAPHIC CONDITIONS For choquinol
(a) Use as the coating silica gel G. To a quantity of the cream containing 25 mg of Clioquinol
add 80 mL of a hot mixture of 6 volumes of water and
24 volumes of 2-methoxyethanol and heat on a water bath for
(c) Apply 5 wL of each solution. J utes. Coolin ice for 10 minutes, allow to warm to
(d) Develop the plate to 15 cm. ‘temperature, dilute to 100 mL with the aqueous
(e) After removal of the plate, allow it to dry in air and spra yethanol, mix and filter. To 10 mL of the filtrate add
with alkaline tetrazolium blue solution. of 2 methonvetang and 2 mL of a solution prepared
MOBILE PHASE
1.2 volumes of water, 8 volumes of methanol, 15 volumes of
ether and 77 volumes of dichloromethane.
CONFIRMATION absorbance of
t 3
The principal spot in the chromatogram obtained with 650 nm,‘Append
solution (1) corresponds to that in the chromatogram prepared by treat
obtained with solution (2). The principal spot in the
chromatogram obtained with solution (3) appears as a single,
compact spot.
B. In the Assay for hydrocortisone, the chromatogram
retention time as the peak due to hydrocortisone in the
C. Fuse a quantity of the cream containing 0.1 g of
24 volumes of 2-methoxyethanol to produce 50 Calculate
Clioquinol with anhydrous sodium carbonate, dissolve the fused
mass in water and acidify with 2m nitric acid. Add silver nitrate
the content of Cp)H5CIINO from the absorbances obtained
and using the declared content of Cp)H5CIINO in
solution; a pale yellow precipitate is produced which is
choquinol BPCRS.
insoluble in 5M ammonia. Add 5M ammonia until the solution
becomes alkaline, boil gently, filter and acidify the filtrate STORAGE
with 2m nitric acid; a white precipitate is produced which Hydrocortisone and Clioquinol Cream should be protected
darkens on exposure to light. from light.
ASSAY
For hydrocortisone
(1) Add 30 mL of 2,2,4-trimethylpentane to a quantity of the
cream containing 10 mg of Hydrocortisone and warm on a
ay water bath until the preparation has melted. Extract the
warm mixture with successive quantities of 30, 20 and
awn
III-668 Hydrocortisone Preparations 2016
octadecylsilyl silica gel for chromatography (Spherisorb ODS | is

Hydrocortisone and Clioquinol Ointment suitable), (b) methanol (65%) as the mobile phase with a flow
Action and use
rate of 1 ml per minute and (c) a detection wavelength of
Corticosteroid.
242 nm.
Calculate the content of C2;H3 ,05 in the oimtment using the
DEFINITION declared content of C,,;H3 905 in hydrocortisone BPCRS.
Hydrocortisone and Clioquinol Ointment contains For clioquinol
Hydrocortisone and Clioquinol, the latter in very fine powder, To a quantity containing 25 mg of Clioquinol add 80 ml of a
in a suitable basis. hot mixture of 24 volumes of 2-methoxy-ethanol and
The ointment complies with the requirements stated under Topical 6 volumes of water and heat on a water bath for 5 minutes.
Semi-solid Preparations and with the following requirements. Cool in ice for 10 minutes, allow to warm to room
temperature, dilute to 100 ml with the aqueous
methoxyethanol, mix and filter. To 10 ml of the filtrate add
10 ml of 2-methoxyethanol and 2 ml of a solution prepared by
Content of c i
dissolving 0.5 g of tron(im) chloride hexahydrate in 80 ml of
90.0 to 110.0
2-methoxyethanol and adding 0.1 ml of hydrochloric acid and
sufficient 2-methoxyethanol to produce 100 ml. Dilute the
solution to 25 ml with 2-methoxyethanol and measure the
650 nm, Appendix IT B, using in the reference cell a solution
of ether, 8 volumes of methan prepared by treating 10 ml of the aqueous methoxyethanol in
the mobile phase. Apply separat 5 wl of each the same manner beginning at the words ‘add 10 ml of
erse, by 2-methoxyethanol...’.
fient containing Repeat the operation beginning at the words ‘add 10 ml of
2.5 g of Hydrocortisonein 10 ml of otha ih 2-methoxyethanol ...’ using 10 ml of a solution prepared in
allow to stand at 0" for 30 minutes, filter a the following manner. Dissolve 0.125 g of choguinol BPCRS
in sufficient 2-methoxyethanol to produce 50 ml, warming to
ethanol (96%). For solution (3) dissolve 12.5 mg of effect solution; add 1 ml of water to 5 ml of the solution and
hydrocortisone BPCRS in 5 ml of solution (1). After re add sufficient of a mixture of 6 volumes of water and
of the plate, allow it to dry in air and spray with alkaline 4 volumes of 2-methoxyethanol to produce 50 ml. Calculate
tetrazolium blue solution. The principal spot in the e content of CgH;CIINO from the absorbances obtained
chromatogram obtained with solution (1) corresponds to th
solution (3) appears as a single, compact spot.
B. In the Assay for hydrocortisone the chromatogram
retention time as the peak due to hydrocortisone in the
C. Fuse a quantity of the ointment containing 0.1 g of
Clioquinol with anhydrous sodium carbonate, dissolve the fused Hydrocortiso
mass in water and acidify with 2m nitric acid. Add silver nitrate
solution; a pale yellow precipitate is produced which is Action and use
insoluble in 5m ammonia. Add 5M ammonia until the solution Corticosteroid + Aminoglyc
becomes alkaline, boil gently, filter and acidify the filtrate
DEFINITION
with 2m nitric acid; a white precipitate is produced which
darkens on exposure to light. Hydrocortisone and Neomycin Crea
Hydrocortisone and Neomycin Sulfate 1
ASSAY
The cream complies with the requirements stated
For hydrocortisone Semi-solid Preparations and with the followingrequi mengs.
Appendix III D, using the following solutions. For solution Content of hydrocortisone, C,,H3 )0;
(1) dissolve 5 mg of hydrocortisone BPCRS in 5 ml of a 90.0 to 110.0% of the stated amount.
4% v/v solution of bromobenzene (internal standard) in IDENTIFICATION
methanol and dilute to 50 ml with methanol (80%). A. Carry out the method for thin-layer chromatography,
For solution (2) add 30 ml of 2,2,4-trimethylpentane to a Appendix III A, using the following solutions.
quantity of the ointment containing 10 mg of Hydrocortisone (1) Add 10 mL of hexane saturated with acetonitrile to a
and warm on a water bath until the preparation has melted. quantity of the preparation being examined containing 5 mg
Extract the warm mixture with successive quantities of 30, 20 of Hydrocortisone and shake for 2 to 3 minutes. Add 10 mL
and 20 ml of methanol (80%), combine the aqueous of acetonitrile saturated with hexane, shake for 10 minutes and
methanolic layers, cool to about 20° and dilute to 100 ml allow the layers to separate. Centrifuge, filter the acetonitrile
with the same solvent. Prepare solution (3) in the same layer if necessary, evaporate 5 mL to dryness and dissolve the
manner as solution (2) but adding 10 ml of a 4% v/v solution residue in 5 mL of a mixture of equal volumes of chloroform
of bromobenzene in methanol to the cooled methanolic extract. and ethanol (96%).
The chromatographic procedure may be carried out using (2) 0.05% w/v of hydrocortisone BPCRS in a mixture of equal
(a) a stainless steel column (25 cm x 5 mm) packed with volumes of chloroform and ethanol (96%).
CHROMATOGRAPHIC CONDITIONS potassium todide in starch mucilage; avoid prolonged exposure

(a) Use as the coating silica gel GF 54. to the cold air. Spray the plate with a 0.5% w/v solution of
(b) Use the mobile phase as described below. potasstum todide in starch mucilage.
(c) Apply 10 uwL of each solution. MOBILE PHASE
(d) Develop the plate to 15 cm. Freshly prepared 3.85% w/v solution of ammonium acetate.
(e) After removal of the plate, dry in air and spray with CONFIRMATION
alkaline tetrazohum blue solution. Any spot corresponding to neamine in the chromatogram
MOBILE PHASE obtained with solution (1) is not more intense than the spot
8 volumes of methanol and 90 volumes of dichloromethane. in the chromatogram obtained with solution (2).
Neomycin C
CONFIRMATION
in the chromatogram obtained with Appendix III D, using the following solutions.
(1) Shake a quantity containing 3500 IU of Neomycin
Sulfate with 10 mL of chloroform, add 5 mL of 0.02m sodium
tetraborate, mix, allow to separate and centrifuge the upper
layer. Proceed as for solution (2) but using 0.5 mL of the
e to hydrocortisone in the clear supernatant liquid in place of 0.5 mL of the neomycin
sqlution (2). sulfate solution.
yer
r chromatography, (2) Add 1.5 mL ofa freshly prepared 2% w/v solution of
1-fluoro-2,4-dinitrobenzene in methanol to 0.5 mL of a
of Neomycin 0.10% w/v solution of neomycin sulfate EPCRS in
. of water, shake, 0.02M sodium tetraborate, heat in a water bath at 60° for
1 hour and cool; dilute the solution to 25 mL with the
mobile phase, allow to stand and use the clear lower layer.
are suitable). with silica gel for chromatography (5 um) (Nucleosil 100-5 is
(b) Use the mobile phase as described below. suitable).
(c) Apply 5 pL of each solution. Use isocratic elution and the mobile phase described
(e) After removal of the plate, dry in air, spray with a 1% w/v
solution of ninhydrin in butan-1-ol and heat at 105° for
2 minutes.
MOBILE PHASE
20 volumes of chloroform, 40 volumes of 13.5M ammonia and shase through the column for several
60 volumes of methanol. hours befor the analysis. Record the chromatogram
for 1.4 times the re yon time of the peak due to
CONFIRMATION
neomycin B.
MOBILE PHASE
chromatogram obtained with solution (2). 0.5 mL of glacial acetic acid, mL of water and 97 mL of
tetrahydrofuran, with sufficient of Lo v/v solution of
TESTS
absolute ethanolin ethanol-free chlotofo produce 250 mL.
Neamine
Carry out the method for thin-layer chromatography, SYSTEM SUITABILITY
Appendix III A, using the following solutions. The chromatogram obtained with soluts
(1) Dissolve a quantity containing 7000 IU of Neomycin principal peak due to neomycin B and a
Sulfate in 10 mL of chloroform, shake gently with 5 mL of due to neomycin C with a retention time relati
water, centrifuge and use the aqueous layer. neomycin B of about 0.6.
(2) 0.004% w/v of neamine EPCRS in water. The column efficiency, determined using the peak due to
neomycin B in the chromatogram obtained with solution (2),
should be at least 13,000 theoretical plates per metre.
(a) Use as the coating silica gel H.
LIMITS
the area of the peak corresponding to neomycin C is 3 to
(d) Develop the plate to 15 cm. 15% of the sum of the areas of the peaks corresponding to
(e) After removal of the plate dry it in a current of warm air, neomycin B and neomycin C.
heat at 110° for 10 minutes and spray the hot plate with a
ASSAY
solution prepared immediately before use by diluting sodium
For hydrocortisone
hypochlorite solution with water to contain 0.5% of available
chlorine. Dry in a current of cold air until a sprayed area of
Appendix III D, using the following solutions in chloroform.
the plate below the line of application gives at most a very
faint blue colour with a drop of a 0.5% w/v solution of
III-670 Hydrocortisone Preparations 2016
(1) Shake together a quantity of the preparation being The ear drops comply with the requirements stated under Ear
examined containing 25 mg of Hydrocortisone, several small Preparations and with the following requirements.
glass beads and 25 mL of a 0.036% w/v solution of Content of hydrocortisone acetate, C,3H3,0¢,
fluoxymesterone BPCRS in chloroform for 15 minutes, add 90.0 to 110.0% w/v of the stated amount.
sufficient chloroform to produce 50 mL, mix and centrifuge.
Remove any excipient material present at the interface and IDENTIFICATION
use the clear supernatant liquid. A. Comply with test A for Identification described under
Hydrocortisone and Neomycin Cream using the following
(2) 0.010% w/v of hydrocortisone BPCRS and 0.018% w/v of
solutions. For solution (1) add 10 mL of chloroform to a
fluoxymesterone BPCRS (internal standard).
quantity of the ear drops containing 5 mg of Hydrocortisone
CHROMATOGRAPHIC CONDITIONS Acetate in a separating funnel, shake for 2 to 3 minutes and
(a) Use a Stainless steel column (30 cm x 3.9 mm) packed allow the layers to separate. Filter if necessary and use the
chloroform layer. Solution (2) contains 0.05% w/v of
hydrocortisone acetate BPCRS in chloroform.
B. In the Assay for hydrocortisone acetate the chromatogram
below. obtained with solution (3) shows a peak with the same
retention time as the peak due to hydrocortisone acetate in
C. Comply with test C for Identification described under
(e) Use a detection wavele
Hydrocortisone and Neomycin Cream. For solution (1)
(f) Inject 20 pL of each solu
dilute a volume containing 3500 IU of Neomycin Sulfate
MOBILE PHASE with water to 2.5 mL, shake with 3 mL of chloroform,
centrifuge and use the clear, upper layer.
TESTS
and 425 volumes of butyl chloride saturat Acidity or alkalinity
DETERMINATION OF CONTENT pH, 6.5 to 8.0, Appendix V L.
Neamine
Comply with the test described under Hydrocortisone and
For neomycin sulfate Neomycin Cream. For solution (1) dilute a volume
Stir a quantity containing 4200 IU with 15 mL of chlorof ontaining 3500 IU of Neomycin Sulfate with 2.5 mL of
until the emulsion is completely broken. Transfer to a atery-shake gently with 3 mL of chloroform, centrifuge and
separating funnel with 25 mL of phosphate buffer pH 8.0 and xe agueous layer.
5 mL of chloroform, shake vigorously, allow to separate and
reserve the aqueous phase. Extract the chloroform layer with
two 25-mL quantities of phosphate buffer pH 8.0 and discard
the chloroform layer. Pass mitrogen through the combined
aqueous solutions to remove dissolved chloroform and dilute
to 100 mL with sterile phosphate buffer pH 8.0. Dilute 10 mL
of the resulting solution to 50 mL with the same solvent and prepared 2% w vSol
carry out the microbiological assay of antibiotics, methanol, heatin a at 60° for 1 hour, cool and
Appendix XIV A. The precision of the assay is such that the ith the mobile phase; allow to
fiducial limits of error are not less than 95% and not more
than 105% of the estimated potency. The upper fiducial limit
ASSAY
of error is not less than 90.0% and the lower fiducial limit of
For hydrocortisone acetate ©
error is not more than 115.0% of the stated amount.
LABELLING
The strength with respect to Neomycin Sulfate is stated as
the number of IU (Units) per g. 0.016% why of fluoxymesterone BPCRS “interwél
chloroform. For solution (2) shake a quantity of £
containing 10 mg of Hydrocortisone Acetate with 2
0.032% w/v solution offluoxymesterone BPCRS in chloroform,
add 25 mL of chloroform, mix and filter through anhydrous
Hydrocortisone Acetate and Neomycin sodium sulfate.
Ear Drops The chromatographic procedure may be carried out using
Hydrocortisone and Neomycin Ear Drops (a) a stainless steel column (30 cm x 3.9 mm) packed with
silica gel for chromatography (10 um) (uPorasil is suitable),
Action and use (b) a mixture of 425 volumes of butyl chloride, 425 volumes
Corticosteroid + Aminoglycoside antibacterial. of butyl chloride saturated with water, 70 volumes of
tetrahydrofuran, 35 volumes of methanol and 30 volumes of
DEFINITION glacial acetic acid as the mobile phase with a flow rate of
Hydrocortisone Acetate and Neomycin Ear Drops are a 1 mL per minute and (c) a detection wavelength of 254 nm.
suspension of Hydrocortisone Acetate in a solution of Calculate the content of C.3H3.0, in the ear drops using the
Neomycin Sulfate in Purified Water. declared content of C.3H320¢ in hydrocortisone
acetate BPCRS.
ob
For neomycin sulfate To 0.5 mL of the resulting solution add 1.5 mL of a freshly
Dilute a volume containing 3500 IU to 50 mL with sterile prepared 2% w/v solution of 1-fluoro-2,4-dinitrobenzene in
phosphate buffer pH 8.0, dilute 10 mL of the resulting solution methanol, heat in a water bath at 60° for 1 hour, cool and
to 100 mL with the same solvent and carry out the dilute the solution to 25 mL with the mobile phase; allow to
microbiological assay of antibiotics, Appendix XIV A. stand and use the clear, lower layer.
The precision of the assay is such that the fiducial limits of ASSAY
error are not less than 95% and not more than 105% of the
For hydrocortisone acetate
estimated potency. The upper fiducial limit of error is not
less than 90.0% and the lower fiducial limit of error is not
more than 115.0% of the stated number of IU per mL.
contains 0.020% w/w of hydrocortisone acetate BPCRS and
LABELLING 0.016% w/v offluoxymesterone BPCRS (internal standard) in
The strét th with respect to Neomycin Sulfate is stated as chloroform. For solution (2) shake a quantity of the eye drops
Ae,
r of J (Units) per mL. containing 10 mg of Hydrocortisone Acetate with 25 mL of a
0.032% w/v solution of fluoxymesterone BPCRS in chloroform,
add 25 mL of chloroform, mix and filter through anhydrous
sodium sulfate.
Eye Drops stca gel for chromatography (10 um) (uPorasil is suitable),
Hydrocortisone and Neo: (b) a mixture of 425 volumes of butyl chloride, 425 volumes
of butyl chloride saturated with water, 70 volumes of
Action and use tetrahydrofuran, 35 volumes of methanol and 30 volumes of
Corticosteroid + Aminogly glacial acetic acid as the mobile phase with a flow rate of
1 mL per minute and (c) a detection wavelength of 254 nm.
DEFINITION
Calculate the content of C,3H3,.0, in the eye drops using the
Hydrocortisone Acetate and Neomycin Ey declared content of C.3H320¢ in hydrocortisone
sterile suspension of Hydrocortisone Acetat acetate BPCRS.
Neomycin Sulfate in Purified Water.
For neomycin sulfate
The eye drops comply with the requirements stated une
Dilute a volume containing 3500 IU to 50 mL with sterile
phosphate buffer pH 8.0, dilute 10 mL of the resulting solution
Content of hydrocortisone acetate, C,3H3,0,¢ 100 mL with the same solvent and carry out the
90.0 to 110.0% w/v of the stated amount. enicrotsological assay of antibiotics, Appendix XIV A.
IDENTIFICATION precision of the assay is such that the fiducial limits of
A. Comply with test A for Identification described under e.not less than 95% and not more than 105% of the
Hydrocortisone and Neomycin Cream using the following otency. The upper fiducial limit of error is not
solutions. For solution (1) add 10 mL of chloroform to a ) and the lower fiducial limit of error is not
quantity of the eye drops containing 5 mg of Hydrocortisone
Acetate in a separating funnel, shake for 2 to 3 minutes and é
allow the layers to separate. Filter if necessary and use the The strength Wit to Neomycin Sulfate is stated as
chloroform layer. Solution (2) contains 0.05% w/v of the numberof I per mL.
hydrocortisone acetate BPCRS in chloroform.
B. In the Assay for hydrocortisone acetate the chromatogram
the chromatogram obtained with solution (1). Hyd rocortisone Acetai
C. Comply with test C for Identification described under Eye Ointment
Hydrocortisone and Neomycin Cream. For solution (1)
dilute a volume containing 3500 IU of Neomycin Sulfate Action and use :
with water to 2.5 mL, shake with 3 mL of chloroform, Corticosteroid + Aminoglycoside antibacteri
centrifuge and use the clear, upper layer.
DEFINITION
TESTS . Hydrocortisone Acetate and Neomycin Eye Ointment is a
Acidity or alkalinity sterile preparation containing Hydrocortisone Acetate and
pH, 6.5 to 8.0, Appendix V L. Neomycin Sulfate in a suitable basis.
Neamine The eye ointment complies with the requirements stated under Eye
Comply we the _ cesemibed (1) dilute a eolame and Preparations and with the following requirements.
eomycin Cream. For solution (1) dilute a volume .
containing 3500 IU of Neomycin Sulfate with 2.5 mL of Content ofhy drocortisone acetate, C23H320¢
; 92.5 to 107.5% of the stated amount.
water, shake gently with 3 mL of chloroform, centrifuge and
use the aqueous layer. IDENTIFICATION
Neomycin C A. Complies with test A for Identification described under
Comply with the test described under Hydrocortisone and Hydrocortisone and Neomycin Cream using the following
Neomycin Cream but using as solution (2) a solution solutions. For solution (1) add 10 mL of hexane saturated
prepared in the following manner. Dilute the eye drops with with acetonitrile to a quantity of the ointment containing 5 mg
0.02m sodium tetraborate to contain 700 IU per mL. of Hydrocortisone Acetate and shake for 2 to 3 minutes.
Ait te tin et oe ee et ted pe Da eS IE OU en eae
FT Ee Pn FD s : :
IWI-672 Hydrocortisone Preparations 2016
Add 10 mL of acetonitrile saturated with hexane, shake for LABELLING

10 minutes and allow the layers to separate. Centrifuge, filter The strength with respect to Neomycin Sulfate is stated as
the acetonitrile layer if necessary, evaporate 5 mL to dryness the number of IU (Units) per g.
and dissolve the residue in 5 mL of a mixture of equal
volumes of chloroform and ethanol (96%). Solution (2)
contains 0.05% w/v of hydrocortisone acetate BPCRS in a
mixture of equal volumes of chloroform and ethanol (96%).
B. In the Assay for hydrocortisone acetate the chromatogram Hydrocortisone Sodium Phosphate
obtained with solution (3) shows a peak with the same Injection
the chromatogram obtained with solution (1). Action and use
ith test C for Identification described under Corticosteroid.
DEFINITION
1taining 7000 IU of Neomycin Sulfate
Hydrocortisone Sodium Phosphate Injection is a sterile
form, add 5 mL of water, shake,
solution of Hydrocortisone Sodium Phosphate in Water for
Injections.
TESTS
Neamine
Complies with the test d
Neomycin Cream. For solut Content of hydrocortisone, C,,;,H3 90;
containing 7000 IU of Neomy 92.5 to 107.5% of the stated amount.
chloroform, shake gently with 5 CHARACTERISTICS
use the aqueous layer. A colourless or very pale yellow solution.
Neomycin C IDENTIFICATION
Complies with the test described under Hydroc A. Carry out the method for thin-layer chromatography,
Neomycin Cream. - Appendix III A, using the following solutions.
ASSAY (1) Dilute a volume of the injection containing the equivalent
For hydrocortisone acetate of 0.25 g of hydrocortisone to 100 mL with water.
Carry out the method for lguid chromatography, 2) 0.34% w/v of hydrocortisone sodium phosphate BPCRS in
Appendix III D, using the following solutions. Solution (1
contains 0.025% w/v of hydrocortisone acetate BPCRS and ture of equal volumes of solutions (1) and (2).
0.050% w/v offluoxymesterone BPCRS (internal standard) in
chloroform. For solution (2) shake a quantity of the ointment re of equal volumes of solution (1) and a
containing 25 mg of Hydrocortisone Acetate with 20 mL ofa solution of betamethasone sodium phosphate BPCRS
0.25% w/v solution offluoxymesterone BPCRS in chloroform
and several glass beads for 30 minutes. Centrifuge; to 10 mL
of the clear, supernatant layer add sufficient chloroform to
produce 50 mL.
silica gel for chromatography (10 um) (uPorasil is suitable),
(b) a mixture of 425 volumes of butyl chloride, 425 volumes (e) After removal of the plat
of butyl chloride saturated with water, 70 volumes of solvent has evaporated, spra
tetrahydrofuran, 35 volumes of methanol and 30 volumes of
glacial acetic acid as the mobile phase with a flow rate of ultraviolet light (365 nm).
1 mL per minute and (c) a detection wavelength of 254 nm. MOBILE PHASE
Calculate the content of C,3H32O0, in the ointment using the A freshly prepared mixture of 20 volumes"6f
declared content of C,3H3.06¢ in hydrocortisone 20 volumes of water and 60 volumes of buta
acetate BPCRS.
CONFIRMATION
For neomycin sulfate
Dissolve a quantity containing 3500 IU in 50 mL of ether,
extract the solution with three 30-mL quantities of sterile
phosphate buffer pH 8.0 and discard the ether phase. Pass
nitrogen through the combined aqueous extracts to remove
dissolved ether, dilute to 100 mL with sterile phosphate buffer solution (3) appears as a single compact spot.
pH 8.0 and carry out the microbiological assay of antibiotics, The chromatogram obtained with solution (4) exhibits two
Appendix XIV A. The precision of the assay is such that the principal spots with almost identical Rf values.
fiducial limits of error are not less than 95% and not more B. Evaporate 0.1 mL to dryness on a water bath and dissolve
than 105% of the estimated potency. The upper fiducial limit the residue in 2 mL of sulfuric acid. A yellowish green
of error is not less than 90.0% and the lower fiducial limit of fluorescence is produced immediately (distinction from
error is not more than 115.0% of the stated number of IU betamethasone sodium phosphate, dexamethasone sodium
per g. phosphate and prednisolone sodium phosphate).
TESTS
Alkalinity
Hydrocortisone Sodium Phosphate Oral
pH, 7.5 to 8.5, Appendix V L. Solution
Related substances NOTE: Hydrocortisone Sodium Phosphate Oral Solution is not
Carry out the method for thin-layer chromatography, currently licensed in the United Kingdom.
Action and use
(1) Dilute a volume of the injection with water to contain the
Corticosteroid.
equivalent of 0.75% w/v of hydrocortisone.
(2) 1.0% w/v of hydrocortisone sodium phosphate BPCRS in DEFINITION
methanol. Hydrocortisone Sodium Phosphate Oral Solution is a
Q% w/v of hydrocortisone BPCRS in methanol. solution containing Hydrocortisone Sodium Phosphate in a
2HIC CONDITIONS
suitable flavoured vehicle. |
Liguids, the requirements stated under Unlicensed Medicines and
Content of hydrocortisone, C,,H3,0;
(d) Develop the | 95.0 to 105.0% of the stated amount.
(e) After removal of |
IDENTIFICATION
5 minutes and examine u raviolet light (254 nm).
MOBILE PHASE Appendix III A, using the following solutions.
1.2 volumes of water, 8 volugrie 1, 15 volumes of (1) Dilute a volume of the oral solution containing the
ether and 77 volumes of dichloromethéne. equivalent of 0.25 g of hydrocortisone to 100 mL with water.
LIMITS (2) 0.34% w/v of hydrocortisone sodium phosphate BPCRS in
Any secondary spot in the chromatogram 68 methanol .
solution (1) is not more intense than the sp (3) A mixture of equal volumes of solutions (1) and (2).
chromatogram obtained with solution (3). (4) A mixture of equal volumes of solution (1) and a
ASSAY 0.25% w/v solution of betamethasone sodium phosphate BPCRS
Dilute a volume containing the equivalent of 0.2 g of in methanol.
hydrocortisone to 1000 mL with water. To 5 mL add 15:mJ A MATOGRAPHIC CONDITIONS
of water, 2.5 g of sodium chloride and 0.5 mL of hydrochloric
se as the coating silica gel G.
acid and extract with three 25-mL quantities of chloroform.
he mobile phase described below.
Wash each chloroform layer with the same 1 mL quantity o
0.1m hydrochloric acid, add the washings to the aqueous 5 uL of each solution.
solution and discard the chloroform. Extract the aqueous yp: plate to 15 cm.
solution with two 10-mL quantities of tributyl orthophosphate, il of the plate, allow it to dry in air until the
discard the aqueous phase and extract the combined tributyl rated, spray with ethanolic sulfuric acid
phosphate solutions with two 25-mL quantities of a solution (20%), heat a€12 (
containing 10% w/v of sodium chloride and 1% w/v of ultraviolet light (36:
anhydrous disodium hydrogen orthophosphate. Filter the extracts
successively through absorbent cotton and wash the filter
MOBILE PHASE
with 10 mL of the chloride—phosphate solution. Dilute the A freshly prepared mixtu volumes of acetic anhydride,
combined filtrates to 100 mL with the chloride-phosphate 20 volumes of water and 6 f butan-1-ol.
solution and measure the absorbance of the resulting solution SYSTEM SUITABILITY
at the maximum at 248 nm, Appendix II B, using in the The test is not valid unless the p
reference cell a solution prepared in the same manner but chromatogram obtained with solutio
using 20 mL of a solution containing 2.5 g of sodium chloride compact spot and the chromatogram obtaiz
and 0.5 mL of hydrochloric acid and beginning at the words (4) exhibits two principal spots with almost
‘Extract the aqueous solution...’. Calculate the content of identical Rf values.
hydrocortisone sodium phosphate as C,,;H3 05 taking 447 as
CONFIRMATION
the value of A(1%, 1 cm) at the maximum at 248 nm.
STORAGE
Hydrocortisone Sodium Phosphate Injection should be obtained with solution (2).
protected from light. The injection should not be allowed to
B. Evaporate 0.1 mL to dryness on a water bath and dissolve
freeze.
the residue in 2 mL of sulfuric acid. A yellowish green
LABELLING fluorescence is produced immediately (distinction from
The strength is stated in terms of the equivalent amount of betamethasone sodium phosphate, dexamethasone sodium
hydrocortisone in a suitable dose-volume. phosphate and prednisolone sodium phosphate).
TESTS
Alkalinity
Related substances
Hydrocortisone Sodium Succinate
Appendix III A, using the following solutions. Injection
(1) Dilute a suitable volume of the oral solution with water to
Action and use
contain the equivalent of 0.75% w/v of hydrocortisone.
Corticosteroid.
(2) 1.0% w/v of hydrocortisone sodium phosphate BPCRS in
methanol. DEFINITION
(3) Equal volumes of solutions (1) and (2). Hydrocortisone Sodium Succinate Injection is a sterile
(4) 0.020% w/v of hydrocortisone BPCRS in methanol. solution of Hydrocortisone Sodium Succinate in Water for
Injections. It is prepared by dissolving Hydrocortisone
Sodium Succinate for Injection in the requisite amount of
Water for Injections immediately before use.
thase described below. The injection complies with the requirements stated under
f eh solution. Parenteral Preparations.
(d) Develop th STORAGE
(e) After removal Hydrocortisone Sodium Succinate Injection deteriorates on
5 minutes and exam storage and should be used immediately after preparation.
MOBILE PHASE
1.2 volumes of water, 8 volut HYDROCORTISONE SODIUM SUCCINATE

ether and 77 volumes of dichlor FOR INJECTION
SYSTEM SUITABILITY
DEFINITION
The test is not valid unless the principa Hydrocortisone Sodium Succinate for Injection is a sterile
chromatogram obtained with solution (3) material prepared from Hydrocortisone Hydrogen Succinate
compact spot. with the aid of a suitable alkali. It may contain excipients.
LIMITS It 1s supplied in a sealed container.
Any secondary spot in the chromatogram obtained wit ‘h The contents of the sealed container comply with the requirements
solution (1) is not more intense than the spot in the for Powders for Injections or Infusions stated under Parenteral
chromatogram obtained with solution (4) (3%). reparations and with the following requirements.
ASSAY fitént of hydrocortisone, C,,;H 390;
Dilute a volume of the oral solution containing the equivalent 05.0% of the stated amount.
of 20 mg of hydrocortisone to 100 mL with water. To 5 mL
add 15 mL of water, 2.5 g of sodium chloride and 0.5 mL of absorption spectrum, Appendix II A, is
hydrochloric acid and extract with three 25 mL quantities of |. the reference spectrum of hydrocortisone
chloroform. Wash each chloroform layer with the same 1 mL
quantity of 0.1M hydrochlonc acid, add the washings to the
B. Carry out thes é
aqueous solution and discard the chloroform. Extract the
aqueous solution with two 10 mL quantities of trbutyl Appendix IIIA, using 1
methanol and 9 volung
orthophosphate, discard the aqueous phase and extract the
combined tributyl phosphate solutions with two 25 mL
quantities of a solution containing 10% w/v of sodium chloride
and 1% w/v of anhydrous disodium hydrogen orthophosphate. si hydrogen succinate BPCRS
Filter the extracts successively through absorbent cotton and and methylprednisolone hydrogen sugcinate’EPCRS.
wash the filter with 10 mL of the chloride-phosphate
CHROMATOGRAPHIC CONDITIONS ;
solution. Dilute the combined filtrates to 100 mL with the
chloride—phosphate solution and measure the absorbance of (a) Use as the coating silica gel GF254.
the resulting solution at the maximum at 248 nm, (b) Use the mobile phase as described bel
Appendix II B, using in the reference cell a solution prepared (c) Apply 5 wL of each solution.
in the same manner but using 20 mL of a solution (d) Develop the plate to 15 cm.
containing 2.5 g of sodium chloride and 0.5 mL of hydrochloric
(e) After removal of the plate, allow to dry in air and
acid and beginning at the words ‘Extract the aqueous
examine in daylight and under ultraviolet light (365 nm).
solution ...’. Calculate the content of hydrocortisone
sodium phosphate as C,,H3 O05 taking 447 as the value of MOBILE PHASE
wand
A(1%, 1 cm) at the maximum at 248 nm. 1 volume of anhydrous formic acid, 10 volumes of absolute
ethanol and 150 volumes of dichloromethane.
STORAGE
Hydrocortisone Sodium Phosphate Oral Solution should be SYSTEM SUITABILITY
protected from light. The oral solution should not be allowed The test is not valid unless, by each method of visualisation,
to freeze. the chromatogram obtained with solution (3) shows two
LABELLING spots which may not be completely separated.
The strength is stated in terms of the equivalent amount of CONFIRMATION
hydrocortisone in a suitable dose-volume. By each method of visualisation, the principal spot in the
Nw AS chromatogram obtained with solution (1) corresponds in
OL I NE PE Ct BRBOLE TL NE, no!
wa ee le we er Ge
2016 Hydroflumethiazide Preparations III-675
position to that in the chromatogram obtained with 0.001% w/v of hydrocortisone. Measure the absorbance of the
solution (2). resulting solution at the maximum at 248 nm,
Appendix II B, and calculate the content of C2;H3905 taking
"ten Nd
TESTS
449 as the value of A(1%, 1 cm) at the maximum at
248 nm. Repeat the procedure with a further nine sealed
pH of a solution containing the equivalent of 5% w/v of
containers and calculate the average content of C2,;H3 905 per
hydrocortisone, 6.5 to 8.0, Appendix V L.
container from the ten individual results thus obtained.
Related substances
LABELLING
Appendix III D, using the following solutions. The label of the sealed container states the quantity of
hydrocortisone sodium succinate contained in it in terms of
the equivalent amount of hydrocortisone.
container,in a mixture of equal volumes of acetonitrile and
aes of solution (1) to 100 volumes with a

ames of acetonitrile and water. Hydroflumethiazide Tablets
Action and use
Thiazide diuretic.
hydrocortisone hydrogen su DEFINITION

dexamethasone BPCRS in Hydroflumethiazide Tablets contain Hydroflumethiazide.
water.
Content of hydroflumethiazide, CsHsF3N3;0,S,
IDENTIFICATION
(b) Use isocratic elution and the mobile phase de
below.
(d) Use an ambient column temperature. g of Hydroflumethiazide with 10 mL of solvent for
(e) Use a detection wavelength of 254 nm. tes and filter.
(f) Inject 20 wL of each solution. w/v of hydroflumethiazide BPCRS.
(g) For solution (1) allow the chromatography to proceed for * ‘TOGRAPHIC CONDITIONS
MOBILE PHASE
330 volumes of acetonitrile, 600 volumes of water and
1 volume of orthophosphoric acid which 1s allowed to
equilibrate and then diluted to 1000 volumes with water.
SYSTEM SUITABILITY
MOBILE PHASE
corresponding to dexamethasone and hydrocortisone
hydrogen succinate is at least 5.0. ethyl acetate.
LIMITS CONFIRMATION

the area of any peak corresponding to hydrocortisone is not
with solution (2).
the area of any other secondary peak is not greater than the TEST
area of the principal peak in the chromatogram obtained with Related substances
solution (2) (2%). Carry out the method for thin-layer chromatography,
The content of hydrocortisone in each of 10 individual (1) Shake a quantity of the powdered tablets containing
containers as determined in the Assay is not less than 92.5% 25 mg of Hydroflumethiazide with 25 mL of solvent for
and not more than 107.5% of the content of hydrocortisone 10 minutes, filter, evaporate the filtrate to dryness and
stated on the label, except that in one container the weight dissolve the residue in 2.5 mL of solvent.
may be not less than 85.0% and not more than 115.0% of (2) Dilute 1 volume of solution (1) to 100 volumes.
the stated content. CHROMATOGRAPHIC CONDITIONS
ASSAY (a) Use as the coating silica gel G.
Tenwe
a
a
ye
ee,
we
ate 2d
Dissolve the contents of a sealed container in sufficient water (b) Use the mobile phase as described below.
to produce a solution containing the equivalent of
WOE PROP
etaee
en
ne. mene
- ett roiny
re hp lite
f PS- fo- AOE OU
wate ane
IlI-676 Hydrogen Peroxide Preparations 2016
(d) Develop the plate to 15 cm. boiling for 2 minutes and filter. Wash the precipitate with
Met IN tet
(e) After removal of the plate, dry in a current of air and 50 mL of a hot 2% w/v solution of ammonium chloride and
Matetet reveal the spots by Method I. dissolve in 15 mL of 2m hydrochloric acid. The resulting
solution yields the reaction characteristic of aluminium salts,
MOBILE PHASE
Appendix VI.
ethyl acetate.
Neutralising capacity
LIMITS Weigh and powder 20 tablets, pass the powder as completely
Any secondary spot in the chromatogram obtained with as possible through a sieve of nominal mesh aperture about
solution (1) is not more intense than the spot in the 225 um and remix the sifted powder. Mix a quantity
chromatogram obtained with solution (2) (1%). equivalent to one tablet with a small quantity of water, added
slowly with stirring, to give a smooth paste and add gradually
sufficient further quantities of water to produce 100 mL.
Warm to 37°, add 100 mL of 0.1m hydrochloric acid VS
previously heated to 37° and stir continuously using a paddle
stirrer at a rate of about 200 revolutions per minute,
maintaining the temperature at 37°. The pH of the solution
at 37°, after 10 minutes and after 20 minutes, is 3.0 to 4.2,
Appendix V L. Add 12 mL of 0.5m hydrochloric acid VS at
37°, stir continuously for 1 hour, maintaining the
value of A(1%, 1 cm)at| a um at 273 nm.
temperature at 37°, and titrate with 0.1M sodium hydroxide VS
to pH 3.5. Subtract the number of mL of 0.1m sodium
hydroxide VS from 160 mL to obtain the number of mL of
0.1m hydrochloric acid VS required for neutralisation. Not less
Hydrogen Peroxide Mouthwa than 130 mL of 0.1m hydrochloric acid VS is required to
neutralise one tablet.
DEFINITION |
Hydrogen Peroxide Mouthwash is Hydroge ASSAY
Solution (6 per cent). ! Weigh and powder 20 tablets. To a quantity of the powder
The mouthwash complies with the requirements stated urider containing 0.3 g of Hydrotalcite add 2 mL of 7m hydrochloric
Oromucosal Preparations and with the following requirements. acid and heat on a water bath for 15 minutes. Allow to cool,
add 250 mL of water and 50 mL of 0.05m disodium edetate
Content of hydrogen peroxide, H,0,
VS and neutralise with 1m sodium hydroxide using methyl red
5.0 to 7.0% w/v.
indicator. Heat the solution on a water bath for
IDENTIFICATION; and allow to cool. Add 3 g of hexamine and
Acidity; Non-volatile matter; Organic stabilisers cess of disodium edetate with 0.05m lead nitrate
Complies with the requirements stated under Hydrogen
Peroxide Solution (6 per cent).
ASSAY
Dilute 10 mL to 100 mL with water. To 10 mL of the
resulting solution add 20 mL of 1M sulfuric acid and titrate
with 0.02m potassium permanganate VS. Each mL of
0.02M potassium permanganate VS is equivalent to 1.701 mg Hydrous Ointment
of H,O>. Oily Cream
STORAGE DEFINITION
We aed
Hydrogen Peroxide Mouthwash should be protected from Wool Alcohols Ointment 500 g
light. Phenoxyethanol 10g
Dried Magnesium Sulfate 5g
Purified Water, freshly boiled and 8 produce
cooled 1000 g
Hydrotalcite Tablets In preparing Hydrous Ointment the proportions
Paraffin, Soft Paraffin and Liquid Paraffin used to‘make the
_ Action and use Wool Alcohols Ointment may be varied to produce Hydrous
Antacid. Ointment having suitable properties.
When Hydrous Ointment is used in a white ointment, it
DEFINITION
should be prepared from Wool Alcohols Ointment made with
Hydrotalcite Tablets contain Hydrotalcite.
White Soft Paraffin; when used in a coloured ointment, it
The tablets comply with the requirements stated under Tablets and should be prepared from Wool Alcohols Ointment made with
with the following requirements. Yellow Soft Paraffin.
Content of hydrotalcite, AlMg,(OH),;CO3,4H,O Extemporaneous preparation
90.0 to 110.0% of the stated amount. The following directions apply.
IDENTIFICATION Dissolve the Phenoxyethanol and the Dried Magnestum
Add 20 mL of 2m hydrochlonc acid to a quantity of the Sulfate in sufficient warm Purified Water to produce about
powdered tablets containing 1.0 g of Hydrotalcite, shake and 500 g. Melt the Wool Alcohols Ointment and heat to about
filter. Add 30 mL of water to the filtrate and boil. 60°; gradually add the aqueous solution at about 60° with
Add 2m ammonia until just alkaline to methyl red, continue vigorous stirring until a smooth cream is obtained. Stir until
2016 Hydroxycarbamide Preparations III-677
cool, add sufficient Purified Water to produce 1000 g and MOBILE PHASE
mix. 19.5 volumes of methanol and 80.5 volumes of a solution
The ointment complies with the requirements stated under Topical containing 1.5% w/v of citric acid and 0.81% w/v of disodium
Semi-solid Preparations. hydrogen orthophosphate.
Hydrous Ointment should be kept in a container made from The test is not valid unless:
non-absorbent material. If, on storage, some aqueous liquid the chromatogram obtained with solution (4) shows three
separates, it is readily reincorporated by stirring. principal peaks and the resolution factor between each pair of
adjacent peaks is not less than 3.0;
the chromatogram obtained with solution (3) shows one
principal peak with a signal-to-noise ratio of not less than 5.
LIMITS
Disregard any peak the area of which is less than that of the
fydroxocobalamin Chloride or principal peak in the chromatogram obtained with solution
ter for Injections containing (3) (0.1%).
sufficient Acetic Acid, Hyd
ASSAY
respectively to adjust the pHs
The injection complies with the requiregiien
Dilute a quantity containing the equivalent of 2.5 mg of
Parenteral Preparations and with the follas
anhydrous hydroxocobalamin to 100 mL with a solution
Content of hydroxocobalamin, C,,H¢of containing 0.8% v/v of glacial acetic acid and 1.09% w/v of
95.0 to 110.0% of the stated amount of a sodium acetate and measure the absorbance of the resulting
hydroxocobalamin. solution at the maximum at 351 nm, Appendix II B.
IDENTIFICATION Calculate the content of C62.Hg9CoN,30,5P taking 195 as
Measure the absorbance at 351 nm and at 361 nm, the value of AU%, 1 cm) at the maximum at 351 nm.
Appendix II B. The ratio of the absorbance at 361 nm
that at 351 nm is about 0.65.
TESTS
Acidity
Related substances
Appendix III D, using the following solutions. Solutions (1) to
(3) are freshly prepared; protect all the solutions from bright light.
(1) Dilute a volume of the injection, if necessary, to produce
a solution containing 0.10% w/v of hydroxocobalamin in the
mobile phase.
(2) Dilute a volume of the injection, if necessary, to produce Action and use
a solution containing 0.005% w/v of hydroxocobalamin in Cytotoxic alkylating drug.
the mobile phase.
(3) Dilute a volume of the injection, if necessary, to produce DEFINITION
a solution containing 0.00010% w/v of hydroxocobalamin in Hydroxycarbamide Capsules contain Hydresyéarbamide.
the mobile phase. The capsules comply with the requirements stated a
(4) Add 0.2 mL ofa freshly prepared 2% w/v solution of and with the following requirements.
chloramine T and 0.1 mL of 0.05m hydrochloric acid to a Content of hydroxycarbamide, CH,N,0,
volume of the injection containing the equivalent of 5 mg of 95.0 to 105.0% of the stated amount.
hydroxocobalamin, dilute to 10 mL with water, shake, allow
IDENTIFICATION
to stand for 5 minutes and inject immediately.
eA A. Shake a quantity of the contents of the capsules
containing 30 mg of Hydroxycarbamide with 10 mL of
soe wef
ve ‘
(a) Use a stainless steel column (25 cm x 4 mm) packed methanol and filter. Evaporate the filtrate to dryness and dry
Oe, oe
with octylsilyl silica gel for chromatography (5 um) (Lichrosorb the residue at 60° at a pressure of 2 kPa for 3 hours. The
.
ow,
:
100 CH8/11 is suitable). infrared absorption spectrum of the residue, Appendix II A, is

CeeGee
:
concordant with the reference spectrum of hydroxycarbamide

a

below. (RS 184).
cp
ee
(c) Use a flow rate of 1.5 mL per minute. B. In the Assay, the chromatogram obtained with solution
*
. oy
(d) Use an ambient column temperature. (1) shows a peak with the same retention time as that of the
e,
Ge

eos
CVO Sea
aete
Mea
OSeh

solution (2).
Oy e!
COE

IWI-678 Hydroxychloroquine Preparations 2016
TEST the area of any peak corresponding to hydroxylamine is not

Urea greater than the area of the corresponding-peak in the
Carry out the method for thin-layer chromatography, chromatogram obtained with solution (2) (1%).
Appendix III A, using the following solutions in water. ASSAY
(1) Shake a quantity of the contents of the capsules Weigh and powder the contents of 20 capsules. Carry out the
containing 0.5 g of Hydroxycarbamide with 10 mL of water method for liquid chromatography, Appendix III D, using the
for 15 minutes and filter through a glass-fibre filter following solutions in water.
(Whatman GF/C is suitable).
(1) Shake a quantity of the capsule contents containing 1 g
(2) 0.025% w/v of urea. of Hydroxycarbamide with 450 mL of water for 5 minutes,
(3) 5.0% wiv of hydroxycarbamide BPCRS and 0.025% w/v of mix for 30 minutes with the aid of ultrasound, add sufficient
urea. water to produce 500 mL and mix well. Filter through a
glass-fibre filter (Whatman GF/Cis suitable) and dilute
1 volume of the filtrate with 1 volume of water.
(2) 0.10% w/v of hydroxycarbamide BPCRS
(3) 0.10% w/v of hydroxycarbamide BPCRS and 0.4% w/v of
hydroxylamine hydrochloride.
(e) After removal of the p
solution of 4-dimethylamino
acid,
(5 um) (Spherisorb ODS 2is suitable).
MOBILE PHASE -
1 volume of pyridine, 1 volume o below.
ethyl acetate. Shake, allow to separate arid
SYSTEM SUITABILITY , (d) Use an ambient column temperature.
The test is not valid unless the chromatogra (e) Use a detection wavelength of 214 nm.
LIMITS
MOBILE PHASE
Any spot corresponding to urea in the chromatogram
obtained with solution (1) is not more intense than the sp
in the chromatogram obtained with solution (2) (0.5%)
Hydroxylamine
containing 0.1 g of Hydroxycarbamide with 8 mL of water £CH,N.O, in the capsules using the
for 5 minutes, add sufficient water to produce 10 mL and declared conteétt NO, in hydroxycarbamide BPCRS.
filter througha glass-fibre filter (Whatman GF/C is suitable).
STORAGE
(2) 1.0% wiv of hydroxycarbamide BPCRS and 0.01% w/v of Hydroxycarbamide Capsules should be protected from
hydroxylamine hydrochloride. moisture. ,
(3) 0.1% w/v of hydroxycarbamide BPCRS and 1.0% w/v of
hydroxylamine hydrochloride.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed Hydroxychloroquine Tab et:
(Spherisorb ODS is suitable). Action and use
(b) Use isocratic elution and the mobile phase described Used in the treatment of rheumatoid arthritis:
below.
DEFINITION |
Hydroxychloroquine Tablets contain Hydroxychloroquine
(d) Use an ambient column temperature. Sulfate. They are coated.
(e) Use a detection wavelength of 214 nm. The tablets comply with the requirements stated under Tablets and
(f) Inject 20 wL of each solution. with the following requirements.
MOBILE PHASE Content of hydroxychloroquine sulfate,
5 volumes of methanol and 95 volumes of water. C;sH26CIN30,H,SO,
SYSTEM SUITABILITY
with solution (3), the resolution between the peaks due to A. Dissolve a quantity of the powdered tablets containing
hydroxycarbamide and hydroxylamine is at least 2.0. 0.1 g of Hydroxychloroquine Sulfate in a mixture of 10 mL
of water and 2 mL of 2m sodium hydroxide and extract with
LIMITS
two 20 mL quantities of chloroform. Wash the chloroform
In the chromatogram obtained with solution (1): extracts with water, dry with anhydrous sodium sulfate,
evaporate to dryness and dissolve the residue in 2 mL of
mone ae ke
. wa altel babs eta a aleetet SE RESte
a ee
.Se
te
vu
ny
eo
wp
2016 Hydroxyzine Preparations III-679

soe
.
'
a
ran
\
.
coe
me
nate
chloroform IR. The infrared absorption spectrum of the resulting the area of any peak corresponding to 2-[4-[(7-chloro-4-
:
solution, Appendix II A, is concordant with the reference quinolinyl)amino]pentyl]aminoethanol is not greater than the
spectrum of hydroxychloroquine (RS 182). area of the principal peak in the chromatogram obtained with
B. Shake a quantity of the powdered tablets containing 0.1 g solution (4) (0.5%);
of Hydroxychloroquine Sulfate with 10 mL of water and the area of any other secondary peak is not greater than the
filter. To the filtrate add 1 mL of 2m hydrochloric acid and principal peak in the chromatogram obtained with
1 mL of barium chloride solution. A white precipitate is solution (2) (0.5%).
produced. the sum of the areas of any other secondary peaks is not
TEST greater than twice the principal peak in the chromatogram
Disintegration obtained with solution (2) (1.0%).
Maximum time, 45 minutes, Appendix XII Al. Disregard any peak with an area less than the area of the
nethod for liquid chromatography, solution (3) (0.05%).
ing the following solutions of the ASSAY
‘.
Dae
i
woe
Carry out the method for Liguid chromatography,

on
. at
Appendix III D, using the following solutions of the

ut
Oy
4
uine Sulfate in 150 mL of mobile substance being examined in mobile phase A.

to
‘
.
a
phase A, dilute to 20 with mobile phase A and filter. (1) Weigh and powder 20 tablets. Shake a quantity of the
sy
‘
Dilute 1 volume of the olution with 10 volumes of

wo
powdered tablets containing 0.20 g of Hydroxychloroquine

st
vy
toe
mobile phase A.
2
Sulfate with 150 mL of mobile phase A, dilute to 200 mL

“@
a foe
’
(2) Dilute 1 volume of solu and filter. Dilute 1 volume of the filtrate to 10 volumes with
:
.
ey
mobile phase A.
ow
(3) Dilute 1 volume of solution (

Le
ee
a
“4.
(4) 0.00005% wiv of 2-[4-[(7-chloro-4 (2) 0.01% w/v hydroxychloroquine sulfate BPCRS.
eh
a
no
:
amino ethanol BPCRS. (3) 0.0001% w/v of hydroxychloroquine sulfate BPCRS and
ee
(5) 0.0001% w/v of hydroxychloroquine s Q 0.0001% w/v of 2-[4-[(7-chloro-4-

oy
:
eat
ee ee
guinolinyl) amino]pentyl]aminoethanol BPCRS.

Co ebow.
0.0001% wy of 2-/4-[(7-chloro-4-quinolinyl).amino]p
woe
soe
amino ethanol BPCRS. ‘ CHROMATOGRAPHIC CONDITIONS

oC
The chromatographic procedure may be carried out using the

toe
(a) Use a stainless steel column (25 cm x 4.6 mm) pa¢ conditions described under the Related substances test.
with octadecylsilyl silica gel for chromatography (5um) (Inertsi M SUITABILITY
ODS3 is suitable). st is not valid unless, in the chromatogram obtained
(b) Use gradient elution and the mobile phase described tion (3), the resolution between 2-[4-[(7-chloro-4-
below. lamino]pentyl] amino ethanol and
(c) Use a flow rate of 1 mL per minute. quine is at least 1.0.
(d) Use a column temperature of 35°. ON_.OF CONTENT ~
(e) Use a detection wavelength of 220 nm Calculate the te ntent of hydroxychloroquine sulfate,
(f) Inject 20 wL of each solution. CisH26CIN30,H28 in the tablets using the declared
content of C,gH56¢ 3 »H2SO04 in hydroxychloroquine
MOBILE PHASE
sulfate BPCRS.
vee ee
Mobile phase A 0.2 volumes of orthophosphoric acid,
ave ee 10 volumes of acetonitrile and 90 volumes of water.
wanes
Mobile phase B- 0.1 volumes of orthophosphoric acid,
Hydroxyzine Oral Sol itio!
Time Mobile phase A Mobile phase B Comment Action and use
(Minutes) (% viv) (% viv) Histamine H, receptor antagonist.
0-2 100 0 isocratic
DEFINITION
Hydroxyzine Oral Solution contains Hydroxyzine
10-18 85-0 15->100 linear gradient
Hydrochloridein a suitable vehicle.
ste aAe
ne Ae
pA
ee te Liquids and with the following requirements.
Content of hydroxyzine hydrochloride,
C,,H,,CIN,O,,2HCl

SYSTEM SUITABILITY

with solution (5), the resolution between 2-[4-[(7-chloro-4- A. Carry out the method for thin-layer chromatography,
quinolinyl)amino]pentyl] amino ethanol and Appendix III A, using the following solutions, prepared in a
hydroxychloroquine is at least 1. solution containing 1 volume of dichloromethane and
ww
ara
ree a
eaad
1 volume of methanol (solution A).
wn on
ci a eo
Blo"
ye my wal
LIMITS
ee
Veete
Ss
Aa
ter ye
IlI-680 Hydroxyzine Preparations 2016
(1) Shake a quantity of the oral solution containing 50 mg of Time Mobile phase A Mobile phase B Comment
Hydroxyzine Hydrochloride with 10 mL of solution A. (Minutes) (% viv) (%viv) -
Centrifuge, allow to separate and use the lower layer. 0-1 80 20 isocratic
(2) 1% wiv of hydroxyzine hydrochloride BPCRS. 1-10 80->70 20->30 linear gradient
(3) 0.5% w/v each of hydroxyzine hydrochloride BPCRS and 10-25 70-510 30-90 linear gradient
meclozine hydrochlonde BPCRS. 25-27 10->80 90-20 linear gradient
CHROMATOGRAPHIC CONDITIONS 27-30 80 20 re-equilibration
(c) Apply 30 uL of solution (1) and 2 wL of each of solutions conditions the retention time relative to hydroxyzine
(retention time, about 9 minutes) are: impurity 1,
about 0.44; impurity 2, about 0.81; impurity 3, about 0.83;
impurity 4, about 0.85; impurity B, about 1.05; impurity 5,
about 1.72 and impurity 6, about 2.0.
allow to cool. SYSTEM SUITABILITY
MOBILE PHASE The test is not valid unless, in the chromatogram obtained
75 volumes of toluene. hydroxyzine hydrochloride and impurity B is at least 1.5.
SYSTEM SUITABILITY LIMITS
At 260 nm_ In the chromatogram obtained with solution (1):

solution (3) shows two clearly separatec identify any peak corresponding to impurity 6 using solution
CONFIRMATION (4);
the area of any peak due to impurity 6 is not greater than the
solution (1) corresponds in position and colou area of the principal peak in the chromatogram obtained with
chromatogram obtained with solution (2). solution (4) (0.5%).
B. In the Assay, the retention time of the principal pe At 230 nm_ In the chromatogram obtained with solution (1):
the chromatogram obtained with solution (1) is the same e area of impurity 1 is not greater than 2.5 times the area
that of the peak due to hydroxyzine hydrochloride in the f the principal peak in the chromatogram obtained with
chromatogram obtained with solution (2). (2) (0.5%);
TESTS ofany other secondary peak is not greater than the
Acidity incipal peak in the chromatogram obtained with
pH, 2.7 to 3.0, Appendix V L. 0.2%);
Related substances tities are not greater than 2.0%.
Carry out the method for liguid chromatography, eak with-an area less than the area of the
Appendix III D, using the following solutions in a mixture of he«hromatogram obtained with solution
1 volume of acetonitrile and 4 volumes of water. (5) (0.05%).
(1) Dilute a quantity of the oral solution containing 5 mg of For formulations conta sugars Identify any peak
Hydroxyzine Hydrochloride to produce 50 mL and filter. corresponding to impurities, 3.and 4 using the retention
(2) Dilute 1 volume of solution (1) to 50 volumes. Further time relative to hydroxyzine: purity 2, about 0.81;
dilute 1 volume of the resulting solution to 10 volumes. impurity 3, about 0.83 and i ity 4, about 0.85.
(3) 0.005% w/v each of hydroxyzine hydrochloride BPCRS and In the chromatogram obtained wit fution (1) at 230 nm:
p-chlorobenzyhydrylpiperazine. the sum of the areas of impurity 2, i 3 and impurity 4
(4) 0.00005% w/v of 4-chlorobenzophenone. is not greater than 4.5 times the area of € principal peak in
the chromatogram obtained with solutio
ASSAY
with octadecylsilyl sihca gel for chromatography (2.7 wm)
(1) To a quantity of the oral solution containing 50 mg of
(Supelco Ascentis Express C18 is suitable).
Hydroxyzine Hydrochloride, add 10 mL of water, 125 mL of
(b) Use gradient elution and the mobile phase described methanol and add a sufficient quantity of a 30% v/v solution
below. of acetonitrile to produce 250 mL. Dilute 5 mL of the filtrate
(c) Use a flow rate of 1.6 mL per minute. to 10 mL with a 30% v/v solution of acetonitrile.
(d) Use a column temperature of 40°. (2) 0.01% w/v of hydroxyzine hydrochloride BPCRS in a
(e) Use detection wavelengths of 230 nm and 260 nm. 30% v/v solution of acetonitrile.
(f) Inject 20 wL of each solution. (3) 0.01% w/v of hydroxyzine hydrochloride BPCRS in the
MOBILE PHASE
mobile phase.
Mobile phase A 0.01M potassium dihydrogen phosphate CHROMATOGRAPHIC CONDITIONS

adjusted to pH 3.0 with dilute phosphonic acid. (a) Use a stainless steel column (15 cm x 4.6 mm) packed
AN
teed a
et
Ae
AY,
Mobile phase B acetonitrile. with octadecylsilyl silica gel for chromatography (5 um) (Luna
C18 is suitable).
aes
wate
M
2016 Hydroxyzine Preparations III-681

below.
retention time of hydroxyzine.
MOBILE PHASE
14 volumes of tnethylamine, 300 volumes of acetonitrile and

of 0.075% w/v solution of sodium
é, adjust the mobile phase to pH 2.7 with
conditions the
SYSTEM SUITA
Hydroxyzine Tablets
H, is the height above the’bs
before the peak due to hydr Action and use
above the baseline of the lov Histamine H, receptor antagonist.
this peak from the peak due to hydro
DEFINITION
DETERMINATION OF CONTENT © Hydroxyzine Tablets contain Hydroxyzine Hydrochloride.
Calculate the content of C2,;H27CIN2O2,24 The tablets comply with the requirements stated under Tablets and
solution using the declared content of Cy Hos with the following requirements.
in hydroxyzine hydrochlonde BPCRS.
Content of hydroxyzine hydrochloride,
IMPURITIES C,,H,,CIN,O,,2HCl
The impurities limited by the requirements of this 95.0 to 105.0% of the stated amount.
monograph include those listed under Hydroxyzine IFICATION
Hydrochloride and:
e Assay, the retention time of the principal peak in
1, (2-(2-2((4-chlorophenyl) (phenyl)methylamino)ethylamino) atogram obtained with solution (1) is the same as
ethanol); e* Peak due to hydroxyzine hydrochloridein the
the following solutions, preparedin a

volume of methanol and 1 volume of
(1) Shake a quanti

100 mg of Hydroxy
A, add sufficient solution:
2, 3 and 4. Isomers of an adduct formed by the interaction (3) 0.5% wiv each of hydroxyzin € BPCRS and
of hydroxyzine and fructose; meclozine hydrochloride BPCRS.
HO
(a) Use a silica gel G plate.
\/ ~
O OH (c) Apply 2 wL of each solution.
oN O OH
(e) After removal of the plate, dry in air, spray with potassium
Nv NY OH todobismuthate solution R2, heat at 110° for 5 minutes and
allow to cool.
MOBILE PHASE
1 volume of 13.5mM ammonia, 24 volumes of ethanol and
5. 4-chlorobenzhydrol; 75 volumes of toluene.
SYSTEM SUITABILITY
III-682 Hyoscine Preparations 2016
CONFIRMATION When the chromatograms are recorded under the prescribed

The principal spot in the chromatogram obtained with conditions the retention time of hydroxyZzine is about 9 min.
solution (1) corresponds in position and colour to that in the SYSTEM SUITABILITY
TESTS with solution (3), the peak-to-valley ratio is at least 10, where
Dissolution H, is the height above the baseline of the peak immediately
Carry out the procedure protected from light. Comply with before the peak due to hydroxyzine and H, is the height
the dissolution test for tablets and capsules, Appendix XII Bl. above the baseline of the lowest point of the curve separating
TEST CONDITIONS this peak from the peak due to hydroxyzine.
(a) Use Apparatus 2, rotating the paddle at 75 revolutions LIMITS

fwater, at a temperature of 37°, as the the area of any secondary peak is not greater than the area of
raw a sample of the medium and the sum of the areas of any secondary peaks is not greater than
xe. filtered sample, suitably diluted 2.5 times the area of the principal peak in the chromatogram
solution expected to conti Disregard any peak with an area less than the area of the
Hydrochloride, at the maxini principal peak in the chromatogram obtained with solution
using water in the reference celi (4) (0.05%).
(2) Measure the absorbance of a : solution of ASSAY
hydroxyzine hydrochlonde BPCRS using 1 the reference
cell. liquid chromatography, Appendix III D, using the following
DETERMINATION OF CONTENT solutions.
Calculate the total content of hydroxyzine hydrochi (1) Shake a quantity of the powdered tablets containing
C2)H27CIN202,2HCl, in the medium from the absorb 50 mg of Hydroxyzine Hydrochloride with 10 mL of water
obtained and using the declared content of og for 20 minutes, add 125 mL of methanol and shake for a
C,,H27CIN,O,,2HCI in hydroxyzine hydrochloride BPCR further 30 minutes. Add a sufficient quantity of a 30% v/v
LIMITS solution of acetonitrile to produce 250 mL, filter and dilute
The amount of hydroxyzine hydrochloride released is not less ° of the filtrate to 10 volumes with a 30% v/v
than 75% (Q) of the stated amount. acetonitrile.
Phe /v of hydroxyzine hydrochloride BPCRS in a
Related substances
phase.
50 mg of Hydroxyzine Hydrochloride with 10 mL of the The chromatographic ¢onditions described under Related
mobile phase, add sufficient mobile phase to produce 50 mL substances may be usec
and filter.
SYSTEM SUITABILITY
(2) Dilute 2 volumes of solution (1) to 100 volumes. Further
The test is not valid unless, the chromatogram obtained
dilute 1 volume of this solution to 10 volumes.
with solution (3);
(3) 0.01% w/v of hydroxyzine hydrochloride BPCRS.
the peak-to-valley ratio is at least 10,<where H, is the height
(4) Dilute 1 volume of solution (1) to 100 volumes. Further above the baseline of the peak immediately before the peak
dilute 1 volume of the resulting solution to 20 volumes. due to hydroxyzine and H, is the height above baseline of
CHROMATOGRAPHIC CONDITIONS the lowest point of the curve separating
(a) Use a stainless steel column (15 cm x 4.6 mm) packed peak due to hydroxyzine.
with octadecylsilyl silica gel for chromatography (5 wm) (Luna DETERMINATION OF CONTENT
C18 is suitable). Calculate the content of C,;H»7CIN»,O.2,2HCI in the tablets
(b) Use isocratic elution and the mobile phase described using the declared content of C2;H»7CIN2O2,2HCI in
below. hydroxyzine hydrochloride BPCRS.
(f) Inject 20 pL of each solution. Hyoscine Eye Drops
retention time of hydroxyzine. Action and use
Anticholinergic.
MOBILE PHASE
14 volumes of tnethylamine, 300 volumes of acetonitrile and DEFINITION
686 volumes of a 0.075% w/v solution of sodium Hyoscine Eye Drops are a sterile solution of Hyoscine
methanesulfonate, adjust the mobile phase to pH 2.7 with Hydrobromide in Purified Water.
OPRRB on Tete
sulfuric acid.
wt a,
2016 Hyoscine Preparations TI-683
The eye drops comply with the requirements stated under Eye IDENTIFICATION
Preparations and with the following requirements. A. Carry out the method for thin-layer-chromatography,
Rw an
Content of hyoscine hydrobromide, Appendix III A, usinga silica gel precoated plate (Merck
C,,H,3NO,,HBr,3H,O plates are suitable) and a mixture of 10 volumes of
90.0 to 110.0% of the stated amount. diethylamine, 40 volumes of acetone and 50 volumes of
dichloromethane as the mobile phase. Apply separately to the
IDENTIFICATION
plate 5 uwL of each of the following solutions. For solution (1)
evaporate a volume of the injection containing 5 mg of
Hyoscine Hydrobromide to dryness on a water bath, triturate
plates are suitable) and a mixture of 10 volumes of
the residue with 1 mL of ethanol (96%), allow to stand and
diethylamine, 40 volumes of acetone and 50 volumes of
use the supernatant liquid. Solution (2) contains 0.5% w/v of
dichloromethane as the mobile phase. Apply separately to the
hyoscine hydrobromide BPCRS in ethanol (96%). After removal
ea h of the following solutions. For solution (1)
of the plate, heat it at 105° for 20 minutes, allow to cool and
ne of the eye drops containing 5 mg of
spray with potasstum todobismuthate solution R1. The principal
romide to dryness on a water bath, triturate
spot in the chromatogram obtained with solution (1)
corresponds to that in the chromatogram obtained with
solution (2).
spray with potassium 16a (1) shows a peak with the same retention as the principal
spot in the chromatogrant peak in the chromatogram obtained with solution (2).
corresponds to thatin the ci ASSAY
solution (2). Carry out the method for guid chromatography,
(1) dilute the injection, if necessary, to produce a solution
time as the principal peak in the cared ? containing 0.04% w/v of Hyoscine Hydrobromide. Solution
with solution (2). (2) contains 0.04% w/v of hyoscine hydrobromide BPCRS.
ASSAY The chromatographic procedure may be carried out using
Carry out the method for hguid chromatography, é (a) a stainless steel column (20 cm x 4.6 mm) anda
Appendix III D, using the following solutionsin wdier stainless steel pre-column (1.0 cm x 4.6 mm) both packed
For solution (1) dilute the eye drops, if necessary, to pr with octadecylsilyl sihca gel for chromatography (10 um)
a solution containing 0.125% w/v of Hyoscine rosorb RP18 is suitable), (b) as the mobile phase with a
Hydrobromide. Solution (2) contains 0.125% w/v of hyoscine e of 2 mL per minute a mixture of 1 volume of a
hydrobromide BPCRS. v solution of perchloric acid, 31 volumes of methanol
The chromatographic procedure may be carried out using lumes of water, adjusted to pH 2.5 with
(a) a stainless steel column (20 cm x 4.6 mm) and a monia and (c) a detection wavelength of 240 nm.
stainless steel pre-column (1.0 cm x 4.6 mm) both packed
with octadecylsilyl silica gel for chromatography (10 wm) ak .7H>1NO,,HBr in hyoscine
(Lichrosorb RP18 is suitable), (b) as the mobile phase with a Each mg of C,7H»,;NO,,HBr is
flow rate of 2 mL per minute a mixture of 1 volume ofa 2g of C,7H2,NO,,HBr,3H,0.
60% w/v solution of perchloric acid, 31 volumes of methanol STORAGE
and 68 volumes of water, adjusted to pH 2.5 with
Hyoscine Injection she rotected from light.
13.5M ammonia and (c) a detection wavelength of 240 nm.
When chlorhexidine is used as a preservative allow the
chromatography for solution (1) to proceed until the
chlorhexidine has eluted (this may be up to 20 times the
retention time of the peak due to hyoscine hydrobromide). Hyoscine Tablets
Calculate the content of C;7H2.;NO,,HBr,3H,O using the
Action and use
declared content of C,;7H2;NO,,HBr in hyoscine
Anticholinergic.
hydrobromide BPCRS. Each mg of C,;7H2;NO,,HBr is
equivalent to 1.141 mg of C,;7H,,;NO,,HBr,3H,O.
DEFINITION
Hyoscine Tablets contain Hyoscine Hydrobromide.
vee
Hyoscine Injection with the following requirements.
Content of hyoscine hydrobromide,
Action and use
C,,H,,NO,,HBr,3H,O
Anticholinergic.
DEFINITION IDENTIFICATION
Hyoscine Injection is a sterile solution of Hyoscine A. Carry out the method for thin-layer chromatography,
Hydrobromide in Water for Injections. Appendix III A, using the following solutions.
The 1njection complies with the requirements stated under (1) Shake a quantity of powdered tablets containing 0.5 mg
Parenteral Preparations and with the following requirements. of Hyoscine Hydrobromide with 5 mL of 0.1m hydrochloric
Content of hyoscine hydrobromide, acid. Mix, with gentle swirling, with three 5-mL quantities of
C,,H,,NO,,HBr,3H,O dichloromethane discarding the dichloromethane layers.
90.0 to 110.0% of the stated amount. Add 1 mL of 5m ammonia to the aqueous phase and extract
IlI-684 Hyoscine Butylbromide Preparations 2016
with two 5-mL quantities of dichloromethane and retain the hyoscine hydrobromide BPCRS. Each mg of C,7H,,;NO,,HBr
dichloromethane extracts. Dry the combined is equivalent to 1.141 mg of C,7H2,;,NO,HBr,3H,O.
dichloromethane extracts over anhydrous sodium sulfate, filter,
yeayl
ASSAY
evaporate the filtrate to dryness and dissolve the residue in
0.5 mL of ethanol (96%).
Appendix III D, using the following solutions. Solution A is a
(2) 0.1% w/v of hyoscine hydrobromide BPCRS in ethanol 0.02% w/v solution of atropine sulfate BPCRS (internal
(96%). standard) in a mixture of 25 volumes of acetonitrile and
CHROMATOGRAPHIC CONDITIONS 75 volumes of water.
(a) Use as the coating silica gel for chromatography (Merck (1) Add to 10 whole tablets 7 mL of acetonitrile (25%),
plates are suitable). disintegrate with the aid of ultrasound and shake the mixture
(b) Use the.mobile phase as described below. for 2 minutes. Add sufficient of a mixture of 25 volumes of
acetonitrile and 75 volumes of water to produce a final
solution containing 0.015% w/v of Hyoscine Hydrobromide,
centrifuge and filter the supernatant liquid using a suitable
0.45-um filter.
allow to cool and (2) Prepare solution (2) in the same manner as solution (1)
solution R1. but using solution A in place of a mixture of 25 volumes of
MOBILE PHASE acetonitrile and 75 volumes of water.
10 volumes of diethylamine;™ (3) 0.015% w/v of hyoscine hydrobromide BPCRS in solution
50 volumes of dichloromethan A.
CONFIRMATION CHROMATOGRAPHIC CONDITIONS
The principal spot in the chromatog | The chromatographic conditions described under Uniformity
solution (1) corresponds in position and of content may be used.
chromatogram obtained with solution (2) | DETERMINATION OF CONTENT
B. In the test for Uniformity of content, the ¢ Calculate the content of C,;7H2;NO,,HBr,3H,O in the
obtained with solution (1) shows a peak with the‘sa tablets using the declared content of C;7H,;NO,,HBr in
retention time as the principal peak in the chromatog hyoscine hydrobromide BPCRS. Each mg of C,7H,,;NO,,HBr
obtained with solution (2). is equivalent to 1.141 mg of C,;7H.,;NO.z,HBr,3H,O.
TESTS
of Hyoscine Hydrobromide comply with the requirements
Appendix III D, using the following solutions. Solution A is a
0.02% w/v solution of atropine sulfate BPCRS (internal
standard) in a mixture of 25 volumes of acetonitrile and
(1) Add 1 mL of solution A to one tablet and disintegrate
with the aid of ultrasound. Shake the mixture for 2 minutes,
centrifuge and filter the supernatant liquid using a suitable
0.45-um filter.
(2) 0.015% w/v of hyoscine hydrobromide BPCRS in solution
A.
IDENTIFICATION
A. Evaporate to dryness a volume conta
(Lichrosorb RP18 is suitable).
(b) Use isocratic elution and the mobile phase described dry the residue at 50° at a pressure not exceeding 0.7 kPa for
below. 1 hour. The infrared absorption spectrum of the residue,
(c) Use a flow rate of 2 mL per minute. Appendix II A, is concordant with the reference spectrum of
tay vad
(d) Use an ambient column temperature. hyoscine butylbromide (RS 185). Retain the residue for use
in test C.
350 nm of the solution obtained in the Assay exhibits
MOBILE PHASE maxima at 252, 257 and 264 nm anda less well-defined
0.05M sodium octanesulfonate in a mixture of 1 volume of a maximum at 247 nm.
60% w/v solution of perchloric acid, 3 volumes of methanol, C. To 1 mg of the residue obtained in test A add 0.2 mL of
21 volumes of acetonitrile and 75 volumes of water. fuming nitric acid and evaporate to dryness on a water bath.
DETERMINATION OF CONTENT Dissolve the residue in 2 mL of acetone and add 0.1 mL ofa
Calculate the content of C;7H,;NO,,HBr,3H,O in each 3% w/v solution of potassium hydroxide in methanol. A violet
tablet using the declared content of C;7H»2;NO.,,HBr in colour is produced.
2016 Hyoscine Butylbromide Preparations III-685
TESTS MOBILE PHASE

~~ wea
Acidity 0.5 volume of anhydrous formic acid, 175 volumes of water,
pH, 3.7 to 5.5, Appendix V L. 9 volumes of absolute ethanol and 9 volumes of
Hyoscine dichloromethane.
Carry out the method for liguid chromatography, SYSTEM SUITABILITY
Appendix III D, using the following solutions in In the chromatogram obtained with solution (1) the principal
0.001m hydrochloric acid. spot has anRf value of about 0.45.
(1) Use the injection diluted, if necessary, to contain
LIMITS
1.0% w/v of Hyoscine Butylbromide.
(2) 0.0010% w/v of hyoscine hydrobromide BPCRS.
any secondary spot with an Rf value less than that of the
(3) Addxdt.0 uL of solution (1) to 10 mL of solution (2).
principal spot is not more intense than the spot in the
PHIC CONDITIONS chromatogram obtained with solution (2) (3%);
not more than two secondary spots with anRfvalue less than
that of the principal spot are more intense than the spot in
the chromatogram obtained with solution (4) (0.25%);
(b) Use isocratic: any secondary spot with an Rf value greater than that of the
below. principal spot is not more intense than the spot in the
not more than one secondary spot with an Rf value greater
than that of the principal spot is more intense than the spot
(f) Inject 20 pL of each solu ion.
ASSAY
MOBILE PHASE
2.0 g of sodium dodecyl sulfate in a mixture
Appendix III D, using the following solutions in
0.001m hydrochloric acid and 680 mL of m
SYSTEM SUITABILITY (1) Dilute the injection to contain 0.04% w/v of Hyoscine
The test is not valid unless the chromatogram obtai Butylbromide.
solution (3), the resolution factor between hyoscine and. (2) 0.04% w/v of hyoscine butylbromide BPCRS.
butylhyoscine is at least 5.0.
OMATOGRAPHIC CONDITIONS
LIMITS
hromatographic conditions described under the test for
In the chromatogram obtained with solution (1): may be used.
the area of any peak corresponding to hyoscine is not greater
NATION OF CONTENT
than the area of the principal peak in the chromatogram
obtained with solution (2) (0.1%). thescontent of C,;H3 .BrNO, using the declared
Related substances
Appendix III A, using the following solutions in.
(1) Dilute the injection, if necessary, to contain 2% w/v of
Hyoscine Butylbromide.
(3) Dilute 1 volume of solution (1) to 50 volumes. Hyoscine Butylbromid
Action and use
CHROMATOGRAPHIC CONDITIONS Anticholinergic.
(a) Use a silica gel F254, high-performance precoated plate
(Merck silica gel 60 F,5, HPTLC plates are suitable). DEFINITION :
(b) Use the mobile phase as described below. Hyoscine Butylbromide Tablets contain Hyoscttie
Butylbromide.
(e) After removal of the plate, dry it at 60° for 15 minutes,
spray with a solution prepared by mixing equal volumes of a Content of hyoscine butylbromide, C,,;H3)BrNQ,
40% w/v solution of potassium iodide in water and a solution
prepared by dissolving 0.85 g of bismuth oxymitrate in a IDENTIFICATION
mixture of 10 mL of glacial acetic acid and 40 mL of water A. Shake a quantity of the powdered tablets containing
and diluting 1 volume of the mixture with 2 volumes of 50 mg of Hyoscine Butylbromide with 20 mL of chloroform,
glacial acetic acid and 10 volumes of water immediately before filter, evaporate the filtrate to dryness and triturate the
use. Allow the plate to dry in air, spray well with a 5% w/v residue with 5 mL of acetonitrile. Evaporate to dryness and
solution of sodium nitrite and examine immediately. dry the residue at 50° at a pressure not exceeding 0.7 kPa for
1 hour. The infrared absorption spectrum of the residue,
hyoscine butylbromide (RS 185).
IlI-686 Hypromellose Preparations 2016
B. To 1 mg of the residue obtained in test A add 0.2 mL of (d) Develop the plate to 4 cm.
fuming nitric acid and evaporate to dryness on a water bath. (e) After removal of the plate, dry it at 60° for 15 minutes,
Dissolve the residue in 2 mL of acetone and add 0.1 mL of a spray with a solution prepared by mixing equal volumes of a
3% w/v solution of potasstum hydroxide in methanol. A violet 40% w/v solution of potassium todide in water and a solution
colour is produced. prepared by dissolving 0.85 g of bismuth oxynitrate in a
C. Shake a quantity of the powdered tablets containing mixture of 10 mL of glacial acetic acid and 40 mL of water
50 mg of Hyoscine Butylbromide with 20 mL of chloroform, and diluting 1 volume of the mixture with 2 volumes of
filter, evaporate the filtrate to dryness, shake the residue with glacial acetic acid and 10 volumes of water immediately before
50 mL of water and filter. The ight absorption of the filtrate, use. Allow the plate to dry in air, spray well with a 5% w/v
Appendix IT B, in the range 230 to 350 nm exhibits maxima solution of sodium nitrite and examine immediately.
at 252, 257 and 264 nm anda less well-defined maximum at MOBILE PHASE
Tete ete
0.5 volumes of anhydrous formic acid, 1.5 volumes of water,
tate
9 volumes of absolute ethanol and 9 volumes of
dichloromethane.
SYSTEM SUITABILITY
Appendix III D, usizi ollowing solutions.
In the chromatogram obtained with solution (1) the principal
(1) Shake a quanti spewdered tablets containing 0.1 g
spot has anRf value of about 0.45.
of Hyoscine Butylbromide with 10 mL of 0.001m hydrochloric
acid with the aid of ultras LIMITS
filter. In the chromatogram obtained with solution (1):

(2) 0.0010% w/v of hyoscine hy any secondary spot with an Rf value less than that of the
0.001m hydrochlonic acid. principal spot is not more intense than the spot in the
(3) Add 10 pL of solution (1) to 10 mf chromatogram obtained with solution (2) (3%);
(a) Use a stainless steel column (25 cm x 4.6 E
with octylsilyl silica gel for chromatography (10 um)< any secondary spot with an Rf value greater than that of the
principal spot is not more intense than the spot in the
10 C8 is suitable). é
(b) Use isocratic elution and the mobile phase describ
below. 10t more than one such spot is more intense than the spot in
he chromatogram obtained with solution (4) (0.25%).
powder 20 tablets. Carry out the method for
ography, Appendix III D, using the following
(f) Inject 20 pL of each solution. Q01m hydrochloric acid.
MOBILE PHASE
2.0 g of sodium dodecyl sulfate in a mixture of 370 mL of <lbromide with 60 mL of the solvent
0.001M hydrochlonc acid and 680 mL of methanol. for 15 minutes, dilute to 100 mL
SYSTEM SUITABILITY
peaks corresponding to hyoscine and butylhyoscine is at least
5.
wee
LIMITS The chromatographic conditions d

Hyoscine may be used. “
the area of any peak corresponding to hyoscine is not greater DETERMINATION OF CONTENT
than the area of the principal peak in the chromatogram Calculate the content of C,,;,H3,)BrNO,
obtained with solution (2) (0.1%). the declared content of C.,;H3 9.BrNO, in hy
Related substances butylbromide BPCRS.
EE ee
aoe

ea,
foe

1
0.01M hydrochloric acid.

SCC
het
(1) Shake a quantity of the powdered tablets containing Hypromellose Eye Drops
20 mg of Hyoscine Butylbromide with 5 mL of
woes
io ey
o.
Alkaline Eye Drops; Artificial Tears

0.01m hydrochloric acid and centrifuge.
(2) Dilute 3 volumes of solution (1) to 100 volumes. Action and use
(3) Dilute 1 volume of solution (1) to 50 volumes. Artificial tears.

DEFINITION
CHROMATOGRAPHIC CONDITIONS Hypromellose Eye Drops area sterile solution of
(a) Use a silica gel F254 high-performance precoated plate Hypromellose in Purified Water. They are isotonic with tear
(Merck silica gel 60 F.5, HPTLC plates are suitable). secretions.
2016 Ibuprofen Preparations III-687
The eye drops comply with the requirements stated under Eye ibuprofen impurity B BPCRS in acetonitrile for chromatography
Preparations and with the following requirements. (prepared by diluting 1 volume oftbuprofen
IDENTIFICATION impurity B BPCRS to 10 volumes with acetonitrile for
chromatography) and sufficient mobile phase A to produce
A. Heat 5 mL in a water bath, with stirring. Above 50° the
10 mL.
solution becomes cloudy or a flocculent precipitate 1s
produced. The solution becomes clear on cooling. CHROMATOGRAPHIC CONDITIONS
B. To 5 mL add 0.15 mL of 2M acetic acid and 1.2 mL of a (a) Use stainless steel column (15 cm x 4.6 mm) packed
10% w/v solution of tannic acid. A yellowish white, flocculent with octadecylsilyl silica gel for chromatography (5 um)
precipitate is produced which dissolves in 6M ammonia. (Spherisorb ODS 2 is suitable).
below.
pH, 8.2 to 8.6, (f) Inject 20 wL of each solution.
Viscosity (g) Equilibrate the column with mobile phase A for about
45 minutes.
MOBILE PHASE
Mobile phase A 0.5 volume of orthophosphoric acid,

340 volumes of acetonitrile for chromatography and
600 volumes of water. Allow to equilibrate and add sufficient
Mobile phase B_ acetonitrile.

(Minutes) (viv) (viv)
whilst complying with the requirements of the monograph,
Action and use 15 85 isocratic

Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory. 15100 85-0 re-equilibration
DEFINITION
Prolonged-release Ibuprofen Capsules contain Ibuprofen.
They are formulated so that the medicament is released over SYSTEM
a period of several hours. The test
PRODUCTION
1.5.
appropriate release of Ibuprofen. The dissolution profile
reflects the in vivo performance which in turn is compatible LIMITS
with the dosage schedule recommended by the manufacturer. In the chromatogram ob
The capsules comply with the requirements stated under Capsules the area of any peak correspordi
and with the following requirements. is not greater than the area of the
Content of ibuprofen, C,3;H,;0, impurity B in the chromatogram o
95.0 to 105.0% of the stated amount. (0.3%);
the area of any other secondary peak is no
IDENTIFICATION
0.3 times the area of the principal peak in the hrematogram
Extract a quantity of the capsule contents containing 0.5 g of
Ibuprofen with 20 mL of acetone, filter and evaporate the
filtrate to dryness in a current of air without heating. The the sum of the areas of any other secondary peaks is not
infrared absorption spectrum of the residue, Appendix II A, is greater than 0.7 times the area of the principal peak in the
concordant with the reference spectrum of ibuprofen (RS 186). chromatogram obtained with solution (2) (0.7%).
TESTS
Related substances
solution (2) (0.05%).
Appendix III D, using the following solutions. ASSAY
(1) Dissolve a quantity of the capsule contents containing Carry out the method for liquid chromatography,
20 mg of Ibuprofen in 2 mL of acetonitrile for chromatography Appendix III D, using the following solutions.
and add sufficient mobile phase A to produce 10 mL. (1) Shake a quantity of the mixed contents of 20 capsules
(2) Dilute 1 volume of solution (1) to 100 volumes with containing 0.2 g of Ibuprofen in 30 mL of mobile phase for
mobile phase A. 30 minutes. Add sufficient mobile phase to produce 100 mL
and mix. Centrifuge an aliquot of the suspension at 2500 g
(3) Dissolve 20 mg of ibuprofen BPCRS in 2 mL of acetonitrile
for 5 minutes and use the supernatant liquid.
for chromatography, add 1 mL of a 0.006% w/v solution of
III-688 Ibuprofen Preparations 2016
(2) 0.2% w/v of ibuprofen BPCRS in the mobile phase. B. In the Assay the retention time of the principal peak in
solution (2).
(Nucleosil C18 is suitable). TEST
(b) Use isocratic elution and the mobile phase described Related substances
below. Carry out the method for liquid chromatography,
(1) Shake vigorously a quantity of the cream containing 0.1 g
of Ibuprofen with 25 mL of methanol for 10 minutes, decant
the solution into a 50 mL graduated flask, rinse the original
flask with two 10-mL quantities of methanol, dilute the
combined solution and rinsings to 50 mL with methanol and
filter (Whatman GEF/C paper is suitable).
methanol.
(3) Dissolve 50 mg of ibuprofen BPCRS in 2.5 mL of a
Calculate the content of
0.006% w/v solution of ibuprofen impurity B BPCRS in
declared content of C,3
methanol (prepared by diluting 1 volume of ibuprofen
IMPURITIES impurity B BPCRS to 10 volumes with methanol) and add
The impurities limited by the sufficient methanol to produce 25 mL.
monograph include: ( CHROMATOGRAPHIC CONDITIONS
(2RS)-2-(4-butylphenyl)propanoic acid ( (a) Use a stainless steel column (15 cm x 4.6 mm) packed
Impurity B). with end-capped octadecylsilyl silica gel for chromatography
(5 um) (Spherisorb ODS2is suitable).
below.
Ibuprofen Cream c) Use a flow rate of 2 mL per minute.
d) Use an ambient column temperature.
Action and use
adetection wavelength of 214 nm.
ate the column with the mobile phase for about
DEFINITION efore starting the chromatography.
Ibuprofen Cream contains Ibuprofen in a suitable basis. uw of each solution.
Content of ibuprofen, C,3;H,,O0,
A. Carry out the method for thin-layer chromatography, 0.5 volume of orthophos, 40 volumes of acetonitrile
Appendix III A, using the following solutions. and 600 volumes of water d 1000 volumes with water
after equilibration.
(1) Shake vigorously a quantity of the cream containing
50 mg of Ibuprofen with 10 mL of dichloromethane for SYSTEM SUITABILITY
5 minutes and filter (Whatman GEF/C paper ts suitable). In the chromatogram obtained with measure the
(2) 0.5% w/v of ibuprofen BPCRS in dichloromethane. height (a) of the peak due to (2RS)-2-(
(a) Use as the coating silica gel H.

(b) Use the mobile phase as described below. If necessary, adjust the concentration of acetonitri
(c) Apply 5 wL of each solution. mobile phase to obtain the required resolution.
(e) After removal of the plate, dry it at 120° for 30 minutes, In the chromatogram obtained with solution (1):
lightly spray the plate with a 1% w/v solution of potassium the area of any peak corresponding to ibuprofen impurity B
permanganate in 1M sulfuric acid, heat at 120° for 20 minutes is not greater than the area of the corresponding peak in the
and examine under ultraviolet light (365 nm). chromatogram obtained with solution (3) (0.3%);
MOBILE PHASE the area of any other secondary peak is not greater than
5 volumes of anhydrous acetic acid, 25 volumes of ethyl acetate 0.3 times the area of the principal peak in the chromatogram
and 75 volumes of n-hexane. obtained with solution (2) (0.3%);
CONFIRMATION the sum of the area of any secondary peaks, other than the
The principal spot in the chromatogram obtained with peak due to impurity B, is not greater than 0.7 times the area
we ow
solution (1) corresponds in position, colour and size to that

in the chromatogram obtained with solution (2). solution (2) (0.7%).
Disregard any peak the area of which is less than 0.1 times (c) Apply 5 uL of each solution.
the area of the principal peak in the chromatogram obtained (d) Develop the plate to 10 cm.
(e) After removal of the plate, dry it at 120° for 30 minutes,
ASSAY lightly spray the plate with a 1% w/v solution of potassium
Carry out the method for liquid chromatography, permanganate in 1M sulfuric acid, heat at 120° for 20 minutes
Appendix III D, using the following solutions. and examine under ultraviolet light (365 nm).
(1) Shake vigorously a quantity of the cream containing MOBILE PHASE
50 mg of Ibuprofen with 25 mL of the mobile phase for 5 volumes of anhydrous acetic acid, 25 volumes of ethyl acetate
10 minutes, decant the solution into a 50 mL graduated and 75 volumes of n-hexane.
flask, rinse the original flask with two 10-mL quantities of the
CONFIRMATION
mobile p
B. In the Assay the retention time of the principal peak in
ONDITIONS
mn (25 cm x 4.6 mm) packed that of the principal peak in the chromatogram obtained with
solution (2).
TEST
Related substances
(1) Disperse a quantity of the gel containing 0.1 g of
(e) Use a detection wavelength of 264 Ibuprofen in 25 mL of warm methanol, cool and dilute to
(f) Inject 20 pL of each solution. 50 mL with methanol.
MOBILE PHASE (2) Dilute 1 volume of solution (1) to 100 volumes with
methanol.
3 volumes of orthophosphoric acid, 247 volumes ofwa
750 volumes of methanol. (3) Dissolve 50 mg of ibuprofen BPCRS in 2.5 mL of a
0.006% w/v solution of ibuprofen impurity B BPCRS in
anol (prepared by diluting 1 volume of ibuprofen
Calculate the content of C;3H gO, in the cream using the uvity B BPCRS to 10 volumes with methanol) and add
declared content of C,3H,gO> in ibuprofen BPCRS. seft methanol to produce 25 mL.
IMPURITIES OGRAPHIC CONDITIONS
tainless steel column (15 cm x 4.6 mm) packed
monograph include: ped-gctadecylsilyl silica gel for chromatography
1. (2RS)-2-(4-butylphenyl)propanoic acid (Ubuprofen thODS 2 is suitable).
Impurity B). (b) Use isocra 1
below. ,
(d) Use an ambient c

lbuprofen Gel (e) Use a detection wavel
Action and use

DEFINITION (h) Allow the chromatography to procted ?

Ibuprofen Gel is a solution of Ibuprofen in a suitable water- retention time of the principal peak. Whe
miscible basis. chromatograms are recorded under the condi ns.giescribed
The gel complies with the requirements stated under Topical Semi- above, the retention time of ibuprofen is about 20 minutes.
mi
solid Preparatnons and with the following requirements. MOBILE PHASE
Content of ibuprofen, C;3;H,,O> 0.5 volume of orthophosphoric acid, 340 volumes of acetonitrile
95.0 to 105.0% of the stated amount. and 600 volumes of water diluted to 1000 volumes with
IDENTIFICATION water. Equilibrate the column with the mobile phase for
A. Carry out the method for thin-layer chromatography, about 45 minutes before starting the chromatography.
Appendix III A, using the following solutions. SYSTEM SUITABILITY
(1) Shake vigorously a quantity of the gel containing 0.125 g In the chromatogram obtained with solution (3) measure the
of Ibuprofen with 25 mL of dichloromethane for 5 minutes height (a) of the peak due to 2-(4-butylphenyl)-propionic
and use the upper layer. acid and the height (6) of the lowest point of the curve
(2) 0.5% wiv of tbuprofen BPCRS in dichloromethane. separating this peak from that due to ibuprofen. The test is
not valid unless a is greater than 1.5b. If necessary, adjust the
concentration of acetonitrile in the mobile phase to obtain
(a) Use as the coating silica gel H. the required resolution.
III-690 Ibuprofen Preparations 2016
In the chromatogram obtained with solution (1): A. Shake a quantity of the oral suspension containing 0.5 g
the area of any peak corresponding to ibuprofen impurity B of Ibuprofen with 20 mL of chloroform, allow to stand until
is not greater than the area of the corresponding peak in the the layers have separated, filter and evaporate the filtrate to
chromatogram obtained with solution (3) (0.3%); dryness in a current of air without heating. The infrared
concordant with the reference spectrum of ibuprofen (RS 186).
obtained with solution (2) (0.3%); B. Carry out the method for thin-layer chromatography,
the sum of the area of any secondary peaks, other than the
peak due to impurity B, is not greater than 0.7 times the area (1) Dilute a quantity of the oral suspension containing 0.1 g
of the principal peak in the chromatogram obtained with of Ibuprofen to 100 mL with absolute ethanol, shake
vigorously for 5 minutes, filter (Whatman GF/C paper is
suitable) and use the filtrate.
he area of which is less than 0.1 times
the area of t 1] peak in the chromatogram obtained (2) 0.1% w/v of tbuprofen BPCRS in absolute ethanol.
with solution (2 CHROMATOGRAPHIC CONDITIONS
ASSAY (a) Use as the coating silica gel H.

Carry out the meth chromatography, (b) Use the mobile phase as described below.
Appendix III D, using wing solutions. (c) Apply 10 uL of each solution.
(1) Disperse a quantity of the taining 50 mg of (d) Develop the plate to 10 cm.
Ibuprofen with 50 mL of warm nol for 1.
10 minutes,
Dilute cool (e) After removal of the plate dry it at 120° for 30 minutes,
and add sufficient methanol to p lightly spray the plate with a 1% w/v solution of potassium
10 volumes of this solution to 20 vo h the mobile permanganate in 1M sulfuric acid, heat at 120° for 20 minutes
phase.
and examine under ultraviolet light (365 nm).
(2) Dilute 10 volumes of a solution containifie’¢
MOBILE PHASE
ibuprofen BPCRS in methanol to 20 volumes Witt
phase. 1 volume of anhydrous acetic acid, 5 volumes of ethyl acetate
and 15 volumes of n-hexane.
CONFIRMATION
(a) Use a stainless steel column (25 cm x 4.6 mm) pack
with end-capped octadecylsilyl silica gel for chromatography he principal spot in the chromatogram obtained with
(10 um) (Nucleosil C18 is suitable). (1) corresponds in position, size and colour to that
matogram obtained with solution (2). Disregard
maining on the line of application.
below.
MOBILE PHASE
3 volumes of orthophosphoric acid, 247 volumes of water and Ibuprofen with 30 mL;
750 volumes of methanol. acetonitrile and 10 mL 6&@
Calculate the content of C,;3H 30>, using the declared

content of C,3H;8O, in zbuprofen BPCRS.
acetonitrile.
IMPURITIES (3) 0.0006% w/w of 4'-isobutylacetophenone
0.2% wy of ibuprofen BPCRS in the mobi
monograph include:
1. (2RS)-2-(4-butylphenyl)propanoic acid (Ibuprofen
The chromatographic conditions described under
Impurity B).
be used.
SYSTEM SUITABILITY
ate,

Ibuprofen Oral Suspension with solution (3), the resolution factor between the peaks
corresponding to ibuprofen and 4’-isobutylacetophenone is at
Action and use
Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory. least 1.0.
LIMITS
DEFINITION
Ibuprofen Oral Suspension is a suspension of Ibuprofen in a any peak corresponding to 4’-isobutylacetophenone is not
suitable flavoured vehicle. greater than the area of the principal peak in the
The oral suspension complies with the requirements stated under chromatogram obtained with solution (2) (0.3%).
Content of ibuprofen, C,3;H,;O0,
ASSAY the filtrate to dryness in a current of air without heating. The

Carry out the method for liguid chromatography, infrared absorption spectrum of the residue, Appendix II A, is
Appendix III D, using the following solutions immediately concordant with the reference spectrum of ibuprofen (RS 186).
after preparation. B. Melting point of the residue obtained in test A, after
(1) Mix a quantity of the oral suspension containing 0.1 g of recrystallisation from petroleum spirit (boiling range, 40° to
Ibuprofen with 30 mL of acetonitrile, add a further 10 mL of 60°), about 75°, Appendix V A.
acetonitrile and 10 mL of 0.01m orthophosphoric acid, shake TEST
vigorously, dilute to 100 mL with 0.01m orthophosphoric acid
Related substances
and filter (Whatman GF/C paper is suitable).
(2) 0.1% w/v of ibuprofen BPCRS prepared by dissolving a Appendix III D, using the following solutions.
suitable quantity in 40 volumes of acetonitrile and adding
(1) Add 30 mL of methanol to a quantity of the powdered
tablets containing 0.2 g of Ibuprofen, shake for 30 minutes,
add 30 mL of methanol and sufficient water to produce
100 mL, mix and filter through a glass microfibre filter paper
with end-capped ottadecs tlica gel for chromatography (Whatman GF/C is suitable).
(10 um) (uBondapak itable). (2) Dilute 1 volume of solution (1) to 100 volumes with the
(b) Use isocratic elut mobile phase described mobile phase.
below. (3) Dissolve 50 mg of ibuprofen BPCRS in 2.5 mL of a
(c) Use a flow rate of 2 mL p af 0.006% w/v solution of ibuprofen impurity B BPCRS in
(d) Use an ambient column temperatiire.”. _... methanol (prepared by diluting 1 volume of ibuprofen
umpurity B BPCRS to 10 volumes with methanol) and add
(e) Use a detection wavelength of220
sufficient methanol to produce 25 mL.
MOBILE PHASE |
400 volumes of acetonitrile and 600 volumes o with end-capped octadecylsilyl silica gel for chromatography
0.01M orthophosphoric acid. (5 um) (Spherisorb ODS2 is suitable).
DETERMINATION OF CONTENT (b) Use isocratic elution and the mobile phase described
Determine the weight per mL of the oral suspension, -below.
Appendix V G, and calculate the content of C;3H,.O,, Use a flow rate of 2 mL per minute.
weight in volume, from the declared content of C,3Hj.O> in mbient column temperature.
ibuprofen BPCRS.
ection wavelength of 214 nm.
STORAGE sL of each solution.
Ibuprofen Oral Suspension should be protected from light.
IMPURITIES rting the chromatography.
monograph include:
MOBILE PHASE
CH; CH;
0.5 volume of orthophosphoric 240 volumes of acetonitrile
and 600 volumes of water diluted 1 olumes with water
H3C after equilibration.
SYSTEM SUITABILITY
1. 4’-isobutylacetophenone; 1-[4-
(2-methylpropyl)phenyl]ethanone) (Ibuprofen Impurity E).
height (a) of the peak due to 2-(4-butylphenyl)=prop
acid and the height (6) of the lowest point of the ¢ :
separating this peak from that due to ibuprofen. The.test is
not valid unless a is greater than 1.5b. If necessary, adjust the
lbuprofen Tablets concentration of acetonitrile in the mobile phase to obtain
the required resolution.
Action and use
LIMITS
DEFINITION the area of any peak corresponding to ibuprofen impurity B
Ibuprofen Tablets contain Ibuprofen. They are coated. is not greater than the area of the corresponding peak in the
The tablets comply with the requirements stated under Tablets and chromatogram obtained with solution (3) (0.3%);
with the following requirements. the area of any other secondary peak is not greater than
Content of ibuprofen, C,,;H,,O, 0.3 times the area of the principal peak in the chromatogram
95.0 to 105.0% of the stated amount. obtained with solution (2) (0.3%);
IDENTIFICATION the sum of the area of any secondary peaks, other than the
peak due to impurity B, is not greater than 0.7 times the area
A. Extract a quantity of the powdered tablets containing
0.5 g of Ibuprofen with 20 mL of acetone, filter and evaporate
IWI-692 Ibuprofen Preparations 2016
of the principal peak in the chromatogram obtained with IDENTIFICATION

solution (2) (0.7%). Extract a quantity of the powdered tablets containing 0.5 g of
Disregard any peak the area of which is less than 0.1 times Ibuprofen with 20 mL of acetone, filter and evaporate the
the area of the principal peak in the chromatogram obtained filtrate to dryness in a current of air without heating. The
with solution (2) (0.1%). infrared absorption spectrum of the residue, Appendix II A, is
concordant with the reference spectrum of ibuprofen (RS 186).
ASSAY
Weigh and powder 20 tablets. Carry out the method for TESTS
liquid chromatography, Appendix III D, using the following Related substances
solutions. Carry out the method for liquid chromatography,
(1) Shake a quantity of the powdered tablets containing 0.2 g Appendix III D, using the following solutions.
of Ibuprofen with 30 mL of the mobile phase for 30 minutes, (1) Dissolve a quantity of the powdered tablets containing
add sufficiert..of the mobile phase to produce 100 mL and 20 mg of Ibuprofen in 2 mL of acetonitrile for chromatography
and add sufficient mobile phase A to produce 10 mL.
mobile phase A.
(3) Dissolve 20 mg of ibuprofen BPCRS in 2 mL of acetonitrile
for chromatography, add 1 mL of a 0.006% w/v solution of
ibuprofen impurity B BPCRS in acetonitrile for chromatography
(prepared by diluting 1 volume of ibuprofen
(10 ym) (Nucleosil C18
wmpurity B BPCRS to 10 volumes with acetonitrile for
(b) Use isocratic elution and chromatography) and sufficient mobile phase A to produce
below. 10 mL.
(c) Use a flow rate of 1.5 mL
(e) Use a detection wavelength of 264 nm. with octadecylsilyl sihca gel for chromatography (5 wm)
(f) Inject 20 pL of each solution. (Spherisorb ODS2 is suitable).
MOBILE PHASE (b) Use gradient elution and the mobile phase described
3 volumes of orthophosphoric acid, 247 volumes of wat below.
750 volumes of methanol. c) Use a flow rate of 2 mL per minute.
DETERMINATION OF CONTENT Use an ambient column temperature.
Calculate the content of C,;3H 30>, using the declared “Sadetection wavelength of 214 nm.
content of C,3H,,O>, in ibuprofen BPCRS. uL, of each solution.
IMPURITIES ‘ate the column with mobile phase A for about
monograph include:
1. (2RS)-2-(4-butylphenyl)propanoic acid (Ibuprofen
Impurity B).
water to produce 10
Mobile phase B acetonit
Prolonged-release Ibuprofen Tablets
Time Mobile phase A Comment
Prolonged-release Ibuprofen Tablets from different manufacturers,
(Minutes) (viv)
interchangeable unless otherwise justified and authorised. 0-25 100 isocratic
25-55 100-15
Action and use
55-70 15
70-75 15100
DEFINITION
Prolonged-release Ibuprofen Tablets contain Ibuprofen. They
are formulated so that the medicament is released over a SYSTEM SUITABILITY
period of several hours.
PRODUCTION with solution (3), the peak-to-valley ratio between the peaks
A suitable dissolution test is carried out to demonstrate the due to ibuprofen and ibuprofen impurity B is not less than
appropriate release of Ibuprofen. The dissolution profile 1.5.
reflects the 17 vivo performance which in turn is compatible LIMITS
the area of the peak corresponding to ibuprofen impurity B is
not greater than the area of the peak corresponding to
Content of ibuprofen, C,,;H,;0, impurity B in the chromatogram obtained with solution (3)
95.0 to 105.0% of the stated amount. (0.3%);
2016 Idoxuridine Preparations III-693
the area of any other secondary peak is not greater than resulting solution, Appendix II B, in the range 230 to
0.3 times the area of the principal peak in the chromatogram 350 nm exhibits a maximum only at 279 nm.
obtained with solution (2) (0.3%); B. In the Assay, the chromatogram obtained with solution
the sum of the areas of any other secondary peaks is not (2) shows a peak having the same retention time as the peak
greater than 0.7 times the area of the principal peak in the due to Idoxuridine in the chromatogram obtained with
chromatogram obtained with solution (2) (0.7%). solution (1).
Disregard any peak with an area less than 0.05 times the area Related substances
of the principal peak in the chromatogram obtained with Carry out the method for liquid chromatography,
solution (2) (0.05%). Appendix III D, using the following solutions.
ASSAY (1) Dilute a suitable volume of the eye drops with sufficient
Weigh and powder 20 tablets. Carry out the method for of a suitable solution of sudfanilamide (internal standard) to
give a final concentration of 0.080% w/v of Idoxuridine and
0.0001% w/v of the internal standard.
of the powdered tablets containing 0.2 g (2) Dilute a suitable volume of the eye drops with water to
of mobile phase for 30 minutes. give a final concentration of 0.080% w/v of Idoxuridine.
e to produce 100 mL and mix. (3) 0.0004% w/v of 2'-deoxyuridine, 0.0008% w/v of
suspension at 2500 g for 5-iodouracil, 0.0004% w/v of 5-bromo-2'-deoxyuridine and
atant liquid. 0.0001% w/v of sulfanilamide (internal standard).
( in the mobile phase. CHROMATOGRAPHIC CONDITIONS
CHROMATOGRAPHIC COND: (a) Use a stainless steel column (30 cm x 4 mm) packed
(a) Use a stainless steel colur with end-capped octadecylsilyl silica gel for chromatography
with octadecylsilyl silica gel for chrom (10 um) (uBondapak C18 is suitable).
(Nucleosil C18 is suitable). (b) Use isocratic elution and the mobile phase described
e
(b) Use isocratic elution and themobil below.
below. (c) Use a flow rate of 1.7 mL per minute.
(c) Use a flow rate of 1.5 mL per minute. (d) Use an ambient column temperature.
(d) Use an ambient column temperature. (e) Use a detection wavelength of 254 nm.
(e) Use a detection wavelength of 264 nm. (f) Inject 20 pL of each solution.
(f) Inject 20 pL of each solution. E PHASE
MOBILE PHASE es of methanol and 96 volumes of water.

3 volumes of orthophosphoric acid, 247 volumes of water and er of elution of the peaks following the internal
Calculate the content of C;3H,.O> in the tablets using the

declared content of C,;3H,gO> in ibuprofen BPCRS.
IMPURITIES
monograph include: the ratio of the area }
the area of the peak
(2RS)-2-(4-butylphenyl)propanoic acid (Ibuprofen
the ratio of the areas of t corresponding peaks in the
Impurity B).
chromatogram obtained with solu i 3) (0.5%);
area of the peak due to sulfanilamide*1g

ratio of the areas of the correspondin
ldoxuridine Eye Drops chromatogram obtained with solution
the ratio of the area of any peak due to 5-bromi0-2'-
Action and use deoxyuridine to the area of the peak due to sulfagiilamide is
Pyrimidine nucleoside analogue; antiviral (herpesviruses). not greater than the ratio of the areas of the corresponding
DEFINITION
(0.5%).
Idoxuridine Eye Drops are a sterile solution of Idoxuridine in
Purified Water. ASSAY
Except that they may be supplied in containers not exceeding Carry out the method for guid chromatography,
15 mL capacity, the eye drops comply with the requirements stated Appendix III D, using the following solutions.
under Eye Preparations and with the following requirements. Solution A Prepare a solution containing 0.12 g of
Content of idoxuridine, C,H, ,IN,O; sulfathiazole (internal standard) in 10 mL of ethanol (96%),
90.0 to 110.0% of the stated amount. warming if necessary, and dilute to 100 mL with water.
Solution B Prepare a solution by diluting a suitable volume
IDENTIFICATION
of the eye drops with water if necessary to give a final
A. Dilute a suitable volume of the eye drops with concentration of 0.10% w/v of Idoxuridine.
0.01M sodium hydroxide to produce a solution containing
(1) Add 2 mL of solution A to 15 mL of solution B and
0.004% w/v of Idoxuridine. The light absorption of the
dilute to 20 mL with water.
III-694 Ifosfamide Preparations 2016
(2) Add 2 mL of a 10% v/v solution of ethanol (96%) to TESTS

15 mL of solution B and dilute to 20 mL with water. Solution A 0
(3) Shake 0.1 g of idoxundine BPCRS with 50 mL of water Dissolve 5.0 g in carbon dioxide-free water and dilute to
until dissolved and then dilute to 100 mL with water; 50.0 mL with the same solvent.
to 15 mL of this solution add 2 mL of solution A and dilute Appearance of solution
to 20 mL with water. Solution A is clear, Appendix IV A, and not more intensely
CHROMATOGRAPHIC CONDITIONS coloured than reference solution Y7, Appendix IV B.
(a) Use a stainless steel column (30 cm x 4 mm) packed Acidity or alkalinity
with end-capped octadecylsilyl silica gel for chromatography pH of an 8% w/v solution, 4.0 to 7.0, Appendix V L.
(10 um) (uBondapak C18 is suitable). Related substances
(b) Use isocrati tion and the mobile phase described A. Carry out the method for thin-layer chromatography,
below. Appendix ITI A, using the following solutions.
(c) Use aflow ¥3 mL per minute. (1) Dissolve a sufficient quantity of the contents of the sealed
(d) Use an ambierit : emperature. container in a mixture of equal volumes of methanol and
(ec) Use a detection wavelk
Ifosfamide.
(f) Inject 20 uwL of each SU
(2) 0.025% w/v of ifosfamide impurity A EPCRS and
MOBILE PHASE 0.025% w/v of chloroethylamine hydrochloride (impurity C) in a
13 volumes of methanol and 87 v y water. mixture of equal volumes of methanol and water.
DETERMINATION OF CONTENT (3) 0.015% w/v of tfosfamide impurity B EPCRS in a mixture
Calculate the content of CoH, ,IN»Os uss of equal volumes of methanol and water.
peaks and the declared content of C)H,,IN; (4) 0.005% w/v of ethanolamine, 0.02% wiv of ifosfamide
idoxunidine BPCRS. impurity A EPCRS and 0.08% w/v of chloroethylamine
hydrochloride (impurity C) in a mixture of equal volumes of
STORAGE
methanol and water.
Idoxuridine Eye Drops should be stored at a temperature n
exceeding 8° but should not be allowed to freeze. CHROMATOGRAPHIC CONDITIONS
a) Use as the coating silica gel G.

se the mobile phase as described below.
uwL of each solution.
lfosfamide Injection
Action and use
Cytotoxic alkylating agent.
DEFINITION
Ifosfamide Injection is a sterile solution of Ifosfamide in tank, avoiding contact of the
Water for Injections or a suitable liquid. It is prepared by stationary phase with ion, and close the tank. Leave
dissolving Ifosfamide for Injection in the requisite amount of the plate in contact with the
a suitable liquid immediately before use. Withdraw the plate and plac
The injection complies with the requirements stated under the excess of chlorine is rem
STORAGE
Ifosfamide Injection should be used immediately after
accordance with the manufacturer’s instructions. MOBILE PHASE
10 volumes of water, 15 volumes of methanol, 25 voluth
IFOSFAMIDE FOR INJECTION acetic acid and 50 volumes of dichloromethane.
SYSTEM SUITABILITY
Ifosfamide for Injection is a sterile material consisting of
Ifosfamide with or without excipients. It is supplied in a The test is not valid unless the chromatogram obtained with
sealed container. solution (4) shows three clearly separated spots.
CAUTION Ifosfamide 1s Cytotoxic. Carry out the procedures LIMITS
described below exercising appropriate precautions. In the chromatogram obtained with solution (1) any spot
The contents of the sealed container comply with the requirements corresponding to impurity A or impurity C is not more
for Powders for Injections or Infusions stated under Parenteral intense than the corresponding spot in the chromatogram
Preparations and with the following requirements. obtained with solution (2) (0.25%); any spot corresponding
Content of ifosfamide, C,H,;CI,N,0,P to impurity B is not more intense than the corresponding
95.0 to 105.0% of the stated amount. spot in the chromatogram obtained with solution (3)
(0.15 %); any other spot is not more intense than the
IDENTIFICATION principal spot in the chromatogram obtained with
The infrared absorption spectrum, Appendix II A, is concordant solution (3) (0.15%).
with the reference spectrum of ifosfamide (RS 428).
2016 Imipramine Preparations III-695
B. Carry out the method for thin-layer chromatography, (c) Use a flow rate of 1.5 mL per minute.
0S
(d) Use a column temperature of 30°. >

vy,
eee

.t acy

container in a mixture of equal volumes of methanol and
ee at

oO
Ifosfamide. MOBILE PHASE

ol
(2) 0.005% w/v of tfosfamide impurity E EPCRS and A mixture of 30 volumes of acetonitrile R1 and 70 volumes of
0.005% w/v of ifosfamide impurity F EPCRS in a mixture of carbon dioxide-free water.
equal volumes of methanol and water. DETERMINATION OF CONTENT
(3) 0.01% w/v of tfosfamide impurity E EPCRS and Calculate the content of C7H;5Cl,N2O.,P in a container of
0.01% w/v of ifosfamide impurity F EPCRS in a mixture of average content weight using the declared content of
C7H,5Cl,N20>P in sfosfamide BPCRS.
STORAGE
The sealed container should be kept protected from light.
(b) Use the IMPURITIES
(c) Apply 5 pL of The impurities limited by the requirements of this
(d) Develop the plate: monograph include those listed under Ifosfamide. Related
(e) After removal of t substances test A is intended to control degradation
impurities and Related substances test B is intended to
control synthetic impurities.
Imipramine Tablets
the platein contact with the chlorine vapoti
Withdraw the plate and place it in a current of a Action and use
the excess of chlorineis removed (about 20 minutes) Monoamine reuptake inhibitor; tricyclic antidepressant.
area of coating below the points of application does 4
a blue colour with a drop of potassium iodide and starch DEFINITION
solution. Avoid prolonged exposure to cold air. Immerse ypramine Tablets contain Imipramine Hydrochloride.
plate in a 0.1% w/v solution of tetramethylbenzidine in ethan rare coated.
(96%) for 5 seconds. Allow the plate to dry and examine. ts comply with the requirements stated under Tablets and
MOBILE PHASE allowing requirements.
1 volume of dichloromethane and 10 volumes of acetone.
SYSTEM SUITABILITY
LIMITS
In the chromatogram obtained with solution (1) any spot ether until a turbidity’
corresponding to impurity E or impurity F is not more The precipitate complies
intense than the corresponding spot in the chromatogram
A. Melting point, after recry
172°, Appendix V A.
Water
B. Dissolve 5 mg in 2 mL of nin
Not more than 0.5% w/w, Appendix IX C. Use 1g.
colour 1s produced.
ASSAY C. Yields the reactions characteristic of
Determine the weight of the contents of 10 containers as Appendix VI.
TESTS
Related substances
phase.
and a mixture of 5 volumes of hydrochloric acid, 5 volumes of
(1) Dissolve a sufficient quantity of the contents of the sealed water, 35 volumes of glacial acetic acid and 55 volumes of
container to produce a solution containing 0.060% w/v of ethyl acetate as the mobile phase but allowing the solvent
Ifosfamide. front to ascend 12 cm above the line of application. Apply
(2) 0.060% w/v of tfosfamide BPCRS. separately to the plate 10 uL of each of the following
CHROMATOGRAPHIC CONDITIONS solutions prepared immediately before use. For solution (1)
shake a quantity of the powdered tablets containing 0.20 g of
Imipramine Hydrochloride with three 10 mL quantities of
with octadecylsilyl silica gel for chromatography (5 um) (Zorbax
chloroform, filter the combined chloroform extracts, evaporate
SB-C18 is suitable).
to dryness and dissolve the residue in 10 mL of methanol.
(b) Use isocratic elution and the mobile phase described For solution (2) dilute 3 volumes of solution (1) to
below. 100 volumes with methanol and dilute 1 volume of the
III-696 Indapamide Preparations 2016
resulting solution to 10 volumes with methanol. Solution (3) B. In the Assay, the principal peak in the chromatogram
contains 0.0060% w/v of iminodibenzyl in methanol. After obtained with solution (1) corresponds to.that in the
removal of the plate, allow it to dry for 5 minutes, spray with chromatogram obtained with solution (2).
a 0.5% w/v solution of potassium dichromate in sulfuric acid
TESTS
(20%) and examine immediately. In the chromatogram
Dissolution
obtained with solution (1) any spot corresponding to
iminodibenzyl is not more intense than the spot in the
chromatogram obtained with solution (3) (0.3%) and any
other secondary spot is not more intense than the spot in the
500 mL of 0.1m hydrochlonc acid and rotate the paddle at
100 revolutions per minute. After 60 minutes, withdraw a
sample of 10 mL of the medium and filter. Measure the
absorbance of the filtrate, Appendix II B, suitably diluted with
0.1m hydrochloric acid if necessary, at 240 nm and at 275 nm
using 0.1m hydrochloric acid in the reference cell. Prepare a
reference solution by diluting 1 volume of a 0.10% w/v
suitable). Diluté’a gitable volume of the filtrate with solution of indapamide BPCRS in methanol to 200 volumes
0.1m hydrochloric a to.,groduce a solution containing with 0.1m hydrochloric acid and measure the absorbance of this
0.0025% w/v of Im solution at 240 nm and at 275 nm using 0.1m hydrochloric
acid in the reference cell. Calculate the total content of
250 nm, Appendix II B. C: indapamide hemihydrate, C,;gH).CIN303S,/2H.,0O, in the
C,9H24N2,HCl taking 264 medium using the differences in absorbance at 240 nm and
the maximum at 250 nm. at 275 nm and using the declared content of
C,6H,6CIN3038S in indapamide BPCRS. Each mg of
C16H 6CIN303S is equivalent to 1.0246 mg of
C 16H 6CIN3038,2H,O. The amount of indapamide
hemihydrate released is not less than 75% of the stated
Indapamide Tablets amount.
Action and use Related substances

Thiazide-like diuretic. Carry out the method for liguid chromatography,
Preparation
solutions. For solution (1) mix 10 whole tablets with 70 mL
Prolonged-release Indapamide Tablets
(96%), mix mechanically until the tablets have
ed and continue mixing for 2 hours. Add sufficient
DEFINITION
%) to produce 100 mL, mix and centrifuge.
Indapamide Tablets contain Indapamide. They are coated.
pernatant liquid with the mobile phase to
The tablets comply with the requirements stated under Tablets and n containing 0.005% w/v of Indapamide.
Content of indapamide hemihydrate,
C,6H,6CIN3;038,’2H,O to 100 volumes with the mobile
95.0 to 105.0% of the stated amount. ilate 1 volume of a 0.00025% w/v
IDENTIFICATION solution of indapamuide i ty B BPCRS in ethanol (96%) to
10 volumes with the mobile hase. For solution (4) dilute
Appendix III A, using a TLC silica gel F254 plate (Merck silica
sulfamoylbenzoic acid in ethano
gel 60 F.5,4 plates are suitable) and a mixture of 20 volumes
mobile phase. For solution (5) nx of
of acetone and 80 volumes of toluene as the mobile phase but
allowing the solvent front to ascend 12 cm above the line of
application. Apply separately to the plate 20 uL of each of
the following solutions. For solution (1) grind a quantity of
the powdered tablets containing 50 mg of Indapamide with
10 mL of acetone, mix for 15 minutes, filter through a fine
filter paper (Whatman 42 is suitable) and use the filtrate. (a) a stainless steel column (15 cm x 4.6 mm) pa¢ked with
Solution (2) contains 0.5% w/v of indapamide BPCRS in octadecylsilyl stlca gel for chromatography (5 um) (Nucleosil
acetone. After removal of the plate, allow it to dry until the C18 is suitable), (b) as the mobile phase with a flow rate of
solvent has evaporated and examine under wltraviolet light 1.6 mL per minute a mixture of 6 volumes of a solution
(254 nm). Spray the plate with a solution prepared by mixing containing 5% w/v of sodium dodecyl sulfate and 3% v/v of
10 volumes of potassium todobismuthate solution and glacial acetic acid, 10 volumes of triethylamine, 20 volumes of
20 volumes of glacial acetic acid and diluting to 100 volumes butan-2-ol, 310 volumes of acetonitrile and 690 volumes of
with water and examine again. Finally, spray the plate with a water, the mixture being adjusted to pH 3.0 with
5% w/v solution of sodium nitrite in a mixture of equal orthophosphoric acid and (c) a detection wavelength of
volumes of water and ethanol (96%) and examine again. 240 nm.
By each method of visualisation, the principal spot in the The test is not valid unless, in the chromatogram obtained
chromatogram obtained with solution (1) is similar in with solution (5), the retention time of impurity B relative to
position, colour and intensity to that in the chromatogram indapamide is about 1.7 and the retention time of 4-chloro-
obtained with solution (2). 3-sulfamoylbenzoic acid relative to indapamide is about 0.3.
2016 Indapamide Preparations III-697
In the chromatogram obtained with solution (1), the area of 15 minutes, filter (Whatman 42 is suitable) and use the
any peak corresponding to indapamide impurity B is not filtrate. -
greater than the area of the peak in the chromatogram (2) 0.5% w/v of indapamide BPCRS in acetone.
obtained with solution (3) (0.5%), the area of any peak
corresponding to 4-chloro-3-sulfamoylbenzoic acid is not
greater than 0.4 times the area of the peak in the (a) Use as the coating TLC silica gel Fo54 (Merck silica gel 60
chromatogram obtained with solution (4) (0.2%) and the F554 plates are suitable).
area of any other secondary peak is not greater than the area (b) Use the mobile phase as described below.
of the peak in the chromatogram obtained with solution (2) (c) Apply 20 pL of each solution.
(0.1%). The sum of the content of impurities, excluding (d) Develop the plate to 12 cm.
indapamide impurity B, is not greater than 0.3%.
(e) After removal of the plate, allow it to dry until the solvent
has evaporated and examine under ultraviolet light (254 nm).
Spray the plate with a solution prepared by mixing
Append 3 10 volumes of potasstum todobismuthate solution and
solutions. 20 volumes of glacial acetic acid and diluting to 100 volumes
echanically until the tablets have with water and examine again. Finally, spray the plate with a
ue mixing for 2 hours. Add sufficient 5% wiv solution of sodium nitrite in a mixture of equal
volumes of water and ethanol (96%) and examine again.
MOBILE PHASE
20 volumes of acetone and 80 volumes of toluene.

For solution (2) dilute 1 vohk
indapamide BPCRS in ethano CONFIRMATION
mobile phase. | By each method of visualisation, the principal spot in the
The chromatographic procedure descri chromatogram obtained with solution (1) is similar in
substances may be used. ~ position, colour and intensity to that in the chromatogram
Calculate the content of CygH6CIN303S, 7] obtained with solution (2).
tablets from the chromatogram obtained and | B. In the Assay, the retention time of the principal peak in
declared content of C;gH6CIN303S in indapamiée B the chromatogram obtained with solution (1) is similar to
Each mg of C,6H,¢CIN303S is equivalent to 1.0246'm that of the principal peak in the chromatogram obtained with
C16H16CIN3038,2H20. solution (2).
STORAGE
Indapamide Tablets should be protected from light.
III D, protected from light, using the following

arepared immediately before use.
Prolonged-release Indapamide Tablets

Prolonged-release Indapamide Tablets from different rs. Add sufficient ethanol (96%) to
manufacturers, whilst complying with the requirements of the d centrifuge. Dilute the supernatant
authorised. 0.005% w/v of Indap ums
(2) Dilute 1 volume of sdjution (1) to 10 volumes with the
Action and use
Thiazide-like diuretic.
mobile phase and further diftite 1 volume of this solution to
100 volumes with the mobile phage:
DEFINITION (3) Dilute 1 volume of a 0.00025%.w/s ution of
Prolonged-release Indapamide Tablets contain Indapamide. indapamide impurity B BPCRS in ethaiol
They are formulated so that the medicament is released over 10 volumes with the mobile phase.
a period of several hours. (4) Dilute 1 volume of a 0.00025% w/v séiutioni
PRODUCTION 3-sulfamoylbenzoic acid in ethanol (96%) to 10:
A suitable dissolution test is carried out to demonstrate the the mobile phase. |
appropriate release of Indapamide. The dissolution profile (5) Mix 1 volume of solution (1), 1 volume of a
reflects the in vivo performance which in turn is compatible 0.00025% w/v solution of indapamide impunity B BPCRS in
with the dosage schedule recommended by the manufacturer. ethanol (96%) and 1 volume of a 0.00025% w/v solution of
The tablets comply with the requirements stated under Tablets and 4-chloro-3-sulfamoylbenzotc acid in ethanol (96%) and add
with the following requirements. 7 volumes of the mobile phase.
Content of indapamide, C,;H,<;<CIN3;03S CHROMATOGRAPHIC CONDITIONS

95.0 to 105.0% of the stated amount. (a) Use a stainless steel column (15 cm x 4.6 mm) packed
with octadecylsilyl sthca gel for chromatography (5 um)
IDENTIFICATION
Appendix III A, using the following solutions. (b) Use isocratic elution and the mobile phase described
below.
(1) Grind a quantity of the powdered tablets containing
50 mg of Indapamide with 10 mL of acetone, mix for
II-698 Indometacin Preparations 2016

OH |
MOBILE PHASE
6 volumes of a solution containing 5% w/v of sodium dodecyl Cl
sulphate and 3% v/v of glacial acetic acid, 10 volumes of SO,NH>
triethylamine, 20 volumes of butan-2-ol, 310 volumes of
acetonitrile and 690 volumes of water, the mixture being 1. 4-chloro-3-sulfamoylbenzoic acid.
SYSTEM SUITABILITY
with solutiot#(5), the retention time of impurity B relative to Indometacin Capsules
indapam} out.1.7 and the retention time of 4-chloro-
Action and use
3-sulfamoylben cid relative to indapamide is about 0.3.
LIMITS
In the chromatogra ed with solution (1): DEFINITION

ing to indapamide impurity B Indometacin Capsules contain Indometacin.
(3) (1.0%), and with the following requirements.
-chloro-3- Content of indometacin, C,;>H,¢CINO,
sulfamoylbenzoic acid is not gre 90.0 to 110.0% of the stated amount.
in the chromatogram obtained
IDENTIFICATION
the area of any other secondary peak is fiot A. Shake a quantity of the contents of the capsules
5 times the area of the peak in the chrom: containing 0.1 g of Indometacin with 5 mL of chloroform,
with solution (2) (0.5%), filter and evaporate the filtrate to dryness. Dry the residue at
The total impurity content is not greater than 1.3. 60° at a pressure not exceeding 0.7 kPa for 1 hour. The
Disregard any peak with an area less than the area o infrared absorption spectrum of the residue, Appendix II A, is
principal peak in the chromatogram obtained with solution concordant with the reference spectrum of indometacin
(2) (0.1%). RS 187).
ASSAY ght absorption, Appendix II B, in the range 300 to
Weigh and powder 20 tablets. Carry out the method for the solution obtained in the Assay exhibits a
liquid chromatography, Appendix III D, protected from light, only at 320 nm.
using the following solutions. wantity of the contents of the capsules containing
(1) To a quantity of the powdered tablets containing 25 mg ndometacin with 2 mL of water and add 2 mL of
of Indapamide add 70 mL of ethanol (96%) and mix
mechanically for 2 hours. Add sufficient ethanol (96%) to
produce 100 mL, mix and centrifuge. Dilute the supernatant
liquid with the mobile phase to produce a solution containing
0.005% w/v of I

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