EUROPEAN PHAR1vfACOPOEIA

EIGHTH EDITION
Supplement 8.2
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 u PE
e o 1
EIGHTH EDITION
Supplement 8.2

Published in accordance with the

Convention on the Elaboration of a European Pharmacopoeia
(European Treaty Series No. 50)

COUNCllOF EUROPE

~~" "",'"c"'e fuc 'he

Quality of Medicines & HealthCare
CONSEll DE ~EUROPE

Council of Europe
Strasbourg
The European Pharmacopoeia is published by the Directorate for the Quality ofMedicines & HealthCare
ofthe Council ofEurope (EDQM).

© Council ofEurope, 67075 Strasbourg Cedex, Franee - 2013

AH rights reserved. Apart from any fair dealing for the purposes of research or private study, this
publication may not be reproduced, stored or transmitted in any form or by any means without the prior
permission in writing of the publisher.

ISB~:978-92-871-7529-8
 ca TE TS
CONTENTS OF SUPPLEMENT 8.2 xxvii
GENERAL CHAPTERS 3895
1. Generalnotices 3897
2. Methods of analysis 3905
2.2. Physical and physicochemical methods 3905
2.2.32. Loss on drying 3907
2.4. Limit tests 3909
2.4.27. Heavy metals in herbal drugs and herbal drug preparations 3911
2.5. Assays 3915
2.5.12. Water: semi-micro determination 3917
2.6. Biological tests 3919
2.6.21. Nudeic acid amplification techniques 3921
2.7. Biological assays 3927
2.7.4. Assay ofhuman coagulation factor VIII 3929
2.7.22. Assay ofhuman coagulation factor XI 3930
2.8. Methods in pharmacognosy ,3931
2.8.13. Pesticide residues 3933
4. Reagents 3935
4.1.l. Reagents 3937
4.1.3. Buffer solutions 3937
5. General texts 3939
5.22. Names of herbal drugs used in traditional Chinese medicine 3941
GENERAL MONOGRAPHS 3943
MONOGRAPHS ON VACCINES FOR HUMAN USE 3949
MONOGRAPHS ON RADIOPHARMACEUTICAL PREPARATIONS AND STARTING
MATERIALS FOR RADIOPHARMACEUTICAL PREPARATIONS 3955
MONOGRAPHS ON HERBAL DRUGS AND HERBAL DRUG PREPARATIONS 3961
MONOGRAPHS ON HOMOEOPATHIC PREPARATIONS 3979
MONOGRAPHS 3993
INDEX 4119

Note: on the first page oJ each chapter/section there is a list of contents.

EUROPEAN PHARMACOPOEIA 8.2 Contents of Supplement 8.2

CO TENTSOFS PPLEME
A verticalline in the margin indicates where part of a text has been revised or corrected. A horizontalline in the margin indicates
where part of a text has been deleted. However, these indications, which are not necessarily exhaustive, are given for information
and do not form an official part of the texts. Editorial changes are not indicated.
Individual copies of texts will not be supplied.
Subscribers to the current version (printed or electronic) of the European Pharmacopoeia have access to an archive version of all
previous editions of the European Pharmacopoeia.

NEWTEXTS

The texts below appear for the first time in the European Pharmacopoeia. They will be implemented on 1 July 2014 at the la test.
GENERAL CHAPTERS Monographs
5.22. Names of herbal drugs used in traditional Chinese Brimonidine tartrate (2760)
medicine
Chlormadinone acetate (2702)
MONOGRAPHS Esomeprazole magnesium dihydrate (2787)
Vacdnes for human use Human coagulation factor IX (rDNA) concentrated solution
Diphtheria, tetanus and pertussis (acel!ular, component) (2522)
vaccine (adsorbed, reduced antigen(s) content) (2764)
Quetiapine fumarate (2541)
Homoeopathic preparations
Magnesium phosphoricum for homoeopathic preparations Valaciclovir hydrochloride, hydrated (2751)
(2505) Vardenafil hydrochloride trihydrate (2782)

REVISED TEXTS

The texts below have been technically revised since their last publicatian. They will be implemented an 1 July 2014.

GENERAL CHAPTERS Valerian dry hydroalcoholic extract (1898)

l. General notices Wild thyme (1891)
2.2.32. Loss on drying Yarrow (1382)

2.4.27. Heavy metals in herbal drugs and herbal drug Homoeopathic preparations
preparations Allium sativum for homoeopathic preparations (2023)
2.5.12. Water: semi-micro determination Anacardium for homoeopathic preparations (2094)
Apis for homoeopathic preparations (2024)
2.6.21. Nucleic acid amplification techniques
Arsenicum album for homoeopathic preparations (1599)
2.7.4. Assay of human coagulation factor VIII
Aurum chloratum natronatum for homoeopathic preparations
2.7.22. Assay ofhuman coagulation factor XI (2141)
2.8.13. Pesticide residues Barium chloratum for homoeopathic preparations (2142)
Cadmium sulfuricum for homoeopathic preparations (2143)
4. Reagents (new, revised, corrected)
Calcium iodatum for homoeopathic preparations (2144)
MONOGRAPHS Cocculus for homoeopathic preparations (2486)
General manographs Crocus for homoeopathic preparations (1624)
Allergen products (1063) Cuprum aceticum for homoeopathic preparations (2146)
Vaccines far human use Cuprum metallicum for homoeopathic preparations (1610)
Rabies vaccine for human use prepared in cel! cultures (0216) Ferrum metallicum for homoeopathic preparations (2026)
Kalium bichromicum for homoeopathic preparations (2501)
Herbal drugs and herbal drug preparations
Coriander (1304) Urtica dioica for homoeopathic preparations (2030)
Coriander oil (1820) Monagraphs
Eucalyptus leaf (1320) Alanine (0752)
Long pepper (2453) Amikacin (1289)
Restharrow root (1879) Amikacin sulfate (1290)
Safflower flower (2386) Arginine (0806)
Sage leaf, three-Iobed (1561) Arginine hydrochloride (0805)
Thyme (0865) Cholesterol (0993)
Turpentine oil (1627) Cilastatin sodium (1408)

xxvii
Contents of Supplement 8.2 EUROPEAN PHARMACOPOEIA 8.2

Cyanocobalamin (0547) Levocabastine hydrochloride (1484)

Diclofenac potassium (1508) Linseed oil, virgin (1908)
Diclofenac sodium (1002) Macrogol stearate (1234)
Esomeprazole magnesium trihydrate (2372) Magnesium gluconate (2161)
Fenticonazole nitrate (1211) Manganese gluconate (2162)
Fibrin sealant kit (0903) Neostigmine bromide (0046)
Fulvestrant (2443) Neostigmine metilsulfate (0626)
Histidine (0911) Pancreas powder (0350)

Histidine hydrochloride monohydrate (0910) Phenylalanine (0782)

Human plasma (pooled and treated for virus inactivation) Rifamycin sodium (0432)
(1646) Selegiline hydrochloride (1260)
Indometacin (0092) Tyrosine (1161)
Interferon gamma-lb concentrated solution (440) Zidovudine (059)

CORRECTED TEXTS

The texts below have been corrected and are republished in their entirety. These corrections are to be taken into account from
the publication date of Supplement 8.2 (1 January 2014).

MONOGRAPHS Monographs
Radiopharmaceutical preparations ana starting materials Dutasteride (2641)
for radiopharmaceuti.cal preparations
Hydroxypropylbetadex (1804)
Fludeoxyglucose (1sP) injection (1325)
Magaldrate (1539)
Mannitol (0559)

TEXTS WHOSE TITLE HAS CHANGED

The titles of the following texts have been changed in Supplement 8.2.

GENERAL CHAPTERS Cadmium sulfuricum for homoeopathic preparations (2143)

2.4.27. Heavy metals in herbal drugs and herbal drug (previously Cadmium sulfate hydrate for homoeopathic
preparations (previously Heavy metals in herbal drugs preparations)
and fatty oi/s) Calcium iodatum for homoeopathic preparations (2144)
(previously Caleium iodide tetrahydrate for homoeopathic
MONOGRAPHS preparations)
Herbal drugs and herbal drug preparations Cocculus for homoeopathic preparations (2486) (previously
Turpentine oil (1627) (previously Turpentine oil, Pinus Anamirta eoeculus for homoeopathic preparations)
pinaster type)
Crocus for homoeopathic preparations (1624) (previously
Homoeopathic preparations Saffron for homoeopathic preparations)
Allium sativum for homoeopathic preparations (2023) Cuprum aceticum for homoeopathic preparations (2146)
(previously Garlie for homoeopathic preparations) (previously Copper acetate monohydrate for homoeopathic
Anacardium for homoeopathic preparations (2094) (previously preparations)
Oriental cashew for homoeopathie preparations)
Cuprum metallicum for homoeopathic preparations (1610)
Apis for homoeopathic preparations (2024) (previously Honey (previously Copper for homoeopathic preparations)
bee for homoeopathie preparations)
Ferrum metallicum for homoeopathic preparations (2026)
Arsenicum album for homoeopathic preparations (1599)
(previously 1ron for homoeopathic preparations)
(previously Arsenious trioxide for homoeopathic preparations)
Aurum chloratum natronatum for homoeopathic preparations Kalium bichromicum for homoeopathic preparations
(2141) (previously Sodium tetrachloroaurate dihydrate for (2501) (previously Potassium dichromate for homoeopathic
homoeopathic preparations) preparations)
Barium chloratum for homoeopathic preparations (2142) Urtica dioica for homoeopathic preparations (2030)
(previously Barium chloride dihydrate for homoeopathic (previously Common stinging nettle for homoeopathic
preparations) preparations)

xxviii
EUROPEAN PHARMACOPOEIA 8.2

1~ General notices
1. General notices ................................................................... 3897

General Natices (1) apply ta all managraphs and ather texts 3895
 EUROPEAN PHARMACOPOElA 8.2

3896 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 82
07/2014:10000
L GENERAL NOTICES
U. GENERAL STATEMENTS
The General Notices apply to all monographs and other texts
of the European Pharmacopoeia.
The ofildal texts of the European Pharmacopoeia are
published in English and French. Translations in other
languages may be prepared by the signatory States of the
European Pharmacopoeia Convention. In case of doubt
or dispute, the English and French versions are alone
authoritative.
In the texts of the European Pharmacopoeia, the word
'Pharmacopoeia' without qualiilcation means the European
Pharmacopoeia. The official abbreviation Ph. Eur. may be
used to indicate the European Pharmacopoeia.
The use of the title or the subtitle of a monograph implies
that the artide complies with the requirements of the relevant
monograph. Such references to monographs in the texts of
the Pharmacopoeia are shown using the monograph title and
reference number in italics.
A preparation must comply throughout its period of validity;
a distinct period of validity and/ or specifications for opened
or broached containers may be dedded by the competent
authority. The subject of any other monograph must comply
throughout its period of use. The period of validity that is
assigned to any given artide and the time from which that
period is to be calculated are decided by the competent
authority in light of experimental results of stability studies.
Unless otherwise indicated in the General Notices or in the
monographs, statements in monographs constitute mandatory
requirements. General chapters become mandatory when
referred to in a 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 to cite it for information.
The active substances, excipients, pharmaceutical preparations
and other articles described in the monographs are intended
for human and veterinary use (unless explicitly restricted to
one of these uses).
Quality systems. The quality standards represented by
monographs are valid only where the artides in question are
produced within the framework of a suitable quality system.
The quality system must assure that the artides 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 alone authoritative.
Demonsíration of compliance with the Pharmacopoeia
(1) An artide is not of Pharmacopoeia quality unless it
complies with al! the requirements stated in the monograph.
This does not imply that performance of all the tests in a
monograph is necessarily a prerequisite for a manufacturer in
assessing compliance with the Pharmacopoeia before releas e
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.
(2) An enhanced approach to quality control could utilise
process analytical technology (PAT) and/or real-time releas e
testing (induding parametric release) strategies as alternatives
to end-product testing alone. Real-time release testing
General Notices (1) apply ta all monographs and other texts
1. General notices
in circumstances deemed appropriate by the competent
authority is thus not preduded by the need to comply with the
Pharmacopoeia.
(3) Reduction of animal testing: the European Pharmacopoeia
is dedicated to phasing out the use of animals for test purposes,
in accordance with the 3Rs (Replacement, Reduction,
Refinement) set out in the European Convention for the
Protection ofVertebrate Animals used for Experimental and
Other Scientific Purposes. In demonstrating compliance with
the Pharmacopoeia as indicated aboye (1), manufacturers
may consider establishing additional systems to monitor
consistency of production. With the agreement of the
competent authority, the choice of tests performed to assess
compliance with the Pharmacopoeia when animal tests are
prescribed is established in such a way that animal usage is
minimised as much as possible.
Grade oí materials. Certain materials that are the subject of
a pharmacopoeial monograph may exist in different grades
suitable for different purposes. Unless otherwise indicated
in the monograph, the requirements apply to al! grades of
the material. In sorne monographs, particularly those on
excipients, a list of functionality-related characteristics that are
relevant to the use of the substance may be appended to the
monograph for information. Test methods for determination
of one or more of these characteristics may be given, also for
information.
General monographs. Substances and preparations that are
the subject of an individual monograph are also required
to comply with relevant, applicable general monographs.
Cross-references to applicable general monographs are not
normally given in individual monographs.
General monographs apply to al! 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 110t 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. lf the provisions of a general monograph do
not apply to a particular product, this is expressly stated in the
individual monograph.
Validation oí pharmacopoeial methods. The test methods
given in monographs and general chapters have been validated
in accordance with accepted scientific practice and current
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 oí pharmacopoeial methods. When
implementing a pharmacopoeial method, the user must assess
whether and to what extent the suitability of the method
under the actual conditions of use needs to be demonstrated
according to relevant monographs, general chapters and
quality systems.
Conventional terms. The ter m 'competent authority'
means the national, supranational or international body or
organisation vested with the authority for making decisions
concerning the issue in question. 1t may, for example, be a
national pharmacopoeia authority, a Iicensing authority or
an official controllaboratory.
The expression 'unless otherwise justified and authorised'
means that the requirements have to be met, unless the
competent authority authorises a modification or an
exemption where justified in a particular case.
Statements containing the word 'should' are informative or
advisory.
3897
1. General notices
In certain monographs or other texts, the terms 'suitable' and
'appropriate' are used to describe a reagent, micro-organism,
test method etc.; if criteria for suitability are not described in
the monograph, suitability is demonstrated to the satisfaction
of the competent authority.
Medicinal producto (a) Any substance or combination of
substances presented as having properties for treating or
preventing disease in human beings and/or animals; or (b)
any substance or combination of substances that may be used
in or administered to human beings and/or animals with a
view either to restoring, correcting or modifying physiological
functions by exerting a pharmacological, immunological or
metabolic action, or to making a medical diagnosis.
Herbal medicinal producto Any medicinal product, exclusively
containing as active ingredients one or more herbal drugs or
one or more herbal drug preparations, or one or more such
herbal drugs in combination with one or more such herbal
drug preparations.
Active substance. Any substance intended to be used in
the manufacture of a medicinal product and that, when so
used, becomes an active ingredient of the medicinal producto with a larger internal diameter may be used provided the
Such substances are intended to furnish a pharmacological
activity or other direct effect in the diagnosis, cure, mitigation, the liquids to be compared are examined down the vertical
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, Any solvent required in a test or assay in which an indicator is
antimicrobial preservatives, diluents, antioxidants, for
example, are excipients.
Interchangeable methods. Certain general chapters contain
a statement that the text in question is 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 regulatory documents. Monographs and
general chapters may contain references to documents
issued by regulatory authorities for medicines, for example
directives and 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 described in the Pharmacopoeia and the reliability of the
mandatory or for guidance.
1.2. OTHER PROVISIONS APPLYING TO GENERAL
CHAPTERS AND MONOGRAPHS
Quantities. In tests with numericallimits 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
measured and the result is calculated from this exact quantity.
In tests where the limit is not numerical, but usually depends
upon comparison with the behaviour of a reference substance
in the same conditions, the stated quantity is taken for
examination. Reagents are used in the prescribed amounts.
Quantities are weighed or measured with an accuracy
commensurate with the indicated degree of precision. For
weighings, the precision corresponds to plus or minus 5 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 the decimal point is a zero or ends
in a zero (for example, 10.0 mL or 0.50 mL), the volume is
3898
EUROPEAN PHARMACOPOEIA 8.2
measured using a pipette, a volumetric flask or a burette, as
appropriate; otherwise, a graduated measuring cylinder or a
graduated pipette may be used. Volumes stated in microlitres
are measured using a micropipette or microsyringe.
It is recognised, however, that in certain cases the precision
with which quantities are stated does not correspond to the
number of significant figures stated in a specified numerical
limito The weighings and measurements are then carried out
with a sufficiently improved accuracy.
Apparatus and procedures. Volumetric glassware complies
with Class A requirements of the appropriate International
Standard issued by the International Organisation for
Standardisation.
Unless otherwise prescribed, analytical procedures are carried
out at a temperature between 15 oC and 25 oc.
Unless otherwise prescribed, comparative tests are carried out
using identical tubes of colourless, transparent, neutral glass
with a flat base; the volumes of liquid prescribed are for use
with tubes having an internal diameter of 16 mm, but tubes
volume ofliquid used is adjusted (2.1.5). Equal volumes of
axis of the tubes against a white background, or if necessary
against a black background. The examination is carried out in
diffuse light.
to be used is previously neutralised to the indicator, unless a
blank test is prescribed.
Water-bath. The term 'water-bath' means a bath ofboiling
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 oC or the
indicated temperature.
Drying and ignition to constant mass. The terms 'dried
to constant mass' and 'ignited to constant mass' mean that
2 consecutive weighings do not differ by more than 0.5 mg,
the 2nd 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 'in vacuo', it is carried out using the conditions
described in chapter 2.2.32. Loss on drying.
Reagents. The proper conduct of the analytical procedures
results depend, in part, upon the quality of the reagents used.
The reagents are described in general chapter 4. It is assumed
that reagents of analytical grade are used; for sorne reagents,
tests to determine suitability are included in the specifications.
Solvents. Where the name of the solvent is not stated, the
term 'solution implies a solution in water.
Where the use of water is specified or implied in the
analytical procedures described in the Pharmacopoeia or
for the preparation of reagents, water complying with the
requirements of the monograph Purified water (0008) is
used, except that for many purposes the requirements for
bacterial endotoxins (Purified water in bulk) and microbial
contamination (Purified water in containers) are not relevant.
The term 'distilled water' indicates purified water prepared
by distillation.
The term 'ethanol' without qualification means anhydrous
ethanol. The term 'alcohol' without qualification means
ethanol (96 per cent). Other dilutions of ethanol are indicated
by the term 'ethanol' or 'alcohol' followed by a statement of the
percentage by volume of ethanol (CZH60) required.
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Expression oí contento In defining content, the expression
'per cent' is used according to circumstances with one oí 2
meanings:
_ per cent m/m (percentage, mass in mass) expresses the
number oí grams oí substance in 100 g of final product;
- per cent V/V (percentage, volume in volume) expresses
the number oí millilitres of substance in 100 mL of final
product.
The expression 'parts per million' (or ppm) refers to mass in
mass, unless otherwise specified.
Temperature. Where an analytical procedure describes
temperature without a figure, the general terms used have the
following meaning:
- in a deep-freeze: below - 15 oC;
- in a reÍrigerator: 2 oC to 8 oC;
- cold or cool: 8 oC to 15 oC;
- room temperature: 15 oC to 25 oc.
1.3. GENERAL CHAPTERS
Containers. Materials used ÍOI containers are described
in general chapter 3.1. General names used for materials,
particularly plastic materials, each cover a range oí products
varying not only in the properties of the principal constituent
but also in the additives used. The test methods and limits
Íor 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 deve!oped for general application to containers
of the stated category, but in view of the wide variety of
containers available and possible new developments, the
publication of a specification does not exdude the use, in
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. Cantainers. The general
monographs for pharmaceutical dosage forms may, under
the heading Definition/Production, require the use of certain substances, excipients, intermediate products, bulk products
types of container; certain other monographs may, under
the heading Storage, indicate the type of container that is
recommended for use.
1.4. MONOGRAPHS
TITLES
Monograph titles are in English and French in the respective
versions and there is a Latín subtitle.
RELATIVE A TOMIC AND MOLECULAR MASSES
The relative atomic mass (A r ) or the relative molecular
mass (Mr ) is shown, as and where appropriate, at the beginning national requirements.
of each monograph. The relative atomic and molecular masses This section constitutes requirements for the whole suppIy
and the molecular and graphic formula e do not constitute
analytical standards for the substances described.
CHEMICAL ABSTRACTS SERVICE (CAS) REGISTRY
NUMBER
CAS registry numbers are induded fOI information in
monographs, where applicable, to provide convenient access
to useful information for users. CAS Registry Number® is a
registered trademark of the American Chemical Society.
General Natices (1) apply ta all manographs and ather texts
1. General notices
DEFINITION
Statements under the heading Definition constitute an official
definition of the substance, preparation or other artide that is
the subject of the monograph.
Limits of contento Where limits of content are prescribed,
they are those determined by the method described under
Assay.
Herbal dmgs. In monographs on herbal drugs, the definition
indicates whether the subject of the monograph is, Íor
example, the whole drug or the drug in powdered formo
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
manuÍacturer on the final article, either on selected batches
or on each batch prior to re!ease. These statements cannot
necessarily be verified on a sample of the final artide 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 aboye is not
required.
Choice of vaccine strain, Choice of vacdne composition.
The Production section of a monograph may define the
characteristics of a vaccine strain or vaccine composition.
Unless otherwise stated, test methods given for verification of
these characteristics are provided for information as examples
of suitable methods. Subject to approval by the competent
authority, other test methods may be used without validation
against the method shown in the monograph.
POTENTIAL ADULTERATION
Due to the increasing number of fraudulent activities and
cases of adulteration, information may be made available to
Ph. Eur. users to help detect adulterated materials (Le. active
and finished products).
To this purpose, a method for the detection of potential
adulterants and relevant limits, together with a reminder that
all stages of production and sourcing are subjected to a suitable
quality system, may be induded in this section of monographs
on substances for which an incident has occurred or that
present a risk of deliberate contamination. The frequency of
testing by manufacturers or by users (e.g. manufacturers of
intermediate products, buIk products and finished products,
where relevant) depends on a risk assessment, taking into
account the leve! of knowledge of the whole supply chain and
chain, from manufacturers to users (e.g. manufacturers of
intermediate products, bulk products and finished products,
where relevant). The absence of this section does not imply
that attention to features such as those referred to aboye is
not required.
CHARACTERS
The statements under the heading Characters are 110t to be
interpreted in a strict sense and are not requirements.
3899
1. General notices
Solubility. In statements of solubility in the Characters
section, the terms used have the following significance,
referred to a temperature between 15 oC and 25 oc.
Descriptive term Approximate volume of solvent in millilitres
Eer gram of solute
Very soluble less than 1 complies with the requirements of the monograph.
Freely soluble from to 10
to
Soluble from 10 30
Sparingly soluble fram 30 to 100
to
Slightly soluble from 100 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 sorne of the components dissolve. The term 'miscible' is
used to describe a liquid that is miscible in all proportions
with the stated solvento
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 'Pirst identification' and 'Second
identification'. The test or tests that constitute the 'Pirst
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 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 prescribed in the
Tests section of the monograph. It may be used to simplify
the work of the analyst carrying out the identification and
the prescribed tests. Por example, one identification set
cross-refers to a test for enantiomeric purity while the other
set gives a test for specific optical rotation: the intended
purpose of the two is the same, that is, verification that the
correct enantiomer is present.
Powdered herbal drugs. Monographs on herbal drugs may
contain schematic drawings of the powdered drug. These
drawings complement the description given in the relevant
identification test.
TESTS AND ASSA YS
Scope. The requirements are not framed to take account of all
possible impurities. It is not to be presumed, for example, that
an impurity that is not detectable by means of the prescribed
tests is tolerated if common sense and good pharmaceutical
practice require that it be absent. See also below under
Impurities.
Calculation. Where the result of a test or assay is required
to be calculated with reference to the dried or anhydrous
substance or on sorne other specified basis, the determination
of loss on drying, water content or other property is carried
out by the method prescribed in the relevant test in the
monograph. The words 'dried substance' or 'anhydrous
substance' etc. appear in parentheses after the result.
Where a quantitative determination of a residual solvent is
carried out and a test for loss on drying is not carried out,
the content of residual solvent is taken into account for the
calculation of the assay content of the substance, the specific
optical rotation and the specific absorbance. No further
indication is given in the specific monograph.
3900
EUROPEAN PHARMACOPOEIA 8.2
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 toleran ces are to be applied to the limits
prescribed to determine whether the article being examined
In determining compliance with a numericallimit, 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
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 les s 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. Por 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 named impurity is not prescribed, this
content may be expressed as a nominal concentration of the
substance used to prepare the reference solution specified in
the monograph, unless otherwise described.
Herbal drugs. Por herbal drugs, the sulfated ash, total ash,
water-soluble matter, alcohol-soluble matter, water content,
content of essential oil and content of active principIe are
calculated with reference to the drug that has not been
specially dried, unless otherwise prescribed in the monograph.
Equivalents. Where an equivalent is given, for the purposes
of the Pharmacopoeia only the figures shown are to be used in
applying the requirements of the monograph.
Culture media. The culture media described in monographs
and general chapters have been found 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 concentration of sorne ingredients, notably:
- peptones and meat or yeast extracts, with respect to their
nutritive properties;
- buffering substances;
- bile salts, bile extract, deoxycholate, and colouring matter,
depending on their selective properties;
- antibiotics, with respect to their activity.
STORAGE
The information and recommendations given under the
heading Storage do not constitute a pharmacopoeial
requirement but the competent authority may specify
particular storage conditions that must be met.
The articles described in the Pharmacopoeia are stored
in such a way as to prevent contamination and, as far as
possible, deterioration. Where special conditions of storage
are recommended, including the type of container (see section
1.3. General chapters) and limits of temperature, 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.
See the information section on general monographs (cover pages)
EVROPEAN PHARMACOPOEIA 8.2
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 sto red in a place from which al!
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 article,
as decided by the competent authority.
WARNINGS
Materials described in monographs and reagents specified
for use in the Pharmacopoeia may be injurious to health
unless adequate precautions are taken. The principIes of
good quality controllaboratory practice and the provisions
of any appropriate regulations are to be observed at aH
times. Attention is drawn to particular hazards in certain
monographs by means of a warning statement; absence of such
a statement is not to be taken to mean that no hazard exists.
IMPURITIES
A list of all known and potential impurities that have been
shown to be detected by the tests in a monograph may be
given. See also chapter 5.10. Control of impurities in substances
for pharmaceutical use. The impurities are designated by a
letter or letters of the alphabet. Where a letter appears to
be missing, the impurity designated by this letter has been
deleted from the list during monograph development prior to
publication or during monograph revision.
FUNCTIONALITY-RELATED CHARACTERISTICS OF
EXCIPIENTS
Monographs on excipients may have a section on
functionality-related characteristics. The characteristics, any
test methods for determination and any tolerances are not
mandatory requirements; they may nevertheless be relevant
for use of the excipient and are given for information (see also
section 1.1. General statements).
REFERENCESTANDARDS
Certain monographs require the use of reference standards
(chemical reference substances, herbal reference standards,
biological reference preparations, reference spectra). See
also chapter 5.12. Reference standards. The European
Pharmacopoeia Commission establishes the official
reference standards, which are alone authoritative in case
of arbitration. These reference standards are available from
the European Directorate for the Quality of Medicines &
HealthCare (EDQM). Information on the available reference
standards and a batch validity statement can be obtained via
the EDQM website.
1.5. ABBREVIATIONS AND SYMBOLS
A Absorbance
Al per cent Specific absorbance
1cm
Ar Relative atomic mass
[o:l~O Specific optical rotation
bp Boiling point
BRP Biological reference preparation
CRS Chemical reference substance
General Notices (1) apply fo all monographs and other texts
1. General notices
20
d 20 Relative density
A Wavelength
HRS Herbal reference standard
IV International Unit
M Molarity
Mr Relative molecular mas s
mp
Melting point
Refractive index
Ph. Eur. U. European Pharmacopoeia Vnit
ppb Parts per billion (micrograms per kilogram)
ppm Parts per million (milligrams per kilogram)
R Substance or solution defined under
4. Reagents
Retardation factor (see chapter 2.2.46)
Rst Vsed in chromatography to indicate the
ratio of the distance travelled by a substance
to the distance travelled by a reference
substance
RV Substance used as a primary standard in
volumetric analysis (chapter 4.2.1)
Abbreviations used in the monographs on
immunoglobulins, immunosera and vaccines
LDso The statistically determined quantity of a
substance that, when administered by the
specified route, may be expected to cause
the death of 50 per cent of the test animals
within a given period
MLD Minimum Iethal dose
L+/lO dose The smallest quantity of a toxin that, in the
conditions of the test, when mixed with
0.1 IV of antitoxin and administered by the
specified route, causes the death of the test
aiümals within a given period
L+ dose The smallest quantity of a toxin that, in the
conditions of the test, when mixed with
1 IV of antitoxin and administered by the
specified route, causes the death of the test
animals within a given period
Ir/lOO dose The smallest quantity of a toxin that, in
the conditions of the test, when mixed
with 0.01 IV of antitoxin and injected
intracutaneously causes a characteristic
reaction at the site of injection within a
given period
Lp/lO dose The smallest quantity of toxin that, in the
conditions of the test, when mixed with
0.1 IV of antitoxin and administered by the
specified route, causes paralysis in the test
animals within a given period
Lol10 dose The largest quantity of a toxin that, in the
conditions of the test, when mixed with
0.1 IV of antitoxin and administered by the
specified route, do es not cause symptoms of
toxicity in the test animals within a given
period
Lf dose The quantity of toxin or toxoid that
flocculates in the shortest time with 1 IV of
antitoxin
CCID so The statistically determined quantity of
virus that may be expected to infect 50 per
cent of the cell cultures to which it is added
3901
1. General notices EUROPEAN PHARMACOPOEIA 8.2

The statistically determined quantity of NCIMB National Collection of Industrial and

virus that may be expected to infect 50 per Marine Bacteria Ltd
cent of the fertilised eggs into which it is 23 St Machar Drive
inoculated
Aberdeen AB2 1RY, Great Britain
The statistically determined quantity of
NCPF National Collection of Pathogenic Fungi
a virus that may be expected to infect
50 per cent of the animals into which it is London School of Hygiene and Tropical
inoculated Medicine
The statistically determined dose of a Keppel Street
vaccine that, in the conditions of the test, London WC1E 7HT, Great Britain
may be expected to protect 50 per cent of NCTC National Collection of Type Cultures
the animals against a challenge dose of the
micro-organisms or toxins against which it Central Public Health Laboratory
is active Colindale Avenue
The statistically determined dose of a London NW9 5HT, Great Britain
vaccine that, in the conditions of the NCYC National Collection ofYeast Cultures
test, may be expected to induce specific
antibodies in 50 per cent of the animal s for AFRC Food Research Institute
the relevant vaccine antigens Colney Lane
PFU Pock-forming units or plaque-forming units Norwich NR4 7UA, Great Britain
NITE Biological Resource Center
SPF Specified -pathogen -free
Department of Biotechnology
Collections of micro-organisms National Institute of Technology and
Evaluation
ATCC American Type Culture Collection
2-5-8 Kazusakamatari, Kisarazu-shi, Chiba,
10801 University Boulevard
292-0818
Manassas, Virginia 20110-2209, USA
Japan
C.LP. Collection de Bactéries de l'Institut Pasteur
S.S.!. Statens Serum Institut
B.P. 52, 25 rue du Docteur Roux
80 Amager Boulevard, Copenhagen,
75724 Paris Cedex 15, France Denmark
IMI International Mycological Institute
Bakeham Lane
Surrey TW20 9TY, Great Britain 1.6. UNITS OF THE INTERNATIONAL SYSTEM (SI) USED
IN THE PHARMACOPOEIA AND EQUIVALEN CE WITH
LP. Collection Nationale de Culture de OTHER UNITS
Microorganismes (C.N. C.M.)
INTERNA TIONAL SYSTEM OF UNITS (SI)
Institut Pasteur
The International System of Units comprises 3 classes of units,
25, rue du Docteur Roux namely base units, derived units and supplementary units(1).
75724 Paris Cedex 15, France The base units and their definitions are set out in Table 1.6-1.
Table 1.6.-1. - SI base units

Quantity Un;t Definition

Name Symbol Name Symbol

m The metre is the length of the path travelled by light in a vacuum during a time
Length 1 metre
interval of 1/299792 458 of a second.
Mass m kilogram kg The kilogram is equal to the mass of the international prototype of the kilogramo

The second is the duration of9 192 631 770 periods ofthe 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 [ ampere A The ampere is that constant current which, maintained in two straight parallel
conductors of infinite length, of negligible circular cross-section and placed 1 metre
apart in vacuum would produce between these conductor s a force equal to 2 x 10- 7
newton per metre oflength.
Thermodynamic T kelvin K The kelvin is the fraction 1/273.16 ofthe thermodynamic temperature ofthe triple
temperature point of water.
Amount of substance n mole mol The mole is the amount of substance of a system containing as many elementary
entities as there are atoms in 0.012 kilogram of carbon-12*.
Luminous intensity [,. candela cd The candela is the luminous intensity in a given direction of a source emitting
monochromatic radiation with a frequency of 540 x 10 12 hertz and whose energy
intensity in that direction is 1/683 watt per steradian.
* When the mole is used, the elementar y entities must be specified and may be atoms, molecules, ions, electrons, other particles or specified
groups of such particJes.

(1) The definitions of the units used in the International System are given in the booklet 'Le Systeme International d'Unités (SI)", published by the Bureau International
des Poids et Mesures. Pavillon de Breteuil, F-92310 Sevres.

3902 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2 l. General notices

The derived units may be formed by combining the Sorne important and widely used units outside the
base units according to the algebraic relationships linking International System are shown in Table 1.6-3.
the corresponding quantities. Sorne of these derived units The prenxes shown in Table 1.6-4 are used to form the names
have special names and symbols. The SI units used in the and symbols of the decimal multiples and submultiples of
Pharrnacopoeia are shown in Table 1.6-2. SI units.
Table 1.6.-2. - SI units used in the European Pharmacopoeia and equivalence with other units
Qnantity Unit

Expression in Conversion of olher units ¡nto SI units

Name Symbol Nan1e Symbol Expression in SI
base units other SI units
1
Wave nUIllber v one per metre l/m m

Wavelength A micrOllletre flm 1O- 6 m

nanOlnetre nn1 lO-'m
Area A, S square metre m' m2

Volume V cubic metre In 3 n1 3 1mL~lcm3~1O-6m3

Frequency v Hz s- 1
hertz

Density P kilogram per cubic kg/m 3 kg·m- 3 1 g/mL ~ 1 g/cm 3 ~ 103 kg.m- 3
metre

Velocity v metre per second mis lTI'S- ¡

Force F newton N m·kg·s -2 1 dyne ~ 1 g·cm·s -2~1O-5N

1 kp ~ 9.806 65 N
Pressure p pascal Pa m-1·kg·s 2 N-m 1 dyne/cm 2 ~ 10- 1 Pa ~ 10- IN·m-- 2
1 atm ~ 101 325 Pa ~ 101.325 kPa
1 bar ~ 10 5 Pa ~ 0.1 MPa
1 mm Hg ~ 133.322 387 Pa
1 Torr ~ 133.322 368 Pa
1 psi ~ 6.894 757 kPa
Dynalnic 1j pascal second Pa·s m- l.kg.s- 1 N-s·m
, 1P ~ 10- 1 Pa.s ~ 10- 1 N-s.m
viscosity 1 cP ~ 1 mPa·s
Kinematic v square metre per m'ls ln2.s- 1
Pa·s·m 3.kg - ! 1 St ~ 1 cm'·s- 1 ~ 10-" m 2.s- 1
viscosity second N·m·s·kg- '
Energy W joule r m'·kg·s-' N-m 1 erg ~ 1 Cl11 2·g·s - 2 ~ 1 dyne,cl11 ~ 10 r
1 cal ~ 4.1868 r
Power P watt W m2.kg.s- 3 N·nl·S- j 1 erg/s ~ 1 dyne,cl11's' ,~
Radian! flux Jos- 1 10- 7 W ~ 10- N-m·s- I ~ 10- 7 r·s- I

-2
Absorbed dose D gray Gy 1112'$
¡'kg l 1 rad ~ 10 2Gy
(of radian!
energy)
Electric U volt V m 2. kg'$ -",A- 1 W·k l
potential,
electromotive
force
Electric R ohm íJ m 2. kg.s- 3·A 2 V·A- 1

resistance

Quantity of Q coulomb e A·s

electricity
A s- 1
1 Ci ~ 37.10 9 Bq ~ 37·10'
Activity of a becquerel Bq S-I

radionuclide
Concentration e mole per cubic mol/m] mo1·m- 3 1 mol/L ~ 1M ~ 1 mol/dm 3 ~ 10 3 mol·m- 3
(of an10unt lnetre
of substance),
molar
concentration

Mass P kilogram per cubic kg/m] kg·¡n- 3 1 giL ~ 1 g/dm J ~ 1 kg.m- 3

concentration metre

General Notices (1) apply to all monographs and other texts 3903
1. General notices EUROPEAN PHARMACOPOEIA 8.2

Table 1.6.-3. - Units used with the International System NOTES

Quantity Unit Value in SI units
1. In the Pharmacopoeia, the Celsius temperature is used
Name Symbol (symbol t). This is defined by the following equation:
Time minute min 1min=60s
t=T-To
hour h 1 h = 60 min = 3600 s

day d 1 d = 24 h = 86 400 s where T o = 273.15 K by definition. The Celsius or centigrade

o temperature is expressed in degrees Celsius (symbol OC).
Plane angle degree 10 = (11/180) rad
The unit 'degree Celsius' is equal to the unit 'kelvin'.
Volume litre L 1 L= 1dm'= lO-3 m'
2. The practical expressions of concentrations used in the
Mass tonne t 1 t = 10 kg
3
Pharmacopoeia are defined in the General Notices.
Rotational revolution r/min 1 r/min = (1/60) S-1
3. The radian is the plane angle between two radii of a circle
frequency per minute
that cut off on the circumference an arc equal in length
Table 1.6.-4. - Decima mu tiD/es an d su b-mu tip es o1 units to the radius.
Factor Prefix Symbol Factor Prefix Symbol 4. In the Pharmacopoeia, conditions of centrifugation are
10 18 exa E 10- 1 deci d defined by reference to the acceleration due to gravity (g) :
peta P 10- 2 c
10 15 centi 9 = 9.806658- 2
10 12 tera T 10- 3 milli m

lO' giga G 10-' micro ¡.t 5. Certain quantities without dimensions are used in the
Pharmacopoeia: relative density (2.2.5), absorbance
lO' mega M 10-' nano n
(2.2.25), specific absorbance (2.2.25) and refractive index
lO' kilo k 10- 12 pico P (2.2.6).
102 hecto h 10- 15
femto f 6. The microkatal is defined as the enzymic activity that,
10 da 10- 18 atto a under defined conditions, produces the transformation
1 deca
(e.g. hydrolysis) of 1 micromole of the substrate per secando

3904 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

2.2. Physical and physicochemical

methods
22.32. Loss on drying ................................... ,. ....................... 3907

General Notices (1) apply to all monographs and other texts 3905
 EUROPEAN PHARMACOPOEIA 8.2

3906 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
0712014:20232
2,2.32. LOSS ON DRYING
Loss on drying is the 10ss of mass expressed as per cent mlm.
Method. Place the prescribed quantity of the substance to
be examined in a weighing bottle previously dried under
the conditions prescribed for the substance to be examined.
Dry the substance to constant mas s or for the prescribed
time by one of the following procedures. Where the drying
temperature is indicated by a single value rather than a range,
drying is carried out at the prescribed temperature ± 2 oc.
a) "in a desiccator": the drying is carried out over
diphosphorus pentoxide R at atmospheric pressure and at
room temperature;
General Notices (1) apply to all monographs and other texts
2.2.32. Loss on drying
b) "in vacuo": the drying is carried out over diphosphorus
pentoxide R, at a pressure of 1.5 kPa to 2.5 kPa at room
temperature;
c) "in vacuo within a specifled temperature range": the
drying is carried out over diphosphorus pentoxide R, at a
pressure of 1.5 kPa to 2.5 kPa within the temperature range
prescribed in the monograph;
d) "in an oven within a specifled temperature range": the
drying is carried out in an oven within the temperature
range prescribed in the monograph; instrument
performance veriflcation may be carried out using
a suitable certifled reference material (for example
amoxicillin trihydrate for performance verification CRS);
e) "under high vacuum": the drying is carried out over
diphosphorus pentoxide R at a pressure not exceeding
0.1 kPa, at the temperature prescribed in the monograph.
If other conditions are prescribed, the procedure to be used is
described in full in the monograph.
3907
 EUROPEAN PHARMACOPOEIA 8.2

3908 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

2.4.27. Heavy metals in herbal drugs and herbal drug

preparations .......................................................................... 3911

General Natices (1) apply ta all manographs and ather texts 3909
 EUROPEAN PHARMACOPOEIA 8.2

3910 See the information section on general monographs (cover pages)

 EUROPEA N PHARMACOPOEIA 8.2 2.4.27. Heavy metals in herbal drugs and herbal drug preparations

07/2014:20427 nitrate R and 1.0 mL of a 100 giL solution of ammonium

2.4.27. HEAVY METALS IN HERBAL
DRUGS AND HERBAL DRUG
PREPARATIONS
CAUTION: when using e/osed high-pressure digestion vessels
and microwave laboratory equípment, be familiar with the
safety and operating instructions given by the manufacturero
APPARATUS
The apparatus typically consists of the following:
dihydrogen phosphate R) and stabilising agents may be used, if
necessary.
Blank solution. Mix 4 mL of heavy metal-free hydrochloric
acid R and 6 mL of heavy metal-free nitric acid R in a digestion
flask. Carry out the digestion in the same manner as for the
test solution.
DETERMINA TION OF ARSENIC, CADMIUM, COPPER,
NICKEL AND LEAD USING AAS (2.2.23) WITH
ELECTROTHERMAL A TOMISA TION
Measure the content of arsenic, cadmium, copper, nickel
and lead by direct calibration (2.2.23, Method I) or by the
standard additions method (2.2,23, Method II), using reference
solutions of each heavy metal and the instrumental parameters
recommended in Table 2.4.27.-1.

- as digestion flasks, polytetrafluoroethylene, perfluoroalkoxy The absorbance value of the blank solution is subtracted from
polymer, quartz or glass flasks with a volume of 20-150 mL, the value obtained with the test solution,
fitted with an airtight closure, a valve to adjust the pressure
inside the container and a polytetrafluoroethylene tube to Table 2.4.27.-1. - Instrumental parameters Íor AAS with
allow releas e of gas; electrothermal atomisation
- a system to make flasks airtight, using the same torsional As Cd en Ni Pb
force for each of them;
Wavelength nm 193.7 228.8 324.8 232 283.5
a programmable microwave oven (e.g. with a magnetron
I- frequency of 2450 MHz, with a selectable output
from O to 1500 ± 70 W in 1 per cent increments), a
Slit width 11n1 0.5 0.5 0.5 0.2 0.5

Lamp current lnA la 6 7 la 5

polytetrafluoroethylene-coated microwave cavity with
a variable speed exhaust fan, a rotating turntable drive
Ignition
temperature
oc 1400 800 800 800 800
system and exhaust tubing to vent fumes; Atomisation oc 2600 1800 2300 2500 2200
temperature
an atomic absorption spectrometer (2.2.23), an inductively Gas f10w rate L/min 3 3 3 3
I - coupled plasma-atomic emission spectrometer (2.2.57), or
an inductively coupled plasma-mass spectrometer (2.2.58). DETERMINATION OF ARSENIC AND MERCURY USING
AAS (2,2.23) WITH COLD- VAPOUR OR HYDRIDE
A TOMISATION
METHOD
Measure the content of arsenic and mercury by direct
Examine by atomic absorption spectrametry (AAS) (2.2.23), calibration (2223, Method I) or by the standard additions
inductively coupled plasma-atomic emission spectrometry method (2.2.23, Method II), using reference solutions of
(ICP-AES) (2,2.57), or inductively coupled plasma-mass arsenic or mercury and an automated continuous-flow hydride
spectrometry (ICP-MS) (2.2.58). vapour generation system,
Deviatiol1s fram the experimental parameters of the sample The absorbance value of the blank solution is subtracted from
preparation procedure and the method description below the value obtained with the test solution.
are acceptable provided that the validation requirements are
met and the system suitability test is fulfilled on the day of Arsenic
the analysis,
Sample solution. To 19.0 mL of the test solution or of the blank
Sample preparation solution as prescribed aboye, add 1 mL of a 200 giL solution
of potassium iodide R. Allow the test solution to stand at room
Clean aH the glassware and laboratory equipment with a temperature for about 50 min or at 70 oC for about 4 mino
10 giL solution of nitric acid R before use.
Test solution. In a digestion flask, place the prescribed quantity Acid reagent. Heavy metal-free hydrochloric acid R.
of the substance to be examined (about 0.50 g of powdered
Reducing reagent. 6 giL solution of sodium tetrahydroborate R
herbal drug (1400) (2.9.12)). Add 4 mL of heavy metal-free
in a 5 giL solution of sodium hydroxide R.
hydrochloric acid R and 6 mL of heavy metal-free nitric acid R.
Make the flask airtight, The recommended instrumental parameters in Table 2.4.27.-2
Place the digestion flasks in the microwave oven. Carry out maybe used.
the digestion in 3 steps according to the following programme, Mercury
used for 7 flasks each containing the test solution: 80 per cent
power for 15 min, 100 per cent power for 5 min, 80 per cent Sample solution. Test solution or blank solution, as prescribed
power for 20 mino aboye.
At the end of the cyele, allow the flasks to cool in air or water, Acid reagent. 515 giL solution of heavy metaljree hydrochloric
After cooling, open each digestion flask and introduce the acid R.
clear, colourless solution obtained into a 50 mL volumetric
flask. Rinse each digestion flask with 2 quantities, each of Reducing reagent. 10 giL solution of stannous chloride R in
15 mL, of heavy metal-free dilute nitric acid R, collect the heavy metal-free dilute hydrochloric acid R.
rinsings in the volumetric flask and dilute to 50.0 mL with
water R. Modifiers (e.g. in the case of AAS with electrothermal The recommended instrumental parameters in Table 2.4.27.-2
atomisation, 1.0 mL of a 10 giL solution of magnesium may be used.

General Notices (1) apply to all monographs and other texts 3911
2.4.27. Heavy metals in herbal drugs and herbal drug preparations EUROPEAN PHARMACOPOEIA 8.2

Table 2.4.27.-2. - Instrumental parameters for AAS with SPECIFICITY

cold-vapour or hydride atomisation Specificity is the ability to ensure that the analytical procedures
As Hg for sample preparation and measurement allow a reliable
determination of the metal(s) in the presence of components
Wavelength nm 193.7 253.7 (e.g. carrier gas, impurities, matrix) that may be expected to
Slit width nm
be presento
0.2 0.5
Acceptance criteria: the procedure must be able to assess
Lamp current mA 10 4 unequivocally each heavy metal to be determined with
Add reagent flow rate this procedure in the presence of components that may be
mLlmin 1.0 1.0
expected to be present, ineluding other heavy metals, matrix
Redudng reagent flow rate mLlmin 1.0 1.0 components and other sources of interference; specificity is
Sample solution flow rate demonstrated by complying with the accuracy requirement
mLlmin 7.0 7.0
for the metal(s) to be determined.

-Absorption cell

Nitrogen flow rate Llmin

Quartz
(heated)

0.1
Quartz
(unheated)

0.1
DETERMINATION OF ARSENIC, CADMIUM, COPPER,
MERCURY, NICKEL AND LEAD USING ICP-AES (2.2.57)
Measure the content of arsenic, cadmium, copper, mercury,
nickel and lead by direct calibration (2.2.23, Method I),
using reference solutions of each heavy metal or a mixture
of all measured metals, and the instrumental parameters
recommended in Table 2.4.27.-3.
The emission value of the blank solution is subtracted from
the value obtained with the test solution.
DETERMINATION OF ARSENIC, CADMIUM, COPPER,
MERCURY, NICKEL AND LEAD USING ICP-MS (2.2.58)
Measure the content of arsenic, cadmium, copper, mercury,
nickel and lead by direct calibration (2.2.23, Method 1)
using reference solutions of each heavy metal and the
analytical isotopes and additional masses recommended in
Table 2.4.27.-4.
The signal intensity of the blank solution is subtracted from
the value obtained with the test solution.
SYSTEM SUITABILITY
A system suitability test must be carried out on the day
of the analysis to ensure that the sample preparation and
measurement system are appropriate.
Acceptance criterio n for preparation of sample solution: a elear
solution is obtained.
Acceptance criterio n for measurement system: the measured
concentration of a standard solution of the metal at a
concentration within the range of the used calibration curve
do es not differ from the actual concentration by more than
20 per cent.
VALIDATION REQUIREMENTS
The analytical procedures used must be validated in
accordance with the relevant general methods AAS (2.2.23),
ICP-AES (2.2.57) and ICP-MS (2.2.58). Additionally, the
following criteria must be fulfilled.
RANGE
The calibration range of each metal is within the linear range
of the method; test solutions containing residues at a level
outside the calibration range may be diluted to concentrations
within the calibration range.
Acceptance criterion: range is demonstrated by complying
with the recovery requirement.
ACCURACY
Verify the accuracy using a certified reference material (CRM)
or by performing a test for recovery.
Recovery. Recovery may be determined on a sample of the
substance to be examined, spiked with a known quantity of a
reference standard of the metal (3 concentration levels in the
range of 50-150 per cent of the intended specification limit,
even if the original concentration of the reference standard is
at the specified value), in triplicate.
Acceptance criterion: spike recovery is within 70 per cent and
150 per cent for the mean of 3 replicates at each concentration.
REPEATABILITY
Test samples: either 6 independent samples of the substance
to be examined spiked with a suitable reference standard at
the specified concentration level, or 3 concentration levels
prepared in triplicate.
Acceptance criterio n : the relative standard deviation is in both
cases not greater than the value indicated in Table 2.4.27.-5.
INTERMEDIA TE PRECISION
The effect of random events (intra-laboratory variations) on
the analytical precision of the method must be established.
Acceptable experiments for establishing intermediate
precision inelude performing the repeatability analysis on
different days, or with different instrumentation, or with
different analysts. Only 1 of the 3 experiments is required to
demonstrate intermediate precision.
Acceptance criterio n : the relative standard deviation is not
greater than the value indicated in Table 2.4.27.-5.
LIMIT OF QUANTIFICATION
Determine the lowest concentration meeting the acceptance
criterion. Use the results from the accuracy study.
Acceptance criterion: the limit of quantification is below the
specification limito

Table 2.4.27.-3. - Instrumental parameters for ICP-AES

As Cd Cn Hg Ni Pb

Wavelength nm 193.696/ 214.438/ 324.754/ 184.950/ 231.604/ 220.351/

197.197/ 226.502/ 327.396/ 253.652/ 231.997/ 283.306/

189.042 228.802 224.700 435.835 352.454 168.215

Ar, Monitorline nm 430.010 430.010 430.010 430.010 430.010 430.010

Plasma energy W 1200 1200 1200 1200 1200 1200

Peak algorithm with yes yes yes yes yes yes
background correction

3912 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 2.4.27. Heavy metals in herbal drugs and herbal drug preparations

Table 2.4.27.-4. - Recommended analytical isotopes and Table 2.4.27.-5

additional masses for ICP-MS Concentration range Repeatability (RSD) Intermediate precision
of the metal (mg!kg) (per cent) (RSD) (per cent)
Isotope Element of Interest
0.01 - 20 32
75 Arsenic
> 1 10 16
106,108,111,114 Cadmium

63,65 Copper
LIMIT OF DETECTION (ONLY APPLICABLE TO LIMIT
TESTS)
202 Mercury Determine the lowest concentration giving a signal clearly
60, 62 Nickel distinct from that obtained with a blank solution.
Acceptance criterio n : the limit of detection is not more than
206, 207, 208 Lead
0.1 times the concentration of the specification limit.

General Notices (1) apply to all monographs and other texts 3913
 EUROPEAN PHARMACOPOEIA 8.2

3914 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

2.5.12. Water: semi-micro determination ........................... 3917

General Notices (1) apply to all monographs and other texts 3915
 EUROPEAN PHARMACOPOEIA 8.2

3916 See the information sectíon on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8,2
0712014:20512
2.5.12. WATER: SEMI-MICRO
DETERMINATION
The semi-micro determination ofwater is based upon the
quantitative reaction of water with sulfur dioxide and iodine
in a suitable anhydrous medium in the presence of a base with quantity of water.
sufficient buffering capacity,
Apparatus
The apparatus consists of a titration vessel with:
- 2 identical platinum electro des ;
- tight inlets for introduction of solvent and titrant;
- an inlet for introduction of air via a desiccant;
- a sample inlet fitted with a stopper or, for liquids, a septum, Thereafter, in the same titration vessel, sequential known
lnlet systems for introduction of dry nitrogen or for aspiration amounts of water, corresponding to about 50-100 per cent
of solvents may also be fitted,
The titration is carried out according to the instrument
supplier's instructions, Care is taken throughout the
determination to avoid exposure of reagents and solvents to
atmospherie moisture, The end-point is determined using
2 identical indicator electro des conneeted to an electrical
souree that maintains between the electro des either a constant
current (2,2,65, Voltametric titration) or a constant voltage
(2,2,19, Amperometric titration), Where direet titration is
used (method A), addition of titrant causes either a decrease
in voltage where constant current is maintained or an increase W 2
in current where constant voltage is maintained, until the
end-point is reached, Instruments with automatic end-point
detection are commonly used, Instrument performance
verification may be carried out using a suitable certified
reference material (for example amoxicillin trihydrate for
performance verification CRS),
Standardisation, To the titration vessel, add methanol R,
dried if necessary, or the solvent recommended by the supplier
of the titrant, Where applicable fOI the apparatus used,
eliminate residual water from the measurement ceH or carry
out a pre-titration, Introduce a suitable amount of water in an
appropriate form (water R or a certified reference material)
and carry out the titration, stirring for the necessary time, The expressions;
water equivalent is not less than 80 per cent of that indicated
by the supplier, Standardise the titrant before the first use and
at suitable intervals thereafter.
Unless otherwise prescribed, use Method A
Method A, Introduce into the titration vessel methanol R, or
the solvent indicated in the monograph or recommended by
the supplier of the titrant Where applicable for the apparatus
used, eliminate residual water from the measurement cell
or carry out a pre-titration, Introduce the substance to be
examined rapidly and carry out the titration, stirring for the
necessary extraction time,
Method B, Introduce into the titration vessel methanol R, or
the solvent indicated in the monograph or recommended by
the supplier of the titrant Where applicable for the apparatus - bis between 0,975 and 1,025,
General Notices (1) apply to all monographs and other texts
2.5.12. Water: semi-micro determination
used, eliminate residual water from the measurement cel!
or carry out a pre-titration, Introduce the substance to be
examined rapidly and in a suítable state of division, Add an
accurately measured volume of the titrant, sufficient to give
an excess of about 1 mL or the prescribed volume, Allow to
stand protected from light for 1 min or the prescribed time,
with stirring, Titrate the excess of reagent using methanol R
or the prescribed solvent, containing an accurately known
Suitability, The accuracy of the determination with the
chosen titrant must be verified for each combination of
substance, titrant and solvent to be examined, The following
procedure, given as an example, is suitable for samples
containing 25-25 mg of water,
The water content of the substance to be examined is
determined using the reagent/solvent system chosen,
of the amount found in the substance to be examined, are
added in an appropriate form (at least 5 additions) and the
water content is determined after each addition, Calculate the
percentage recovery (r) after each addition using the following
expression:
W¡ amount of water added, in milligrams;
amount of water found, in milligrams,
Calculate the mean percentage recovery (r), The
reagent/solvent system is considered to be acceptable ifr- is
between 975 per cent and 1025 per cent.
Calculate the regression line, The x-axis represents the
cumulative water added whereas the y-axis represents the sum
of the initial water content determined for the substance (M)
and the cumulative water determined after each addition,
Calculate the slope (b), the intercept with the y-axis (a) and
the intercept of the extrapolated calibration line with the
x-axis (d),
Calculate the percentage errors (e¡ and e2 ) using the following
a-M
el = 100--¡¡:¡-
Idl-M
e2 = 100"--'--
M
a the y-axis intercept, in milligrams of water;
d the x-axis intercept, in milligrams of water;
M water content of the substance, in milligrams of
water.
The reagent/solvent system is considered to be acceptable if:
- lell and le21 are not greater than 25 per cent;
3917
 EUROPEAN PHARMACOPOEIA 8.2

3918 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

2.6. Biological tests

2.6.21. Nucleic acid amplification techniques ..................... 3921

General Natíces (1) apply ta all managraphs and ather texts 3919
 EUROPEAN PHARMACOPOEIA 8.2

3920 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2 2.6.21. Nl1deÍC acid amplification techniques

07/2014:20621 5. TEST METHOD

5.1. Prevention of contamination
2.6.21. NUCLEIC ACID The risk of contamination requires a striet segregation of the
AMPLIFICATION TECHNIQUES areas depending on the material handled and the technology
used. Points to consider indude movement of personnel,
L INTRODUCTION gowning, material tlow and air supply and decontamination
Nudeie acid amplification techniques are based on 2 different procedures.
approaches: The system should be sub-divided into compartments such as:
1. amplification of a target nudeie acid sequence using, for - master-mix are a (area where exclusively template-free
example, polymerase chain reaction (PCR), ligase chain material is handled, e.g. primers, buffers, etc.);
reaction (LCR), or isothermal ribonudeie acid (RNA) - pre-PCR (area where reagents, samples and controls are
amplification; handled);
2. amplification of a hybridisation signal using, for example, - PCR amplification (amplified material is handled in a
for deoxyribonudeie acid (DNA), the branched DNA dosed system);
(bDNA) method; in this case signal amplification is - post-PCR detection (the only are a where the amplified
achieved without subjecting the nudeie acid to repetitive material is handled in an open system).
cydes of amplification.
If dosed systems are used, the striet segregation of areas is
In this general chapter, the PCR method is described as the not required.
reference technique. Alternative methods may be used, if they
comply with the quality requirements described below. 5.2. Sample preparation
When preparing samples, the target sequence to be amplified
2. SCOPE needs to be efficiently extracted or liberated from the test
This section establishes the requirements for sample material in a reproducible manner and in such a way that
preparation, in vitro amplification of DNA sequences and amplification under the selected reaction conditions is
detection of the specific PCR product. With the aid of PCR, possible. A variety of physieo-chemieal extraction procedures
defined DNA sequences can be detected. RNA sequences can and/or enrichment procedures may be employed.
also be detected following reverse transcription of the RNA to Additives present in test material may interfere with PCR.
complementary DNA (cDNA) and subsequent amplification. The procedures described under 7.3.2. must be used as a
control for the presence of inhibitors originating from the
3. PRINCIPLE OF THE METHOD test material.
PCR is a procedure that allows specific in vitro amplification In the case of RNA-templates, care must be taken to avoid
of segments of DNA or of RNA after reverse transcription ribonudease activity.
into cDNA.
5.3. AmpHfication
Following denaturation of double-stranded DNA into
single-stranded DNA, 2 synthetie oligonudeotide primers of PCR amplification of the target sequence is conducted
under defined cycling conditions (temperature profile
opposite polarity anneal to their respective complementary
sequences in the DNA to be amplified. The short for denaturation of double-stranded DNA, annealing
and extension of primers; incubation times at selected
double-stranded regions that form as a result of specific base
temperatures; ramp rates). These depend on various
pairing between the primers and the complementary DNA
sequence border the DNA segment to be amplified, and serve parameters such as:
as starting positions for in vitro DNA synthesis by means of a - the length and base composition of primer and target
heat-stable DNA polymerase. sequences;
Amplification of the DNA occurs in cyeles consisting of: - the type of DNA polymerase, buffer composition and
reaction volume used for the amplification;
- heat denaturation of the nudeie acid (target sequence) into
2 single strands; - the type of thermocyder used and the thermal conductivity
rate between the apparatus, reaction tube and reaction tluid.
- specific annealing af the primers to the target sequence
under suitable reaction conditions; 5.4. Detection
- extension of the primers, whieh are bound to both single The amplicon generated by PCR may be identified by
strands, by DNA polymerase at a suitable temperature size, sequence, chemical modification or a combination
(DNA synthesis). of these parameters. Detection and characterisation by
size may be achieved by gel electrophoresis (using agarose
Repeated cydes of heat denaturation, primer annealing and or polyacrylamide slab geIs or capillary electrophoresis)
DNA synthesis results in an exponential amplification of the or column chromatography (for example, liquid
DNA segment limited by the primers. chromatography). Detection and characterisation by sequence
The specific PCR product known as an amplicon can be composition may be achieved by the specific hybridisation
detected by a variety of methods of appropriate specificity and of probes having a sequen ce complementary to the target
sensitivity. sequence or by deavage of the amplified material retlecting
Multiplex PCR assays use several primer pairs designed far target-specific restriction-enzyme sites. Detection and
simultaneous amplification of different targets in one reaction. characterisation by chemical modification may be achieved by,
for example, incorporation of a tluorophore into the amplicons
4. TEST MATERIAL and subsequent detection of tluorescence following excitation.
Because of the high sensitivity of PCR, the samples must Detection of amplicons may also be achieved by using
be protected against external contamination with target probes labelled to permit a subsequent chemiluminescent,
sequences. Sampling, storage and transport of the test material radioisotopie or immuno-enzyme-coupled detection.
are performed under conditions that minimise degradation
of the target sequence. In the case of RNA target sequences, 6. EVALUATION AND INTERPRETATION OF RESULTS
special precautions are necessary since RNA is highly sensitive A valid result is obtained within a test only if the positive
to degradation by ribonudeases. Care must be taken since control(s) is unambiguously positive and the negative
sorne added reagents, such as anticoagulants or preservatives, control(s) is unambiguously negative. Due to the very high
may interfere with the test procedure. sensitivity of the PCR method and the inherent risk of

General Notices (1) apply to all monographs and other texts 3921
2.6.21. Nuc1eic acid amplification techniques
contamination, it is necessary to confirm positive results by
repeating the complete test procedure in duplicate, where
possible on a new aliquot of the sample. The sample is
considered positive if at least one of the repeat tests gives a
positive resulto As soon as a measurable target threshold is
defined, a quantitative test system is required.
7. QUALITY ASSURANCE
7.1. Validation ofthe PCR assay system
The validation programme must include validation of
instrumentation and the PCR method employed. Reference
should be made to the ICH guideline Q2(Rl) Validation of
Analytical Procedures: Text and Methodology.
Appropriate official working reference preparations
or in-house reference preparations calibrated against
International Standards for the target sequences are used for
validation of a PCR test, when available.
7.1.1. Determination of the positive cut-off point
During validation of qualitative tests, the positive cut -off point
must be determined. The positive cut-off point is defined
as the minimum number of target sequences per volume
sample that can be detected in 95 per cent of test runs. The
positive cut-off point depends on interrelated factors such as
the volume of the sample extracted and the efficacy of the
extraction methodology, the transcription of the target RNA
into cDNA, the amplification process and the detection.
To define the detection limit of the assay system, reference
must be made to the positive cut-off point for each target
sequence and the test performance aboye and below the
positive cut-off point.
7.1.2. Quantitative assay systems
For a quantitative assay, the following parameters are
determined during validation: accuracy, precision, specificity,
quantitation limit, linearity, range and robustness.
7.2. Quality control of reagents
All reagents crucial for the methodology used have to
be controlled prior to use in routine applications. Their
acceptance/withdrawal is based on pre-defined quality criteria.
Primers are a crucial component of the PCR assay and as
such their design, their purity and the validation of their use
in a PCR assay require careful attention. Primers may be
modified (for example, by conjugation with a fluorophore or
antigen) in order to permit a specific method of detection
of the amplicon, provided such modifications do not inhibit
accurate and efficient amplification of the target sequence.
7.3. Run controls
7.3.1. External controls
In order to minimise the risk of contamination and to ensure
adequate sensitivity, the following external controls are
included in each PCR assay:
- positive control: this contains a defined number of
target-sequence copies, the number being close to the
positive cut-off value, and determined individually for each
assay system and indicated as a multiple of the positive
cut -off value of the assay system;
- negative control: a sample of a suitable matrix already
proven to be free of the target sequences.
7.3.2. Internal control
Internal controls are defined nucleic acid sequences
containing, unless otherwise prescribed, the primer binding
sites. Internal controls must be amplified with defined efficacy,
and the amplicons must be clearly discernible. Internal
controls must be of the same type of nucleic acid (DNA/RNA)
as the material to be tested. The internal control is preferably
added to the test material before isolating the nucleic acid
and therefore acts as an overall control (extraction, reverse
transcription, amplification, detection).
3922
EUROPEAN PHARMACOPOEIA 8.2
7.3.3. Threshold control
The threshold control for quantitative assays is a test sample
with the analyte at a concentration that is defined as the
threshold not to be exceeded. It contains the analyte suitably
calibrated in International Units and is analysed in parallel in
each run of a quantitative assay.
7.4. External quality assessment
Participation in external quality assessment programmes
is an important PCR quality assurance procedure for each
laboratory and each operator.
The following sections are published for information.
Validation of nucleic acid amplification
techniques (NAT) for the detection of
hepatitis e virus (HCV) RNA in plasma
pools: guidelines
1. SCOPE
The majority of nucleic acid amplification analytical
procedures are qualitative (quantal) tests for the presence of
nucleic acid with sorne quantitative tests (either in-house or
commercial) being available. For the detection of HCV RNA
contamination of plasma pools, qualitative tests are adequate
and may be considered to be a limit test for the control
of impurities as described in the Pharmeuropa Technical
Guide for the elaboration of monographs, December 1999,
Chapter III 'Validation of analytical procedures: These
guidelines describe methods to validate only qualitative
nucleic acid amplification analytical pro ce dures for assessing
HCV RNA contamination of plasma pools. Therefore, the
2 characteristics regarded as the most important for validation
of the analytical procedure are the specificity and the detection
limito In addition, the robustness of the analytical procedure
should be evaluated.
However, this document may also be used as a basis for the
validation of nucleic acid amplification in general.
For the purpose of this document, an analytical procedure is
defined as the complete procedure from extraction of nucleic
acid to detection of the amplified products.
Where commercial kits are used for part or all of the analytical
procedure, documented validation points already covered by
the kit manufacturer can substitute for the validation by the
user. Nevertheless, the performance of the kit with respect
to its intended use has to be demonstrated by the user (e.g.
detection limit, robustness, cross-contamination).
2. SPECIFICITY
Specificity is the ability to assess unequivocally nucleic acid
in the presence of components that may be expected to be
presento
The specificity of nucleic acid amplification analytical
procedures is dependent on the choice of primers, the choice
of probe (for analysis of the final product) and the stringency
of the test conditions (for both the amplification and the
detection steps).
When designing primers and probes, the specificity of
the primers and probes to detect only HCV RNA should
be investigated by comparing the chosen sequences with
sequences in published data banks. For HCV, primers
(and probes) will normally be chosen from areas of the 5'
non-coding region of the HCV genome which are highly
conserved for all genotypes.
The amplified product should be unequivocally identified by
using one of a number of methods such as amplification with
nested primers, restriction enzyme analysis, sequencing, or
hybridisation with a specific probe.
See the informatíon section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
In order to validate the specificity of the analytical procedure,
at least 100 HCV RNA-negative plasma pools should be
tested and shown to be non-reactive. Suitable samples of
non-reactive pools are available from the European Directorate
for the Quality of Medicines & HealthCare (EDQM).
The ability of the analytical procedure to detect al! HCV
genotypes will again depend on the choice of primers, probes
and method parameters. This ability should be demonstrated
using characterised reference panels. However, in view of
the difficulty in obtaining samples of sorne genotypes (e.g.
genotype 6), the most prevalent genotypes (e.g. genotypes 1
and 3 in Europe) should be detected at a suitable level.
3. DETECTION LIMIT
The detection limit of an individual analytical procedure is the
!owest amount of nucleic acid in a sample that can be detected
but not necessarily quantitated as an exact value.
The nucleic acid amplification analytical procedure used for
the detection of HCV RNA in plasma pools usually yields
qualitative results. The number of possible results is limited
to 2: either positive or negative. Although the determination
of the detection limit is recommended, for practical purposes,
a positive cut-off point should be determined for the nucleic
acid amplification analytical procedure. The positive cut -off
point (as defined in the general chapter 2.6.21) is the minimum
number of target sequences per volume sample that can be
detected in 95 per cent of test runs. This positive cut-off
point is influenced by the distribution of viral genomes in the
individual samples being tested and by factors such as enzyme
efficiency, and can result in different 95 per cent cut -off values
for individual analytical test runs.
In order to determine the positive cut-off point, a dilution
series of a working reagent or of the hepatitis C virus BRP,
which has been calibrated against the WHO HCV International
Standard, should be tested on different days to examine
variation between test runs. At least 3 independent dilution
series should be tested with a sufficient number of replicates at
each dilution to give a total number of 24 test results for each
dilution, to enable a statistical analysis of the results.
For example, a laboratory could test 3 dilution series on
different days with 8 replicates for each dilution, 4 dilution
series on different days with 6 replicates for each dilution,
or 6 dilution series on different days with 4 replicates for
each dilution. In order to keep the number of dilutions at
a manageable level, a preliminary test (using, for example,
10glO dilutions of the plasma pool sample) should be carried
out in order to obtain a preliminary value for the positive
cut-off point (Le. the highest dilution giving a positive
signal). The range of dilutions can then be chosen around the
predetermined preliminary cut-off point (using, for example,
a dilution factor of 0.5 log¡O or less and a negative plasma pool
for the dilution matrix). The concentration of HCV RNA
that can be detected in 95 per cent of test runs can then be
calculated using an appropriate statistical evaluation.
These results may also serve to demonstrate the intra-assay
variation and the day-to-day variation of the analytical
procedure.
4. ROBUSTNESS
The robustness of an analytical procedure is a measure of
its capacity to remain unaffected by small but deliberate
variations in method parameters and provides an indication
of its reliability during normal usage.
The evaluation of robustness should be considered during
the development phase. It should show the reliability of the
analytical procedure with respect to deliberate variations in
method parameters. For NAT, small variations in the method
parameters can be crucial. However, the robustness of the
method can be demonstrated during its development when
small variations in the concentrations of reagents (e.g. MgCI 2,
General Notices (1) apply to a/l monographs and other texts
2.6.21. Nudeic add amplification techniques
primers or dNTP) are tested. To demonstrate robustness, at
least 20 HCV RNA negative plasma pools (selected at random)
spiked with HCV RNA to a final concentration of 3 times
the previously determined 95 per cent cut -off value should
be tested and found positive.
Problems with robustness may also arise with methods that
use an initial ultracentrifugation step prior to extraction of the
viral RNA. Therefore, to test the robustness of such methods,
at least 20 plasma pools containing varying levels of HCV
RNA, but lacking HCV-specific antibodies, should be tested
and found positive.
Cross-contamination prevention should be demonstrated
by the accurate detection of a panel of at least 20 samples
consisting of alternate samples of negative plasma pools and
negative plasma pools spiked with high concentrations of
HCV (at least 102 times the 95 per cent cut-off value or at
least 104 IV/mL).
5. QUALITY ASSURANCE
For biological tests such as NAT, specific problems may arise
that influence both the validation and the interpretation of
results. The test procedures must be described precisely in the
form of standard operating procedures (SOPs). These should
cover:
- the mode of sampling (type oí container, etc.);
- the preparation of mini-pools (where appropriate);
- the conditions of storage before analysis;
- the exact description of the test conditions, including
precautions taken to prevent cross-contamination or
destruction of the viral RNA, reagents and reference
preparations used;
- the exact description of the apparatus used;
- the detailed formula e for calculation of results, including
statistical evaluation.
The use of a suitable run control (for example, an appropriate
dilution of hepatitis C virus BRP or plasma spiked with an
HCV sample calibrated against the WHO HCV International
Standard) can be considered a satisfactory system-suitability
check and en sures that the reliability of the analytical
procedure is maintained whenever used.
Technical qualificatíon. An appropriate installation and
operation qualification programme should be implemented
for each critical piece of the equipment used. For confirmation
of analytical procedure performance after a change of
critical equipment (e.g. thermocyclers), the change should
be documented by conducting a parallel test 011 8 samples
of a plasma pool that is spiked with HCV RNA to a final
concentration of 3 times the previously determined 95 per
cent cut -off value. Al! results should be positive.
Operator qualification. An appropriate qualification
programme should be implemented for each operator involved
in the testing.
Validation of nudeic acid amplification
techniques (NAT) for the quantification of
B19 virus (B19V) DNA in plasma pools:
guidelines
1. SCOPE
The European Pharmacopoeia requires that plasma pools used
for manufacture of certain products are tested for the presence
of B 19 virus (B 19V) DNA with a threshold concentration
that must not be exceeded. In order to comply with these
requirements, quantitative NAT tests are preferred. The
characteristics regarded as the most important for validation
of the quantitative NAT procedure are accuracy, precision,
specificity, quantitation limit, linearity and range. In addition,
the robustness of the analytical procedure should be evaluated.
3923
2.6.21. Nucleic acid amplificatiou techniques
This guideline describes methods to validate NAT analytical
procedures for assessing B19V DNA contamination of plasma
pools based on the ICH guidelines. However, this document
may also be used as a basis for the validation of quantitative
NAT in general.
For the purpose of this document, an analytical procedure is
defined as the complete procedure from extraction of nucleic conditions (for both the amplification and the detection steps).
acid to detection of the amplified products.
Where commercial kits are used for part or all of the analytical be investigated by comparing the chosen sequences with
procedure, documented validation points already covered by
the kit manufacturer can substitute for the validation by the
user. Nevertheless, the performance of the kit with respect
to its intended use has to be demonstrated by the user (e.g.
precision, accuracy, range, robustness).
2. ACCURACY
Accuracy expresses the closeness of agreement between the
value that is accepted as either a conventional true value
or an accepted reference value and the value found. The
accuracy of an assay is dependent on the calibration of
the assay and on the variance of the different assay steps.
Though it is recommended to establish the accuracy across
the specified range of the analytical procedure, the most
important assessment of accuracy is in the range of the
threshold concentration. In the case of B19V NAT assays for
investigation of plasma pools it is recommended to assess
the accuracy of the calibrated assay by assaying at least
5 concentrations (dilution factor ofO.5log¡o) of B19 virus DNA genotypes. Reference materials should be used to check the
for NAT testing BRP or another material, suitably calibrated
in International Units against the actual WHO B19 DNA
International Standard, covering the range of the currently
recommended threshold concentration of 10.0 IU/IlL B19V
DNA (e.g. 105 IU/mL, 104 .5 IU/mL, 104 IU/mL, 103.5 IU/mL
and 103 IU/mL), with at least 3 replicates for each dilution.
Accuracy should be reported for the different concentrations
in terms of percentage determined compared with the known
amount ofB19V DNA. It should reflect the level oftechnology
of the respective assays, which should also be defined, for
example in collaborative studies.
3. PRECISION
Precision expresses the closeness of agreement between a
series of measurements, obtained from multiple sampling of
the same homogenous sample. The precision is defined at
3 levels:
- repeatability expresses the precision under the same
operating conditions over a short interval of time
(intra -assay precision); it is assessed by using 1 assay and the whole quantitative range. The interval between the upper
testing 3 replicates of appropriate dilutions of a B19V
DNA-positive sample suitably calibrated in International
Units and covering the whole quantitative range of the
assay; the coefficient of variation for the individual samples
is calculated (intra-assay variability);
- intermediate precision expresses the intra-Iaboratory
variations (inter-assay precision); it is established by
assaying replicates (as routinely used for the assay) of
appropriate dilutions of a B19V DNA-positive sample
suitably calibrated in International Units covering the
whole quantitative range of the assay under different
circumstances (e.g. different days, different analysts,
different equipment, different reagents); the coefficient of concentration that can be expressed with an acceptable degree
variation for the individual samples is calculated;
- reproducibility expresses the precision between different
laboratories (inter-Iaboratory precision); it is assessed
by participation in quantitative collaborative studies on
B19V DNA-NAT assays, e.g. under the Proficiency Testing
Scheme (PTS), including the comparative analysis of the
obtained quantitative results, where appropriate.
3924
EUROPEAN PHARMACOPOEIA 8.2
4. SPECIFICITY
Specificity expresses the ability to assess unequivocally nucleic
acid in the presence of components that may be expected to
be presento The specificity ofNAT analytical procedures is
dependent on the choice of primers, the choice of probe (for
analysis of the final product) and the stringency of the test
When designing primers and probes, the specificity of the
primers and probes to detect only human B19V DNA should
sequences in published data banks. There should be no major
homology found with sequences unrelated to B19V.
The amplified product should be unequivocally identified by
using one of a number of methods such as amplification with
nested primers, restriction enzyme analysis, sequencing, or
hybridisation with a specific probe.
In order to examine the specificity of the analytical procedure,
at least 20 B19V DNA-negative plasma pools should be tested
and shown to be non-reactive.
Parvovirus B19 genotypes. The International Committee on
Taxonomy ofViruses (ICTV) has classified representatives
ofthe 3 genotypes as strains ofhuman parvovirus B19.
Genotype 1 represents prototype B19V, genotype 2 represents
viral sequences like A6, and genotype 3 represents V9-like
sequences. By performing sequence alignment with respective
B19V genotype sequences available from nucleic acid sequence
databases, primers and pro bes should be designed to detect
and quantify consistently the different human parvovirus B19
approach chosen. Since biological reference preparations
reflecting sorne genotypes might be difficult to obtain,
respective plasmid preparations or synthetic nucleic acids may
also serve as a characterised target sequence source. However,
those cannot be used to validate the extraction procedure.
5. QUANTITATION LIMIT
The quantitation limit is the lowest amount of nucleic acid
in a sample that can be determined quantitatively with
suitable precision and accuracy. The quantitation limit of
the B19V NAT assay is assessed during the repeatability and
intermediate-precision studies by limiting dilution analysis.
The lowest concentration of target nucleic acids that is
quantitated with suitable precision and accuracy is defined.
6. LINEARITY
The linearity of an assay is its ability to obtain test results that
are directly proportional to the concentration of the nucleic
acid. The linearity of the B19V NAT assay is assessed during
the repeatability and intermediate-precision studies by testing
replicates of diluted samples with the concentrations covering
and the lower concentration of the target nucleic acid where
test results are directly proportional to the concentrations is
defined.
7. RANGE
The range of an assay is the interval between the upper and
the lower concentration of nucleic acid in the sample for
which it has been demonstrated that the procedure has a
suitable level of precision, accuracy and linearity. The range
of the B19V NAT assay is assessed during the repeatability
and intermediate-precision studies by testing replicates of
diluted samples. The interval between the upper and the lower
of accuracy and precision is defined.
8. ROBUSTNESS
The robustness of an analytical procedure is a measure of its
capacity to remain unaffected by small but deliberate variations
in method parameters and provides an indication of its
reliability during normal usage. The evaluation of robustness
should be considered during the development phase. It should
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
show the reliability of the analytical procedure with respect
to deliberate variations in method parameters. For NAT,
small variations in the method parameters can be crucial.
Nonetheless, the robustness of NAT can be demonstrated
during the development of the method when small variations
in the concentrations of reagents, for example MgCI 2, primers
or dNTP, are tested. To demonstrate robustness, at least 20
B19V DNA-negative plasma pool samples spiked with B19V
DNA at the threshold concentration should be tested and
found to have acceptable quantitative values.
Cross-contamination prevention should be demonstrated
by the accurate detection of a panel of at least 20 samples
cOl1sisting of alternate samples of plasma pools without
B19V DNA 01' with levels below the threshold concentration
(lO samples) and plasma pools spiked with high
concentrations ofB19V DNA (at least 10 2 times the threshold
leve!, 10 samples).
9. QUALITY ASSURANCE
For biological tests such as NAT, specific problems may arise
that may influence both the validation and the interpretation
of results. The test procedures must be described precisely
in the form of standard operating procedures (SOPs). These
should cover:
- the mode of sampling (type of container, etc.);
- the preparation of mini-pools by manufacturers (where
appropriate) ;
General Notices (1) apply to all monographs and o/her texts
2.6.21. Nudeic acid amplification techniques
- the conditions of storage before analysis;
- the exact description of the test conditions including
precautions taken to prevent cross-contamination or
destruction of the viralnucleic acids, reagents and reference
preparations used;
- the exact description of the apparatus used;
- the detailed formula e for calculation of results, including
statistical evaluation.
The inclusion of an appropriate threshold control (for
example, plasma spiked with a B19V DNA sample suitably
calibrated in International Units, such as B19 virus DNA
for NAT testing BRP) is considered to be a satisfactory
system -suitability check and en sures that the reliability of the
analytical procedure is maintained whenever used.
Technical qualification. An appropriate installation and
operation qualification programme should be implemented
for each critical piece of the equipment used. For confirmation
of analytical procedure performance after a change of critical
equipment (e.g. thermocyclers), the change should be
documented by conducting a paralle! test on 8 samples of a
plasma pool that is spiked with a concentration ofB19V DNA
around the threshold concentration. AH results should be
acceptable and reflect the features of the assay as determined
during the validation phase.
Operator qualification. An appropriate qualification
programme should be implemented for each operator involved
in the testing.
3925
 EUROPEAN PHARMACOPOEIA 8.2

3926 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

iological assays
2.7.4. Assay of human coagulation factor VIII ................... 3929 2.7.22. Assay of human coagulation factor XI.. .................. 3930

General Natices (1) apply ta all managraphs and ather texts 3927
 EUROPEAN PHARMACOPOEIA 8.2

3928 See the information section on general monographs (cover pages)

 EUROPEAN PHARMACOPOEIA 8.2 2.7.4. Assay ofhuman coagulation factor VIII

0712014:20704 synthetically prepared, and must, to a substantial extent,

2,7.4, ASSAY OF HUMAN
COAGULATION FACTOR VIII
Human coagulation factor VIII is assayed by its biological
activity as a cofactor in the activation of factor X by activated
factor IX (factor IXa) in the presence of calcium ion s and
phospholipid. Factor VIII activity may be measured in plasma
preparations and therapeutic concentrates (plasma-derived
and recombinant). The potency of a factor VIII preparation is
estimated by comparing the quantity necessary to achieve a
certain rate of factor Xa formation in a test mixture containing
the substances that take part in the activation of factor X, and
the quantity of the International Standard, or of a reference
preparation calibrated in International Units, required to
produce the same rate of factor Xa formation.
Quantification of factor VIII activity in plasma preparations is
expressed in International Units defined by the International
Standard for blood coagulation factor VIII in plasma, and
coagulation factors V; VIII, XI and XIII plasma BRP is
suitable for use as a reference preparation. Quantification of
factor VIII activity in therapeutic concentrates is expressed
in International Units defined by the International Standard
for blood coagulation factor VIII concentrate, and human
coagulation factor VIII concentrate BRP is suitable for use as a
reference preparation.
lIliII
The chromogenic assay method consists of 2 consecutive
steps: the factor VlII-dependent activation of factor X in a
coagulation-factor reagent composed of purified components,
and the enzymatic cleavage of a chromogenic factor Xa
substrate to yield a chromophore that can be quantified
spectrophotometrically. Under appropriate assay conditions,
there is a linear relation between the rate of factor Xa
formation and the factor VIII concentration. The assay is
summarised by the following scheme.
Step 1
(activated) factor VIII )o factor Xa
factor X
factor IXa, phospholipid, Ca 2 +
Step :2
chromogenic substrate factor Xa)o peptide + chromophore
Both steps employ reagents that may be obtained commercially reagent or a combination of its separate constituents, and
from a variety of sources. Although the composition of
individual reagents may be subject to sorne variation, their
essential features are described in the following specification. time, terminating the reaction (step 2) when the factor Xa
Deviations from this description may be permissible provided concentration has reached approximately 50 per cent of the
that it has been shown, using the appropriate International
Standard for blood coagulation factor VIII as the standard,
that the results obtained do not differ significantly.
It is important to demonstrate by validation the suitability of reagent containing a chromogenic substrate. Quantify
the kit used, notably by checking the time course of factor Xa
generation in order to determine the time taken to reach
50 per cent of the maximal factor Xa generation.
REAGENTS
The coagulation factor reagent comprises purified proteins
derived from human or bovine sources. These indude
factor X, factor IXa, and a factor VIII activator, usually
thrombin. These proteins are partly purified, preferably to at
least 50 per cent, and do not contain impurities that interfere to achieve a linear development of chromophore over time.
with the activation of factor VIII or factor X. Thrombin
may be present in its precursor form prothrombin, provided
that its activation in the reagent is sufflciently rapid to give dose-response
almost instantaneous activation of factor VIII in the assay.
Phospholipid may be obtained from natural sources or be
consist of the species phosphatidylserine. The components of
the complete reagent are usually divided into at least 2 separate
reagents, each lacking the ability to generate factor Xa on
its own. One of the reagents contains calcium ions. After
reconstitution, the reagents may be combined provided
that no substantial amounts of factor Xa are generated in
the absence of factor VIII. In the final incubation mixture,
factor VIII must be the only rate-limiting component.
The 2 nd step comprises the quantification of the formed
factor Xa, employing a chromogenic substrate that is
specific for factor Xa. Generally this consists of a derivatised
short peptide ofbetween 3 and 5 amino acids, joined to a
chromophore group. On deavage of this group from the
peptide substrate, its chromophoric properties shift to a
wavelength allowing its spectrophotometric quantification.
The substrate must also contain appropriate inhibitors to
stop further factor Xa generation, e.g. chelating agents, and
to suppress thrombin activity.
ASSAY PROCEDURE
For the assay of therapeutic concentra tes, add sufficient
prediluent to the reference and test preparations to produce
solutions containing 0.5-2.0 IU/mL. The prediluent consists
of haemophilia A plasma, or of an artiflcially prepared
reagent that contains sufficient von Willebrand factor and
that gives results that do not differ significantly from those
obtained employing haemophilia plasma. The prediluted
materials must be stable beyond the time required for the
assay. Pre-dilution in haemophilia A plasma is not required
for the assay of factor VIII in plasma preparations.
Prepare dilutions of the pre-diluted reference and test
concentrate preparations (or the reference and test plasma
preparations) using a non -chelating, appropriately buffered
solution, for example, tris(hydroxymethyl)aminomethane or
imidazole, containing 1 per cent of human or bovine albumino
Prepare at least 2 dilution series of at least 3 further dilutions
for each material. Prepare the dilutions such that the final
factor VIII concentration in the reaction mixture is preferably
below 0.01 IU/mL, during the step of factor Xa generation.
Prepare a control solution that indudes al! components except
factor VIII.
Prepare al! dilutions in plastic tubes and use immediately.
Step l. Mix prewarmed dilutions of the factor VIII reference
preparation and of the preparation to be examined with an
appropriate volume of the prewarmed coagulation factor
incubate the mixture in plastic tubes or microplate wells at
37°C. Allow the activation of factor X to proceed for a suitable
maximal (plateau) level. Appropriate activation times are
usually between 2 min and 5 mino
Step 2. Terminate the activation by addition of a prewarmed
the rate of substrate deavage, which must be linear with
the concentration of factor Xa formed, by measuring the
absorbance change at an appropriate wavelength using
a spectrophotometer, either monitoring the absorbance
continuously, thus allowing the initial rate of substrate cleavage
to be calculated, or terminating the hydrolysis reaction after a
suitable interval by lowering the pH by addition of a suitable
reagent, such as a 50 per cent V/V solution of acetic acid, or a
1 M pH 3 citrate buffer solution. Adjust the hydrolysis time
Appropriate hydrolysis times are usually between 3 min and
15 min, but deviations are permissible if better linearity of the
relationship is thus obtained.
Calculate the potency of the test preparation by the usual
statistical methods (for example, 5.3).

General Notices (1) apply to all monographs and other texts 3929
2.7.22. Assay of human coaguIation factor XI EUROPEAN PHARMACOPOEIA 8.2

07/2014:20722 and the reference preparation in factor XI -deficient plasma

2.7.22. ASSAY OF HUMAN
COAGULATION FACTOR XI
The principIe of the assay is to measure the ability of a
factor XI preparation to reduce the prolonged coagulation
time of factor XI -deficient plasma. The reaction is accelerated times or perform the assay with incubation tubes maintained
by addition of a reagent containing phospholipid and a
contact activator, e.g. kaolin, silica or ellagic acid. The
potency is as ses sed by comparing the dose-response curve
of the preparation to be examined to that of a reference
(for example plasma substrate R3) to produce solutions
containing 0.5-2.0 units/mL. Prepare at least 3 appropriate
dilutions for each material, preferably in duplicate, using a
suitable buffer solution (for example imidazole buffer solution
pH 7.3 R) containing 10 giL ofbovine or human albumino Use
these dilutions immediately.
Use an apparatus suitable for measurement of coagulation
in a water bath at 37 oc. Place in each tube 0.1 mL of
factor XI-deficient plasma (for example plasma substrate R3)
and 0.1 mL of one of the dilutions of the reference preparation
or ofthe preparation to be examined. Add to each tube 0.1 mL

-
plasma calibrated against the International Standard for blood of a suitable Activated Partial Thromboplastin Time (APTT)
coagulation factor XI in plasma. reagent containing phospholipid and contact activator and
incubate the mixture for a recommended time at 37 oc.
Reconstitute separately the preparation to be examined To each tube, add 0.1 mL of a 3.7 giL solution of calcium
and the reference preparation as stated on the label and chloride R previously heated to 37 oc. Using a timer, measure
use immediately. Coagulation factors V; VIII, XI and XIII the coagulation time, Le. the interval between the moment of
plasma BRP is suitable for use as a reference preparation. the addition of the calcium chloride and the first indication
Where applicable, determine the amount of heparin present of the formation of fibrin. The volumes given aboye may be
(2.7.12) and neutralise the heparin, for example by addition adapted to the APTT reagent and apparatus used. Calculate
of protamine sulfate R (10 flg of protamine sulfate neutralises the potency using the usual statistical methods (for example,
1 IU ofheparin). Predilute the preparation to be examined 5.3).

3930 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

2.8. Methods in pharmacognosy

2.8.13. Pesticide residues .. ..................................................... 3933

General Natices (1) apply ta all managraphs and ather texts 3931
 EUROPEAN PHARMACOPOEIA 8.2

3932 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 2.8.13. Pesticide residues

0712014:20813 Table 2.8.13.-1

Substance Limit
(mg/kg)
Acephate 0.1
2.8.13. PESTICIDE RESIDUES
Alachlor 0.05

Aldrin and dieldrin (sum of) 0.05

Definition. For the purposes of the Pharmacopoeia, a
Azinphos-ethyl 0.1
pesticide is any substance or mixture of substances intended
for preventing, destroying or controlling any pest, unwanted
species of plants or animal s causing harm during or otherwise
ínterfering with the production, processing, storage, transport
or marketing of herbal drugs. The item íneludes substances
intended for use as growth-regulators, defolíants or desiccants
Azinphos-methyl

Bromophos-ethyl 0.05
-
Bromophos-methyl 0.05
and any substance applied to crops, either before or after
harvest, to protect the commodity from deterioration during Brompropylate
storage and transport. Pestícide residues can be present and
Chlordane (sum of cis-, trans - and oxychlordane) 0.05
are controlled in herbal drugs and herbal drug preparatíons.
Chlorfenvinphos 0.5
Limits. Unless otherwise indicated in the monograph, the
herbal drug to be examined at least complíes with the limits Chlorpyriphos-ethyl 0.2
indicated in Table 2.8.13.-l. The limits applying to pesticides
Chlorpyriphos-methyl 0.1
that are not listed in Table 2.8.13.-1 and whose presence
is suspected for any reason comply with the limits (levels) Chlorthal-dimethyl 0.01
cross referred to by Regulation (EC) No. 396/2005, ineluding
Cyfluthrin (sum of) 0.1
annexes and successive updates. Limits for pesticides that are
not listed in Table 2.8.13.-1 nor in European Union texts are A-Cyhalothrin
calculated using the following expression:
Cypermethrin and isomers (sum 00
ADlxM DDT (sum of o,p' -DDE, p,p' -DDE, o,p' -DDT, p,p' -DDT,
MDDHD X 100 o,p' -TDE and p,p' -TDE)
Deltamethrin 0.5

ADI acceptable daily intake, as published by Diazinon 0.5

FAO-WHO, in milligrams per kilogram of Dichlofluanid 0.1
body mass;
Dichlorvos
M body mass in kilograms (60 kg) ;
Dicofol 0.5
MDD HD = daily dose of the herbal drug, in kilograms.
Dimethoate and omethoate (sum of) 0,1

The limits for pesticides in herbal drug preparations are Dithiocarbamates (expressed as CS2) 2
calculated using the following expressions: Endosulfan (sum of isomers and endosulfan sulfate) 3

Endrin 0.05

Ethion 2
If DER '" 10: MRLHDXDER
Etrimphos 0.05

Fenchlorophos (sum of fenchlorophos and 0.1

fenchlorophos-oxon)
Fenitrothion 0.5
IfDER> 10: ADI x M
MDD HP X 100 Fenpropathrin 0.03

Fensulfothion (sum of fensulfothion, fensulfothion-oxon, 0.05

fensulfothion-oxonsulfon and fensulfothion-sulfon)
maximum residue limit of the pesticide in the
Fenthion (sum of fenthion, fenthion-oxon, 0.05
herbal drug as given in Table 2.8.13.-1 or in fenthion -oxon -sulfon, fenthion -oxon-sulfoxid,
EU texts or calculated using the express ion fenthion-sulfon and fenthion-sulfoxid)
mentioned above; Fenvalerate 1.5
DER drug/extract ratio, i.e. the ratio between the
Flucytrinate 0.05
quantity of herbal drug used in the manufacture
of a herbal drug preparation and the quantity of T - Fluvalinate 0.05
herbal drug preparation obtained; 0.05
Fonophos
daily dos e of the herbal drug preparation, in Heptachlor (sum of heptachlor, cis- heptachlorepoxide and 0.05
kilograms. trans-heptachlorepoxide)
Hexachlorbenzene 0.1

The competent authority may grant total or partial exemption Hexachlorocyclohexane (sum of isomers a-, ~-, 0- and E) 0.3
from the test when the complete history (nature and
Lindan (y-hexachlorocyclohexane) 0.6
quantity of the pesticides used, date of each treatment during
cultivation and after the harvest) of the treatment of the batch Malathion and malaoxon (sum of)
is known and can be checked precisely according to good 0.05
Mecarbam
agricultural and collection practice (GACP).

General Natices (1) apply ta all managraphs and ather texts 3933
2.8.13. Pestidde residues EUROPEAN PHARMACOPOEIA 8.2

Substance Lirnit Sampling of herbal drugs. Sampling is done according to

(rng/kg) general chapter 2.8.20. Herbal drugs: sampling and sample
Methacriphos 0.05 preparation.
Methamidophos 0.05 Qualitative and quantitaHve analysis of pesticide residues.
The analytical procedures used are validated (e.g. according
Methidathion 0.2 to Document N° SANCOIl0232/2006). In particular, they
Methoxychlor 0.05 satisfy the following criteria:
Mirex 0.01 - the chosen method, especially the purification steps, is
suitable for the combination pesticide residue/substance
Monocrotophos 0.1 to be examined, and not susceptible to interference from
Parathion -ethyl and Paraoxon -ethyl (sum of) 0.5 co-extractives;
Parathion-methyl and Paraoxon-methyl (sum 00 0.2 - natural occurrence of sorne constituents is considered in the
interpretation ofresults (e.g. disulfide from Cruciferaceae);
Pendimethalin 0.1
- the concentration of test and reference solutions and the
Pentachloranisol 0.01 setting of the apparatus are such that the responses used
Permethrin and isomers (sum of) for quantification of the pesticide residues are within the
dynamic range of the detector; test solutions containing
Phosalone 0.1 pesticide residues at a level outside the dynamic range,
Phosmet 0.05 may be diluted within the calibration range, provided
that the concentration of the matrix in the solution is
Piperonyl butoxide 3 adjusted in the case where the calibration solutions must
Pirimiphos-ethyl 0.05 be matrix-matched;

Pirimiphos-methyl (sum of pirimiphos-methyl and 4 - between 70 per cent to 110 per cent of each pesticide is
N-desethyl-pirimiphos-methyl) recovered;
Procymidone 0.1 - repeatability of the method: RSD is not greater than the
Profenophos 0.1 values indicated in Table 2.8.13.-2;

Prothiophos 0.05
- reproducibility of the method: RSD is not greater than the
values indicated in Table 2.8.13.-2.
Pyrethrum (sum of cinerin I, cinerin II, jasmolin 1, 3
jasrnolin II, pyrethrin I and pyrethrin III Tabie 2.8.13.-2
Quinalphos 0.05
Concentration range Repeatability (RSD) Reproducibility (RSD)
Quintozene (sum of quintozene, pentachloraniline and of lhe pestidde (per cent) (per cen!)
methyl penthachlorphenyl sulfidel (mg/kg)
S-421 0.02 0.001 - 0.01 30 60

Tecnazene 0.05 > 0.01 - 0.1 20 40

Tetradifon 0.3 > 0.1 - 1 15 30

Vinclozolin 0.4 > 1 10 20

3934 See the informatiorl section on general monographs (caver pages)

EUROPEA N PHARMACOPOEIA 8.2

4~ Reagents
4.1.1. Reagents ........................................................................ 3937 4.1.3. Buffer solutions ............................................................ 3937

General Notices (1) apply to all monographs and other texts 3935
 EUROPEAN PHARMACOPOEIA 8.2

3936 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
0712014:40101
4.1.1. REAGENTS
L-Histidine. 1187900. [71-00-1]. (2S)-2-Amino-3-(1H-
imidazol-4-yl)propanoic acid.
Lysyl endopeptidase. 1188000. [78642-25-8].
Achromobacter endoproteinase 1. Lysyl bond specific
proteinase (EC 3.4.21.50).
It belongs to the serine endopeptidase family. Initially isolated
from Achromobacter lyticus. Enzymes with similar specificity
are produced by Lysobacter enzymogenes (endoproteinase
Lys-C) and Pseudomonas aeruginosa (Ps-l). It cleaves
peptide bonds at the carboxy-terminal ofboth lysine residues
and S-aminoethylcysteine residues with a high degree of
specificity. 1 amidase unit (U) is the amount of enzyme
that will produce 1 micromole of p-nitroaniline from
N-benzoyl-DL-lysine-p-nitroaniline per minute at 30 oC at
pH 9.5.
Nitric add. 1058400.
Nitric add, dilute, heavy metal-free. 1058410.
Complies with the requirements prescribed for dilute nitric
acid R with the following maximum contents of heavy
metals.
As: 0.005 ppm.
Cd: 0.005 ppm.
Cu: 0.001 ppm.
Fe: 0.02 ppm.
Hg: 0.002 ppm.
Ni: 0.005 ppm.
Pb: 0.001 ppm.
Zn: 0.01 ppm.
Picrotin. C 1s H 1S 0?, (M, 310.3). 1188100. [21416-53-5].
(lR,3R,5S,8S,9R,12S,13R,14S)-1-hydroxy-14-(2-
hydroxypropan -2-yl)-13- methyl-4, 7,1 O-trioxapenta-
cyelo [6.4. l. 1.9.12.03.S.0S.13]tetradecane-6, ll-dione.
White or colourless crystalline powder or crystals, soluble
in boiling water and in ethanol (96 per cent), practically
insoluble in methylene chloride.
mp: 248 oC to 250 oc.
Picrotoxinin. ClsH1606' (M, 292.2). 1188200.
[17617-45-7]. (lR,3R,5S,8S,9R,12S,13R,14R)-1-
hydroxy-13-methyl-14-(prop-1-en-2-yl)-4,7,l O-trioxa-
pentacyclo [6.4.1.1 9,12.03.S.05,13]tetradecane-6, Il-dione.
White or colourless crystalline powder or crystals, soluble in
methylene chloride, in ethanol (96 per cent) and in alkaline
solutions.
mp: 207 to 210 oc.
General Notices (1) apply to all monographs and other texts
4.1.3. Buffer solutions
Polyamine grafted poly(vinyl alcohol) copolymer. 1188300.
Copolymer beads of poly(vinyl alcohol) to which polyamine
is covalently bonded. The size range of the beads is specified
after the name of the reagent in the tests where it is used.
Silica gel for chromatography compatible with 100 per
cent aqueous mobile phases, octadecylsilyl, end-capped.
1188400.
A very finely divided silica gel with bonded octadecylsilyl
groups suitable for use with highly aqueous mobile phases
including 100 per cent aqueous phases. To minimise any
interaction with basic compounds it is carefully end-capped to
cover most of the remaining silanol groups. The particle size
is indicated after the name of the reagent in the tests where
it is used.
Silica gel for chromatography, octadecylsilyl, extra-dense
bonded, end-capped. 1188500.
A very finely divided silica gel, chemically modified at the
surface by the extra-dense bonding of octadecylsilyl groups.
To minimise any interaction with basic compounds it is
carefully end-capped to cover most of the remaining silanol
groups. The particle size is indicated after the name of the
reagent in the tests where it is used.
Fine, white or almost white, homogenous powder, practically
insoluble in water and in ethanol (96 per cent).
Sulfuric add. 1086800.
Sulfuric acid 5 M. 1086809.
Dilute 28 mL of sulfuric acid R to 100 mL with water R.
1,2,4-Trimethylbenzene. C 9H 12 . (M, 120.2). 1188600.
[95-63-6]. Pseudocumene.
07/2014:40103
4.1.3. BUFFER SOLUTIONS
Phosphate buffer solution pH 3.25. 4014900.
Dissolve about 1.36 g of potassium dihydrogen phosphate R in
1000 mL of water R and adjust to pH 3.25 ± 0.05 with dilute
phosphoric acid R. Filter through a membrane filter (nominal
pore size 0.45 11m or finer).
3 M Tris-hydrochloride buffer solution pH 8.8. 4015000.
Dissolve 363.3 g of tris(hydroxymethyl)aminomethane R in
500 mL of water R. Adjust the pH with hydrochloric acid R
and dilute to 1 L with water R.
3937
 EUROPEAN PHARMACOPOEIA 8.2

3938 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

5.22. ames of herbal drugs used in

traditional Chinese medicine
5.22. Names of herbal drugs used in traditional Chinese
medicine ................................................................................ 3941

General Notices (1) apply to all monographs and other texts 3939
 EUROPEAN PHARMACOPOEIA 8.2

3940 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 5.22. Names of herbal drugs used in traditional Chinese medicine
------~.-------------------------------------------------------------------------------------------------------------

0712014:52200 For transparency, this chapter provides cross-references to the

Chinese names in pinyin and in sinograms for herbaI drugs
5.22. NAMES OF HERBAL DRUGS used in traditional Chinese medicine for which a mOl1ograph
is published in the Ph. Eur.
USED IN TRADITIONAL CHINESE
However, the titIes in English, French and Latin are the only
MEDICINE official names; the samples of herbal drugs must be labelled
This chapter is published for information. with at least one official title.
Mouograph Latín title Euglish title Pinyiu Siuogram
Ilumber
2432 Acanthopanacis gracilistyli cortex Acanthopanax bark wujiapi 3J. 1m.$.
2554 Amomi fructus Amomum fruit sharen li'y1=
2555 Amomi fructus rotundus Round amomum tJ:uit doukou ~~

2556 Angelicae dahuricae radix Angelica dahurica root baizhi Él]!:

2557 Angelicae pubescentis radix Angelica pubescens root duhuo 3g¡ )¡5
2558 Angelicae sinensis radix Angelica sinensis roo! danggui ~Y3

2435 Astragali mongholici radix Astragalus mongholicus root huangqi jitBS

2559 Atractylodis lanceae rhizoma Atractylodes lancea rhizome cangzhu e#
2560 Atractylodis macrocephalae rhizoma Atractylodes rhizome, largehead baizhu Él#
2561 Belamcandae chinensis rhizoma Belamcanda chinensis rhizome shegan ~j+

2384 Bistortae rhizoma Bistort rhizome quanshen ~~

2386 Carthami t10s Satllower t10wer honghua un
2430 Citri reticulatae epicarpium et mesocarpium Mandarin epicarp and mesocarp chenpi Il*.$.
2463 Clematidis armandii caulis Clematis armandii stem chuanmutong JII:tlm
2454 Coicis semen Coix seed yiyiren ~Y1=
2473 Dioscoreae oppositifoliae rhizoma Dioscorea oppositifolia rhizome shanyao ¡l¡g<j
2563 Drynariae rhizoma Drynaria rhizome gusuibu ~W~~
2564 Ecliptae herba Eclipta herb mohanlian ~~ji

2412 Eucommiae cortex Eucommia bark duzhong fUi'

2451 Ephedrae herba Ephedra herb mahuang Jffjit
2452 Fraxini rhynchophyllae cortex Fraxinus rhynchophylla bark qinpi *.$.
2566 Isalidis radix Isatis root banlangen 1.&llilm
2567 Magnoliae officinalis cortex Magnolia officinalis bark houpo ~;j+

2568 Magnoliae officinalis t10s Magnolia officinalis flower houpohua ~f~n

2383 Notoginseng radix Notoginseng roo! sanqi .=:1:;

2477 Piperis fructus Pepper hujiao ¡I;jj:¡;jJ(

2453 Piperis longi fruc!us Long pepper bibo ~&

2433 Polygoni multit10ri radix Fleeceflower root heshouwu j1iJ§~

2475 Poria Poria fuling *,.,

1*"'"
2439 Prunellae spica Common selfheal fmil -spike xiakucao !'[:f¡I¡:1¡l:

2434 Puerariae lobatae radix Kudzuvine root gegen (yege) ~m (!H~)

2483 Puerariae thomsonii radix Thomson kudzuvine roo! fenge ;j9J~

2663 Salviae miltiorrhizae radix el rhizoma Salvia miltiorrhiza rool and rhizome danshen fJ-~

2385 Sanguisorbae radix Sanguisorba root diyu ±t!J 1;jtr

2428 Schisandrae chinensis fructus Schisandra fruit wuweizi 3J.~*T
(bei wuweizi) (:lC3J.Il;i¡T)
2438 Seu!ellariae baicalensis radix Baical slculleap root huangqin jit~

2450 Sinomenii caulis Orientvine stem qingfengteng ~JXl.~

2639 Sophorae japonieae flos Sophora t10wer huaihua fllln
2427 Sophorae japonicae flos immaturus Sophora t1ower-bud huaimi
flll*
2478 Stephaniae tetrandrae radix Fourstamen stephania root fenfangji mJJe.
(hanfangji) (5)1JJJ e.)

General Notices (1) apply to all monographs and other texts 3941
 EUROPEAN PHARMACOPOEIA 8.2

3942 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2

General monographs
Allergen products .. ................................................................. 3945

General Natices (1) apply ta all managraphs and ather texts 3943
 EUROPEAN PHARMACOPOEIA 8.2

3944 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2 AUel"gen products
~-------------------------------------------------------------------------------------------------

07/2014:1063 by a microscopic particle count. Detectable mouId spores

must not exceed 1 per cent. The contamination with particles
of plant origin other than pollen must be kept to a minimum.
ALLERGEN PRODUCTS The maximum allowed contamination must be justified.
Moulds. Biologically active contaminants such as mycotoxins
Producta allergenica in moulds must be minimised and any presence justified.
Appropriate measures have to be implemented to avoid
This monograph does not apply to: chemicals that are used contamination by foreign mould strains. Care must be taken
solely for diagnosis of contact dermatitis; chemically synthesised to minimise any allergenic constituents of the media used for
products; allergens derived by recombinant DNA technology. the cultivation of moulds as source materials. Culture media
It do es not necessarily apply to allergen products for veterinary that contain substances of human or animal origin must be
use. justified and, when required, must be suitably treated to ensure
the inactivation or elimination of possible transmissible agents
DEFINITION of disease.
Allergen products are pharmaceutical preparations derived The production method is validated to demonstrate that
from extracts of naturally occurring source materials allergen products obtained from moulds and intended for
containing allergens, which are substances that lead to and/or parenteral administration, if tested, would comply with the
provoke allergic reactions. The allergenic components are test for abnormal toxicity for immunosera and vaccines for
most often of a proteinaceous nature. Allergen products are human use (2.6.9).
intended for in vivo diagnosis or treatment of allergic diseases
Miles. Appropriate measures have to be implemented to avoid
attributed to these allergens.
contamination by foreign mite strains. Care must be taken to
Allergen products are available as finished products, and as minimise any allergenic constituents of the media used for
finished products used on a named-patient basis. Allergen the cultivation of mites as source materials. Culture media
products are generally presented as parenteral preparations, that contain substances of human or animal origin must be
eye preparations, preparations for inhalation, preparations for justified and, when required, must be suitably treated to ensure
oral use, sublingual preparations or preparations for skin tests. the inactivation or elimination of possible transmissible agents
For in vivo diagnostic use, allergen products are usually of disease.
prepared as unmodified extracts in a 50 per cent V/V solution Animal epithelia and outgrowths and/or dander. They
of glycerol for skin testing. For intradermal diagnosis or for are obtained from healthy animals selected to avoid possible
provocation tests by nasal, ocular or bronchial administration, transmissible agents of disease.
suitable dilutions of allergen products may be prepared
by dilution of aqueous or glycerinated extracts, or by Hymenoptera venoms. The species of hymenoptera from
which the venom is extracted is identified and specified.
reconstitution of unmodified freeze-dried extracts.
The methods of insect collection and venom extraction are
For specific immunotherapy, allergen products may be either described and must ensure that the source material is of
unmodined extracts or extracts modined chemically and/or proper quality.
by adsorption onto different carriers (for exampIe, aluminium
hydroxide, calcium phosphate or tyrosine). Food. The scientific name (species, variety, strain etc.) of the
animal or vegetable species is indicated and the part used is
stated, if applicable. Foods must be of a quality suitable for
PRODUCTION
human consumption. The origin of the food stuff as well as
SO URCE MATERIALS its processing stage is stated.
Source materials for the preparation of allergen products MANUFACTURING PROCESS
are products of animal or vegetable origin, mostly pollens,
Allergen products are generally obtained by extraction, and
moulds, mites, animal epithelia and outgrowths (such as hair
may be purified, from the source materials using appropriate
and feathers) and/or dander, hymenoptera venoms, insects
methods shown to preserve the allergenic properties of
and certain foods.
the components. Allergens for which there are not enough
Where allergen products are manufactured using materials of patients to determine the total allergenic activity in vivo
human or animal origin, the requirements of chapter 5.1.7. or in vitro, the extraction ratio indicating the relative
Viral safety apply. proportions (m/V) of allergenic source materials and solvents
The source materials are defined by their origin, nature, is a minimum requirement. Allergen products presented as
method of collection or production and pretreatment. Control parenteral preparations, eye preparations, preparations for
methods and acceptance criteria relating to identity and purity inhalation and preparations for skin testing are manufactured
are established. The acceptance criteria must ensure the under aseptic conditions.
consistency of the allergenic source material from a qualitative In the manufacture, packaging, storage and distribution of
and quantitative point of view. The source materials are sto red allergen products intended for administration by other routes,
under controlled conditions justified by stability data. suitable measures are taken to ensure their microbial quality;
The collection or production, as well as the handling of the recommendations on this aspect are provided in chapter 5.1.4.
source materials are such that uniform composition is ensured Microbial quality of non-sterile pharmaceutical preparations
as far as possible from batch to batch. and substances for pharmaceutical use.
The content of the relevant residual solvents, heavy metals and Al! allergen preparations are manufactured under conditions
pesticides is determined on a number of batches according designed to minimise exogenous and endogenous enzymatic
to a justified sampling plan. Residual solvents and pesticides degradation.
are limited according to the principIes defined in general
chapter 2.4.24. Identification and control of residual solvents Any purification procedure is designed to minimise the
and 2.8.13. Pesticide residues respectively. content of any potential irritant low molecular mass
components and non-allergenic components.
Pollens. Potential chemical contaminants, such as pesticides,
heavy metal s and solvents, must be minimised. The content Allergen products may contain suitable antimicrobial
of foreign pollen must be limited to 1 per cent of total mixed preservatives, the nature and concentration of which have to
pollens and 0.5 per cent of any individual pollen as determined be justified.

General Notices (1) apply to all monographs and other texts 3945
AHergen products
The manufacturing process comprises various stages:
- source material;
- active substance: it is gene rally a modified or an unmodified
allergen extract; where applicable it is sto red under
conditions ensuring its stability, for example freeze-dried;
- finished product.
All other stages of the manufacturing process are considered
as intermediates.
IN-HOUSE REFERENCE PREPARATION
An appropriate representative preparation is selected as
the in-house reference preparation (IHRP), characterised
and used to verify batch-to-batch consistency. The IHRP is
stored in suitably sized aliquots under conditions ensuring its
stability, for example freeze-dried.
Characterisation of the in-house reference preparation.
The extent of characterisation of the IHRP depends on the
source material, knowledge of the allergenic components and
availability of suitable reagents, as well as the in tended use. The
characterised IHRP is used as the reference in the batch control
of active substances and intermediates and, if possible, in the
batch control offinished products.
The IHRP is characterised by the protein content
determination and a protein profile using appropriate
methods (such as isoelectric focusing, sodium dodecyl sulfate
polyacrylamide gel electrophoresis, immunoelectrophoresis,
capillary electrophoresis, chromatographic techniques and
mass spectrometry).
Allergenic components may be detected by appropriate
methods (for example, immunoblotting or crossed
radio-immunoelectrophoresis). Characterisation oí the
allergenic components may indude identificatiol1 of relevant
allergens based 011 serological or other techniques using pooled
or individual sera from allergic patients, or allergen-specif1c
polyclonal or monoclonal antibodies.
Determination of the content of relevant allergens is performed relevant allergen components is verified, where possible. The
wherever possible. This determination may be made using
individual allergen-speciflc reference standards, when
available. The choice of the relevant allergen components
subjected to the determination must be justified. Individual
allergens are identified and named according to internationally but in any case for allergen producís in tended for therapeutic
established nomenclature wherever possible.
The biological potency of the first IHRP is determined in
patients by in vivo techniques such as skin testing, and
expressed in units of biological activity except when not
enough patients are availab1e. In this case, the potency
of the first IHRP is determined by an in vitro method.
SubsequentIy, the biologica1 activity of future IHRPs is
demonstrated by in vitro methods by comparison with the
results obtained with the first IHRP. The in vitro potency may amount when calcium phosphate is used as adsorbent.
be measured by a suitable immunoassay (for example, an assay
based on the inhibition oí the binding capacity of specif1c
immunoglobulin E antibodies).
IDENTIFICATION
The tests for identification are performed as late as possible in the stated amount as assayed by inhibition of the binding
the manufacturing process. In the case of products used on
a named-patient basis, the control is performed on the active
substance and/or at the intermediate stage between the active Individual allergens: 50 per cent to 200 per cent of the stated
substance and the finished product.
Identity is confirmed by comparison with the IHRP using
protein profiling by appropriate methods (for example,
isoelectric focusing, sodium dodecyl sulfate polyacrylamide
gel electrophoresis, immunoelectrophoresis, immunoblotting, Adsorbed aJIergen products are not to be frozen, unless
liquid chromatography or mass spectrometry).
In exceptional cases, if no IHRP is available, a represelltative
batch may be used to confirm identity.
Identity may a1so be confirmed by comparison with individual The label states:
allergen-specific reference standards, when available.
3946
EUROPEAN PHARMACOPOEIA 8.2
TESTS
The tests are performed as late as possible in the manufacturing
process. In the case of products used on a named-patient
basis, the control is performed on the active substance and/or
at the intermediate stage between the active substance and the
finished product.
Various biochemical and immunological tests have been
developed in order to characterise allergens qualitatively and
quantitativelyo In those cases where such methods cannot
be applied, particularly for the determination of allergenic
activity and allergen and/or protein profile, justification must
be provided.
Water (2.5.12 or 2.5.32): maximum 5 per cent for freeze-dried
products.
In the case of orallyophilisates, the water content may be
higher than 5 per cent, where justified and authorised.
Sterility (2.6.1). Allergen products presented as parenteral
preparations, eye preparations, preparatiol1s for inhalation or
preparations fo1' skin testing comply with the test for sterility.
Microbial contamination. For non-sterile allergen products,
recommendations are provided in 5.1.4. Microbial quality of
non-sterile pharmaceutical preparations and substances for
pharmaceutical use.
Protein (ouient (2.5.33): 80 per cent to 120 per cent of the
stated content, unless otherwise justified and authorised. If
the biological potency can be determined then the test for
protein content is performed as a batch-to-batch consistency
test and the protein content is within 50 per cent to 150 per
cent of the stated content. When the finished product
contains proteinaceous excipients, the test for protein content
is performed as late as possible during production before
addition of the proteinaceous excipient.
Pmtein profile. The protein profile determined by suitab1e
methods corresponds to that of the IHRP. The presence of
choice of relevant allergen components to be tested for must
be justified.
Various additional tests, sorne with increasing selectivity,
depending on the allergen product concerned can be applied,
use, a validated test measuring the potency (total allergenic
activity, determinalion of individual allergens or any other
justified tests) must be applied.
Aluminium (2.5.13): 80 per cent to 120 per cent of the stated
amount but in any case not more than 1.25 mg per human dose
unless otherwise justified and authorised, when aluminium
hydroxide or aluminium phosphate is used as adsorbent.
Calcium (2.5.14) : 80 per cent to 120 per cent of the stated
Allergen profiJe. Relevant allergenic components
are identified by means of suitable techniques using
allergen-specific human or animal antibodies.
Total aUergenic activity: 50 per cent to 150 per cent of
capacity of specific immunoglobulin E antibodies or a suitable
equivalent in vitro method.
amount of each relevant allergen component, determined by a
suitable method.
STORAGE
otherwise justified and authorised.
LABELLING
- the name of the allergen product;
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
the biological potency and/or the protein content and/or
the extraction concentration;
_ the route of administration and the intended use;
_ the storage conditions;
_ where applicable, the name and amount of added
antimicrobial preservative;
where applicable, for freeze-dried preparations:
General Natices (1) apply fa all managraphs and ather texts
Allergen producís
- the name, composition and volume of the reconstituting
liquid to be added;
the period of time within which the preparation is to be
used after reconstitution;
- where applicable, that the preparation is sterile;
- where applicable, the name and amount of adsorbent.
3947
 EUROPEAN PHARMACOPOEIA 8.2

3948 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

Vaccines for human use

Diphtheria, tetanus and pertussis (acellular, component) Rabies vaccine for human use prepared in ceH cultures .... 3952
vaccine (adsorbed, reduced antigen(s) content) ............... 3951

General Natices (1) apply ta all managraphs and ather texts 3949
 EUROPEAN PHARMACOPOEIA 8.2

3950 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
0712014:2764
DIPHTHERIA, TETANUS AND
PERTUSSIS (ACELLULAR,
COMPONENT) VACCINE (ADSORBED,
REDUCED ANTIGEN(S) CONTENT)
Vaccinum diphtheriae, tetani et pertussis
sine cellulis ex elementis praeparatum,
antigeni-o( -is) minutum, adsorbatum
DEFINITION
Diphtheria, tetanus and pertussis (acellular, component)
vaccine (adsorbed, reduced antigen(s) content) is a combined
vaccine containing: diphtheria formol toxoid; tetanus
formol toxoid; individually purified antigenic components of
Bordetella pertussis; a mineral adsorbent such as aluminium
hydroxide or hydrated aluminium phosphate.
The formol toxoids are prepared from the toxins produced by
the growth of Corynebacterium diphtheriae and Clostridium
tetani respectively.
The amount of diphtheria toxoid per single human dose is
reduced compared to vaccines generally used for primary
vaccination; the amounts oí tetanus toxoid and pertussis
components may also be reduced.
The vaccine contains either pertussis toxoid or a
pertussis-toxin-like protein free from toxic properties,
produced by expression of a genetically modified form of
the corresponding gene. Pertussis toxoid is prepared from
pertussis toxin by a method that renders the toxin harmless
while maintaining adequate immunogenic properties
and avoiding reversion to toxin. The vaccine may also
contain filamentous haemagglutinin, pertactin (a 69 kDa
outer-membrane protein) and other defined components
of B. pertussis such as fimbrial-2 and fimbrial-3 antigens.
The latter 2 antigens may be co-purified. The antigenic
composition and characteristics are based on evidence of
protection and freedom from unexpected reactions in the
target group for which the vaccine is intended.
PRODUCTION
GENERAL PROVISIONS
The production method shall have been shown to yield
consistently vaccines comparable with the vaccine of proven
clinical efficacy and safety in mano
Reference vaccine(s). Provided valid assays can be performed,
monocomponent reference vaccines may be used for the
assays on the combined vaccine. If this is not possible because
of interaction between the components of the combined
vaccine or because of differences in composition between
the monocomponent reference vaccine and the test vaccine,
a batch of combined vaccine shown to be effective in clinical
trials or a batch representative thereof is used as a reference
vaccine. For the preparation of a representative batch, strict
adherence to the production process used for the batch tested
in clinical trials is necessary. The reference vaccine may be
stabilised by a method that has been shown to have no effect
on the assay procedure.
Spedfic toxicity of the diphtheria and tetanus components.
The production method is validated to demonstrate that
the product, if tested, would comply with the following test:
inject subcutaneously 5 times the single human dos e stated on
the label into each of 5 healthy guinea-pigs, each weighing
250-350 g, that have not previously been treated with any
material that will interfere with the test. lf within 42 days of
the injection any of the animals shows signs of or dies from
diphtheria toxaemia or tetanus, the vaccine does not comply
General Notices (1) apply to all monographs and other texts
DIP-TET-PERa' reduced antigen(s) content
with the test. If more than 1 animal die s from non-specific
causes, repeat the test once; if more than 1 animal dies in the
second test, the vaccine does not comply with the test.
The content ofbacterial endotoxins (2.6.14) in bulk
purified pertussis components is determined to monitor
the purification procedure and to limit the amount in the
final vaccine. For each component, the content of bacterial
endotoxins is less than the limit approved for the particular
vaccine and, in any case, the contents are such that the final
vaccine contains less than 100 IU per single human dose.
PRODUCTION OF THE COMPONENTS
The production of the components complies with the
requirements of the monographs Diphtheria vaccine
(adsorbed) (0443), Tetanus vaccine (adsorbed) (0452) and
Pertussis vaccine (acellular, component, adsorbed) (1356).
FINAL BULK VACCINE
The final bulk vaccine is prepared by adsorption onto a
mineral carrier such as aluminium hydroxide or hydrated
aluminium phosphate, separately or together, of suitable
quantities ofbulk purified diphtheria toxoid, tetanus toxoid
and acellular pertussis components. Suitable antimicrobial
preservatives may be added.
Only a final bulk vaccine that complies with the following
requirements may be used in the preparation of the finallot.
Antimicrobial preservative. Where applicable, determine the
amount of antimicrobial preservative by a suitable chemical
method. The amount is not less than 85 per cent and not
greater than 115 per cent of the intended contento
SterHity (2.6.1). Carry out the test using 10 mL for each
medium.
FINALLOT
The final bulk vaccine is distributed aseptically into sterile,
tamper-proof containers. The containers are closed so as to
prevent contamination.
Only a finallot that is satisfactory with respect to the test for
osmolality and with respect to each of the requirements given
below under Identification, Tests and Assay may be released
for use.
Provided the test for residual pertussis toxin and irreversibility
of pertussis toxoid, the test for antimicrobial preservative
and the assays for the diphtheria, tetanus and pertussis
components have been carried out with satisfactory results on
the final bulk vaccine, they may be omitted on the finallot.
Provided the free formaldehyde content has been determined
on the bulk purified antigens or on the final bulk and it has
been shown that the content in the finallot will not exceed
0.2 giL, the test for free formaldehyde may be omitted on the
finallot.
Where there is a significant change in the manufacturing
process of the antigens or their formulation, any impact on
the in vivo and in vitro assays must be evaluated, and the need
for revalidation considered.
Osmolality (2.2.35). The osmolality of the vaccine is within
the limits approved for the particular preparation.
IDENTIFICATION
A. Diphtheria toxoid is identified by a suitable
immunochemical method (2.7.1). The following
method, applicable to certain vaccines, is given as an
example. Dissolve in the vaccine to be examined sufficient
sodium citrate R to give a 100 giL solution. Maintain
at 37 oC for about 16 h and centrifuge until a clear
supernatant is obtained. The clear supernatant reacts with
a suitable diphtheria antitoxin, giving a precipitate. If a
satisfactory result is not obtained with a vaccine adsorbed
on aluminium hydroxide, carry out the test as follows.
Centrifuge 15 mL of the vaccine to be examined and
suspend the residue in 5 mL of a freshly prepared mixture
of 1 volume of a 56 giL solution of sodium edetate R and
49 volumes of disodium hydrogen phosphate solution R.
3951
Rabies vaccine for human use prepared in ceH cultures
Maintain at 37 oC for not les s than 6 h and centrifuge.
The cIear supernatant reacts with a suitable diphtheria
antitoxin, giving a precipitate.
B. Tetanus toxoid is identified by a suitable immunochemical
method (2.7.1). The following method, applicable to certain
vaccines, is given as an example. The clear supernatant
obtained as described in identification test A reacts with a
suitable tetanus antitoxin, giving a precipitate.
C. The pertussis components are identified by a suitable
immunochemical method (2.7.1). The following method,
applicable to certain vaccines, is given as an example. The
cIear supernatant obtained as described in identification
test A reacts with specific antisera to the pertussis
components of the vaccine.
TESTS
Residual pertussis toxin and irreversibility of pertussis
toxoid (2.6.33). It complies with the test.
Aluminium (2.5.13): maximum 1.25 mg per single human
dose, if aluminium hydroxide or hydrated aluminium
phosphate is used as the adsorbent.
Free formaldehyde (2.4.18): maximum 0.2 giL.
Antimicrobial preservative. Where applicable, determine the
amount of antimicrobial preservative by a suitable chemical
method. The content is not les s than the minimum amount
shown to be effective and is not greater than 115 per cent of
the quantity stated on the label.
Sterility (2.6.1). It complies with the test.
ASSAY
Diphtheria component. Carry out one of the prescribed
methods for the assay of diphtheria vaccine (adsorbed) (2.7.6).
The lower confidence limit (P = 0.95) of the estimated potency
is not les s than 2 IV per single human dose.
Tetanus component. Carry out one of the prescribed methods
for the assay of tetanus vaccine (adsorbed) (2.7.8).
The lower confidence limit (P = 0.95) of the estimated potency
is not less than 20 IV per single human dose.
Pertussis component. Carry out one of the prescribed
methods for the assay of pertussis vaccine (acellular) (2.7.16).
The capacity of the vaccine to induce antibodies for each
incIuded acellular pertussis antigen is not significantly
(P = 0.95) less than that of the reference vaccine.
LABELLING
The label states:
- the minimum number ofInternational Vnits of diphtheria
and tetanus toxoid per single human dose;
- the names and amounts of the pertussis components per
single human dose;
- where applicable, that the vaccine contains a pertussis
toxin-like protein produced by genetic modification;
- the name and the amount ofthe adsorbent;
- that the vaccine must be shaken before use;
- that the vaccine is not to be frozen.
3952
EVROPEAN PHARMACOPOElA 8.2
07/2014:0216
RABIES VACCINE FOR HUMAN USE
PREPARED IN CELL CULTURES
Vaccinum rabiei ex cellulis
ad usum humanum
DEFINITION
Rabies vaccine for human use prepared in cell cultures is a
freeze-dried preparation of a suitable strain of fixed rabies
virus grown in cell cultures and inactivated by a validated
method.
The vaccine is reconstituted immediately before use as stated
on the label to give a cIear or opalescent liquid that may be
coloured owing to the presence of a pH indicator.
PRODVCTION
GENERAL PROVISIONS
The production of the vaccine is based on a virus seed-lot
system and, if a cellline is used for virus propagation, a
cell-bank system. The production method shall have been
shown to yield consistently vaccines that comply with the
requirements for immunogenicity, safety and stability. Vnless
otherwise justified and authorised, the virus in the final
vaccine must not have undergone more passages from the
master seed lot than were used to prepare the vaccine shown
in cIinical studies to be satisfactory with respect to safety
and efficacy; even with authorised exceptions, the number of
passages beyond the level used for clinical studies must not
exceed 5.
The production method is validated to demonstrate that the
product, if tested, would comply with the test for abnormal
toxicity for immunosera and vaccines for human use (2.6.9).
SUBSTRATE POR VIRUS PROPAGATION
The virus is propagated in a human diploid cellline, or in
a continuous cellline (5.2.3) approved by the competent
authority, or in cultures of chick-embryo cells derived from a
flock free from specified pathogens (5.2.2).
SEEDLOTS
The strain of rabies virus used shall be identified by historical
records that include information on the origin of the strain
and its subsequent manipulation.
Working seed lots are prepared by not more than 5 passages
from the master seed lot.
Only a working seed lot that complies with the following tests
may be used for virus propagation.
Identification. Each working seed lot is identified as rabies
virus using specific antibodies.
Virus concentration. The virus concentration of each
working seed lot is determined by a cell-culture method using
immunofluorescence, to ensure consistency of production.
Extraneous agents (2.6.16). The working seed lot complies
with the requirements for virus seed lots. If the virus has been
passaged in mouse brain, specific tests for murine viruses are
carried out.
VIRUS PROPAGATION AND HARVEST
All processing of the cell bank and subsequent cell cultures is
done under aseptic conditions in an area where no other cells
are handled. Approved animal (but not human) serum may be
used in the media, but the final medium for maintaining cell
growth during virus multiplication do es not contain animal
serum; the media may contain human albumino Serum and
trypsin used in the preparation of cell suspensions and media
are shown to be free from extraneous agents. The cell culture
media may contain a pH indicator such as phenol red and
approved antibiotics at the lowest effective concentration. Not
less than 500 mL of the cell cultures employed for vaccine
See the information section on general monographs (cover pages)
EVROPEAN PHARMACOPOEIA 8.2
production are set aside as uninfected ceH cultures (control
celis). The virus suspension is harvested on one or more
occasions during incubation. Successive harvests from the
same production ceH culture may be pooled and cOl1sidered as
a single harvest.
Only a single harvest that complies with the following
requirements may be used in the preparation of the inactivated
viral harvest.
Identification. The single harvest contains virus that is
identified as rabies virus using specific antibodies.
Virus concentration. Titrate for infective virus in ceH
cultures; the titre is used to monitor consistency of production.
Control censo The control cells of the production cell culture
from which the single harvest is derived comply with a test
for identification and with the requirements for extraneous
agents (2.6.16).
PURIFICATION AND INACTIVATION
The virus harvest may be concentrated and/or purified by
suitable methods; the virus harvest is inactivated by a validated
method at a fixed, well-defined stage of the process, which may FINALLOT
be before, during or after any concentration or purification.
In order to ensure that the virus inactivation process is
effective, conditions that could lead to virus aggregation
should be avoided at process steps preceding virus inactivation. then closed so as to avoid contamination and the introduction
aggregates present in the preparation to be inactivated
must be removed immediately before the inactivation process, Only a finallot that complies with each of the requirements
for example by a suitable filtration method. It shall have
been demonstrated in process validation studies that the
inactivation process is consistently effective in inactivating
rabies virus in such a way that it assures consistent protective final bulk vaccine, it may be omitted on the finallot.
immunogenic activity.
The demonstration of consistency must be based on the
following:
- the inactivation kinetics are shown to be consistent using at antibodies, preferably monoclonal; alternatively, the assay
least 5 consecutive batches. Samples of virus, collected at
appropriate times, are inoculated into a sensitive substrate
to establish the inactivation curve. lf necessary, the agent
used for inactivation is neutralised prior to inoculation;
- the time needed to achieve complete inactivation is
determined in order to define the required inactivation
time. The test for residual infectious virus is used for
this purpose. The total inactivation time used in routine
production must be at least twice the time needed for
complete virus inactivation.
lf betapropiolactone is used, the concentration shall at no
time exceed 1:3500 V/V.
Only an inactivated viral suspension that complies with the
following requirements may be used in the preparation of the
final bulk vaccine.
Residual infectiol.l.s virus. Carry out an amplification test for
residual infectious rabies virus immediately after inactivation Pyrogens (2.6.8). The test for pyrogens is performed only in
or using a sample frozen immediately after inactivation and
stored at - 70 oc. Inoculate a quantity of inactivated viral
suspension equivalent to not less than 25 mi of bulk vaccine
corresponding to at least 25 human doses of vaccine into ceH
cultures of the same type as those used for production of the
vaccine or of another approved cel! type. Cells used for the test
must be of optimal sensitivity regarding residual infectious
rabies virus, for example, Vero, BHK-21 or neuroblastoma
cells that are known to be highly sensitive to rabies virus may the dose necessary to protect mice against the effects of a
be used. If other cells are used, they must have been shown
to possess at least the same sensitivity as those specified. A
passage may be made after 7 days. Maintain the cultures
for a total of 21 days and then examine the cel! cultures for
rabies virus using an immunofluorescence test or another
suitable method of comparable sensitivity. The inactivated
virus harvest complies with the test if no replicating infectious Alternatively, in the interest of animal welfare, a validated
rabies virus is detected.
General Notices (1) apply to all monographs and other texts
Rabies vacdne for human use prepared in cen cultures
Residual host-cell DNA. rf a continuous cellline is used for
virus propagation, the content of residual host-cell DNA,
determined using a suitable method, is not greater than lOng
per single human dose.
FINAL BULK VACCINE
The final bulk vaccine is prepared from one or more
inactivated viral suspensions. An approved stabiliser may be
added to maintain the activity of the product during and after
freeze-drying.
Only a final bulk vaccine that complies with the following
requirements may be used in the preparation of the finallot.
Glycoprotein content. Determine the glycoprotein
content by a suitable immunochemical method (2.7.1), for
example, single-radial immunodiffusion, enzyme-linked
immul1osorbent assay or an antibody-binding test. The
content is within the limits approved for the particular
product.
Sterility (2.6.1). The final bulk vaccine complies with the test
for sterility, carried out using 10 mL for each medium.
The final bulk vaccine is distributed aseptically into sterile
containers and freeze-dried to a moisture content shown to be
favourable to the stability of the vaccine. The containers are
of moisture.
given below under Identification, Tests and Assay may be
released for use. Provided that the test for bovine serum
albumin has been carried out with satisfactory results 011 the
IDENTIFICATION
The vaccine is shown to contain rabies virus antigen by a
suitable immunochemical method (2.7.1) using specific
serves also to identify the vaccine.
TESTS
Glycopmtein contento Determine the glycoprotein
content by a suitable immunochemical method (2.7.1), for
example, single-radial immunodiffusion, enzyme-linked
-
immunosorbent assay or an antibody-binding test. The
content is within the limits approved for the particular
product.
Bovine serum albumin: maximum 50 ng per single human
dose, determined by a suitable immunochemical method
(2.7.1).
Sterility (2.6.1). It complies with the test.
Bacteria! endotoxins (2.6.14): less than 25 IV per single
human dose.
cases of evidence of the presence of non -endotoxin pyrogenic
substances. It complies with the test. Unless otherwise justified
and authorised, inject into each rabbit 1 mL of a single human
dose of the vaccine diluted to 10-100 times its volume.
Water (2.5.12): maximum 3.0 per cent.
ASSAY
The potency of rabies vaccine is determined by comparing
lethal dose of rabies virus, administered intracerebrally, with
the quantity of a reference preparation of rabies vaccine
necessary to provide the same protection. For this comparison
a reference preparation of rabies vaccine, calibrated in
International Units, and a suitable preparation of rabies
virus for use as the challenge preparation are necessary.
serology potency assay or an immunochemical assay (2.7.1)
3953
Rabies vacdne for human use prepared in cen cultures
for a native glycoprotein content is recommended. The
alternative method is validated against a challenge assay and
approved for a given product by the competent authority.
The International Unit is the activity contained in a stated
quantity of the International Standard. The equivalence in
International Units of the International Standard is stated by
the World Health Organization.
The challenge test described below uses a parallel-line model
with at least 3 points for the vaccine to be examined and
the reference preparation. Once the analyst has experience
with the method for a given vaccine, it is possible to carry
out a simplified test using a single dilution of the vaccine
to be examined and of the reference preparation. Such a
test enables the analyst to determine that the vaccine has a
potency significantly higher than the required minimum,
but does not give full information on the validity of each
individual potency determination. The use of a single
dilution allows a considerable reduction in the number of
animals required for the test and must be considered by each
laboratory in accordance with the provisions of the European
Convention for the Protection of Vertebrate Animals Used for
Experimental and Other Scientific Purposes.
Selection and distribution of the test animals. Use healthy
female mice, about 4 weeks old, each weighing 11-15 g, and
from the same stock. Distribute the mice into 6 groups of a
size suitable to meet the requirements for validity of the test
and, for titration of the challenge suspension, 4 groups of 5.
Preparation of the challenge suspension. Inoculate mice
intracerebrally with the Challenge Virus Standard (CVS) strain
of rabies virus and when the mice show signs of rabies, but
before they die, euthanise them, then remove the brains and
prepare a homogenate of the brain tissue in a suitable diluent.
Separate gross particulate matter by centrifugation and use
the supernatant as the challenge suspension. Distribute the
suspension in small volumes in ampoules, seal and sto re at a
temperature below - 60 oc. Thaw 1 ampoule of the suspension
and make serial dilutions in a suitable diluent. Allocate each
dilution to a group of 5 mice and inject intracerebrally into
each mouse 0.03 mi of the dilution allocated to its group.
Observe the mice for 14 days. Calculate the iDso ofthe
undiluted suspension using the number in each group that,
between the 5th and 14th days, die or develop signs ofrabies.
Determination of potency of the vaccine. Prepare 3 fivefold
serial dilutions of the vaccine to be examined and 3 fivefold
serial dilutions of the reference preparation. Prepare the
dilutions such that the most concentrated suspensions may
be expected to protect more than 50 per cent of the animals
to which they are administered and the least concentrated
suspensions may be expected to protect less than 50 per cent
of the animal s to which they are administered. Allocate the
6 dilutions, 1 to each of the 6 groups of mice, and inject
by the intraperitoneal route into each mouse 0.5 mi of the
dilution allocated to its group. After 7 days, prepare 3 identical
dilutions of the vaccine to be examined and of the reference
preparation and repeat the injections. Seven days after the
second injection, prepare a suspension of the challenge
virus such that, on the basis of the preliminary titration,
0.03 mL contains about 50 LDso. lnject intracerebrally into
each vaccinated mouse 0.03 mL of this suspension. Prepare
3 suitable serial dilutions of the challenge suspension. Allocate
the challenge suspension and the 3 dilutions, 1 to each of the
4 groups of 5 control mice, and inject intracerebrally into each
mouse 0.03 mL of the suspension or dilution allocated to its
group. Observe the animals in each group for 14 days and
record the number in each group that die or show signs of
rabies in the period 5-14 days after challenge.
3954
EUROPEAN PHARMACOPOEIA 8.2
The test is not valid unless:
- for both the vaccine to be examined and the reference
preparation the 50 per cent protective dose lies between the
largest and smallest doses given to the mice;
- the titration of the challenge suspension shows that 0.03 mL
of the suspension contained not less than 10 LDso;
- the statistical analysis shows a significant slope and no
significant deviations fram linearity or parallelism of the
dose- response curves;
- the confidence limits (P = 0.95) are not less than 25 per cent
and not more than 400 per cent of the estimated potency.
The vaccine complies with the test if the estimated potency is
not less than 2.5 IU per human dose.
Application of alternative end-points. Once a laboratory
has established the aboye assay for routine use, the lethal
end-point is replaced by an observation of clinical signs and
application of an end-point earlier than death to reduce
animal suffering. The following is given as an example.
The progress of rabies infection in mice following intracerebral
injection can be represented by 5 stages defined by typical
clinical signs:
Stage 1: ruffled fur, hunched back;
Stage 2: slow movements, loss of alertness (circular movements
may also occur);
Stage 3: shaky movements, trembling, convulsions;
Stage 4: signs of paresis or paralysis;
Stage 5: moribund state.
Mice are observed at least twice daily from day 4 after
challenge. Clinical signs are recorded using a chart such as
that shown in Table 0216.-1. Experience has shown that using
stage 3 as an end-point yields assay results equivalent to those
found when a lethal end-point is used. This must be verified
by each laboratory by scoring a suitable number of assays
using both the clinical signs and the lethal end-point.
Table 0216.-1. - Example of a chart used to record clinical signs
in the rabies vaccine potency test
Days after challenge
CHnleal signs 4 5 6 7 8 9 10 11
Ruffled fur
Hunched back
Slow movements
Los5 of alertness
Circular movements
Shaky movements
Trembling
Convlllsions
Paresis
Paralysis
Moribllnd 5tate
LABELLING
The label states the biological origin of the cells used for the
preparation of the vaccine.
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2

Radiopharmaceutical preparations
and starting materials for
radiopharmaceutical preparations
Fludeoxyglucose (lsP) injection ............................................ 3957

General Notices (1) apply to all monographs and other texts 3955
 EUROPEAN PHARMACOPOEIA 8.2

3956 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOElA 8.2
01/2014:1325
corrected 8.2
FLUDEOXYGLUCOSE (lSF) INJECTION
Fludeoxyglucosi (lSP) solutio iniectabilis
HO~O,
0'"
HN:{ 18F
M, 181.1
DEFINITION
Sterile solution containing 2-[ 18 F]fluoro-2-deoxy-
D-glucopyranose (2- [18P]fluoro-2-deoxy-D-glucose)
prepared by nucleophilic substitution. It may also contain
2- [18 P] fluoro- 2-deoxy-D-mannose.
Content:
- fluorine-18: 90 per cent to 110 per cent of the declared
fluorine-18 radioactivity at the date and time stated on
the labe!'
- 2-fluoro-2-deoxy-D-glucose: maximum 0.5 mg per
maximum recommended dose in millilitres.
CHARACTERS
Appearance: clear, colourless or slightly yellow solution.
Half-life and nature of radiation offluorine-18: see general
chapter 5.7. Table of physical characteristics of radionuclides.
IDENTIPICATION
A. Gamma-ray spectrometry.
Result: the principal gamma photons have an energy of
0.511 MeV and, depending on the measurement geometry,
a sum peak of 1.022 MeV may be observed.
B. Determine the approximate half-life by no fewer than
3 measurements of the activity of a sample in the same
geometrical conditions within a suitable period of time (for
example, 30 min).
Result: 105 min to 115 mino
e. Examine the chromatograms obtained in test A for
radiochemical purity (see Tests).
Result: the principal peak in the radiochromatogram
obtained with the test solution is similar in retention time
to the principal peak in the chromatogram obtained with
reference solution (a).
TESTS
Particular tests for ehemieal impurities may be omitted if the
substances mentioned are not used or eannot be formed in the
produetion proeess.
pH (2.2.3): 4.5 to 8.5.
2-Fluoro-2-deoxy-D-glucose amI impurity A. Liquid
chromatography (2.2.29).
Test solution. The preparation to be examined.
Referenee solution (a). Dissolve 1.0 mg of 2-fluoro-2-deoxy-
D-glueose R in water R and dilute to 2.0 mL with the same
solvent. Dilute 1.0 mL of the solution to V with water R, V
being the maximum recommended dose in millilitres.
Referenee solution (b). Dissolve 1.0 mg of 2-ehloro-2-deoxy-D-
glueose R (impurity A) in water R and dilute to 2.0 mL with the
same solvent. Dilute 1.0 mL of the solution to V with water R,
V being the maximum recommended dose in millilitres.
Reference solution (e). Dissolve 1.0 mg of 2-fluoro-2-deoxy-D-
mannose R in water R and dilute to 20.0 mL with the same
solvent. Mix 0.5 mL of this solution with 0.5 mL of reference
solution (a).
General Notíees (1) apply to all monographs and other texts
Fludeoxyglucose (lsF) injection
Column:
- size: l = 0.25 m, (7) = 4.0 mm;
- stationary phase: strongly basic anion-exchange resin for
eh ro m atography R (lO f!m);
- tempera tu re: 25 0e.
Mobile phase: 4 giL solution of sodium hydroxide R in earbon
dioxide-free water R, protected from the atmosphere during
chromatography.
Flow rate: 1 mL/min.
Deteetion: detector suitable for carbohydrates in the required
concentration range, su eh as a pulsed amperometric detector
and radioactivity detector connected in series.
Injection: 20 f!L.
Run time: twice the retention time of 2-fluoro-2-deoxy-D-
glucose.
Relative retention with reference to 2-fluoro-2-deoxy-D-glucose
(retention time = about 12 min): 2-fluoro-2-deoxy-D-
mannose = about 0.9; impurity A = about 1.1.
System suítabilíty: reference solution (c) using the
carbohydrate detector:
resolution: minimum 1.5 between the peaks
due to 2-fluoro-2-deoxy-D-mannose and
2-fluoro- 2-deoxy-D-glucose;
signal-to-noise ratio: minimum 10 for the peak ciue to
2-fluoro- 2- deoxy -D-glucose.
Limits: in the chromatogram obtained with the carbohydrate
detector:
- 2-fluoro-2-deoxy-D-glucose: not more than the are a of the
corresponding peak in the chromatogram obtained with
reference solution (a) (0.5 mg/V);
- impurity A: not more than the area of the corresponding
peak in the chromatogram obtained with reference
solution (b) (0.5 mglV).
Impurity S. Spot test.
Test solution. To 100 f!L ofthe preparation to be examined
add 400 f!L of water R and mix.
Reference solution (a): water R.
Reference solution (b). Dissolve 11.0 mg of aminopolyether R
(impurity B) in water R and dilute to 25.0 mL with the same
solvent. Dilute 1.0 mL of the solution to V with water R, V
being the maximum recommended dose in millilitres.
Plate: TLC siliea gel plate for aminopolyether test R.
Applieation: 2.5 f!L; in addition, apply 2.5 f!L ofthe test
solution and then 2.5 f!L of reference solution (b) at the same
place.
Deteetion: visually compare the spots 1 mi11 after application.
System suitability:
- the spot due to the successive application of the test solution
and reference solution (b) is similar in appearance to the
spot due to reference solution (b), whieh is characterised
by a number of concentric circles; the darker innermost
circle (of il1tensity proportional to the concentration
of impurity B) may be surrounded by a bluish-black
ring, outside of which is a lighter circle surrounded by a
peripheral dark edge;
- the spot due to reference solutio11 (a) has a more diffuse
inner circle, which is brownish-pink and without a distinct
margin between it and the surrounding lighter zone;
- the spot due to reference solution (b) is clearly different
from the spot due to reference solution (a).
Limit:
- the central portion of the spot due to the test solution is
110t more inte11se than that of the spot due to reference
solution (b) (2.2 mg/V).
Impurity e. Liquid chromatography (2.2.29).
Test solution. The preparation to be examined.
3957
Fludeoxyglucose (1sP) injection
Referenee solution (a). Dissolve 0.170 g of tetrabutylammonium
hydroxide R in water R and dilute to 20.0 mL with the same
solvent. Dilute 1.0 mL of the solution to V with water R, V
being the maximum recommended dose in millilitres.
Referenee solution (b). Dissolve 80.0 mg of tetrabutyl-
ammonium hydroxide R in water R and dilute to 10.0 mL with
the same solvent. Dilute l.0 mL of the solution to 25.0 mL
with water R.
Column:
- size: 1= 0.10 m, (2) = 4.6 mm;
- stationary phase: octadeeylsilyl si/ica gel for
ehromatography R (3 [lm).
Mobile phase: 25 volumes of a 0.95 giL solution of
toluenesulfonic acid R and 75 volumes of acetonitrile R.
Plow rate: 0.6 mLlmin.
Deteetion: spectrophotometer at 254 nm.
Injection: 20 [lL.
Run time: twice the retention time of impurity C.
Retention time: impurity C = about 3.3 mino
System suitability: reference solution (b) :
- signal-to-noise ratio: minimum 10 for the principal peak;
- symmetry factor: maximum 1.8 for the principal peak.
Limit:
- impurity C: not more than the are a of the corresponding
peak in the chromatogram obtained with reference
solution (a) (2.6 mglV).
Impurity D: maximum 0.02 mglV.
Ultraviolet and visible absorption spectrophotometry (2.2.25).
Test solution. The preparation to be examined.
Reference so/utian. Dissolve 20.0 mg of 4-(4-methylpiperidin-
l-yl)pyridine R (impurity D) in water R and dilute to 100.0 mL
with the same solvent Dilute 0.1 mL of the solution to V
with water R, V being the maximum recommended dose in
millilitres.
Measure the absorbanee of the test solution and the referenee
solution at the absorption maximum of 263 11m.
Result: the absorbanee of the test solution is 110t greater than
that of the reference solution.
Residual solvents: limited aeeording to the principIes defined
in general chapter 5.4. The preparation may be released for
use before completion of the test.
SteriHty. 1t complies with the test for sterility preseribed in
the monograph Radiopharmaceutical preparations (0125).
The preparation may be released for use before completion
of the test.
Bacteria} endotoxins (2.6.14): less than 175IVIU/mL,
V being the maximum recommended dose in millilitres. The
preparation may be released for use before eompletion of the
test.
RADIONUCLIDIC PURITY
The preparation may be released for use before completion of
test B.
Fluodne-18: minimum 99.9 per cent of the total radioaetivity.
A. Gamma-ray spectrometry.
Limit: peaks in the gamma speetrum eorresponding to
photons with an energy different from 0.511 MeV or
1.022 Me V represent not more than 0.1 per cent of the
total radioactivity.
B. Gamma-ray speetrometry.
Determine the amount of fiuorine-18 and radionuclidic
impurities with a half-life longer than 2 h. Por the deteetion
and quantification of impurities, retain the preparation to
be examined for at least 24 h to allow the fiuorine-18 to
decay to a level that permits the detection of impurities.
3958
EUROPEAN PHARMACOPOEIA 8.2
Results: the total radioactivity dne to radionuclidic
impurities is not more than 0.1 per cent.
RADIOCHEMICAL PURITY
A. Liquid chromatography (2.2.29) as described in the test for
2-fluoro-2-deoxy-D-glueose and impurity A. If necessary,
dilute the test solution with water R to obtain a radioactivity
concentration suitable for the radioactivity detector.
: test solution and refe·ence solutions and (c).
Relative retention with reference to 2- [18F]fluoro-2-
deoxy-D-glucose (retention time = about 12 min):
2- [lSP]fiuoro-2-deoxy-D-mannose = about 0.9. Partially
or fully acetylated derivatives of both compounds
hydrolyse under the chromatographic conditions and
therefore elute as 2-[18F]fluoro-2-deoxy-D-glueose and
2- [18P]fluoro-2-deoxy-D-mannose.
Locate the peaks due to 2-[18F]fluoro-2-deoxy-D-glueose
and 2-[lSF]fiuoro-2-deoxy-D-mannose using the
chromatograms obtained with the carbohydrate detector
and referenee solutions (a) and (e).
Limits:
- [1sP]fluorine in the form of 2-[lsP]fluoro-2-deoxy-D-
glucase and 2-[lsP]fluoro-2-deoxy-D-mannose: minimum
95 per cent of the total radioactivity due to fluorine-18;
- 2-[18P]fluoro-2-deoxy-D-mannase: maximum
10 per cent of the total radioactivity due
to 2- [lSF]fluoro-2-deoxy-D-glucose and
2- [lSP] fluoro- 2-deoxy-D-mannose.
B. Thin-layer chromatography (2.2.27).
Test solution. The preparation to be examined.
Reference so/ution. Dissolve, with gentle heating, 30 mg of
1,2,3,4-tetra-O-acetyl-[3-D-glucopyranose R and 20 mg of
glucose R in 1 mL of water R.
Plate: TLC siliea gel plate R.
Mobíle phase: water R, acetonitrile R (5:95 V/V).
Application: about 5 ¡.tL
Development: over a path of 8 cm.
Drying: in air for 15 mino
Deteetion: suitable detector to determine the distribution
of radioaetivity; immerse the plate in a 75 giL solution
of sulfuric acid R in methanol R and dry with a heat gun
or at 150 oC until the appearance of dark spots in the
chromatogram obtained with the reference solution.
Retardatian factors: [18F]fluoride = about O;
2- [lSP]fluoro-2-deoxy-D-glucose and 2- [18P]fiuoro-
2-deoxy-D-mannose = about 0.45; partially or fully
acetylated derivatives of 2-[18P]fluoro-2-deoxy-D-glueose
and 2-[18F]fluoro-2-deoxy-D-mannose = about 0.8 to 0.95.
System suitability: reference solution:
- the ehromatogram shows 2 clearly separated spots.
Limits:
- [lsP]fluorine in the form of 2-[1sP]fluoro-2-deoxy-D-
glucase and 2-[18P]fluoro-2-deoxy-D-mannose: minimum
95 per cent of the total radioactivity due to fiuorine-18;
- [,8P]fluorine in the form offluoride and partially or fully
acetylated derivatives of 2-[18P]fluoro-2-deoxy-D-glucose
and 2-[18P]fluoro-2-deoxy-D-mannase: maximum 5 per
cent of the total radioactivity due to fluorine-18.
RADIOACTIVITY
Determine the radioactivity using a calibrated instrument.
IMPURITIES
Specified impurities: A, B, C, D, E.
See the infarmation section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2 Fludeoxyglucose (IsP) injection

"O~o, OH

HH el
C. N,N,N- tributylbutan-l-aminium (tetrabutylammonium),

A. 2-chloro-2-deoxy-D-glucopyranose (2-chloro-2-deoxy-D-
glucose),
í\
(;0 00
/i \\
( 0"'-------10 \
Lo oJ D. 4-(4-methylpiperidin-l-yl)pyridine,
"'-------1
B. 4,7,13,16,21,24-hexaoxa-l,lO-diazabicyclo[8.8.8]-
hexacosane (aminopolyether), E. [18P]fluoride.

General Notices (1) apply to all monographs and other texts 3959
 EUROPEAN PHARMACOPOEIA 8.2

3960 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
Herbal drugs and herbal drug
preparations
Coriander..................................... ., .............. .,.,.,., .............. ., .... 3963
Coriander oil.. ......................................................................... 3963
Eucalyptus leaf. ....................................................................... 3965
Long pepper............................................................................. 3966
Restharrow root.. .................................................................... 3967
Safflower flower ....................................................................... 3968
General Notices (1) apply ta all monographs and other texts
Sage leaf, three-lobed., .......... ., ............................. ., ................ 3970
Thyme ...................................................................................... 3971
Turpentine oil.. ........................................................................ 3973
Valerian dry hydroalcoholic extract.. ................................... 3974
Wild thyme .............................................................................. 3974
Yarrow...................................................................................... 3976
3961
 EUROPEAN PHARMACOPOEIA 8.2

3962 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2 Coriander oH

07/2014: 1304 Top of the plate

A bluish-violet zone

CORIANDER --- - - -

Geranyl acetate: a violet-blue zone

Coriandri fructus --- ---

Linalal: an intense violet zone A viole! zone (linalal)

DEFINITION A violet-blue zone

Dried cremocarp of Coriandrum sativum L. Reference solution Tes! solution

Content: minimum 3 mLlkg of essential oil (dried drug).

IDENTIFICATION
A. The fruit is brown or light brown, more or less spherical,
about 1.5-5 mm in diameter, or oval and 2-6 mm long.
It consists of the entire cremocarp, with the mericarps
usually tightly connected. The fruit is glabrous and has 10
wavy, slightly raised primary ridges and 8 straight, more
prominent secondary ridges. The meriearps are concave on
the internal surfaee. The stylopod crowns the apex and a
small fragment of the pedicel may be present.
B. Microscopic examination (2.8.23). The powder is
brown. Examine under a microscope using chloral
hydrate solution R. The powder shows the following
diagnostic characters (Figure 1304.-1): numerous oil
droplets [B]; fragments of endosperm [A] with small,
thick-walled, regular cells containing microrosettes [Aa]
and microcrystals of calcium oxalate and oil droplets [Ab];
fragments of endocarp (surface view [C, Jl, transverse
section [H]), with very narrow cells having a parquetry
arrangement [Ca, Ha] and usually associated with a
layer of thin-walled [Cb, Hb] or thicker-walled Da]
rectangular sclereids of the mesocarp; fragments from the
sclerenchymatous layer of the mesocarp [G] with short,
strongly thickened, pitted, fusiform cells occurring in
layers with the cells of adjacent layers approximately at
right angles to one another; fragments of parenchyma
of the mesocarp (transverse section [E]) with small cells
with slightly thickened walls [Ea], the remains of seeretory
canals [Eb] and sclereids [Ec]; fragments of epicarp
(surface view [F]) with thin-walled polyhedral cells, sorne Figure 1304.-1. - Illustration for identificatían test B af
of which contain small prisms of calcium oxalate [Fa]; rare powdered herbal drug of coriander
fragments of secretory canals with browl1 cells, (surfaee
view [D]); oceasional fragments of vascular bundles [K]. TESTS
C. Thin-Iayer chromatography (2.2.27). Foreign matter (2.8.2). It eomplies with the test. None of the
eremocarps show perforations due to insects.
Test solution. To 0.5 g of the freshly powdered herbal drug
L055 on drying (2.2.32): maximum 10.0 per cent, determined
(355) (2.9.12) add 5 mL of methanol R. Sonicate for 10 min
on 1.000 g ofthe powdered herbal drug (355) (2.9.12) by
and eentrifuge or filter; use the supernatant or filtrate.
drying in an oven at 105 oC for 2 h.
Reference solution. Dissolve 10 flL of linalol R and 2 flL of Total ash (2.4.16): maximum 8.0 per eent.
geranyl acetate R in 1.0 mL of toluene R.
ASSAY
Plate: TLC silica gel F254 plate R (5-40 flm) [or TLC silica
gel F254 plate R (2-10 flm)]. Essential oH (2.8.12). Use a 500 mL round-bottomed flask,
200 mL of water R as the distillation liquid and 0.5 mL of
Mobile phase: ethyl acetate R, toluene R (5:95 VIV). xylene R in the graduated tube. Reduce the herbal drug
to a eoarse powder and immediately use 30.0 g for the
Application: 10 flL [or 2 flL] as bands of 15 mm [or 8 mm]. determination. Distil at arate of 2-3 mLlmin for 2 h.
Development: over a path of 10 cm [or 6 cm].
Drying: in air for 5 mino 07/2014:1820

Deteetion: treat with anisaldehyde solution R and heat at CORIANDER OIL

100-105 oC for 5 min; examine in daylight.
Results: see below the sequence of zones present in the Coriandri aetheroleum
chromatograms obtained with the reference solution and
the test solution. Furthermore, other faint zones may DEFINITION
be present in the chromatogram obtained with the test Essential oil obtained by steam distillation from the fruits of
solutioll. Coriandrum sativum L.

General Notices (1) apply to all monographs and other texts 3963
Coriander oil EUROPEAN PHARMACOPOElA 8.2

CHARACTERS Flow rate: 1 mL/min.

-
Appearance: clear, colourless or pale yellow liquido

IDENTIFICATION
First identification: B.
Split ratio: 1:65.
Temperature:
Time
(min)
Temperature
(oC)
Second identification: A. Column 0-10 60
10 - 75 60 190
-';>
A. Examine by thin-Iayer chromatography (2.2.27).
75 - 120 190
Test solution. Dissolve 10 f.lL of the substance to be
Injection port 220
examined in 1.0 mL of toluene R.
Reference solution. Dissolve 10 f.lL of linalol R and 2 f.lL of Detector 240
geranyl acetate R in 1.0 mL of toluene R.
Detection: flame ionisation.
Plate: TLC silica gel F254 plate R (5-40 f.lm) [or TLC silica
gel F254 plate R (2-10 f.lm)]. Injection: 0.2 f.lL.
Mobile phase: ethyl acetate R, toluene R (5:95 V/V). Elution order: order indicated in the composition of reference
solution (a). Record the retention times of these substances.
Application: 10 f.lL [or 2 f.lL] as bands of 15 mm [or 8 mm].
System suitability: reference solution (a):
Development: over a path of 10 cm [or 6 cm].
- resolution: minimum 1.5 between the peaks due to linalol
Drying: in air for 5 mino and camphor.
Detection: treat with anisaldehyde solution R and heat at Using the retention times determined from the chromatogram
100-105 oC for 5 mini examine in daylight.
obtained with reference solution (a), locate the components
Results: see below the sequence of zones present in the of reference solution (a) in the chromatogram obtained with
chromatograms obtained with the reference solution and the test solution.
the test solution. Furthermore, other faint zones may
Determine the percentage content of each of these
be present in the chromatogram obtained with the test
components. The percentages are within the following ranges:
solution.
- a-pinene: 3.0 per cent to 7.0 per cent;
Top of the plate
- limonene: 1.5 per cent to 5.0 per cent;
A bluish-violet zone - y-terpinene: 1.5 per cent to 8.0 per cent;
--- --- - p-cymene: 0.5 per cent to 4.0 per cent;
Geranyl acetate: a violet-blue - camphor: 3.0 per cent to 6.0 per cent;
zone - linalol: 65.0 per cent to 78.0 per cent;
--- ---
- a-terpineol: 0.1 per cent to 1.5 per cent;
Linalol: an intense violet zone An intense violet zone (linalol) - geranyl acetate: 0.5 per cent to 4.0 per cent;
A violet-blue zone - geraniol: 0.5 per cent to 3.0 per cent;
- disregard limit: area of the peak in the chromatogram
Reference solution Test solution
obtained with reference solution (b) (0.05 per cent).
B. Examine the chromatograms obtained in the test for Chiral purity. Gas chromatography (2.2.28).
chromatographic profile. Test solution. Dissolve 0.02 g of the substance to be examined
Results: the characteristic peaks in the chromatogram in pentane R and dilute to 10 mL with the same solvent.
obtained with the test solution are similar in retention time Reference solution. Dissolve 10 f.lL of linalol R and 5 mg of
to those in the chromatogram obtained with the reference borneol R in pentane R and dilute to 10 mL with the same
solution. solvento
TESTS Column:
Relative density (2.2.5): 0.860 to 0.880. - material: fused silica;
Refractive index (2.2.6): 1.462 to 1.470. - size: l = 25 m, 0 = 0.25 mm;
- stationary phase: modified f3-cyclodextrin for chiral
Optical rotation (2.2.7): + 7 to + l3 0 0
•
chromatography R (film thickness 0.25 f.lm).
Acid value (2.5.1): maximum 3.0, determined on 5.00 g of Carrier gas: helium for chromatography R.
the substance to be examined.
Flow rate: 1.3 mL/min.
Chromatographic profile. Gas chromatography (2.2.28) : use
Split ratio: 1:30.
the normalisation procedure.
Temperature:
Test solution. The substance to be examined.
Reference solution (aJ. Dissolve 10 f.lL of a-pinene R, 10 f.lL Time Temperature
(min) (oC)
of limonene R, 10 f.lL of y-terpinene R, 10 f.lL of p-cymene R,
10 mg of camphor R, 20 f.lL of linalol R, 10 f.lL of a-terpineol R, Column 0-65 50 -';> 180
10 f.lL of geranyl acetate R and 10 f.lL of geraniol R in 1 mL Injection port 230
of heptane R.
Detector 230
Reference solution (b J. Dissolve 5 f.lL of geraniol R in heptane R
and dilute to 10 mL with the same solvent.
Detection: flame ionisation.
Column:
Injection: 1 f.lL.
- material: fused silica;
System suitability: reference solution:
- size: l = 60 m, 0 = 0.25 mm;
resolution: minimum 5.5 between the peaks due to
- stationary phase: macrogol20 000 R (film thickness (R)-linalol (1 st peak) and (S)-linalol (2 nd peak) and
0.25 f.lm). minimum 2.9 between the peaks due to (S)-linalol and
Carrier gas: helium for chromatography R. borneol (3 rd peak).

3964 See the information section on general monographs (caver pagesJ

EUROPEAN PHARMACOPOEIA 8.2
Limit: calculate the percentage content of (R)-linalol using
the expression:
As area of the peak due to (S)-linalol;
area of the peak due to (R)-linalol.
- (R)-linalol: maximum 14 per cent.
STORAGE
At a temperature not exceeding 25 0e.
07/2014:1320
EUCALYPTUS LEAF
Eucalypti folium
DEFINITION
Whole or cut, dried leaves of older branches of Euealyptus
globulus Labill.
Essentíal oil content:
- for the whole drug, mínimum 20 mL/kg (anhydrous drug);
- for the cut drug, minimum 15 mLlkg (anhydrous drug).
CHARACTERS
Aromatic odour of cine ole.
IDENTIFICATION
A. The leaves, which are mainly greyish-green and relatively
thick, are elongated, elliptical and slightly sickle-shaped
and usually up to 25 cm in length and up to 5 cm in width.
The petiole is twisted, strongly wrinkled and is 2-3 cm,
rarely 5 cm, in length. The coriaceous, stiffleaves are entire
and glabrous and have a yellowish-green midrib. Lateral
veins anastomose near the margin to a continuous lineo The
margin is even and somewhat thickened. On both surfaces
there are minute, irregularly distributed, warty, dark brown
spots. Small oil glands may be seen in transmitted light.
B. Microscopic examination (2.8.23). The powder is
greyish-green. Examine under a microscope using eh/oral
hydrate solution R. The powder shows the following
diagnostic characters (Figure 1320.-1): fragments
of glabrous lamina (surface view [A, L], transverse
section [F, H]), with small, thick-walled epidermal ceUs
bearing a thick cuticle [Fa, Ha], numerous anomocytic
stomata (2.8.3) greater than 80 ~m in diameter [Aa, La]
with occasional groups of brown cork cells, 300 ~m
in diameter and brownish-black in their centre, and
underlying palisade parenchyma [Ab, Fb]; fragments of
bilateral mesophyll (side view [G]), with 2-3 layers of
palisade parenchyma [Ga] on each side and in the centre
severallayers of spongy mesophyll [Gb 1with elongated
ceUs having the same orientation as the palisade cells
and containing prisms [B, Gd] and cluster crystals of
calcium oxalate [Gc, K] ; large schizogenous oil glands,
whole [E] or usually broken, accompanied by palisade
parenchyma [Ea]; fragments of vessels [J] and thick-walled
and slightly channelled fibres [C] accompanied by crystal
sheaths [Ca, Ja]; crystal sheaths containing prisms of
calcium oxalate [D].
General Notices (1) apply to all monographs and other texts
Eucalyptus leaf
Figure 1320.-1. - Illustration for identificatíon test B of
powdered herbal drug of euealyptus leaf
e. Thin-Iayer chromatography (2.2.27).
Test so/ution. Shake 0.5 g of the freshly powdered herbal
drug (355) (2.9.12) with 5 mL oftoluene R for 2-3 min and
filter over about 2 g of anhydrous sodium sulfate R.
Reference solution. Dissolve 50 ~L of cineole R in toluene R
and diJute to 5 mL with the same solvento
Plate: TLC si/iea gel plate R.
Mobile phase: ethyl aceta te R, toluene R (10:90 V/V).
Applieation: 10 flL as bands.
Development: over a path of 15 cm.
Drying: in airo
Deteetion: treat with anisaldehyde solution R and heat at
100-105 oC for 10-15 min; examine in daylight.
Results: the chromatogram obtained with the reference
solution shows in the middle a zone due to cineole. The
chromatogram obtained with the test solution shows a
principal zone similar in position and colour to the zone
due to cineole in the chromatogram obtained with the
reference solution, it also shows an intense violet zone
(hydrocarbons) near the solvent front and there may also
be other fainter zones.
TESTS
Foreign maUer (2.8.2): maximum 3 per cent of dark and
brown leaves, maximum 5 per cent of stems and maximum
2 per cent of other foreign matter. Cordate or ovate sessile
leaves of young branches, with numerous glands on both
sides, visible as points in transmitted light, are not presento
Carry out the determination using 30 g of the herbal drug to
be examined.
Water (2.2.13): maximum 100 mL/kg, determined on 20.0 g
ofthe powdered herbal drug (355) (2.9.12).
Total ash (2.4.16): maximum 6.0 per cent.
3965
Longpepper EUROPEAN PHARMACOPOEIA 8.2

ASSAY
Essential oil (2.8.12). Use 10.0 g of the herbal drug, cut
immediately before determination, a 500 mL round-bottomed
flask, 200 mL of water R and 100 mL of glycerol R as the
distillation liquid and 0.5 mL of xylene R in the graduated
tube. Distil at arate of 2-3 mLlmin for 2 h.

07/2014:2453

LONG PEPPER

Piperis longi fructus

DEFINITION
Dried, ripe or nearly ripe fruiting spikes of Piper longum L.
or Piper retrofractum Vahl (syn. P. chaba Hunter and
P. officinarum (Miq.) e. De.) or a mixture ofboth species.
Content:
essential oil: minimum 6.0 mLlkg (dried drug);
- piPerine (C17H19N03; M, 285.3) : minimum 3.0 per cent
(dried drug).
IDENTIFICATION
A. P. longum. The fruiting spikes are cylindrical or irregularly
cylindrical, 1-2.5 cm long (rarely longer than 2.5 cm),
3-5 mm in diameter, blackish-brown or almost black. The
spikes are quite compact, tough, composed of small fruits
firmly fixed on the receptacle in regular or oblique rows.
The berries are spherical, about 1 mm in diameter. The
bracts are black, small, punctiform, confined to depressions Figure 2453.-1. - Illustration for identification test B of
between adjacent berries. The remains ofthe peduncle may powdered herbal drug of long pepper
be present at the base of the cylinder. Spikes can be easily e. Thin-layer chromatography (2.2.27).
broken; the fracture is irregular and granular.
Test solution. To 0.5 g of the powdered herbal drug (355)
P. retrofractum. The fruiting spikes are similar to those of (2.9.12) add 5 mL of methanol R. Sonicate for 10 min,
P. longum but clearly more robust, straight and cylindrical, centrifuge and use the supernatant.
2.5-4 cm long (rarely smaller than 2.5 cm), 5-8 mm in
diameter, brown or reddish-brown. The berries are also
Reference solution. Dissolve 10 mg of borneol R and 15 mg
of piperine R in 10 mL of methanol R.
firmly fixed on the receptacle but, in contrast to those of
P. longum, arranged more obviously in spiral rows. The Plate: TLC silica gel F254 plate R (5-40 flm) [or TLC silica
bracts are more prominent than those of P. longum. gel F254 plate R (2-10 flm)].
B. Microscopic examination (2.8.23). The powder is grey or Mobile phase: ethyl acetate R, cyclohexane R (30:50 V/V).
light brown. Examine under a microscope using chloral Application: 10 flL [or 5 flL] as bands of 10 mm [or 8 mm].
hydrate solution R. The powder shows the following Development: over a path of 15 cm [or 6 cm].
diagnostic characters (Figure 2453.-1): fragments of the Drying: in airo
endocarp (surface view [A]), consisting of sclereids, more
or less elongated, about 75 flm long, pitted, with irregularly Detection A: examine in ultraviolet light at 254 nm.
thickened walls and wide channels [Aa], associated with the Results A: see below the sequence of zones present in the
reddish-brown pigmented layer of the testa with indistinct chromatograms obtained with the reference solution and
cells [Ab] and also associated with the inner testa with the test solution. Furthermore, other faint quenching zones
rectangular, brown, thin-walled cells [Ac]; fragments of may be present in the chromatogram obtained with the
the endocarp (transverse section [D]), showing sclereids test solution.
with irregularly thickened inner walls on the 3 lower Top of the plate
sides [Da], usually associated with the testa (namely the
pigmented layer with indistinct cells [Db] and the layer --- --
ofthe inner testa [De]); fragments ofthe parenchyma of 2 strong quenching zones
the mesocarp [B, C] containing more or less polygonal
sclereids, isolated [Ba] or in groups [Bb], and oil cells about A quenching zone
50 flm in diameter [Ca]; numerous ovoid or polygonal --- ---
cells of the parenchyma of the seed [Dd]; fragments of the
epicarp [F] with thin-walled cells; rare fragments from A quenching zone
the centre of the spike [E], consisting of parenchymatous Piperine: a quenching zone A strong quenching zone
cells [Eb] and elongated sclereids up to 400 flm long [Ea]; a (piperine)
few fragments of vascular tissue [H] with spiral or striated
vessels [Ha] and fibres [Hb]. Examine under a microscope
using a 50 per cent V/V solution of glycerol R. Starch is
visible as rounded, compound granules, each about 20 flm Reference solution Test solution
in diameter [Ga], made up oftiny individual granules,
ovoid or polyhedral by compression, free [Gb] or included Detection B: treat with anisaldehyde solution R and heat at
in the parenchymatous cells ofthe seed [G]. 100 oC for 5 min; examine in daylight.

3966 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 Restharrow root

Results B: see below the sequence of zones present in the F/ow rate: 1.0 mL/min.
chromatograms obtained with the reference solution and Deteetíon: spectrophotometer at 343 nm.
the test solution. Furthermore, other zones may be present
in the chromatogram obtained with the test solution. Injection: 10 flL.
Identification of peaks: use the chromatogram supplied with
Top oí the plate
long pepper for system suitability HRS and the chromatogram
A purple-grey zone obtained with reference solution (b) to identify the peak due
to piperine and peak 2.
--- - - -

Retention time: piperine = about 10 mino

A purple zone
System suitability: reference solution (b):
Borneol: a yellowish-brown zone A viole! zone
- peak-to-valley ratio: minimum 4, where Hp = height aboye
A purple-grey zone the baseline of peak 2 and H" = height aboye the baseline
of the lowest point of the curve separating the peak due to
--- ---
piperine from peak 2.
Piperine: a green ar brownish A green or brownish zone Calculate the percentage content of piperine using the
zone (piperine)
following expression:
Al x m2 x p
A 2 x mI x 2
Reference solution Test solution
are a of the peak due to piperine in the
TESTS chromatogram obtained with the test solution;

Foreign matter (2.8.2): maximum 3 per cent.
Loss on drying (2.2.32): maximum 11.0 per cent, determined
on 1.000 g of the freshly powdered herbal drug (355) (2.9.12)
by drying in an oven at 105 oC for 2 h.
Total ash (2.4.16): maximum 5.0 per cent.
ASSAY
Essential oil (2.8.12). Use 25.0 g of the freshly, coarsely
powdered herbal drug (1400) (2.9.12), a 1000 mL
round-bottomed flask, 400 mL of water Ras the distillation
liquid and 0.5 mL of xylene R in the graduated tube. Distil at
arate of 2-3 mLlmin for 3 h.
Piperine. Liquid chromatography (2.2.29). Carry out the
assay protected from light.
Test solution. Disperse 0.250 g of the powdered herbal drug
(355) (2.9.12) in 40 mL of ethanol (96 per cent) R. Sonicate
for 20 min and filter. Rinse the flask and the filter with 5 mL
of ethanol (96 per eent) R, combine the filtrate and washings
and dilute to 50.0 mL with the same solvent. Filter through a
membrane filter (nominal pore size 0.45 flm).
Referenee solution (a). Dissolve 15.0 mg of piperine CRS in
ethanol (96 per cent) R and dilute to 100.0 mL with the same
solvent
Reference so/ution (b). Disperse 0.250 g of long pepper for
system suitabi/ity HRS (355) (2.9.12) in 40 mL of ethano/
(96 per cent) R. Sonicate for 20 min and filter. Rinse the flask
and the filter with 5 mL of ethano/ (96 per cent) R, combine
the filtrate and washings and dilute to 50.0 mL with the same
solvent. Filter through a membrane filter (nominal pore size
0.45 ~lm).
Co/umn:
- size: / = 0.15 m, 0 = 4.6 mm;
- stationary phase: end-capped oetadecy/sily/ silica gel for
chromatography R (5 flm).
Mobile phase:
- mobi/e phase A: water R;
- mobile phase B: acetonitrile R;
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0-5 50
5 - 20 50 -7 5
20 - 22 5-70
area of the peak due to piperine in the
chromatogram obtained with reference
solution (a);
mass of the herbal drug to be examined used to
prepare the test solution, in grams;
mass of PiPerine CRS used to prepare reference
solution (a), in grams;
p percentage content of piperine in Piperíne CRS.
07/2014:1879
RESTHARROW ROOT
Ononidis radix
DEFINITION
Whole or cut, dried root of Ononis spinosa L.
IDENTIFICATION
A. The root is more or less flattened, twisted and branched,
deeply wrinkled, brown and grooved longitudinally. The
transversely cut surface shows a thin bark and a xylem
cylinder with a conspicuously radiate structure. The
fracture of the root is short and fibrous.
B. Microscopic examination (2.8.23). The powder is light
brown or brown. Examine under a microscope using
ehloral hydrate solutíon R. The powder shows the
following diagnostic characters (Figure 1879.-1): brown
fragments of cork composed of thin-walled, polygonal
cells (surface view [G]); groups ofthick-walled, narrow
fibres, often accompanied by a parenchymatous crystal
sheath containing prisms of calcium oxalate [C] ; vascular
fragments [D, E] consisting of vessels with numerous
bordered pits, often accompanied by lignified fibres with
pitted walls [Ea]; thin-walled parenchymatous cells from
the bark, sorne containing a single prism of calcium
oxalate [H]; ligneous parenchyma cells with slightly
thickened and pitted walls [A, B], sorne of which contain
prisms of calcium oxalate [Aa]; numerous free prisms of
50
calcium oxalate [F]. Examine under a microscope using a
50 per cent V/V solution of g/yeerol R. The powder shows
50 -7 95 very numerous, rounded starch granules, 5-10 ¡.tm in
95 -7 100
diameter, simple or sometimes 2-4 compound, free [J] or
inside parenchymatous cells [K].

Genera/ Notices (1) app/y to all monographs and other texts 3967
Safflower flower
Figure 1879.-1. - Illustration for identification test B of
powdered herbal drug of restharrow root
C. Thin-layer chromatography (2.2.27).
Test solution. To 1.0 g of the powdered herbal drug (180)
(2.9.12) add 15.0 mL of methanol R and boil under a reflux
condenser for 30 mino Cool and filter.
Reference solution. Dissolve 10 mg of resorcinol R and
50 mg of vanillin R in 10 mL of methanol R.
Plate: TLC silica gel F254 plate R (5-40 !lm) [or TLC silica
gel F254 plate R (2-10 !lm)].
Mobile phase: ethanol (96 per cent) R, methylene chloride R,
toluene R (10:45:45 V/V/V).
Application: 20 !lL [or 5 !lL] as bands of 15 mm [or 8 mm].
Development: over a path of 15 cm [or 6 cm].
Drying: in airo
Detection A: examine in ultraviolet light at 254 nm and
365 nm.
Results A: see below the sequence of zones present in the
chromatograms obtained with the reference solution and
the test solution. Furthermore, other fluorescent zones are
present in the middle third of the chromatogram obtained
with the test solution.
Top of the plate
Vanillin: a zone visible at 254 nm
---
Resorcinol: a zone visible at An intense blue fluoreseent zone
254nm visible at 365 nm
---
Referenee solution Test solution
Detection B: treat with anisaldehyde solution R. Heat at
100-105 oC for 5-10 mino Examine in daylight.
3968
EUROPEAN PHARMACOPOEIA 8.2
Results B: see below the sequence of zones present in the
chromatograms obtained with the reference solution and
the test solution.
Top of the plate
Vanillin: a greyish-violet zone
--- ---
A violet zone (onoeol)
Resorcinol: a red zone
--- ---
Reference solution Test solution
TESTS
L088 on drying (2.2.32): maximum 10.0 per cent, determined
on 1.000 g of the powdered herbal drug (355) (2.9.12) by
drying in an oven at 105 oC for 2 h.
Total a8h (2.4.16): maximum 8.0 per cent.
Extractable matter: minimum 15.0 per cent.
To 2.00 g ofthe powdered herbal drug (250) (2.9.12) add a
mixture of 8 g of water R and 12 g of ethanol (96 per cent) R
and allow to macerate for 2 h, shaking frequently. Filter,
evaporate 5 g of the filtrate to dryness on a water-bath and
dry in an oven at 100-105 oC for 2 h. The residue weighs a
minimum of 75 mg.
07/2014:2386
SAFFLOWER FLOWER
Carthami flos
DEFINITION
Dried flower of Carthamus tinctorius L.
Content: minimum 1.0 per cent of total flavonoids, expressed
as hyperoside (C21 H 2aÜ12; M r 464.4) (dried drug).
IDENTIFICATION
A. The orange-yellow or reddish-orange, tubular,
gamopetalous, actinomorphic florets are separate from
the capitulum. Each floret consists of a long, filiform tube,
about 1 cm long divided into 5 equal, narrow, lanceolate
lobes, about 0.5 cm long. From the opening of the tube
emerges the hollow cylinder formed by the fused yellow
anthers, in which the filiform style persists, thickened near
the apex.
B. Microscopic examination (2.8.23). The powder is
orange-yellow. Examine under a microscope using chloral
hydrate solution R. The powder shows the following
diagnostic characters (Figure 2386.-1): fragments ofthe
corolla tube [E] with epidermis consisting of elongated,
thin-walled, finely striated cells whose margins are lobed [B,
Ea, J], and with parenchyma consisting of small polygonal
cells containing prisms of calcium oxalate [Eb]; outer
epidermis bearing glandular trichomes, usually sheared
off, with only the base [Ja] persisting on the epidermis;
these trichomes are isolated, biseriate with a multicellular
stalk and a bicellular head [C] ; fragments of the lobes
--- of the corolla showing at their apices a large number of
small, rounded, very prominent papillae [G]; fragments of
parenchyma containing vascular bundles [Ed] surrounded
--- by secretory canals with reddish-brown contents [Ec];
fragments of the filaments of the anthers consisting of
elongated, thick-walled, pitted cells [K] and fragments of
the characteristic layer of the anther whose walls show
thickenings in bands [H]; fragments of the stigma, covered
with rather long, conical papillae [D], usually accompanied
See the information section on general monographs (caver pages)
EUROPEAN PHARMACOPOEIA 8.2 Saffiower ftower

by pollen grains; rounded or elliptical pollen grains up Top of the plate

to 60 flm in diameter with 3 pares and an echinulate
Quercetin: a light yellow zone
exine [A]; isolated prisms of calcium oxalate [F].
--- ---

--- ---

Rutin: a light yellow zone

A red zone

A
~~e
A yellow zone

A yellow zone
Reference solution Test solution

Detection B: heat at 100 oC for 3 min; treat the pIate

whilst still hot with a 10 giL solution of diphenylboric acid
aminoethyl es ter R in methanol R and then with a 50 giL
solution of macrogol 400 R in methanol R; allow to dry in
air for about 30 min; examine in ultraviolet light at 365 nm.
Results B: see below the sequence of zones present in the
chromatograms obtained with the reference solution and
the test solution. Furthermore, other faint zones may
be present in the chromatogram obtained with the test
solution.
Top of the plate
Quercetin: an orange fluorescent
zone
A blue fluorescent zone
--- ---

A green fluorescent zone

A brown fluorescent zone

A green fluorescent zone

--- ---

Rutin: a yellow fluorescent zone

A yellow fluorescent zone

Figure 2386.-1. - Illustration for identification test B of

powdered herbal drug of safflower flower A green fluorescent zone

A brown fluorescent zone

C. Thin-layer chromatography (2.2.27).
Test solution. To l.0 g of the powdered herbal drug (355)
(2.9.12) add 10 mL of methanol R. Sonicate for 10 min and
centrifuge.
Referenee solution. Dissolve 1 mg of rutin R and 5 mg of
quercetin dihydrate R in 50 mL of methanol R.
Piafe: TLC si/ica gel plate R (5-40 flm) [or TLC si/ica gel
plate R (2-10 flm)].
Mobile phase: aeetic acid R, anhydrous formic aeid R,
water R, ethyl acetate R (11:11:27:100 V/V/V/V).
Application: 25 flL [or 10 flL] as bands of 15 mm [or 8 mm].
Development: over a path of 12 cm [or 7 cm].
Drying: in airo
Deteetion A: examine in daylight.
Results A: see below the sequence of zones present in the
chromatograms obtained with the reference solution and
the test solution. Furthermore, other faint zones may
be present in the chromatogram obtained with the test
solution.
Reference solution Test solution
TESTS
Absorbance (2.2.25).
A. Yellow pigment: macerate 0.1 g of the powdered herbal
drug (355) (2.9.12) in 150 mL of water R, stir for 1 h,
filter through a sintered-gIass filter (40) (2.1.2) and dilute
to 500.0 mL, washing the residue, with water R. The
absorbance is not less than 0.40 at 401 nm.
B. Red pigment: to 0.25 g of the powdered herbal drug (355)
(2.9.12) add 50 mL of a mixture of 20 volumes of water R
and 80 volumes of acetone R. Heat on a water-bath at 50 oC
for 90 mino Allow to cool, filter through a sintered-glass
filter (40) (2.1.2) and diIute to 100.0 mL, washing the
residue with a mixture of 20 volumes of water R and
80 volumes of acetone R. The absorbance is not les s
than 0.40 at 518 nm.
Loss on drying (2.2.32) : maximum 11.0 per cent, determined
on 1.000 g of the powdered herbaI drug (355) (2.9.12) by
drying in an oven at 105 oC for 2 h.
Total ash (2.4.16): maximum 10.0 per cent.
Ash insoluble in hydrochloric add (2.8.1): maximum 3.0 per
cent.

General Notices (1) apply to all monographs and other texts 3969
Sage leaf, three-Iobed EUROPEAN PHARMACOPOEIA 8.2

ASSAY glandular trichomes [Ae, Af, Gb]; the lower epidermis

Solution A. Place 0.250 g of the powdered herbal drug (180) (surface view [H], transverse section [D]) with sinuous
(2.9.12) in a 250 mL flask and add 95 mL of methanol R. Heat or wavy-walled cells [Ha] and numerous diacytic stomata
under a reflux condenser on a water-bath for 30 mino Allow (2.8.3) [Hb], glandular trichomes [Db, Hd, He] and
to cool and filter. Rinse the filter with 5 mL of methanol R. covering trichomes [Da, Hc], sorne of which are unicellular
Combine the filtrate and the rinsing solution in a volumetric and short, with finely pitted walls [Dc].
flask and dilute to 100.0 mL with methanol R. Ad
Test solution. Place 5.0 mL of solution A in a volumetric flask
and dilute to 20.0 mL with a 20 gIL solution of aluminium
ehloride R in methanol R.
Compensation solution. Place 5.0 mL of solution A in a
volumetric flask and dilute to 20.0 mL with methanol R.
After exactly 15 min, measure the absorbance (2.2.25) of the
test solution at 420 nm by comparison with the compensation
solution. Calculate the percentage content of total flavonoids,
expressed as hyperoside, using the following expression:
A
m
taking the specific absorbance of hyperoside at 420 nm to be
400.
A absorbance of the test solution at 420 nm;
m mas s of the herbal drug to be examined, in grams.

07/2014:1561

SAGE LEAF, THREE-LOBED

Salviae trilobae folium
DEFINITION
Whole or cut, dried leaves of Salvia fruetieosa Mill. (syn.
Salvia tri/oba L. fil).
Essential oil eontent:
- for the whole drug, minimum 18 mLlkg (anhydrous drug);
- for the cut drug, minimum 12 mLlkg (anhydrous drug).
CHARACTERS
Spicy odour when ground, similar to eucalyptus oil.
IDENTIFICATION
A. The lamina of whole three-lobed sage leaf is about
8-50 mm long and about 4-20 mm wide, and oblong-ovate
or lanceolate. The margin is finely crenate and undulate
but indistinct owing to the dense, hairy covering on both
surfaces. The base is obtuse and sometimes bears 1 or
2 more or less developed lobes. The upper surface is
grey-tomentose pubescent, the lower surface is densely
white-tomentose pubescent; the venation is indistinct. The
densely white-tomentose pubescent petiole is about 1 mm
in diameter.
B. Microscopic examination (2.8.23). The powder is
greyish-green and tomento se. Examine under a microscope
using ehloral hydrate solution R. The powder shows the
following diagnostic characters (Figure 1561.-1): very
numerous covering and glandular trichomes, whole
and attached to fragments of the epidermis es [A, D,
G, H] or fragmented and free [B, C, E, F] ; uniseriate
covering trichomes, either unicellular [Ab] or multicellular
articulated and thick-walled [Ad]; those on the upper
epidermis are straight [Ga], those on the lower epidermis
are tortuous [Da]; glandular trichomes of 2 types: sorne
with a unicellular [Hd] or multicellular [Ca, Gb, He] stalk
and a unicellular [Cb, Hd] or bicellular [Cc] head; others
of lamiaceous type, with a unicellular stalk and a head
composed of 8-12 radiating cells with a raised common
cuticle [Ae, B]; the upper epidermis (surface view [A],
transverse section [G]) with pitted and beaded cells [Aa],
somewhat polygonal, with a few diacytic stomata (2.8.3),
covering trichomes [Ab, Ad, Ga] or their scars [Ac] and
Figure 1561.-1. - Illustration for identification test B of
powdered herbal drug of three-Iobed sage leaf
C. Examine the chromatograms obtained in the test for
thujone.
Results: the chromatogram obtained with the test solution
shows a blue zone due to cine ole, equal or greater in size
and intensity to the zone in the chromatogram obtained
with the reference solution. Further zones are presento
TESTS
Thujone. Thin-layer chromatography (2.2.27).
Test solution. Shake 0.3 g of the freshly powdered herbal drug
(355) (2.9.12) with 5.0 mL of anhydrous ethanol R for 5 mino
Referenee solution. Dilute 20 flL of thujone R and 25 flL of
eineole R in 20 mL of anhydrous ethanol R.
Plate: TLC si/iea gel plate R.
Mobile phase: ethyl aeetate R, toluene R (5:95 V/V).
Application: 20 flL as bands.
Development: over a path of 15 cm.
Drying: in airo
Deteetion: treat with a 200 gIL solution of phosphomolybdie
acid R in anhydrous ethanol R and heat at 100-105 oC for
10 mino Examine in daylight.
Results: the chromatogram obtained with the reference
solution shows in the middle part a blue zone (cineole) and in
the upper part a pink-blue zone (thujone). The chromatogram
obtained with the test solution shows no zone or a very faint
pink-blue zone due to thujone.
Foreign matter (2.8.2): maximum 8 per cent of stems and
maximum 2 per cent of other foreign matter.
Water (2.2.13): maximum 100 mLlkg, determined on 20.0 g.

3970 See the information seetion on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2
Total asn (2.4.16): maximum 10.0 per cent.
ASSAY
Essential oH (2.8.12). Use 20.0 g ofthe herbal drug, cut, if
necessary, immediately before the assay, a 500 mL flask and
250 mL of water R as the distillation liquido Add 0.50 mL of
xylene R in the graduated tube. Distil at arate of 2-3 mL/min
for 2 h.
0712014:0865
THYME
Thyrni herba
DEFINITION
Whole leaves and flowers separated from the previously dried
stems of Thymus vulgaris 1. or Thymus zygis 1. or a mixture
of both species.
Cantent:
- essential ail: mínimum 12 mL/kg (anhydrous drug);
- sum af the cantents af thymal and carvacral (both C lO H 140;
M r 150.2): minimum 40 per cent in the essential oil.
CHARACTERS
Strong odour reminiscent of thymol.
IDENTIFICATION
A. The leaf of Thymus vulgaris is usually 4-12 mm long and
up to 3 mm wide, sessile or with a very short petiole. The
lamina is tough, entire, lanceolate or ovate, covered on
both surfaces by a grey or greenish-grey indumentum; the
edges are markedly roUed up towards the abaxial surface.
The midrib is depressed on the adaxial surface and is very
prominent on the abaxial surface. The calyx is green, often
with violet spots and is tubular; at the end are 2 lips of
which the upper one is bent back and at the end has 3 lobes,
the lower is longer and has 2 hairy teeth. After flowering,
the calyx tube is dosed by a crown of long, stiff hairs. The
corolla, about twice as long as the calyx, is usually brownish
in the dry state and is slightly bilabiate.
The leaf of Thymus zygis is usually 1.7-6.5 mm long and
0.4-1.2 mm wide; it is acicular or linear-Ianceolate and
the edges are markedly roUed towards the abaxial surface.
Both surfaces of the lamina are green or greenish-grey and
the midrib is sometimes violet; the edges, in particular at
the base, have long, white hairs. The dried flowers are very
similar to those of T. vulgaris.
B. Microscopic examination (2.8.23). The powder of both
species is greyish-green or greenish-brown. Examine under
a microscope using chIoral hydrate solution R. The powder
shows the following diagnostic characters (Figure 0865.-1
and Figure 0865.-2): fragments of the outer epidermis
of the corolla (surface view [A, C, F]), consisting of ceUs
with wavy and slightly thickened [Fc] or unthickened
[Ac] walls, numerous uniseriate, multicellular, covering
trichomes, often with 1 ceH collapsed [Aa], glandular
trichomes with a unicellular head and a unicellular [Ca,
Fb] or multicellular [Ab] stalk, diacytic sto mata (2.8.3) [Fa]
and glandular trichomes generally with 12 cells [D]; cells
of the epidermis from the base of the corolla, isodiametric
with slightly thickened walls [C] ; pollen grains, relatively
rare, spherical and smooth, with 6 germinal slit-like pores,
measuring about 35 11m in diameter [B]; the powder of
General Natices (1) apply ta all manographs and other texts
Tnyme
T. zygis also contains numerous thick bundles of fibres
from the main veins and from fragments of stems; the
epidermis es of the leaves (surface view [G, K]) have cells
with antidinal walls that are sinuous and beaded [Ga, Ka],
and diacytic stomata (2.8.3) [Gb]; numerous glandular
trichomes made up of 12 secretory cells, the cutide of
which is generally raised by the secretion to form a globular
or ovoid, bladder-like covering [Kb]; glandular trichomes
with a unicellular stalk and a globular or ovoid head [Kc] ;
in both species, the adaxial epidermis bears covering
trichomes with warty walls that are shaped as pointed teeth
[Gc], and is usually associated with underlying palisade
parenchyma [Gd, Kd]; the abaxial epidermis (transverse
section [H, L]) bears covering trichomes of different types:
unicellular, straight or slightly curved [Ha, La]; bicellular
or tricellular, articulated and most often elbow-shaped
[Hb, Jl (T. vulgaris); bicellular or tricellular, more or less
straight [N], or very large, multicellular [M), at the base
of the lamina (T. zygis); fragments of calyx covered by
numerous, uniseriate trichomes with 5-6 cells and a weakly
striated cutide (surface view [EJ).
e. Thin-layer chromatography (2.2.27).
Test solutian. To 0.5 g of the powdered herbal drug (355)
(2.9.12) add 5 mL of methanol R. Sonicate for 10 mino
Centrifuge or filter; use the supernatant or the filtrate.
Reference solut¡on. Dissolve 1 mg of rutin R and 1 mg of
rosmarinic acid R in 5 mL of methanol R.
Plate: TLC si/iea gel F254 plate R (5-40 11m) [or TLC si/ica
gel F254 plate R (2-10 !lm)].
Mobile phase: anhydrous formic acid R, water R, ethyl
acetate R (1:1:15 V/V/V).
Applieatian: 20 I1L [or 5 !lL1as bands of 20 mm [or 8 mm l.
Development: over a path of 15 cm [or 6 cm].
Drying: in airo
Deteetían: heat at 100 oC for 3 min, treat the still-hot plate
with a 5 giL solution of diphenylboric acid aminoethyl
ester R in ethyI aceta te R, then treat with a 50 giL solution
of macrogol400 R in methylene eh/oride R; examine in
ultraviolet light at 365 nm.
Results: see below the sequence of zones present in the
chromatograms obtained with the reference solution and
the test solution. Furthermore, other faint fluorescent
zones may be present in the chromatogram obtained with
the test solution.
Top of fue plate
2 red fluorescent zones
Rosmarinic acid: a blue A blue fluorescent zone
fluorescent zone (rosmarinic acid)
--- ---
1 or 2 blue fluorescent zones
--- ---
2 yellow or orange fluorescent
zones
A green fluorescent zone may be
present
Rutin: an orange-yellow
fluorescent zone
Reference solutio!1 Test solutio!1
3971
Thyme EUROPEAN PHARMACOPOEIA 8.2

.
(2)
, .. :, \:l',
B D. Examine the chromatograms obtained in the assay for
thymol and carvacrol.
':~'."',: Results: the characteristic peaks in the chromatogram
obtained with the test solution are similar in retention time
to those in the chromatogram obtained with reference
solution (a).
TESTS
,[
Foreign matter (2.8.2): maximum 10 per cent of stems and
maximum 2 per cent of other foreign matter. Stems must not
be more than 1 mm in diameter and 15 mm in length.
Thymus serpyllum L. Adulteration with T. serpyllum 1. is
indicated by the presence of leaves with long trichomes at
their base and with weakly pubescent other parts.
Water (2.2.13): maximum 100 mL!kg, determined on 20.0 g
of the powdered herbal drug (355) (2.9.12).
Total ash (2.4.16): maximum 15.0 per cent.
E
Ash insoluble in hydrochloric acid (2.8.1): maximum 3.0 per
cent.
ASSAY
Essential oil (2.8.12). Use 30.0 g ofthe herbal drug, a 1000 mL
round-bottomed flask and 400 mL of water Ras the distillation
liquido Distil at arate of 2-3 mL!min for 2 h without xylene R
in the graduated tube.
Thymol and carvacrol. Gas chromatography (2.2.28): use
the normalisation procedure.
Test solution. Filter the essential oil obtained in the
determination of essential oil over a small amount of
anhydrous sodium sulfate R and dilute to 5.0 mL with
heptane R by rinsing the apparatus and the anhydrous sodium
Figure 0865.-1. - Illustration for identification test B of sulfate. Dilute a volume of the filtered solution corresponding
powdered herbal drug of thyme to 100 flL of the essential oil to 5.0 mL with heptane R.
Reference solution (a). Dissolve 0.20 g of thymol R and 50 mg
of carvacrol R in heptane R and dilute to 5.0 mL with the same
solvent.
Reference solution (b). Dilute 10 flL of carvacrol R to 10.0 mL
with heptane R. Dilute 100 flL of the solution to 10.0 mL with
heptane R.
Column:
material: fused silica;
- size: l = 30-60 m, 0 = 0.25 mm;
- stationary phase: macrogol20 000 R (film thickness
0.25 flm).
Carrier gas: nitrogen for chromatography R or helium for
chromatography R.
Flow rate: 1-2 mL!min.
Split ratio: 1:100.
Temperature:
Time Temperature
(min) (oC)
Column 0-45 40 -¿ 220

Injection port 190

Detector 210

Detection: flame ionisation.

Figure 0865.-2. - Illustration for identification test B of
powdered herbal drug of thyme
Injection: 0.2 fl1.
Elution order: order indicated in the composition of reference
solution (a); record the retention times of these substances.
System suitability: reference solution (a):
- resolution: minimum 1.5 between the peaks due to thymol
and carvacrol.
Using the retention times determined from the chromatogram
obtained with reference solution (a), locate the components
of the reference solution in the chromatogram obtained with
the test solution.

3972 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
Determine the percentage content ofthymol and carvacrol.
Dísregard any peak due to the solvent or with an area less than
the area of the principal peak in the chromatogram obtained
with reference solution (b) (0.05 per cent).
07/2014:1627
TURPENTINE OIL
Terebinthinae aetheroleum
DEFINITION
Essential oil obtained by steam distillation, followed by
rectification at a temperature below 180 oC, from the oleoresin
obtained by tapping Pinus pinaster Aiton and/or Pinus
massoniana D.Don. A suitable antioxidant may be added.
CHARACTERS
Appearance: clear, colourless or pale yellow liquido
Odour reminiscent of a-pinene and j3-pinene.
IDENTIFICATION
First identification: B.
Second identification: A.
A. Thin-layer chromatography (2.2.27).
Test solution. Dilute 1 mL of the oil to be examined in
10 mL of toluene R.
Reference solution. Dissolve 10 flL of f3-caryophyllene R and
10 !lL of caryophyllene oxide R in 10 mL oftoluene R.
Plate: TLC si/ica gel plate R (5-40 !lm) [or TLC silica gel
plate R (2-10 !lm)].
Mobile phase: ethyl acetate R, toluene R (5:95 VIV).
Application: 10 flL [or 2 !lL] as bands of 10 mm [or 8 mm].
Development: over a path of 15 cm [or 6 cm].
Drying: in airo
Detection: treat with anisaldehyde soluNon R and heat at
100-105 oC for 5-10 min; examine in daylight.
Results: see below the sequence of zones present in the
chromatograms obtained with the reference solution and
the test solution. Furthermore, other faint zones may be
present below the zone due to caryophyllene oxide in the
chromatogram obtained with the test solution.
Top of the plate
~-Caryophyllene: a pink zone A pink zone
---
Caryophyllene oxide: a pink zone A pink zone (caryophyllene
oxide)
---
A brownish-violet zone
Reference solution Test solution
B. Examine the chromatograms obtained in the test for
chromatographic profile.
Results: the peaks in the chromatogram obtained with the
test solution are similar in retention time to those in the
chromatogram obtained with reference solution (a).
TESTS
Relative density (2.2.5) : 0.856 to 0.872.
Refractive index (2.2.6): 1.465 to 1.475.
General Notices (1) apply to all monographs and other texts
Turpentine oil
Optical rotation (2.2.7): - 40° to - 28°.
Add value (2.5.1): maximum 1.0.
Peroxide value (2.5.5, Method B): maximum 20.
Fatty oils and resinined essential oHs (2.8.7). It complies
with the test.
Chromatographic profl1e. Gas chromatography (2.2.28): use
the normalisation procedure.
Test solution. Dilute 1.0 mL ofthe oil to be examined in
heptane R and dilute to 10.0 mL with the same solvento
Reference solution (a). Dissolve 30 !lL of rx-pinene R, 10 mg of
camphene R, 20 flL of f3-pinene R, 10 !lL of car-3-ene R, 10 !lL
of f3-myrcene R, 20 !lL of limonene R, 10 !lL of longifolene R,
10 !lL of f3-caryophyllene R and 10 mg of caryophyllene oxide R
in 1.0 mL of heptane R.
Reference solution (b). Dissolve 5 flL of f3-caryophyllene R in
heptane R and dilute to 10.0 mL with the same solvent. Dilute
0.1 mL of the solution to 1.0 mL with heptane R.
Column:
- material: fused silica;
- size: 1 = 60 m, 0 = 0.25 mm;
- stationary phase: macrogol20 000 R (film thickness
0.25 flm).
Carrier gas: helium for chromatography R.
Flow rate: 1.0 mL/min.
Split ratio: 1:200.
Temperature:
Time Temperature
(min) (oC)
0- 10 60
Column
10 - 80 60 -7 200
80 - 120 200
Injection port 200
Detector 250
Detection: flame ionisation.
Injection: 1.0 !lL.
Elution arder: order indicated in the composition of reference
solution (a); record the retention times of these substances.
System suitability: reference solution (a):
- resolution: minimum 1.5 between the peaks due to
car-3-ene and j3-myrcene.
Using the retention times determined from the chromatogram
obtained with reference solution (a), locate the components
of reference solution (a) in the chromatogram obtained with
--- the test solution.
Determine the percentage content of these components. The
limits are within the following ranges:
- a-pinene: 70.0 per cent to 85.0 per cent;
---
- camphene: 0.5 per cent to 2.0 per cent;
- f3-pinene: 5.0 per cent to 20.0 per cent;
- car-3-ene: maximum 1.0 per cent;
- f3-myrcene: 0.4 per cent to 1.5 per cent;
- limonene: 1.0 per cent to 7.0 per cent;
- longifolene: 0.2 per cent to 4.0 per cent;
- f3-caryophyllene: 0.1 per cent to 3.0 per cent;
- caryophyllene oxide: maximum 1.0 per cent;
- disregard limit: the area of the peak in the chromatogram
obtained with reference solution (b) (0.05 per cent).
Residue on evaporation (2.8.9): maximum 2.5 per cent,
determined after heating on a water-bath for 3 h.
STORAGE
At a temperature not exceeding 25 oc.
3973
Valerian dry hydroakoholic extract EUROPEAN PHARMACOPOEIA 8.2

07/2014:1898 Column:
- size: 1= 0.25 m, 0 = 4.6 mm;
VALERIAN DRY HYDROALCOHOLIC - stationary phase: octadecylsilyl silica gel for
EXTRACT chromatography R (5 ¡.tm).
Mobile phase:
Valerianae extractum hydroalcoholicum - mobile phase A: acetonitrile Rl, 5 giL solution of phosphorie
acid R (20:80 V/V);
siccum - mobile phase B: 5 giL solution of phosphoric acid R,
DEFINITION acetonitrile Rl (20:80 V/V);
Extract produced from Valerian root (0453). Time Mobile phase A Mobile phase B
(min) (per cení V/V) (per cent V/V)
Content: minimum 0.25 per cent mlm of sesquiterpenic acids,
expressed as valerenic acid (C ls H 2zÜ2; M, 234.3) (anhydrous 0-5 55 45
extract). 5 - 18 55 -7 20 45 -7 80

PRODUCTION
The extract is produced from the herbal drug by a suitable
procedure using ethanol (30-90 per cent V/V) or methanol
(40-55 per cent V/V).
CHARACTERS
Appearance: brown, hygroscopic powder.
IDENTIFICATION
Thin-layer chromatography (2.2.27).
Test solution. Suspend 1 g of the extraet to be examined in
10 mL of methanol R and sonicate for 10 mino Filter the
supernatant through a membrane filter (nominal pore size
0.45 ¡.tm).
Reference solution. Dissolve 5 mg of acetoxyvalerenic acid R
and 5 mg of valerenic acid R in 20 mL of methanol R.
Plate: TLC silica gel plate R (5-40 ¡.tm) [or TLC silica gel plate R
(2-10 ¡.tm)].
Mobile phase: glacial acetic acid R, ethyl acetate R,
cyclohexane R (2:38:60 V/V/V).
Application: 20 flL [or 5 ¡.tL] as bands of 10 mm [or 8 mm].
Development: over a path of 10 cm [or 6 cm].
Drying: in airo
Deteetion: treat with anisaldehyde solution R and heat at
100-105 oC for 5-10 min; examine in daylight.
Results: see below the sequence of zones present in the
chromatograms obtained with the reference solution and the
test solution. Furthermore, other violet zones may be present
in the chromatogram obtained with the test solution.
Top of the plate
---
Valerenic acid: a violet zone A violet zone (valerenic acid)
Acetoxyvalerenic acid: a violet zone A violet zone (acetoxyvalerenic
acid)
---
18 - 22 20 80
Flaw rate: 1.5 rnL/min.
Deteetion: speetrophotometer at 220 nm.
Injection: 20 ¡.tL.
Identificatian of peaks: use the chromatogram supplied with
valerian dry extraet HRS and the chromatogram obtained
with the reference solution to identify the peaks due to
hydroxyvalerenic acid, acetoAJValerenic acid and valerenic
acid.
System suitability: referenee solution:
- relative retention with reference to valerenic acid (retention
time = about 19 min) : hydroxyvalerenic acid = about 0.2;
acetoxyvalerenic acid = about 0.5.
Calculate the percentage content of sesquiterpenic acids,
expressed as valerenie acid, using the following expression:
(Al + A 2 + A3) x m2 x p x 5
A4 x mI
Al area of the peak due to hydroxyvalerenic acid in
the chromatogram obtained with the test solution;
Al area of the peak due to acetoxyvalerenic acid in the
chromatogram obtained with the test solution;
area of the peak due to valerenic acid in the
chromatogram obtained with the test solution;
area of the peak due to valerenic acid in the
chromatogram obtained with the reference
solution;
mass of the extraet to be examined used to prepare
the test solution, in grams;
--- mass of va/erian dry extraet HRS used to prepare
the reference solution, in grams;
P percentage content of valerenic acid in valerian dry
extract HRS.
---

07/2014:1891
2 faint or very faint violet zones

Reference solution Test solution WILDTHYME

TESTS
Water (2.5.12): maximum5.0 per cent, determined on 0.5 g.
ASSAY
Liquid chromatography (2.2.29).
Test solution. Suspend 1.00 g of the extract to be examined in
50.0 mL of methanol R1, sonicate for 10 min and filter through
a membrane filter (nominal pore size 0.45 ¡.tm).
Reference solution. Dissolve a quantity of valerian dry
extraet HRS corresponding to 0.5 mg of valerenic acid in
methanol R1 and dilute to 10.0 mL with the same solvent.
Sonicate for 10 min and filter through a membrane filter
(nominal pore size 0.45 ¡.tm).
Serpylli herba
DEFINITION
Whole or cut, dried, flowering aerial parts of Thymus
serpyllum L.
Content: minimum 3.0 mL/kg of essential oil (dried drug).
IDENTIFICATION
A. The stem is much branched, up to about 1.5 mm in
diameter, cylindrical or indistinctly quadrangular, green,
reddish or purplish, the older stems brown and woody, the
younger stems pubescent. The leaves are opposite, 3-12 mm
long and up to 4 mm wide, elliptical to ovate-lanceolate
with an obtuse apex, cuneate and shortly petiolate at the

3974 See the information sectian on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8,2 Wild thyme

base; the margin is entire and markedly ciliate, especially Top of the plate
near the base; both surfaces are more OI less glabrous but
A red fluorescent zone
distinctly punctate, The inflorescence is composed of about
6-12 flowers in rounded to ovoid, terminal heads, The calyx
is tubular, 2-lipped with the upper lip dividing to form
Rosmarinic acid: a blue A bIne fluorescent zone
3 teeth, the lower lip with 2 teeth, edged with long hairs; fluorescent zone (rosmarinic acid)
the inner surfaces are strongly pubescent, the hairs forming --- ---
a closed tube after flowering, The corolla is purplish-violet
or red, 2-lipped, the lower lip with 3 lobes and the upper 1 or 2 blue fluorescent zones
lip notched, the inner surÍace is strongly pubescent; 4
epipetalous stamens project from the corolla tube,
- - - ---
B, Microscopic examination (2,8,23), The powder is
A yellow or orange fluorescent
greyish-green or greenish-brown, Examine under a zone
microscope using ehloral hydrate solution R, The powder
A green or bIne fluorescent zone
shows the following diagnostic characters (Figure 1891.-1): may be present
fragments of the leaf epidermis es [A, B, F] covered by a Rutin: an orange-yellow
finely striated cuticle and consisting of cells with sinuous fluorescent zone
anticlinal walls [Aa, Ba, Fa] and diacytic stomata (2,8,3) Reference soll.ltion Test soll.ltion
[Ab, Bb, Fb]; cells of the adaxialleaf epidermis [B] with
wavy, irregularly thickened anticlinal walls [Ba]; numerous
covering trichomes on both epidermis es and the leaf
margins, with some of the ceUs containing very small
crystals of calcium oxalate [Af, Ca, Fd], the majority are
short, conical, unicellular, with thickened and warty walls
(surface view [Bc], side view [Fe]); fewer multieellular
covering trichomes, long, tapering to a point, eomposed
of up to 8 eells, slightly swollen at the joints, with finely
pitted walls, on an epidermis [Ae] or fragmented [e];
abundant glandular trichomes, mostly multieellular of
the lamiaceous type [Ac] with a unicellular stalk and a
glandular head consisting of 12 inconspieuous cells, others
with a unicellular stalk and a unicellular globular or ovoid
head [Ad]; purplish-violet fragments of the corolla whose
inner epidermis consists of cells with rounded papillae [D]
and whose outer epidermis [E], with a striated euticle,
consists of eells with lobed walls [Ea], unicellular [Eb 1or
multicellular [Ee] uniseriate covering trichomes, glandular
trichomes with a unicellular head and a unicellular stalk
[Ed] and glandular trichomes of the lamiaceous type;
relatively rare pollen grains, spherical, about 30 flm in
diameter, with a finely pitted exine and 6 germinal pores
[G],

C. Thin-layer ehromatography (2.2,27),

Test solution, To 0.5 g of the powdered herbal drug (355)

(2,9,12) add 5 mL of methanol R, Sonicate Íor 10 min,
Centrifuge or filter; use the supernatant or the filtrate,
Reference solution, Dissolve 1 mg of rutin R and 1 mg oí
rosmarinic acid R in 5 mL of methanol R.

Plate: TLC si/ica gel F254 plate R (5-40 flm) [or TLC si/ica
gel pIate R (2-10 flm)] ,
Mobile phase: anhydrous formic acid R, water R, ethyl
acetate R (1:1:15 V/V/V),
Application: 20 flL [or 51lL] as bands of20 mm [or 8 mm],
Development: over a path of 15 cm [or 6 cm],
Drying: in air,
Detection: heat at 100 oC for 3 min; treat the still-hot plate
with a 5 giL solution of diphenylboric acid aminoethyl
ester R in ethyl acetate R, then treat with a 50 giL solution
of macrogol 400 R in methylene chloride R; examine in
ultraviolet light at 365 nm,
Results: see below the sequence of zones present in the
chromatograms obtained with the reference solution and
the test solution, Furthermore, other faint fluorescent
zones may be present in the chromatogram obtained with
the test solution,
Figure 1891.-1.- Illustration for identification test B of
powdered herbal drug of wild thyme
TESTS
Foreign matter (2,8.2): maximum 3 per eent, determined on
30 g,
Thymus vulgaris L. or Thymus zygis L. Adulteration with
T. vulgaris L. or T. zygis L. is indicated by the presenee of
acicular to linear-lanceolate leaves with a strongly bent margin,
the adaxial surface showing covering trichomes shaped as
pointed teeth with warty walls, the abaxial surface showing
many types of warty covering trichomes : unicellular, straight
or slightly curved, bicellular or tricellular, often elbow-shaped,
and bicellular or trieellular, more or less straight,
Loss on drying (2,2,32): maximum 10,0 per cent, determined
on l.000 g of the powdered herbal drug (355) (2,9,12) by
drying in an oven at 105 oC for 2 h,
Total ash (2.4,16): maximum 10,0 per cent.

General Notices (1) apply to all monographs and other texts 3975
Yarrow EUROPEAN PHARMACOPOEIA 8.2

Ash insoluble in hydrochloric acid (2.8.1): maximum 3.0 per

cent.

ASSAY
Essential oil (2.8.12). Use 50.0 g of the cut herbal drug, a
1000 mL round-bottomed flask and 500 mL of water Ras
the distillation liquido Distil at arate of 2-3 mLlmin for 2 h
without xylene R in the graduated tube.

07/2014:1382

YARROW

Millefolii herba
DEFINITION
Whole or cut, dried flowering tops of Aehillea millefolium L.
Content:
essential oil: minimum 2 mLlkg (dried drug) ;
proazulenes, expressed as ehamazulene (C 14H 16 ; M r 184.3):
minimum 0.02 per cent (dried drug).

IDENTIFICATION
A. The leaves are green or greyish-green, faintIy pubescent on
the upper surface and more pubescent on the lower surface,
2-3 pinnately divided with linear lobes and a finely pointed
whitish tipo The capitula are arranged in a corymb at the
end of the stem. Each capitulum, 3-5 mm in diameter,
consists of the receptacle, usually 4-5ligulate ray-florets and
3-20 tubular disk-florets. The involucre consists 00 rows of
imbricate lanceolate, pubescent green bracts arranged with
a brownish or whitish, membranous margino The receptacle
is slightIy convex and, in the axillae of paleae, bears ligulate
ray-florets with a three-Iobed, whitish or reddish ligule and
tubular disk-florets with a radial, five-Iobed, yellowish or
light brownish corolla. The pubescent green, partIy brown
or violet stems are longitudinally furrowed, up to 3 mm
thick with a light-coloured medulla.
B. Microscopic examination (2.8.23). The powder is green
or greyish-green. Examine under a microscope using
ehloral hydrate solution R. The powder shows the following
diagnostic characters (Figure 1382.-1): fragments of the
stem epidermis (surface view [K]), with cells having a
smooth cuticle and anomocytic stomata (2.8.3); fragments
of leaf and bract epidermis es (surface view [B]), with
cells having wavy and irregularly thickened walls, a finely
striated cuticle and anomocytic stomata (2.8.3); very rare
glandular trichomes with a short stalk and a head formed of
2 rows of 3-5 cells enclosed in a bladder-like membrane [H] ;
uniseriate, whole or fragmented covering trichomes [A]
consisting of 4-6 small, more or les s isodiametric cells at the
base and a thick-walled, often somewhat tortuous terminal
cell, about 400 flm to greater than 1000 flm long; fragments
of the ligulate corolla with papillary epidermal cells [D];
fragments of the corolla tubes, with sinuous epidermal
cells, covered by a thin striated cuticle (surface view [F]);
small-celled parenchyma from the corolla tubes containing
cluster crystals of calcium oxalate [E]; groups oflignified
and pitted cells from the bracts [G]; spherical pollen grains,
about 30 flm in diameter, with 3 germinal pores and a spiny
exine [C]; groups of sclerenchymatous fibres and small
vessels with spiral or annular thickening, from the stem (Jl.
Figure 1382.-1. - Illustration for identification test B of
powdered herbal drug of yarrow
C. To 2.0 g ofthe powdered herbal drug (710) (2.9.12)
add 25 mL of ethyl aeetate R, shake for 5 min and filter.
Evaporate to dryness on a water-bath and dissolve the
residue in 0.5 mL of toluene R (solution A). To 0.1 mL of
this solution add 2.5 mL of dimethylaminobenzaldehyde
solution R8 and heat on a water-bath for 2 mino Allow
to coo1. Add 5 mL of light petroleum R and shake the
mixture vigorously. The aqueous layer shows a blue or
greenish-blue colour.
D. Thin-Iayer chromatography (2.2.27).
Test solution. Use solution A prepared in identification
test C.
Referenee solution. Dissolve 10 mg of cineole R and 10 mg
of guaiazulene R in 20 mL of toluene R.
Plate: TLC si/ica gel plate R.
Mobile phase: ethyl aeetate R, toluene R (5:95 VIV).
Applieation: 20 flL as bands.
Development: over a path of 10 cm.
Drying: in airo
Deteetion: treat with anisaldehyde solution R, heat at
100-105 oC for 5-10 min and examine in daylight.
Results: the chromatogram obtained with the reference
solution shows in the upper part a red zone (guaiazulene)
and in the middle part a blue or greyish-blue zone (cineole).
The chromatogram obtained with the test solution shows a
violet zone a little aboye the zone due to guaiazulene in the
chromatogram obtained with the reference solution; below
this zone a reddish-violet zone; belowwhich, 1-2 not clearly
separated greyish-violet or greyish zones (which changes to
greenish-grey after a few hours) and a reddish-violet zone a
little aboye the zone due to cine ole in the chromatogram
obtained with the reference solution. Furthermore, other
faint zones may be presento

3976 See the information seetion on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
TESTS
Foreign matter (2.8.2): maximum 5 per cent of stems with a
diameter greater than 3 mm and maximum 2 per cent of other 10 mino
foreign matter.
L088 on drying (2.2.32) : maximum 12.0 per cent, determined
on 0.500 g of the powdered herbal drug (355) (2.9.12) by
drying in an oven at 105 oC for 2 h.
Total ash (2.4.16): maximum 10.0 per cent
Ash insoluble in hydrochlork add (2.8.1): maximum 2.5 per Measure the absorbance (2.2.25) at 608 nm using xylene R
cent.
ASSAY
Essential oH (2.8.12). Use 20.0 g of cut herbal drug, a 1000 mL
round-bottomed flask and 500 mL of a mixture of 1 volume of
water R and 9 volumes of ethylene g/yeol R as the distillation
liquido Add 0.50 mL of 1,2,4-trimethylbenzene R in the
graduated tube. Distil at arate of 3-4 mLlmin for 4 h.
Stop cooling at the end of distillation and continue distilling
until the blue, steam-volatile components have reached the
General Natices (1) apply ta all manographs and other texts
Yarrow
lower end of the cooler. Immediately start cooling again, to
avoid warming the separation space. Stop the distillation after
Proazulenes. To ensure that as httle water as possible is
transferred, transfer the blue mixture of essential oil and
1,2,4-trimethylbenzene obtained in the assay of essential oil
into a 50 mL volumetric flask with the aid of small portions
of xylene R, rinsing the graduated tube of the apparatus
with xy/ene R, and dilute to 50.0 mL with the same solvento
as the compensation liquido
Calculate the percentage content of proazulenes, expressed as
chamazulene, using the following expression:
A x 2.1
m
Le. taking the specific absorbance of chamazulene to be 23.8.
A absorbance at 608 nm;
m mass of the herbal drug to be examined, in grams.
3977
 EUROPEAN PHARMACOPOEIA 8.2

3978 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
Homoeopathic pre arations
Allium sativum for homoeopathic preparations ................ 3981
Anacardium for homoeopathic preparations ...................... 3981
Apis for homoeopathic preparations .................................... 3983
Arsenicum album for homoeopathic preparations ............ 3983
Aurum chloratum natronatum for homoeopathic
preparations .......................................................................... 3984
Barium chloratum for homoeopathic preparations ........... 3984
Cadmium sulfuricum for homoeopathic preparations ...... 3985
Calcium iodatum for homoeopathic preparations ............. 3985
General Notices (1) apply to all monographs and other texts
Cocculus for homoeopathic preparations ........................... 3986
Crocus for homoeopathic preparations ............................... 3987
Cuprum aceticum for homoeopathic preparations ............ 3988
Cuprum metallicum for homoeopathic preparations ........ 3989
Ferrum metallicum for homoeopathic preparations ......... 3989
Kalium bichromicum for homoeopathic preparations ...... 3990
Magnesium phosphoricum for homoeopathic
preparations .......................................................................... 3991
Urtica dioica for homoeopathic preparations ..................... 3991
3979
 EUROPEAN PHARMACOPOEIA 8.2

3980 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2 Anacardium for homoeopathic preparations

07/2014:2023 Detection: examine in ultraviolet light at 254 nm and

identify gallic acid; spray with anisaldehyde solution R, heat
ALLIUM SATIVUM FOR to 105-110 oC for 5-10 mino Examine in daylight within
10 mino
HOMOEOPATHIC PREPARATIONS(1) Results: see below the sequence of the zones present in the
chromatograms obtained with the reference solution and
Allium sativum ad praeparationes the test solution. Other zones may also be visible in the
homoeopathicas chromatogram obtained with the test solution.
Top of the plate
DEFINITION
An intense reddish-violet zone
Fresh bulb of Allium sativum L.
Thymol: an orange-red zone
CHARACTERS
An intense reddish-violet zone
It has a characteristic odour after cutting.
A viole! zone
IDENTIFICATION
A yellowish or greenish zone
The bulb is generally 3 cm to 5 cm broad and almost
spherical; the flat base bears the remnants of numerous short ~~- ~~-

greyish-brown adventitious roots. The bulb consists of about Resorcinol: an intense orange-red
10 daughter bulbs (cloves) arranged roughly in a circle around zone
a central axis. Individual daughter bulbs are 1 cm to 3 cm ~~- ~~-

long, laterally compressed and convex on the dorsal side. Each

daughter bulb has a tough, white or reddish skin around a Gallic acid: a yellow zone A violet zone
fleshy tubular leaf, investing a more or less rounded elongated (UV at 254 nm: a fluorescent A greenish -yellow zone
cone of leaf primordia and vegetative apex. quenching zone)
A violet zone may be present
TESTS
Reference soludou Test solution
Water (2.2.13): minimum 55.0 per cent, determined on
10.0 g of the finely cut drug, if performed to demonstrate the
freshness of the drug. TESTS
Relative density (2.25): 0.885 to 0.960.
Mother tincture Ethanol (2.9.10): 50 per cent V/V to 70 per cent V/V.
The mother tincture complies with the requirements of Dry residue (2.8.16): minimum 4.0 per cent.
the general monograph Mother tinctures for homoeopathic
STORAGE
preparations (2029).
In an airtight container.
PRODUCTION
The mother tincture of Allium sativum L. is prepared by 07/2014:2094
maceration of the cut drug using alcohol of a suitable
concentration.
ANACARDIUM FOR HOMOEOPATHIC
CHARACTERS PREPARATIONS(2)
Appearance: brownish-yellow liquido
1t has a peculiar and unpleasant aromatic odour. Semecarpus anacardium ad praeparationes
IDENTIFICATION homoeopathkas
A. To 2 mL of the mother tincture to be examined, add 0.2 mL DEFINITION
of dilute sodium hydroxide solution R. A yellowish-white
Dried fruit of Semecarpus anacardium L. (Anacardium
precipitate develops.
orientale L.).
B. Thin-Iayer chromatography (2.2.27).
Content: minimum 6.0 per cent m/m of total phenol
Test solution. Extract 5 mL of the mother tincture to be derivatives expressed as eugenol (C IO H 12 0 2 ; M,. 164.2) (dried
examined with 2 quantities, each of 10 mL, of ether R. drug).
Combine the ether layers and dry over anhydrous sodium
sulfate R. Filter and evaporate the filtrate in a water-bath IDENTIFICATION
at low temperature. Dissolve the residue in 0.4 mL of A. The dried fruit is oval and more or les s heart-shaped; about
methanol R. 2 cm long, nearly 2 cm wide and 0.5 cm thick. Its surface is
Reference solution. Dissolve 10 mg of resorcinol R, 10 mg of smooth, shiny and blackish. A transverse section shows a
thymol R and 30 mg of ga/lic acid R in 10 mL of methanol R. rather well developed, tough pericarp riddled with rather
Plate: TLC silica gel F254 plate R. wide lacunae containing an abundant thick reddish-brown
juice. The pericarp covers a white kernel under a reddish
Mobile phase: anhydrous formic acid R, toluene R, skin. The fruit may include the blackish, fleshy, wrinkled,
di-isopropyl ether R (10:40:50 V/V/V). cupuliferous receptacle.
Application: 40 IlL of the test solution and 10 IlL of the B. Thin-layer chromatography (2.2.27).
reference solution.
Test solution. To 1.0 g of suitably cut herbal drug, add
Development: over a path of 10 cm. 10 mL of ethanol (90 per cent V/V) R. Heat under reflux on
Drying: in airo a water-bath at 60 oC for 15 mino AlIow to cool and filter.

(1) FRENCH TITLE: Allium sativum pour préparations homéopathiques

(2) FRENCH TITLE: Anacardium orientale pour préparations homéopathiques

General Notices (1) apply to all monographs and other texts 3981
Anacardium for homoeopathic preparations
Reference solution. Dissolve 5 mg of gallic acid R and 5 mg
of caffeic acid R in methanol R and dilute to 10 mL with
the same solvent.
Plate: TLC si/ica gel plate R.
Mobi/e phase: methanol R, toluene R (15:85 V/V).
Application: 20 flL of the test solution and 10 flL of the
reference solution, as bands.
Development: over a path of 15 cm.
Drying: in airo
Detection: spray with a solution containing 10 giL of
diphenylboric acid aminoethyl ester R and 50 giL of
macrogol 400 R in methanol R. Examine in ultraviolet light
at 365 nm.
Results: see below the sequence of zones present in the
chromatograms obtained with the reference solution and
the test solution. Furthermore, other fainter zones may
be present in the chromatogram obtained with the test
solution.
Top of the plate
A greenish-blue fluorescent zone
--- ---
Several violet-blue fluorescent
zones
A yellow fluorescent zone
Caffeic acid: a violet-blue
fluorescent zone
--- ---
Gallic acid: a violet -blue A violet-blue fluorescent zone
fluorescent zone (gallic acid)
Reference solution Test solution
TESTS
Anacardium occidentale L. Fruits of Anacardium occidentale L.
IDENTIFICATION
are not present. These are up to 35 mm long, 30 mm large,
20 mm thick, light brown and distinctly kidney-shaped. The Thin-Iayer chromatography (2.2.27) as described under
pericarp is smooth or slightly crinkled with dark marbling Identification B of the drug with the following modification.
in places. Test solution. The tincture to be examined.
Loss on drying (2.2.32) : maximum 12.0 per cent, determined Results: see identification B for the drug.
on 1.000 g of the Cnely divided herbal drug by drying in an
TESTS
oven at 105 oC for 2 h.
Relative density (2.2.5): 0.815 to 0.845.
Total ash (2.4.16): maximum 5.0 per cent.
Ethanol (2.9.10): 85 per cent V/V to 95 per cent V/V.
ASSAY Dry residue (2.8.16): minimum 1.50 per cent mimo
Total phenol derivatives. Absorption spectrophotometry
(2.2.25).
Stock solution. Place 4.500 g of the crushed herbal drug in a
flask. Add 200 mL of ethanol (90 per cent V/V) R. Boil in a
water-bath under reflux for 4 h. Cool the flask. Quantitatively
transfer into a volumetric flask. Dilute to 250.0 mL with
ethanol (90 per cent V/V) R. Filter the liquid through a paper
filter 125 mm in diameter. Discard the first 50 mL of the
filtrate. Dilute 5.0 mL of filtrate to 50.0 mL with ethanol
(90 per cent V/V) R and shake. Dilute 5.0 mL of this solution
to 10.0 mL with ethanol (90 per cent V/V) R and shake.
Test solution. To 2.0 mL of stock solution add 1.0 mL of
phosphomolybdotungstic reagent R and 10 mL of water R,
mix and dilute to 25.0 mL with a 290 giL solution of sodium
carbonate R. Wait exactly 3 min then filter the solution through
a fibre-glass filter with a 1 flm mesh aperture, discarding the
first 5 mL.
Reference solution. Dissolve 80.0 mg of eugenol R in ethanol
(90 per cent V/V) R and dilute to 250.0 mL with the same
solvento Dilute 5.0 mL of the solution to 25.0 mL with
ethanol (90 per cent V/V) R. To 2.0 mL of this solution add
3982
EUROPEAN PHARMACOPOEIA 8.2
1.0 mL of phosphomolybdotungstic reagent R and 10 mL of
water R, mix and dilute to 25.0 mL with a 290 giL solution
of sodium carbonate R. Wait exactly 3 min then filter the
solution through a fibre-glass filter with a 1 flm mesh aperture,
discarding the first 5 mL.
Measure the absorbance (2.2.25) of the test solution and the
reference solution at 755 nm after 30 min using water R as
compensation liquido
Calculate the percentage content m/m of total phenol
derivatives, expressed as eugenol, from the following
expression:
absorbance of the test solution;
absorbance of the reference solution;
mas s of the drug to be examined, in milligrams;
mass of eugenol in the reference solution, in
milligrams.
Mother tincture
The mother tincture complies with the requirements of
the general monograph Mother tinctures for homoeopathic
preparations (2029).
DEFINITION
The mother tincture of Anacardium is prepared by maceration
using ethanol of a suitable concentration from the dried fruit
of Semecarpus anacardium L. (Anacardium orientale L.).
Content: 0.5 per cent m/m to 1.0 per cent m/m oftotal phenol
derivatives expressed as eugenol.
CHARACTERS
Appearance: yellowish-brown or reddish-brown liquido
ASSAY
Total phenol derivatives. Absorption spectrophotometry
(2.2.25) as described in the assay of the drug to be examined
with the following modifications.
Stock solution. Place 8.000 g of the mother tincture to be
examined in a volumetric flask and dilute to 250.0 mL with
ethanol (90 per cent V/V) R. Dilute 5.0 mL of this solution to
20.0 mL with ethanol (90 per cent V/V) R.
Test solution. To 2.0 mL of stock solution add 1.0 mL of
phosphomolybdotungstic reagent R and 10 mL of water R,
mix and dilute to 25.0 mL with a 290 giL solution of sodium
carbonate R. Wait exactly 3 min then filter the solution through
a fibre-glass filter with a 1 flm mesh aperture, discarding the
first 5 mL.
Reference solution. Dissolve 80.0 mg of eugenol R in ethanol
(90 per cent V/V) R and dilute to 250.0 mL with the same
solvent. Dilute 5.0 mL of the solution to 25.0 mL with
ethanol (90 per cent V/V) R. To 2.0 mL of this solution add
1.0 mL of phosphomolybdotungstic reagent R and 10 mL of
water R, mix and dilute to 25.0 mL with a 290 giL solution
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2 Arsenicum album for homoeopathic preparations

of sodium carbonate R. Wait exactly 3 min then fiIter the Test soIution. The mother tincture to be examined.
solution through a fibre-glass filter with a 1 flm mesh aperture, Reference soIution. Dissolve 12 mg of 4-aminobutanoic acid R,
discarding the first 5 mL. 12 mg of leucine R and 12 mg of proline R in 5 mL of water R
Measure the absorbance (2.2.25) of the test solution and the and dilute to 50 mL with alcohol R.
reference solution at 755 nm after 30 min, using water Ras PIate: TLC si/ica gel pIate R.
compensation liquido Mobile phase: water R, ethanol R (17:63 V/V).
Calculate the percentage content m/m of total phenol Application: 20 flL, as bands.
derivatives expressed as eugenol, using the following
Development: over a path of 10 cm.
expression:
Drying: in airo
Detection: spray with ninhydrin solution R and heat at
100-105 oC for 10 min; examine in daylight.
Results: see below the sequence of the zones present in the
A¡ absorbance of the test solution;
chromatograms obtained with the reference and test solutions.
A2 absorbance of the reference solution; Other zones may also be visible.
m¡ mass of the mother tincture to be examined, in Top oí the plate
milligrams ; --- ---
m2 mass of eugenol in the reference solution, in
A pinkzone
milligrams.
Leucine: a pink zone A pinkzone

07/2014:2024 A pink zone

A pinle zone
APIS FOR HOMOEOPATHIC --- ---
PREPARATIONS(3)
Pro!ine: an orange-yellow zone An orange-yellow zone

Apis mellifera ad praeparationes 4-Aminobutanoic acid: a pink zone A pink zone

homoeopathicas
DEFINITION
Live worker honey bee (Apis mellifera L.). Reference solution Test solution

CHARACTERS
Characters described under Identification.
PRODUCTION
If the bee has been exposed to treatment to prevent or cure
diseases, appropriate measures are taken to ensure that the
levels of residues are as low as possible.
IDENTIFICATION
The body is about 15 mm long, black, with a silky sheen,
and covered with red hairs with a touch of grey. The broad
tibiae are without spines. The posterior margins of the
segments and legs are brown, with gradual transition to
orange-red. The claws are two-membered, the maxillary palps
single-membered. On the hind legs are baskets or scoops
invested with bristles. The wings have 3 complete cubital cells,
with the radial ceH twice as long as it is wide; the 3 cells on
the lower margin and the 3 middle cells are closed. A duct
connects the barbed sting with the poison sac.
Mother tincture
The mother tincture complíes with the requirements of
the general monograph Mother tinctures for homoeopathic
preparations (2029).
PRODUCTION
The mother tincture of Apis mellifera L. is prepared by
maceration using alcohol of a suitable concentration.
CHARACTERS
Pale yellow liquid that may darken on storage.
IDENTIFICATION
Thin-layer chromatography (2.2.27).
TESTS
Relative density (2.2.5): 0.890 to 0.910.
Ethanol (2.9.10): 60 per cent V/V to 70 per cent V/V.
Dry residue (2.8.16): minimum 0.30 per cent.
0712014:1599
ARSENICUM ALBUM FOR
HOMOEOPATHIC PREPARATIONS(4)
Arsenii trioxidum ad praeparationes
homoeopathicas
AsZO) M r 197.8
[1327-53-3]
DEFINITION
Content: 99.5 per cent to 100.5 per cent of As 2 0).
CHARACTERS
Appearance: white or almost white powder.
Solubility: practically insoluble to sparingly soluble in water.
It dissolves in solutions of alkali hydroxides and carbonates.
IDENTIFICATION
A. Dissolve 20 mg in 1 mL of dilute hydrochloric acid R, add
4 mL of water R and 0.1 mL of sodium sulfide solution R.
The resulting yellow precipitate is soluble in dilute
ammonia Rl.
B. Dissolve 20 mg in 1 mL of hydrochloric acid Rl, add 5 mL
of hypophosphorous reagent R and heat for 15 min Oil a
water-bath. A black precipitate develops.

(3) FRENCH TITLE: Apis mellifica pour préparations homéopathiques

(4) FRENCH TITLE: Arsenicum album pour préparations homéopathiques

General Notices (1) apply to al! monographs and other texts 3983
Aurum chloratum natronatum for homoeopathic preparations
TESTS
Appearance of solution. A 100 giL solution in dilute
ammonia R1 is clear (2.2.1) and colourless (2.2.2, Method Il).
Sulfides: maximum 20 ppm.
Dissolve 1.0 g in 10.0 mL of dilute sodium hydroxide solution R.
Add 0.05 mL of lead acetate solution R. Any colour in the test
solution is not more intense than that in a standard prepared
at the same time and in the same manner using a mixture of
10.0 mL of a 0.015 giL solution of sodium sulfide R in dilute
sodium hydroxide solution R and 0.05 mL of lead acetate
solution R.
ASSAY
Dissolve 40.0 mg in a mixture of 10 mL of water R and 10 mL
of dilute sodium hydroxide solution R. Add 10 mL of dilute
hydrochloric acid R and 3 g of sodium hydrogen carbonate R
and mix. Add 1 mL of starch solution R and titrate with 0.05 M
iodine.
1 mL of 0.05 M iodine is equivalent to 4.946 mg of ASP3.
07/2014:2141
AURUM CHLORATUM NATRONATUM
FOR HOMOEOPATHIC
PREPARATIONS(5)
Natrii tetrachloroauras dihydricus ad
praeparationes homoeopathicas
Na [AuC14 J,2Hp M r 397.8
DEFINITION
Sodium tetrachloroaurate( 1-) dihydrate.
Content: 97.0 per cent to 101.0 per cent ofNa[AuC14 J,2Hp.
CHARACTERS
Appearance: orange-yellow, hygroscopic powder or crystals.
Solubility: very soluble or freely soluble in water and in
ethanol (96 per cent).
IDENTIFICATION
A. Dissolve 20 mg in 2.0 mL of 0.1 M nitric acid. Add 0.1 g
of oxalic acid R and boil in a water-bath for 1 h. A deposit
of metallic gold is formed.
B. Solution S (see Tests) gives reaction (a) of chlorides (2.3.1).
C. Solution S gives reaction (b) of sodium (2.3.1).
TESTS
Solution S. Ignite 0.20 g in a porcelain crucible at
600 oC ± 50 oC for 30 mino Allow to cool and extract with
3 mL of water R, heating if necessary. Use the supernatant.
Free hydrochloric acid. When a glass rod impregnated with
concentrated ammonia R is held close to the substance to be
examined, no white fumes are produced.
Nitrates: maximum 200 ppm.
Dissolve 0.20 g in 10 mL of nitrate-free water R. Add 0.2 g of
oxalic acid R. Heat the solution on a water-bath for 30 min,
allow to cool and filter. Rinse the filter with nitrate-free
water R and dilute the filtrate to 20 mL with the same solvento
To 1.0 mL of the solution obtained add 4.0 mL of nitrate-free
water R, 0.4 mL of a 100 giL solution of potassium chloride R,
0.1 mL of diphenylamine solution R and, dropwise with
shaking, 5 mL of nitrogen-free sulfuric acid R. Transfer the
tube to a water-bath at 50 oc. After 15 min, any blue colour
in the solution is not more intense than that in a reference
(5) FRENCH TITLE: Aurum muriaticum natronatum pour préparations homéopathiques
(6) FRENCH TITLE: Baryta muriatica pour préparations homéopathiques
3984
EUROPEAN PHARMACOPOEIA 8.2
solution prepared at the same time in the same manner using
a mixture of 0.2 mL of nitrate standard solution (10 ppm
NOJ R and 4.8 mL of nitrate-free water R.
Heavy metals (2.4.8): maximum 100 ppm.
Dissolve 0.20 g in 15 mL of water R. Add 0.25 g of hydrazine
sulfate R. Heat the solution on a water-bath for 30 min, allow
to cool and filter. Rinse the filter with water R and dilute the
filtrate to 20 mL with the same solvento 12 mL of the solution
complíes with test A. Prepare the reference solution using lead
standard solution (1 ppm Pb) R.
ASSAY
Dissolve 40.0 mg in 10 mL of potassium iodide solution R.
Allow to stand for 5 mino Titrate with 0.01 M sodium
thiosulfate until decolourised. Shortly before reaching the
endpoint, add 0.5 mL of starch solution R.
1 mL of 0.01 M sodium thiosulfate is equivalent to 1.989 mg of
Na [AuC14 J,2Hp.
STORAGE
In an airtight container, protected from líght.
07/2014:2142
BARIUM CHLORATUM FOR
HOMOEOPATHIC PREPARATIONS(6)
Barii chloridum dihydricum ad
praeparationes homoeopathicas
BaC12 ,2HP M r 244.3
[10326-27-9]
DEFINITION
Content: 99.0 per cent to 101.0 per cent of BaC12,2H 2 0.
CHARACTERS
Appearance: white or almost white, crystalline powder or
colourless crystals.
Solubility: freely soluble in water, very slíghtly soluble or
practically insoluble in ethanol (96 per cent).
IDENTIFICATION
A. Dissolve 0.1 g in 1 mL of water R. Add 0.3 mL of dilute
sulfuric acid R. A white precipitate is formed; it is insoluble
in dilute hydrochloric acid R and in dilute nitric acid R.
B. It gives reaction (a) of chlorides (2.3.1).
TESTS
Solution S. Dissolve 10.0 g in water R and dilute to 100 mL
with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and
colourless (2.2.2, Method Il).
Acidity or alkalinity. To 10 mL of solution S add 0.1 mL of
phenolphthalein solution R. Not more than 0.2 mL of 0.01 M
hydrochloric acid or 0.01 M sodium hydroxide is required to
change the colour of the indicator.
Heavy metals (2.4.8): maximum 10 ppm.
12 mL of solution S complíes with test A. Prepare the reference
solution using lead standard solution (1 ppm Pb) R.
ASSAY
Dissolve 0.200 g in 100 mL of water R. Add 100 mL of
methanol R, 10 mL of concentrated ammonia R and 2 mg of
phthalein purple R. Titrate with 0.1 M sodium edetate until the
colour changes from violet to colourless.
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
1 mL of 0.1 M sodium edetate is equivalent to 24.43 mg
of BaC1 2 ,2Hp.
0712014:2143
CADMIUM SULFURICUM POR
HOMOEOPATHIC PREPARATIONS(7)
Cadmii sulfas hydricus ad praeparationes
homoeopathicas
CdS0 4 ,8/3HP
DEFINITION
Content: 98.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance: white or almost white, crystalline powder.
Solubility: freely soluble in water, practically insoluble in
ethanol (96 per cent).
IDENTIFICATION
A. It gives reaction (a) of sulfates (2.3.1).
B. To 2 mL of solution S (see Tests) add 2 mL of sodium sulfide
solution R. A precipitate is formed.
TESTS
Solution S. Dissolve 5.0 g in carbon dioxide-free water R and
dilute to 50 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and
colourless (2.2.2, Method IJ).
Addity or alkalinity. To 10 mL of solution S add 0.3 mL
of methyl orange solution R. Not more than 0.5 mL of
0.01 M hydrochloric acid or 0.01 M sodium hydroxide is
required to change the colour of the indicator.
Nitraíes: maximum 100 ppm.
Dissolve 1.0 g in water R and dilute to 20.0 mL with the same
solvent. To 1.0 mL of this solution add 0.2 mL of a 10 giL
solution of sulfanilic acid R in acetic acid R and 0.2 mL of a
recently prepared 3 giL solution of naphthylamine R in acetic
acid R. Add a turning of zinc R. A pink colour is produced
within 5 mino It is not more intense than that of a mixture
of 0.5 mL of nitrate standard solution (la ppm N0 3) R and
0.5 mL of water R, prepared at the same time.
Zinc sulfate, alkaline-earth sulfates, rare-earth sulfates.
Dissolve 1.0 g in 17 mL of water R. Add 0.5 mL of hydrochloric 0.100 g.
acid R and 1 g of thioacetamide R. Heat in a water-bath for
10 mino Dilute to 20.0 mL with water R and filter. Evaporate
10.0 mL of this solution to dryness in an oven. Ignite the
residue at about 800 ± 50 oC to constant mass. The residue
weighs a maximum of 2 mg.
Arsenic (2.4.2, Method A): maximum 2 ppm, determined on reddish -yellow.
5 mL of solution S.
Water (2.5.12): 16.0 per cent to 20.0 per cent, determined
on 80 mg. Shake for 10 min before carrying out the
determination.
(7) f<RENCH TITLE: Cadmium sulfuricum pour préparations homéopathiques
(8) FRENO! TITLE: Calcarea ioda!a pour préparations homéopathiques
General Notices (1) apply to all monographs and other texts
Cakium iodafum for homoeopathi.c preparations
ASSAY
Dissolve 0.200 g in 50 mL of water R. Add 10 mL of ammonium
chloride buffer solution pH 10.0 R and 50 mg of mordant
black 11 triturate Rl. Titrate with 0.1 M sodium edetate until
the colour changes from red to green.
1 mL of 0.1 M sodium edetate is equivalent to 20.85 mg
ofCdS0 4 •
07/2014:2144
CALCIUM IODATUM POR
HOMOEOPATHIC PREPARATIONS(8)
Calcii iodidum tetrahydricum ad
M r 256.5
praeparationes homoeopathicas
CaI 2,4Hp M r 366.0
[13640-62-5]
DEFINITION
Content: 97.0 per cent to 102.0 per cent of CaI2 (anhydrous
substance) .
CHARACTERS
Appearance: white or almost white, very hygroscopic powder.
Solubi/ity: very soluble or freely soluble in water and in
ethanol (96 per cent).
IDENTIFICATION
A. Solution S (see Tests) gives reaction (a) of calcium (2.3.1).
B. Solution S (see Tests) gives reaction (b) ofiodides (2.3.1).
TESTS
Solution S. Dissolve 10.0 g in distilled water R and dilute to
100.0 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solution GY s (2.2.2,
Method IJ).
Free iodine, iodates. To 5 mL of solution S add 2 mL of
methylene chloride R. Shake and allow to stand. The organic
layer is colourless (2.2.2, Method I) (free iodine). Add 0.2 mL
of dilute sulfuric acid R. Shake and allow to stand. The organic
layer remains colourless (2.2.2, Method 1) (iodates).
Sulfates (2.4.13): maximum 150 ppm.
Dilute 10 mL of solution S to 15 mL with distilled water R.
!ron (2.4.9): maximum 10 ppm, determined on 10 mL of
solution S.
Heavy metals (2.4.8): maximum 10 ppm.
12 mL of solution S complies with test A. Prepare the reference
solution using lead standard solution (1 ppm Pb) R.
Water (2.5.12): 18.0 per cent to 22.0 per cent, determined on
ASSAY
Dissolve 0.300 g in 50 mL of water R. Add 5 mL of dilute
nitric acid R and 25.0 mL of 0.1 M si/ver nitrate. Shake. Add
2 mL of ferric ammonium sulfate solution R2 and titrate with
0.1 M ammonium thiocyanate until the colour changes to
1 mL of 0.1 M si/ver nitrate is equivalent to 14.70 mg of Cal 2 •
STORAGE
In an airtight container.
3985
Cocculus for homoeopathic preparations EUROPEAN PHARMACOPOEIA 8.2

07/2014:2486 Deteetion: spray with anisaldehyde solution R, heat at

100-105 oC for 5-10 min and examine immediately in
COCCULUS FOR HOMOEOPATHIC daylight.
Results: see below the sequence of zones present in the
PREPARATIONS(9) chromatograms obtained with the reference solution and
the test solution. Above the zone due to picrotoxinin,
Anamirta cocculus ad praeparationes several pink or violet zones may also be visible in the
homoeopathicas chromatogram obtained with the test solution.
Top of the plate
DEFINITION
Dried, ripe fruit of Anamirta coeeulus (1.) Wight & Arn. (syn. --- ---
A. panieulata Colebr.).
Picrotoxinin: a blue zone A blue zone (picrotoxinin)
Content: minimum 0.80 per cent ofpicrotoxinin (ClsH1606;
M r 292.3) (dried drug). --- --
IDENTIFICATION Picrotin: a blue zone A blue zone (picrotin)

First identifieation: A, B, D. Reference solution Test solution

Seeond identifieation: A, B, C.
A. The fruits are dark greyish-brown or black, reniform or
sub-spherical, about 6-10 mm in diameter and 9-12 mm
long; the outer surface is irregularly wrinkled with a ridge
about 4-6 mm long running between the pale, circular
scar left by the stalk and the small beak of the remains of
the stigma. The pericarp is hard, about 1 mm thick and
the inner surface is brownish-grey, hard and woody. Cut
transversely, the fruit shows a single, cup-shaped seed
into the hollow of which an ingrowth of the mesocarp
and endocarp projects. Cut longitudinally, the endosperm
shows the presence of 2 narrow cavities in each of which is
enclosed 1 of the foliaceous cotyledons.
B. Microscopic examination (2.8.23). Reduce to a
powder (710) (2.9.12). The powder is brown. Examine
under a microscope using ehloral hydrate solution R. The
powder shows the following diagnostic characters (Figure
2486.-1): fragments of the epicarp (surface view [D])
consisting of thin-walled, polygonal cells, about 30-50 flm
in diameter [Da], anomocytic stomata (2.8.3) [Db], and
cells in a pattern consisting of a cell with slight1y thickened
walls, pitted at the centre, surrounded by 4-6 cells [Dc];
fragments of the epicarp and outer layers of the mesocarp
(transverse section [C]) showing the epicarp covered by
a fine cuticle [Ca] and cells of the mesocarp, ovoid or
rounded, sorne containing prisms of calcium oxalate [Cb];
numerous fragments of the inner layers of the mesocarp
and of the endocarp [A] consisting of sclereids [Aa]
and short fibres with pitted walls [Ab]; fragments of the
endocarp consisting of layers of variously oriented fibres Figure 2486.-1. - Illustration for identifieation test B of
(surface view [E]); sclereids and isolated fibres [B]; vascular powdered herbal drug of coeeulus
bundles (longitudinal section [F]), accompanied by fibres D. Examine the chromatograms obtained in the assay.
[Fa]; fragments of the endosperm [G, H] containing very
Results: the peaks due to picrotoxinin and picrotin in
numerous small acicular crystals.
the chromatogram obtained with the test solution are
C. Thin-Iayer chromatography (2.2.27). similar in retention time to the corresponding peaks in the
Test solution. To 2.00 g of the powdered herbal drug (710) chromatogram obtained with the reference solution.
(2.9.12) add 20 mL of ethanol (90 per eent V/V) R, shake for
2 h and then centrifuge (IOOO g). Use the supernatant. TESTS
Referenee solution. Dissolve 10 mg of pierotin R and 10 mg Loss on drying (2.2.32): maximum 10.0 per cent, determined
of pierotoxinin R in ethanol (96 per eent) R and dilute to on 1.000 g of the powdered herbal drug (710) (2.9.12) by
10 mL with the same solvent. drying in an oven at 105 oC for 2 h.
Plate: TLC si/ica gel plate R (5-40 flm) [or TLC si/iea gel Total ash (2.4.16): maximum 6.0 per cent.
plate R (2-10 flm)].
ASSAY
Mobi/e phase: methanol R, ethyl aeetate R, heptane R
(10:40:50 V/V/V). Liquid chromatography (2.2.29).
Applieation: 40 flL [or 10 flL] as bands of 20 mm [or Test solution. To 2.000 g of the powdered herbal drug (710)
10 mm]. (2.9.12) add 20.0 mL of ethanol (90 per cent VIV) R, shake for
2 h and then centrifuge at 1000 g for 5 mino Dilute 2.0 mL of
Development: over a path of 10 cm [or 6 cm]. the supernatant to 20.0 mL with the mobile phase and filter
Drying: in airo through a membrane filter (nominal pore size 0.45 flm).

(9) FRENCH TITLE: Cocculus indicus pour préparations homéopathiques

3986 See the information seetion on general monographs (eover pages)

EUROPEAN PHARMACOPOEIA 8.2
Reference solution. Dissolve 5.0 mg of picrotin CRS and 5.0 mg
of picrotoxinin CRS in 10.0 mL of acetonitrile R. Dilute 2.0 mL
of the solution to 20.0 mL with the mobile phase.
Column:
- size: 1 = 0.125 m, 0 = 4.0 mm;
- stationary phase: octadecylsilyl silica gel for
chromatography R (5 ¡.tm).
Mobile phase: acetonitrile for chromatography R1, water R
(30:70 V/V).
Flow rate: 0.5 mL/min.
Detection: spectrophotometer at 200 nm.
Injection: 10 ¡.tL.
Run time: twice the retention time of picrotoxinin CRS.
Retention time: picrotin = about 6 min;
picrotoxinin = about 9.5 mino
System suitability: reference solution:
- resolution: minimum 2.0 between the peaks due to picrotin
and picrotoxinin.
Calculate the percentage content of picrotoxinin using the
following expression:
area of the peak due to picrotoxinin in the
chromatogram obtained with the test solution;
are a of the peak due to picrotoxinin in the
chromatogram obtained with the reference
solution;
mass of the herbal drug to be examined used to
prepare the test solution, in grams;
mass of picrotoxinin CRS used to prepare the
reference solution, in grams;
p assigned percentage content of picrotoxinin in
picrotoxinin CRS.
Mother tincture
The mother tincture complíes with the requirements of
the general monograph Mother tinctures for homoeopathíc
preparations (2029).
DEFINITION
Content: 0.07 per cent m/m to 0.15 per cent m/m of
picrotoxinin (ClsH1606)'
PRODUCTION
The mother tincture is prepared from the dried, ripe fruit
of A. cocculus (L.) Wight & Am. according to the following
methods prescribed in the monograph Methods of preparatíon
of homoeopathic stocks and potentisation (2371):
- method 1.1.8 using the powdered herbal drug (710)
(2.9.12) and ethanol (90 per cent V/V); use ethanol (70 per
cent V/V) to prepare the 4 th decimal dilution and ethanol
(50 per cent V/V) for subsequent dilutions;
- method 1.1.10 using the crushed drug in fragments of
about 2-3 mm, ethanol (90 per cent V/V) and a maceration
time of about 3 weeks.
CHARACTERS
Appearance: yellow or dark yellow liquido
(10) FRENCH 'HTLE: Crocus sativus pour préparations homéopathiques
General Notices (1) apply to all monographs and other texts
Crocus for homoeopathic preparations
IDENTIFICATION
A. Thin-Iayer chromatography (2.2.27) as described in
identification test C for the herbal drug with the following
modification.
Test solution. The mother tincture to be examined.
B. Examine the chromatograms obtained in the assay.
Results: the peaks due to picrotoxinin and picrotin in
the chromatogram obtained with the test solution are
similar in retention time to the corresponding peaks in the
chromatogram obtained with the reference solution.
TESTS
Relative density (2.2.5): 0.830 to 0.845 (method 1.1.8).
Ethanol (2.9.10): 85 per cent V/V to 95 per cent V/V
(method 1.1.10).
Dry residue (2.8.16): minimum 0.7 per cent.
ASSAY
Liquid chromatography (2.2.29) as described in the assay of
the herbal drug with the following modification.
Test solution. Dilute 0.500 g of the mother tincture to be
examined to 10.0 mL with the mobile phase and filter using a
membrane filtre (nominal pore size 0.45 ¡.tm).
Calculate the percentage content of picrotoxinin using the
following expression:
Al x m2 x p
A 2 x ml x 10
area of the peak due to picrotoxinin in the
chromatogram obtained with the test solution;
area of the peak due to picrotoxinin in the
chromatogram obtained with the reference
solution;
mass of the mother tincture to be examined used
to prepare the test solution, in grams;
mass of pícrotoxinin CRS used to prepare the
reference solution, in grams;
p assigned percentage content of picrotoxinin in
picrotoxinin CRS.
07/2014:1624
CROCUS POR HOMOEOPATHIC
PREPARATIONS(1o)
Crod sativi stigma ad praeparationes
homoeopathicas
DEFINITION
Dried stigmas of Crocus sativus L. usually joined by the base
to a short style.
CHARACTERS
Characteristic, aromatic odour.
IDENTIFICATION
A. The dark brick-red stigmas, when dry, are 20 mm to
40 mm long and after soaking with water, about 35 mm to
50 mm long. The tubes, gradually widening at the top, are
incised on one side, the upper margin is open and finely
crenated. The style connecting the 3 stigmas is pale yellow
and not more than 5 mm long.
3987
 Cuprum aceticum for homoeopathic preparations EUROPEAN PHARMACOPOEIA 8.2

B. Examine under a microscope using chloral hydrate E. Dilute 0.1 mL ofthe test solution (see Identification D) with
solution R. It shows the following diagnostic characters: 1 mL of methanol R. Deposit 0.1 mL of this solution on a
elongated epidermal cells, frequently with a short, central filter paper, allow to dryand spray with a 10 g/L solution
papilla; in water they release a yellow colouring matter; the of diphenylboric acid aminoethyl ester R in methanol R.
upper border of the stigma has finger-shaped papillae, up Examine in ultraviolet light at 365 nm. The spot shows an
to 150 flm long; between them are single, globular pollen intense orange-yellow fluorescence.
grains, about 100 flm wide, with a finely pitted exine,
vascular bundles with small spirally thickened vessels and TESTS
no fibres. Colouring intensity. Introduce 0.10 g into a 5 mL volumetric
C. Carefully crush pieces of the herbal drug to coarse flask and dilute to 5.0 mL with distilled water R. Close the
particles and moisten with 0.2 mL of phosphomolybdic acid flask and shake every 30 min for 8 h. Then allow to stand
solution R. The particles turn blue within 1-2 min or they for 16 h. Dilute 1.0 mL to 500.0 mL with distilled water R.
have a blue are ole around them. The absorbance (2.2.25) measured at 440 nm using distilled
D. Thin-layer chromatography (2.2.27). water R as the compensation liquid, is not less than 0.44.
Test solution. Carefully crush 0.1 g of the herbal drug with Foreign matter. Examine the herbal drug microscopically.
a glass rod and moisten with 0.2 mL of water R. After No parts with rough walls, no crystals and no pollen grains
3 min add 5 mL of methanol R, allow to stand for 20 min, containing 3 germinal pores are presento
protected from light, and filter through a plug of glass wool. Loss on drying (2.2.32): maximum 10.0 per cent, determined
Reference solution. Dissolve 5 mg of naphthol yellow R in on 0.200 g by drying in an oven at 105 oc.
5 mL of methanol R and add a solution of 5 mg of Sudan Total ash (2.4.16): maximum 7.0 per cent, determined on the
red G R in 5 mL of methylene chloride R. residue obtained in the test for loss on drying.
Plate: TLC silica gel F254 plate R.
Mobile phase: water R, 2-propanol R, ethyl acetate R 07/2014:2146
(10:25:65 V/V/V).
Application: 10 flL of the test solution and 5 flL of the CUPRUM ACETICUM FOR
reference solution as bands. HOMOEOPATHIC PREPARATIONS(1J)
Development: over a path of 10 cm.
Drying: in airo Cupri acetas monohydricus ad
Detection A: examine in daylight. praeparationes homoeopathicas
Results A: see below the sequence of zones present in the
chromatograms obtained with the reference solution and Cu( C2HP2)2,HzÜ M r 199.7
the test solution. [6046-93-1)
Top of the plate DEFINITION
A red zone Content: 99.0 per cent to 101.0 per cent of Cu(C 2HP2)2,HzÜ.
A yellowzone CHARACTERS
2 yellow zones
Appearance: greenish -blue crystals or green powder.
Solubility: soluble in water, slightly soluble or very slightly
An intense yellow zone (crocine) soluble in ethanol (96 per cent).
Reference solution Test solution
IDENTIFICATION
Detection B: examine in ultraviolet light at 254 nm. A. It gives reaction (a) of acetates (2.3.1).
Results B: see below the sequence of zones present in the B. Dissolve 0.1 g in 10 mL of water R and add dilute
chromatograms obtained with the reference solution and ammonia R1 dropwise. A dark bIue colour is produced.
the test solution.
TESTS
Top of the plate
Solution S. Dissolve 3.0 g in a mixture of 40 mL of distilled
A red zone 1 or 2 quenching zones water R and 0.6 mL of glacial acetic acid R, with heating at
70 oc. Cool and dilute to 45 mL with distilled water R.
A yellowzone A quenching zone
Appearance of solution. Solution S is clear (2.2.1).
Reference solution Test solution
Impurities not precipitating with hydrogen sulfide:
Detection C: treat with anisaldehyde solution R and examine maximum 0.1 per cent, calculated as sulfates.
in daylight while heating at 100-105 oC for 5-10 mino To 2.000 g add 92 mL of water R and 8.0 mL of dilute sulfuric
Results C: see below the sequence of zones present in the acid R. Heat to 70 oc. Pass a current of hydrogen sulfide R until
chromatograms obtained with the reference solution and there is no longer precipitation of copper sulfide. Allow to
the test solution. cool and stand, then filter. Evaporate to dryness 50.0 mL ofthe
filtrate in a crucible. Ignite the residue at about 600 ± 50 oC
Top of the plate to constant mass.
A red zone 1 or 2 red to reddish-violet zones Chlorides (2.4.4): maximum 50 ppm, determined on
A blue to bluish-green zone A red to reddish-violet zone
solution S.
Sulfates (2.4.13): maximum 150 ppm, determined on
2 blue to bluish-green zones
solution S.
An intense blue to bluish-green Iron (2.4.9): maximum 20 ppm.
zone (crocine)
Reference solution Test solution
Dissolve 0.500 g in 10 mL of water R. Transfer to a separating
funnel. Add 20 mL of hydrochloric acid R1 and 10 mL of

I (11) FRENCH TITLE: Cuprum aceticum pour préparations homéopathiques

3988 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
methyl isobutyl ketone R. Shake vigorously for 3 mino Allow
to stand. Transfer the organic layer to a second separating
funnel and add 10 mL of water R. Shake vigorously for 3 mino
Allow to stand. The aqueous layer complies with the limit
test for iron.
Nkkel: maximum 10 ppm.
To the residue obtained in the test for impurities not
precipitating with hydrogen sulfide, add 2.0 mL of hydrochloric
acid R and 1.0 mL of sulfuric acid R. Evaporate to dryness.
Dissolve the residue in a mixture of 3.0 mL of dilute sulfuric
acid R and 17.0 mL of water R. To 4.0 mL of this solution
add 4.0 mL of water R, 5.0 mL of bromine water R, 7.0 mL
of dilute ammonia Rl and 3.0 mL of a 10 giL solution of
dimethylglyoxime R in ethanol (90 per cent V/V) R. This
solution is not more intensely coloured within 1 min than a
solution prepared as follows: mix 4.0 mL of a 1 ppm solution
of nickel (Ni) prepared from nickel standard solution (10 ppm
Ni) R, 4.0 mL of water R and 5.0 mL of bromine water R;
carefully add 7.0 mL of dilute ammonia R1 and 3.0 mL of
a 10 giL solution of dímethylglyoxíme R in ethanol (90 per
cent V/V) R.
ASSAY
Dissolve 00400 g in water R and dilute to 50 mL with the
same solvent. Add 6.0 mL of glacial acetic acid R, 10.0 g of
potassíum íodide R and 1 mL of starch solution R. Titrate with
0.1 M sodium thiosulfate.
1 mL of 0.1 M sodium thiosulfate is equivalent to 19.97 mg of
Cu(C 2 H 3 0 2 )2,H 20.
07/2014:1610
CUPRUM METALLICUM FOR
HOMOEOPATHIC PREPARATIONS(12)
Cuprum ad praeparationes homoeopathicas
eu A, 63.5
[7440-50-8]
DEFINITION
Content: 99.0 per cent to 101.0 per cent of eu.
CHARACTERS
Appearance: reddish-brown powder.
Solubility: practically insoluble in water, soluble in
hydrochloric acid and in nitric acid, practically insoluble in
ethanol (96 per cent).
IDENTIFICATION
A. To 2 mL of solution S (see Tests) add 0.5 mL of potassium
ferrocyanide solution R. A reddish-brown precipitate is
formed.
B. To 5 mL of solution S add 0.6 mL of ammonia R. A blue
precipitate is formed. Add 2 mL of ammonia R. The
precipitate disappears; the soIution has an intense bIue
colour.
TESTS
Solution S. Dissolve 2.0 g in 10 mL of nitric acid R. After
nitrous fumes are no longer evolved, dilute to 60 mL with
distilled water R.
Acidity or alkalinity. To 5.0 g add 20 mL of carbon
dioxide-free water R. Boíl for 1 mino Coo!. Filter and dilute
to 25.0 mL with carbon dioxide-free water R. To 10 mL of
the solution add 0.1 mL of bromothymol blue solution R1.
(12) FRENCH TITLE: Cuprum metallicum pour préparations homéopathigues
(13) FRENCH TITLE: Ferrum metallicum pour préparations homéopathigues
General Notices (1) apply to all monographs and other texts
Ferrum metaHicum for homoeopathk preparations
Not more than 0.5 mL of 0.01 M hydrochloric acid or 0.01 M
sodium hydroxide is required to change the colour of the
indicator.
Chlorides (2.4.4): maximum 100 ppm, determined on
solution S.
Sulfates (2.4.13): maximum 300 ppm, determined on
solution S.
Iron: maximum 50 ppm.
Atomic absorption spectrometry (2.2.23, Method I).
Test solution. Dissolve 1.00 g in 5 mL of nitric acid R and
dilute to 50.0 mL with water R.
Reference solutions. Prepare the reference solutions using iron
standard solution (20 ppm Fe) R, diluted as necessary with a
1 per cent V/V solution of nitric acid R.
Source: iron hollow-cathode lampo
Wavelength: 248.3 nm.
Flame: air-acetylene.
Lead: maximum 100 ppm.
Atomic absorption spectrometry (2.2.23, Method I).
Test solution. Use the test solution prepared for the test for
iron.
Reference solutions. Prepare the reference SOIUtiOllS using lead
standard solution (0.1 per cent Pb) R, diluted as necessary with
a 1 per cent V/V solution of nitric acid R.
Source: ¡ead hollow -cathode lampo
Wavelength: 283.3 nm.
Flame: air-acetylene.
Zinc: maximum 50 ppm.
Atomic absorption spectrometry (2.2.23, Method I).
Test solution. Use the test SOlUtiOll prepared for the test for
iron.
Reference solutions. Prepare the reference solutions using zinc
standard solution (100 ppm Zn) R, diluted as necessary with a
1 per cent V/V solution of nitric acid R.
Source: zinc hollow -cathode lampo
Wavelength: 213.9 nm.
Flame: air-acetyIene.
ASSAY
Dissolve 0.100 g in 5 mL of nitric acid R. Heat to expel the
nitrous fumes. Add 200 mL of water R and neutralise (2.2.3)
with dilute ammonia Rl. Add 1 g of ammonium chloride R
and 3 mg of murexide R. Titrate with 0.1 M sodium edetate
until the colour changes from green to violet.
1 mL of 0.1 M sodium edetate is equivalent to 6.354 mg of eu.
0712014:2026
FERRUM METALLICUM FOR
HOMOEOPATHIC PREPARATIONS(l3)
Ferrum ad praeparationes homoeopathicas
Fe Ar 55.85
[7439-89-6]
DEFINITION
lron obtained by reduction or sublimation as a fine
blackish-grey powder.
Content: 97.5 per cent to 101.0 per cent.
3989
Kalium bichromicum for homoeopathic preparations
CHARACTERS
Appearance: fine, blackish-grey powder, without metallic
lustre.
Solubility: practically insoluble in water and in ethanol (96 per a ground-glass stopper. Filter rapidly and wash the filter.
cent). It dissolves with heating in dilute mineral acids.
IDENTIFICATION
Dissolve 50 mg in 2 mL of dilute sulfuric acid R and dilute to
10 mL with water R. The solution gives reaction (a) ofiron
(2.3.1).
TESTS
Solution S. To 10.0 g add 40 mL of water R. Boil for 1 mino
Cool, filter and dilute to 50.0 mL with water R.
Alkalinity. To 10 mL of solution S add 0.1 mL of bromothymol
blue solution R1. Not more than 0.1 mL of 0.01 M hydrochloric
acid is required to change the colour of the indicator to yellow.
Substances insoluble in hydrochloric acid. Dissolve 2.00 g
in 40 mL of hydrochloric acid R. Heat on a water-bath. As soon
as fumes are no longer evolved, filter through a sintered-glass
filter (16) (2.1.2). Rinse with water R. Dry the residue in an
oven at 100-105 oC for 1 h. The residue weighs a maximum
of 20 mg (1.0 per cent).
Substances soluble in water. Evaporate 10.0 mL of solution S
on a water-bath and dry at 100-105 oC for 1 h. The residue
weighs a maximum of 2 mg (0.1 per cent).
Chlorides (2.4.4): maximum 50 ppm.
Dilute 5 mL of solution S to 15 mL with water R.
Sulfides and phosphides. In a 100 mL conical flask carefully
mix 1.0 g with 10 mL of dilute hydrochloric acid R. Within
30 s lead acetate paper R moistened with water R and placed
over the mouth of the flask is not coloured more intensely
than light brown by the resulting fumes.
Arsenic (2.4.2): maximum 5 ppm.
Boil 0.2 g in 25 mL of dilute hydrochloric acid R until
completely dissolved. The solution complies with limit test A.
Copper: maximum 50 ppm.
Atomic absorption spectrometry (2.2.23, Method 1).
Test solution. Dissolve 1.00 g in a mixture of 60 mL of dilute
hydrochloric acid R and 10 mL of dilute hydrogen peroxide
solution R. Reduce to a volume of 5 mL and dilute to 50.0 mL
with water R.
Reference solutions. Prepare the reference solutions using
copper standard solution (0.1 per cent CuY R, diluting with a
1 per cent V/V solution of hydrochloric acid R.
Source: copper hollow-cathode lampo
Wavelength: 324.8 nm.
Flame: air-acetylene.
Lead: maximum 50 ppm.
Atomic absorption spectrometry (2.2.23, Method 1).
Test solution. In a separating funnel, place 20 mL of the
test solution prepared for the test for copper. Add 25 mL of
lead-free hydrochloric acid R. Stir with 3 quantities, each of
25 mL, of di-isopropyl ether R. Collect the aqueous layer. Add
0.10 g of sodium sulfate decahydrate R. Evaporate to dryness.
Take up the residue with 1 mL of lead-free nitric acid R and
dilute to 20 mL with water R.
Reference solutions. Prepare the reference solutions using lead
standard solution (0.1 per cent Pb) R, diluting with a 10 per
cent V/V solution of nitric acid R containing 5 giL of sodium
sulfate decahydrate R.
Source: lead hollow-cathode lampo
Wavelength: 217 nm.
Flame: air-acetylene.
(14) FRENCH TITLE: Kaliurn bichrornicurn pour préparations hornéopathiques
3990
EUROPEAN PHARMACOPOEIA 8.2
ASSAY
Stir for 10 min 0.100 g in a hot solution of 1.25 g of copper
sulfate R in 20 mL of water R in a 100 mL conical flask with
Combine the filtrate and the washings, acidify with dilute
sulfuric acid R and titrate with 0.02 M potassium permanganate
until a pink colour is obtained.
1 mL of 0.02 M potassium permanganate is equivalent to
5.585 mg of Fe.
LABELLING
The label indicates whether the substance is obtained by
reduction or sublimation.
07/2014:2501
KALIUM BICHROMICUM FOR
HOMOEOPATHIC PREPARATIONS(J4)
Kalii bichromas ad praeparationes
homoeopathicas
K 2Cr2 0 7 M r 294.2
[7778-50-9]
DEFINITION
Content: 99.0 per cent to 101.0 per cent of K 2Cr2 0 7 •
CHARACTERS
Appearance: orange crystals.
Solubility: freely soluble in water, practically insoluble in
ethanol (96 per cent).
IDENTIFICATION
A. It gives reaction (b) of potassium (2.3.1).
B. Dissolve 10 mg in 5 mL of water R. Add 0.25 mL of
dilute sulfuric acid R, 0.5 mL of strong hydrogen peroxide
solution R and 1 mL of ether R. Shake. The upper layer is
blue.
TESTS
Solution SI. Dissolve 5.0 g in distilled water R and dilute to
50.0 mL with the same solvento
Solution S2. To 20.0 mL of solution SI add 20 mL of
hydrochloric acid R and 50 mL of tributyl phosphate R. Stir for
2 mino Remove the lower layer and shake it with 10 mL of
ether R. Evaporate the lower layer to dryness under reduced
pressure. Dissolve the residue in 10 mL of distilled water R.
Add dilute ammonia R1 until the solution is neutral to blue
litmus paper R and dilute to 20.0 mL with distilled water R.
Appearance of solution. Solution SI is clear (2.2.1).
Calcium (2.4.3): maximum 500 ppm.
Dilute 2.0 mL of solution S2 to 15 mL with distilled water R.
Chlorides (2.4.4): maximum 50 ppm.
Dissolve 1.0 g in 15 mL of dilute nitric acid R. Use 1 mL of
nitric acid R instead of the prescribed dilute nitric acid R.
Sulfates (2.4.13): maximum 150 ppm.
Dilute 10 mL of solution S2 to 15 mL with distilled water R.
ASSAY
Dissolve 0.100 g in 25 mL of water R. Add 2 g of potassium
iodide R and 25 mL of dilute sulfuric acid R. Allow to stand in
the dark for 10 mino Add 150 mL of water R. Titrate with 0.1 M
sodium thiosulfate until the colour changes from blue to green,
adding 1 mL of starch solution R near the end of the titration.
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
1 mL of 0.1 M sodium thiosulfate is equivalent to 4.903 mg
of K 2Cr 207"
0712014:2505
MAGNESIUM PHOSPHORICUM FOR
HOMOEOPATHIC PREPARATIONS(J5)
Magnesii hydrogenophosphas trihydricus ad
praeparationes homoeopathicas
MgHP04,3H 20
[7782-75-4]
DEFINITION
Content: 98.0 per cent to 102.0 per cent.
CHARACTERS
Appearance: white powder.
Solubility: very slightly soluble in water, practically insoluble
in ethanol (96 per cent). It dissolves in dilute acids.
IDENTIFICATION
A. Dissolve 0.1 g in a mixture of 2 mL of dilute nitric acid R
and 8 mL of water R. The solution gives reaction (b) of
phosphates (2.3.1).
B. Dissolve 0.1 g in a mixture of 2 mL of dilute nitric acid R
and 8 mL of water R. Add 10 mL of ammonium molybdate
solution R and filter. The filtrate gives the reaction of
magnesium (2.3.1).
TESTS
Solution S. Dissolve 5.0 g in 30 mL of dilute hydrochloric
acid R and dilute to 50.0 mL with the same add.
Arsenic (2.4.2, Method B): maximum 5 ppm, determined on
1.0 g.
Chlorides (2.4.4): maximum 200 ppm.
Dissolve 0.25 g in 5 mL of dilute nitric acid R and dilute to
15 mL with water R.
Magnesium dihydmgen phosphate and magnesil.l.m
phosphate. Dissolve 2.00 g in 30.0 mL of 1 M hydrochloric
acid. Add 20 mL of water R and 0.05 mL of methyl orange
solution R. Titrate the excess of hydrochloric add with 1 M
sodium hydroxide. The volume of 1 M hydrochloric acid used
is between 11.0 mL and 12.5 mL.
Sulfates (2.4.13): maximum 300 ppm.
Dilute 5 mL of solution S to 15 mL with distilled water R.
Iron (2.4.9): maximum 50 ppm.
Dilute 2 mL of solution S to 10 mL with water R.
Heavy metals (2.4.8): maximum 40 ppm.
Dilute 10 mL of solution S to 20 mL with dilute hydrochloric
acid R. 12 mL of the solution complies with test A. Prepare the
reference solution using lead standard solution (2 ppm Pb) R.
ASSAY
Dissolve 0.280 g in a mixture of 1 mL of hydrochloric acid R1
and 5 mL of water R. Add 25.0 mL of 0.1 M sodium edetate and
dilute to 200 mL with water R. Neutralise with concentrated
ammonia R, add 10 mL of ammonium chloride buffer solution
pH 10.0 R and about 50 mg of mordant black 11 triturate R.
Titrate the excess of 0.1 M sodium edetate with 0.1 M zinc
sulfate until the colour changes from pure blue to violet.
1 mL of 0.1 M sodium edetate is equivalent to 17.43 mg of
MgHP0 4,3Hp.
(15) FRENCH TITLE: Magnesia phosphorica pour préparations homéopathiques
(16) FRENCH TITLE: Uftica dioica pour préparations homéopathiques
General Notices (1) apply to all monographs and other texts
Urtica dloica for homoeopathic preparations
0712014:2030
URTICA DIOICA FOR
HOMOEOPATHIC PREPARATIONS(16)
Urtica dioica ad praeparationes
homoeopathicas
DEFINITION
Whole, fresh, flowering plant of Urtica dioica L.
CHARACTERS
M r 174.3 The plant causes an itching, burning sensation on the skin.
IDENTIFICATION
A. The perennial plant has a taproot that sends out creeping
subterranean rhizomes, more or less 4-angled in transverse
section, from which extend adventious secondary root5
and very numerous brownish hairy rootlets. The stipes
are erect, generally unbranched, 3-5 mm in diameter
and 0.3-1.5 m high, rareiy up to 2.5 m high, 4-angled,
greyish-green and covered in short hairs and stinging hairs.
The decussate leaves are 30-150 mm long and 20-80 mm
wide. The petiole is hispid and usually slightly less than
one-third the length of the lamina. The leaf blade is ovate,
acuminate, cordate or rounded at the base, and coarsely
dentate; the apica! tooth is distinctly larger than the lateral
teeth. The upper side of the leaves is dark green and usually
matt, both sides bear short serried hairs intermingled with
long stinging hairs. The 2 stipules are iinear-subulate and
free. The inflorescences growing from the leafaxils are
complex, the flowers unisexual, and, particularly in male
plants, generally distinctly longer than the petiole. After
shedding their pollen, male inflorescences are erect at
an oblique angle or horizontal; female inflorescences are
pendent when the fruit is ripe. AH flowers have long stalks.
The perianth of the male flowers is divided half-way down
into equal green lobes, widest at their base, with short
bristles and stinging hairs at the margins. The stamens are
equal and opposite to the perianth segments, each with a
long, whitish filament that curves inwards befo re pollen is
shed and spreads out afterwards. The ovary is rudimentary,
button or cup-shaped. The perianth of the female flowers
is downy or bristly on the outside and consists of outer, and
2 inner segments; the inner segments are about twice the
length of the outer ones. The hypogynous, ovate, unilocular
ovary bears a large capitate stigma with a brush-like shock
of hair. As the one-seeded fruit grows ripe, the 2 inner
segments of the perianth fold around it like wings.
B. It complíes with the test for Urtica urens (see Tests).
TESTS
Urtica urens. The margin of the lamina is not serrate with
teeth twice as long as wide. The c1usters of flowers in the axils
are longer than the petiole of the leaf. Unisexual, apetalous
flowers are not together on the same plant and in the same
cluster.
Foreign matter (2.8.2): maximum 5 per cent.
L088 on drying (2.2.32): minimum 65.0 per cent, determined
on 5.0 g of finely cut herbal drug by drying in an oven at
105 oC for 2 h, if performed to demonstrate the freshness of
the herbal drug.
Mother tincture
The mother tincture complies with the requirements of
the general monograph Mother tinctures for homoeopathic
preparations (2029).
3991
Urtica dioica for homoeopathic preparations EUROPEAN PHARMACOPOEIA 8.2

PRODUCTION Detection: spray with a 1 giL solution of ninhydrin R in

ethanol (96 per cent) R, heat at 105-110 oC for 5-10 min and
The mother tincture ofUrtica dioica is prepared by maceration
examine in daylight within 10 mino
using ethanol of a suitable concentration.
Results: see below the sequence of the zones present in the
chromatograms obtained with the reference solution and the
CHARACTERS test solution.
Appearance: greenish-brown or orange-brown liquido Top of the plate
--- ---
IDENTIFICATION
Phenylalanine: a violet to
Thin-layer chromatography (2.2.27). reddish-brown zone
4 red to violet zones
Test solution. The mother tincture to be examined.
--- ---
Reference solution. Dissolve 10 mg of phenylalanine R and
10 mg of serine R in a mixture of equal volumes of methanol R Serine: a reddish-violet zone A violet zone
and water R and dilute to 10 mL with the same mixture of
A violet zone
solvents.
Reference solution Test solution
Plate: TLC silica gel pIate R.
Mobile phase: glacial acetic acid R, water R, acetone R, TESTS
butanol R (10:20:35:35 V/V/V/V).
Relative density (2.2.5): 0.930 to 0.950.
Application: 20 flL, as bands. Ethanol (2.9.10): 40 per cent V/Vto 56 per cent V/V.
Development: over a path of 10 cm. Methanol (2.9.11): maximum 0.10 per cent V/V.
Drying: in airo Dry residue (2.8.16): minimum 1.1 per cent.

3992 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2

A
Alanine ..................................................................................... 3995 Arginine ................................................................................... 4001
Amikacin ................................................................................. 3996 Arginine hydrochloride ......................................................... 4002
Amikacin sulfate ..................................................................... 3998

General Notices (1) apply to all monographs and other texts 3993
 EUROPEAN PHARMACOPOEIA 8.2

3994 See the information section on general monographs (cover pages)

 EUROPEAN PHARMACOPOEIA 8.2 Alanine

07/2014:0752 The concentrations of the test solution and the reference

ALANINE
Alaninum
C3H 7N0 2 M r 89.1
[56-41-7]
DEFINITION
(2S)-2-Aminopropanoic acid.
Content: 98.5 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance: white or almost white, crystalline powder or
colourless crystals.
Solubility: freely soluble in water, very slightly soluble in
ethanol (96 per cent).
IDENTIFICATION
First identification: A, B.
Second identification: A, C, D.
A. Specific optical rotation (see Tests).
B. Infrared absorption spectrophotometry (2.2.24).
lIliiII
Comparison: alanine CRS.
C. Thin-Iayer chromatography (2.2.27).
Test solution. Dissolve 10 mg of the substance to be
examined in water R and dilute to 50 mL with the same
solvent.
Reference solution. Dissolve 10 mg of alanine CRS in
water R and dilute to 50 mL with the same solvent.
Plate: TLC siliea gel plate R.
Mobile phase: glacial acetie aeid R, water R, butanol R
(20:20:60 V/V/V).
Applieation: 5 ¡.tL.
Development: over 2/3 of the plateo
Drying: in airo
Deteetion: spray with ninhydrin solution R and heat at
105 oC for 15 mino
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size
to the principal spot in the chromatogram obtained with
the reference solution.
D. Dissolve 0.5 g in a mixture of 0.25 mL of hydrochlorie
acid Rl, 0.5 mL of a 100 giL solution of sodium nitrite R
and 1 mL of water R. Shake; gas is given off. Add 2 mL of
dilute sodium hydroxide solution R, followed by 0.25 mL of
iodinated potassium iodide solution R. After about 30 min,
a yellow precipitate is formed.
TESTS
Solution S. Dissolve 2.5 g in distilled water R and dHute to
50 mL with the same solvent.
Appearance of solution. The solution is clear (2.2.1) and not
more intensely coloured than reference solution BY6 (2.2.2,
Method 11).
Dilute 10 mL of solution S to 20 mL with water R.
Specific optical rotation (2.2.7): + 13.5 to + 15.5 (dried
substance).
Dissolve 2.50 g in hydroehloric acid Rl and dilute to 25.0 mL
with the same acid.
Ninhydrin-positive substances. Amino acid analysis
(2.2.56). For analysis, use Method 1.
solutions may be adapted according to the sensitivity of the
equipment used. The concentrations of al! solutions are
adjusted so that the system suitability requirements described
in general chapter 2.2.46 are fulfilled, keeping the ratios of
concentrations between al! solutions as described.
Solution A: dilute hydrochloric acid Rl or a sample preparation
buffer suitable for the apparatus used.
Test so/ution. Dissolve 30.0 mg of the substance to be
examined in solution A and dilute to 50.0 mL with solution A.
Reference solution (a). Dilute 1.0 mL of the test solution to
100.0 mL with solution A. Dilute 2.0 mL of this solution to
10.0 mL with solution A.
Reference solution (b). Dissolve 30.0 mg of proline R in
solution A and dilute to 100.0 mL with solution A. Dilute
1.0 mL of the solution to 250.0 mL with solution A.
Reference solution (e). Dilute 6.0 mL of ammonium standard
solution (100 ppm NH,J R to 50.0 mL with solution A. Dilute
1.0 mL of this solution to 100.0 mL with solution A.
Reference solution (d). Dissolve 30 mg of isoleucine R and
30 mg of leucine R in solution A and dilute to 50.0 mL with
solution A. Dilute 1.0 mL of the solution to 200.0 mL with
solution A.
Blank solution: solution A.
Inject suitable, equal amounts of the test, blank and reference
solutions into the amino acid analyser. Run a program suitable
for the determination of physiological amino acids.
System suitability: reference solution (d):
- resolution: mínimum 1.5 between the peaks due to
isoleucine and leucine. -
Calculation of percentage contents:
- for any ninhydrin-positive substance detected at 570 nm,
use the concentration of alanine in reference solution (a);
- for any ninhydrin-positive substance detected at 440 nm,
use the concentration of proline in reference solution (b) ; if
a peak is aboye the reporting threshold at both wavelengths,
use the result obtained at 570 nm for quantification.
Limits:
- any ninhydrin-positive substanee: for each impurity,
maximum 0.10 per cent;
- total: maximum 0.5 per cent;
- reporting threshold: 0.05 per cent.
Chlorides (2.4.4): maximum 200 ppm.
Dilute 5 mL of solution S to 15 mL with water R.
Sulfates (2.4.13): maximum 300 ppm.
Dilute 10 mL of solution S to 15 mL with distilled water R.
Arnrnonium. Amino acid analysis (2.2.56) as described in
the test for ninhydrin-positive substances with the following
modifications.
Injeetion: test solution, reference solution (c) and blank
solution.
Limit:
- ammonium at 570 nm: not more than the area of the
corresponding peak in the chromatogram obtained with
reference solution (c) (0.02 per cent), taking into account
the peak due to ammonium in the chromatogram obtained
with the blank solution.
lron (2.4.9): maximum 10 ppm.
In a separating funnel, dissolve 1.0 g in 10 mL of dilute
hydrochloric acid R. Shake with 3 quantities, each of 10 mL, of
methyl isobutyl ketone Rl, shaking for 3 min each time. To the
combined organic layers add 10 mL of water R and shake for
3 mino Use the aqueous layer.
Heavy rnetals (2.4.8): maximum 10 ppm.
Dissolve 2.0 g in water R and dilute to 20 mL with the same
solvent. 12 mL of the solution complies with test A. Prepare

General Notiees (1) apply to all monographs and other texts 3995
Amikacin
the reference solution using lead standard solution (1 ppm
Pb)R.
Loss on drying (2.2.32): maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 105 oc.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Dissolve 80.0 mg in 3 mL of anhydrous formic acid R. Add
30 mL of anhydrous acetic aeid R. Titrate with 0.1 M perchloric
aeid, determining the end-point potentiometrically (2.2.20).
1 mL of 0.1 M perchlorie aeid is equivalent to 8.91 mg of
C3H 7N OZ·
STORAGE
Protected from light.
IMPURITIES
Other detectable impurities (the following substances would,
if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaeeutieal use
(2034). It is therefore not necessary to identify these impurities
for demonstration of compliance. See also 5.10. Control of
impurities in substances for pharmaceutical use): A, B.
H NHz
H02C~
C02H
A. (2S)-2-aminobutanedioic acid (aspartic acid),
B. (2S)-2-aminopentanedioic acid (glutamic acid).
07/2014:1289 Related substances. Liquid chromatography (2.2.29).
AMIKACIN
Amikacinum
C ZZ H43 N S013 M r 585.6 Column:
[37517-28-5]
DEFINITION
6-0-(3-Amino-3-deoxy-a-D-glucopyranosyl)-4-0-(6-
amino-6-deoxy-a-D-glucopyranosyl)-l-N- [(2S)-4-amino-2-
hydroxybutanoyl]-2-deoxy-D-streptamine.
Antimicrobial substance obtained from kanamycin A.
Semi-synthetic product derived from a fermentation producto
Content: 96.5 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearanee: white or almost white powder.
Solubility: sparingly soluble in water, slight1y soluble in
methanol, practically insoluble in acetone and in ethanol
(96 per cent).
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24).
3996
EUROPEAN PHARMACOPOEIA 8.2
Comparison: amikacin CRS.
B. Thin-Iayer chromatography (2.2.27).
Test solution. Dissolve 25 mg of the substance to be
examined in water R and dilute to 10 mL with the same
solvent.
Reference solution (a). Dissolve 25 mg of amikacin CRS in
water R and dilute to 10 mL with the same solvent.
Reference solution (b). Dissolve 5 mg of kanamycin
monosulfate CRS in 1 mL of the test solution and dilute to
10 mL with water R.
Plate: TLC silica gel plate R.
Mobile phase: methylene chloride R, ammonia R, methanol R
(25:30:40 V/V/V).
Application: 5 ¡..tL.
Development: over 3/4 of the plateo
Drying: in airo
Detection: spray with ninhydrin solution R1 and heat at
11 O oC for 5 mino
System suitability: reference solution (b):
- the chromatogram shows 2 clearly separated spots.
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size
to the principal spot in the chromatogram obtained with
reference solution (a).
TESTS
pH (2.2.3): 9.5 to 11.5.
Dissolve 0.1 g in earbon dioxide-free water R and dilute to
10 mL with the same solvent.
Specific optical rotation (2.2.7): + 97 to + 105 (anhydrous
substance).
Dissolve 0.50 g in water R and dilute to 25.0 mL with the same
solvent.
Test solution. Dissolve 25 mg of the substance to be examined
in mobile phase A and dilute to 50.0 mL with mobile phase A.
Referenee solution (a). Dilute 1.0 mL of the test solution to
100.0 mL with mobile phase A.
Reference solution (b). Dilute 1.0 mL of reference solution (a)
to 10.0 mL with mobile phase A.
Reference solution (e). Dissolve 5 mg of amikacin for system
suitability CRS (containing impurities A, B, F and H) in mobile
phase A and dilute to 10 mL with mobile phase A.
Reference solution (d). Dissolve 5.0 mg of amikacin
impurity 1 CRS in mobile phase A and dilute to 20.0 mL with
mobile phase A. Dilute 1.0 mL ofthe solution to 100.0 mL
with mobile phase A.
- size: 1 = 0.25 m, (2) = 4.6 mm;
- stationary phase: end-eapped octadeeylsilyl silica gel for
ehromatography R (5 ¡..tm);
- temperature: 40 oc.
Mobile phase:
- mobile phase A: a mixture prepared with carbon dioxide-free
water R, containing 1.8 gIL of sodium octanesulfonate R,
20 gIL of anhydrous sodium sulfate R1, 1.4 per cent V/V of
tetrahydrofuran R, and 5 per cent V/V of 0.2 M potassium
dihydrogen phosphate R previously adjusted to pH 3.0 with
dilute phosphoric acid R; degas;
mobile phase B: a mixture prepared with carbon dioxide-free
water R, containing 1.8 gIL of sodium octanesulfonate R,
28 gIL of anhydrous sodium sulfate R1, 1.4 per cent V/Vof
tetrahydrofuran R, and 5 per cent V/V of 0.2 M potassium
dihydrogen phosphate R previously adjusted to pH 3.0 with
dilute phosphoric acid R; degas;
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2 Amikacin

Time Mobile phase A Mobile phase B - stationary phase: end-capped octadecylsilyl si/iea gel for
(min) (per cent V/V) (per cent V/V) chromatography R (5 flm);
0-3 100 O
- temperature: 40 oc.
3 - 38.0 100 -7 30 O -7 70
Mobile phase: a mixture prepared with carbon dioxide-free
38.0 - 38.1 30 -7 O 70 -7 100 water R, containing 1.8 giL of sodium octanesulfonate R,
20 giL of anhydrous sodium sulfate Rl, 5.8 per cent V/V
38.1 - 68 O 100
of acetonitrile R1, and 5 per cent V/V of 0.2 M potassium
dihydrogen phosphate R previollsly adjusted to pH 3.0 with
Flow rate: 1.0 mLlmin. dilute phosphorie aeid R; degas.
Post-column so/ution: mixture of 1 volume of carbonate-free Flow rate: 1.0 mL/min.
sodium hydroxide solution R and 24 volumes of previously
degassed carbon dioxide-free water R, which is added in Deteetíon: spectrophotometer at 200 nm.
a pulseless manner to the eolumn effluent using a 375 flL Injection: 20 flL.
polymerie mixing eoil.
Run time: 1.3 times the retention time of amikacin.
Flow rate of post-eolumn solution: 0.3 mLlmin.
Retention time: amikacin = about 30 mino
Deteetion: pulsed amperometric detector or equivalent with
a gold indieator electro de, a silver-silver ehloride referenee System suitability: reference solution:
electro de, and a stainless steel auxiliary electro de whieh is the - symmetry factor: maximum 1.5 for the peak due to
eeH body, held at respeetively + 0.05 V deteetion, + 0.75 V amikacin; if necessary, adjust the amount of aeetonitrile Rl
oxidation and - 0.15 V reduetion potentials, with pulse in the mobile phase; peak splitting may be observed when
durations aeeording to the instrument used. the retention time becomes too short;
Injeetion: 20 flL. - repeatability: maximum relative standard deviation of
Identification of impurities: use the chromatogram 1.5 per cent after 6 injections.
supplied with amikacin for system suitability CR5 and the Calculate the percentage content of C22H43NS013 taking into
ehromatogram obtained with referenee solution (e) to account the assigned content of amikacin CRS.
identify the peaks due to impurities A, B, F and H; use the
chromatogram obtained with reference solution (d) to identify
the peak due to impurity 1. IMPURITIES

Relative retention with referenee to amikacin (retention Speeified impurities: A, B, F, H, 1.

time = about 28 min): impurity 1 = about 0.13; Other detectable impurities (the following substances would,
impurity F = about 0.92; impurity B = about 0.95; if present at a sufficient level, be detected by one or other of
impurity A = about 1.62; impurity H = about 1.95. the tests in the monograph. They are limited by the general
System suitability: reference solution (c): acceptance criterion for other/unspecifled impurities and/or
by the general monograph Substances for pharmaceutical use
- peak-to-valley ratio: minimum 5, where H p = height (2034). It is therefore not necessary to identify these impurities
aboye the baseline of the peak due to impurity B and for demonstration of complianee. See also 5.10. Controlof
H" = height aboye the baseline of the lowest point of the impurities in substances for pharmaceutical use): C, D, E, G.
curve separating this peak from the peak due to amikacin;
if necessary, adjust the volume of tetrahydrofuran in the
mobile phase.
Calculation of percentage contents:
- for impurity I, use the eoncentration of impurity I in
reference solution (d);
- for impurities other than 1, use the concentration of
amikacin in reference solution (a).
Limits:
- impurities A, B, F, H, 1: for each impurity, maximum 0.5 per
cent;
- any other impurity: for each impurity, maximum 0.5 per
cent; A. 4-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-6-0-(6-
amino-6-deoxy-a-D-glucopyranosyl)-1-N- [(2S)-4-amino-
- total: maximum 1.5 per cent; 2-hydroxybutanoyl] -2-deoxy-L-streptamine,
- reporting threshold: 0.1 per cent.
Water (2.5.12): maximum 8.5 per cent, determined on 0.200 g. HO

H2N~~O' ~'-./ '"o

Sulfated ash (2.4.14): maximum 0.5 per cent, determined on
1.0 g.

ASSAY H~O HN'

1X
Liquid chromatography (2.2.29). o OH>={\
" H 'cm
OH HO"
Test solution. Dissolve 50.0 mg of the substance to be HO '. O
examined in the mobile phase and dilute to 10.0 mL with the OH O HN----(
mobile phase.
H~
OH NH 2
Reference solution. Dissolve 50.0 mg of amikacin CR5 in the
mobile phase and dilute to 10.0 mL with the mobile phase.
B. 4-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-6-0-(6-
Column: amino-6-deoxy-a -D-glucopyranosyl)-l ,3-N-bis [(25)-4-
- size: 1 = 0.25 m, 0 = 4.6 mm; amino- 2-hydroxybutanoyl] -2-deoxy-L-streptamine,

General Notices (1) apply to all monographs and other texts 3997
Amikadn sulfate EUROPEAN PHARMACOPOEIA 8.2

H2N~O
HO

HO H
HN
2~O o
~H
,'NH,
H2N~~O'
H~
o OHp'
HN'
1Y ~~ "e,
H 'OH
OH o OHp
HO-- OH HO--

HO \ HO \
OH O NH, NH 2 O NH2

C. 4-0-(6-amino-6-deoxy-a-D-glucopyranosyl)-6-0-[3- H. 6-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-l-N- [(2S)-

[[ (2S) -4-amino-2-hydroxybutanoyl] amino]- 3-deoxy-a -D- 4-amino-2-hydroxybutanoyl]-4-0-(2,6-diamino-2,6-
glucopyranosyl]-2-deoxy-D-streptamine, dideoxy -a -D-glucopyranosyl) -2 -deoxy-D-streptamine,
H02C~NH,

H OH

HO~ 1. (2S)-4-amino-2-hydroxybutanoic acid.

NH

H'N~'
HO o 2 ?H,
0712014:1290

OH o OHp
HO'- AMIKACIN SULFATE
HO \
OH O NH, Amikacini sulfas
HO

H'N~~O' ~'",
D. 6-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-4-0-
(6-amino-6-deoxy-a -D-glucopyranosyl)-2-deoxy-D-
streptamine (kanamycin),
H~ HN'
1Y ~
HO
o OHp' H 'OH '

""~~E~'"'
OH HO--

HO \
OH O NH,

C22H47N5021S2 M r 782
O O OHp
[39831-55-5]
OH HO--

HO \
DEFINITION
OH O NH, 6-0-( 3-Amino-3-deoxy-a -D-glucopyranosyl) -4- 0-( 6-
amino-6-deoxy-a-D-glucopyranosyl)-1-N- [(2S)-4-amino-2-
E. 4-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-6-0-[6- hydroxybutanoyl]-2-deoxy-D-streptamine sulfate.
[[ (2S) -4-amino-2-hydroxybutanoyl] amino ]-6-deoxy-a -D- Antimicrobial substance obtained from kanamycin A.
glucopyranosyl]-2-deoxy-L-streptamine, Semi-synthetic product derived from a fermentation producto
Content: 96.5 per cent to 102.0 per cent (dried substance).
HO
CHARACTERS

""~~E~ ~,~"",
Appearance: white or almost white powder.
Solubility: freely soluble in water, practically insoluble in
acetone and in ethanol (96 per cent) ,
O O OHp H OH
OH HO-- IDENTIFICATION
HO \
A. Infrared absorption spectrophotometry (2.2.24).
OH O NH 2 Comparison: amikacin sulfate CRS,
B. Thin-Iayer chromatography (2,2.27).
F. 6-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-4-0-[6- Test so/ution. Dissolve 25 mg of the substance to be
[(2S)-4-amino-2-hydroxybutanoyl] amino-6-deoxy-a -D- examined in water R and dilute to 10 mL with the same
glucopyranosyl]-l-N- [(2S)-4-amino-2-hydroxybutanoyl]- solvent.
2-deoxy-D-streptamine, Reference so/u/ion (a). Dissolve 25 mg of amikacin
sulfate CRS in water R and dilute to 10 mL with the same
HO solvent.

H'N~~O' 1X ~"",
Reference so/ution (b). Dissolve 5 mg of kanamycin
monosulfate CRS in 1 mL of the test solution and dilute to

H~ ~
10 mL with water R.
HN' Plate: TLC silica gel plate R.
o OHp' H,' OH Mobile phase: methy/ene chloride R, ammonia R, methanol R
OH HO--
(25:30:40 V/V/V).
HO \
Application: 5 flL.
OH O NH,
Development: over 3/4 of the plate.
G. 6-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-4-0-(6- Drying: in airo
amino-6-deoxy-a -D-glucopyranosyl) -1-N- [(2R) -4-amino- Deteetion: spray with ninhydrin so/ution Rl and heat at
2-hydroxybutanoyl]-2-deoxy-D-streptamine, 110 oC for 5 mino

3998 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2
System suitability: reference solution (b):
- the chromatogram shows 2 clearly separated spots.
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size
to the principal spot in the chromatogram obtained with
reference solution (a).
C. 1t gives reaction (a) of sulfates (2.3.1).
TESTS
pH (2.2.3): 2.0 to 4.0.
Dissolve 0.1 g in carbon dioxide-free water R and dilute to
10 mL with the same solvent.
Spedfic optical rotation (2.2.7): + 76 to + 84 (dried
substance).
Dissolve 0.50 g in water R and dilute to 25.0 mL with the same
solvent.
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 33 mg of the substance to be examined
in mobile phase A and dilute to 50.0 mL with mobile phase A.
Reference solution (a). Dilute 1.0 mL of the test solution to
100.0 mL with mobile phase A.
Reference solution (b). Dilute 1.0 mL of reference solution (a)
to 10.0 mL with mobile phase A.
Reference so/ution (e). Dissolve 5 mg of amikacin for system
suitability CRS (containing impurities A, B, F and H) in mobile
phase A and dilute to 10 mL with mobile phase A.
Reference solution (d). Dissolve 6.6 mg of amikacin
impurity I CRS in mobile phase A and dilute to 20.0 mL with
mobile phase A. Dilute 1.0 mL of the solution to 100.0 mL
with mobile phase A.
Column:
- size: 1 = 0.25 m, 0 = 4.6 mm;
- stationary phase: end-capped octadecylsilyl silica gel for
chromatography R (5 flm);
- tempera tu re : 40 oc.
Mobile phase:
- mobile phase A: a mixture prepared with carbon dioxide-free
water R, containing 1.8 giL of sodium octanesulfonate R,
20 giL of anhydrous sodium sulfate R1, l.4 per cent V/V of
tetrahydrofuran R, and 5 per cent V/V of 0.2 M potassium
dihydrogen phosphate R previously adjusted to pH 3.0 with
dilute phosphoric acid R; degas;
- mobile phase B: a mixture prepared with carbon dioxide-free
water R, containing 1.8 giL of sodium octanesulfonate R,
28 giL of anhydrous sodium sulfate R1, 1.4 per cent V/V of
tetrahydrofuran R, and 5 per cent V/V of 0.2 M potassium
dihydrogen phosphate R previously adjusted to pH 3.0 with
dilute phosphoric acid R; degas;
Time Mobile phase A Mobile phase B
(rnin) (per cent V/V) (per cent V/V)
O~ 3 100 O
3 ~ 38.0 100 -7 30 0-770
38.0 ~ 38.1 30 -7 O 70 -7 100
38.1 ~ 68 O 100
Flow rate: l.0 mL/min.
Post-column solution: mixture of 1 volume of carbonate-free
sodium hydroxide solution R and 24 volumes of previously
degassed carbon dioxide-free water R, which is added in
a pulseless manner to the column effluent using a 375 flL
polymeric mixing coil.
Flow rate of post-column solution: 0.3 mL/min.
Detection: pulsed amperometric detector or equivalent with
a gold indicator electrode, a silver-silver chloride reference
electro de, and a stainless steel auxiliary electro de which is the
General Notices (1) apply to all monographs and other texts
Amikadn sulfate
ceH body, held at respectively + 0.05 V detection, + 0.75 V
oxidation and 0.15 V reduction potentials, with pulse
durations according to the instrument used.
Injection: 20 flL.
Identification of impurities: use the chromatogram
supplied with amíkacin for system suitability CRS and the
chromatogram obtained with reference solution (c) to
identify the peaks due to impurities A, B, F and H; use the
chromatogram obtained with reference solution (d) to identify
the peak due to impurity I.
Relative retention with reference to amikacin (retention
time = about 28 min): impurity 1 = about 0.13;
impurity F = about 0.92; impurity B = about 0.95;
impurity A = about 1.62; impurity H = about 1.95.
System suítabílity: reference solution (c):
- peak-to-valley ratio: minimum 5, where Hp = height
aboye the baseline of the peak due to impurity B and
H" = height aboye the baseline of the lowest point of the
curve separating this peak from the peak due to amikacin;
if necessary, adjust the volume of tetrahydrofuran in the
mobile phase.
Calculatian of percentage contents:
- for impurity 1, use the concentration of impurity 1 in
reference solution (d);
- for impurities other than 1, use the concentration of
amikacin sulfate in reference solution (a).
Limits:
- impurítíes A, B, F, H, I: for each impurity, maximum 0.5 per
cent;
- any other ímpurity: for each impurity, maximum 0.5 per
cent;
- total: maximum 1.5 per cent;
- reporting threshold: 0.1 per cent.
Sulfate: 23.3 per cent to 25.8 per cent (dried substance).
Dissolve 0.250 g in 100 mL of water R and adjust the solution
to pH 11 using concentrated ammonia R. Add 10.0 mL of
0.1 M barium chloride and about 0.5 mg of phthalein purple R.
Titrate with 0.1 M sodium edetate adding 50 mL of ethanol
(96 per cent) R when the colour of the solution begins to
change and continue the titration until the violet-blue colour
disappears.
1 mL of 0.1 M barium chloride is equivalent to 9.606 mg of
sulfate (S04).
Loss on drying (2.2.32): maximum 13.0 per cent, determined
on 0.500 g by drying in an oven at 105 oC at a pressure not
exceeding 0.7 kPa for 3 h.
Pyrogens (2.6.8). lf intended for use in the manufacture
of parenteral preparations without a further appropriate
procedure for the removal of pyrogens, it complies with the
test for pyrogens. Inject per kilogram of the rabbit's mass
5 mL of a solution containing 25 mg of the substance to be
examined in water for injections R.
ASSAY
Liquid chromatography (2.2.29).
Test solution. Dissolve 50.0 mg of the substance to be
examined in the mobile phase and dilute to 10.0 mL with the
mobile phase.
Reference solution. Dissolve 50.0 mg of amikacin sulfate CRS in
the mobile phase and dilute to 10.0 mL with the mobile phase.
Column:
- size: 1 = 0.25 m, 0 = 4.6 mm;
- stationary phase: end-capped octadecylsilyl si/iea gel for
chromatography R (5 flm);
- tempera tu re: 40 oc.
Mobile phase: a mixture prepared with carbon dioxide-free
water R, containing 1.8 giL of sodium octanesulfonate R,
20 giL of anhydrous sodium sulfate Rl, 5.8 per cent V/V
3999
Amikacin sulfate EUROPEAN PHARMACOPOEIA 8.2

H'N~O
of acetonitrile Rl, and 5 per cent V/V of 0.2 M potassium
dihydrogen phosphate R previously adjusted to pH 3.0 with
dilute phosphoric aeid R; degas.
HO H
HN
~H
Flow rate: 1.0 mLlmin.
2~0 o :NH,
Deteetíon: spectrophotometer at 200 nm. o OH)=<
OH Ha--
Injeetion: 20 f!L. Ha '.
OH O NH 2
Run time: 1.3 times the retention time of amikacin.
Retention time: amikacin == about 30 mino C. 4- 0- (6-amino-6-deoxy-a -D-glucopyranosyl)-6-0- [3-
System suitability: reference solution: [[ (25) -4-amino-2-hydroxybutanoyl] amino ]-3-deoxy-a -D-
glucopyranosyl]-2-deoxy-D-streptamine,
- symmetry factor: maximum 1.5 for the peak due to
amikacin; if necessary, adjust the amount of acetonitrile Rl
in the mobile phase; peak splitting may be observed when HO

""E~N"'
the retention time becomes too short;
- repeatability: maximum relative standard deviation of
1.5 per cent after 6 injections.
Calculate the percentage content of C22H47Ns021S2 taking into
account the assigned content of amikacin sulfate CRS.
OH o H~_HK
HO
OH O
~NH 2
STORAGE
If the substance is sterile, sto re in a sterile, airtight, D. 6-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-4-0-
tamper-proof container. (6-amino-6-deoxy-a -D-glucopyranosyl)-2-deoxy-D-
streptamine (kanamycin),
IMPURITIES
5pecified impurities: A, B, F, H, 1.
Other detectable impurities (the following substances would,
Ha
HO~
if present at a sufflcient leve!, be detected by one or other of H
the tests in the monograph. They are limited by the general
acceptance criterio n for other/unspecifled impurities and/or H'N~~~O NH
2
O .NH,

by the general monograph Substances for pharmaceutical use O

OH
O OH)'--<
HO--
.
(2034). 1t is therefore not necessary to identify these impurities
for demonstration of compliance. See also 5.10. Controlof HO '.
OH O NH,
impurities in substances for pharmaceutical use): C, D, E, G.

E. 4-0- (3-amino-3-deoxy-a-D-glucopyranosyl)-6-0- [6-

[[ (2S)-4-amino-2-hydroxybutanoyI] amino ]-6-deoxy-a -D-
Ha

H2N~~,",
glucopyranosyl]-2-deoxy-L-streptamine,

HO

Ha
OH~?
OH o

OH
HO'-

O
" O
HN--\

H~
OH NH 2
""~~E~ ~N~'"' o
HO
OH o OH> •..
HO-- ~
"
H OH

A. 4-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-6-0-(6-
amino-6-deoxy-a-D-glucopyranosyl)-l-N- [(2S)-4-amino-
2-hydroxybutanoyl]-2-deoxy-L-streptamine,
HO
OH O NH,
F. 6-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-4-0- [6-
[(25) -4-amino-2-hydroxybutanoyl] amino-6-deoxy-a -D-
glucopyranosyl]-l-N- [(25)-4-amino-2-hydroxybutanoyl]-
2 -deoxy-D-streptamine,

H2N~~O' 1X~'../ '"'

H'N~~'O'
Ha

H~)=<~N'1 ~'",
HO~ HN'
o OHQ' H 'OH
OH HO--
HXOH '../
HO '. O
OH HO--
OH O HN--\

H~
OH NH 2
HO
OH O
"
NH,

B. 4-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-6-0-(6- G. 6-0-(3-amino-3-deoxy-a-D-glucopyranosyl)-4-0-(6-
amino-6-deoxy-a -D-glucopyranosyl)-l ,3-N-bis [(25) -4- amino-6-deoxy-a-D-glucopyranosyl)-1-N- [(2R)-4-amino-
amino-2-hydroxybutanoyl]-2-deoxy-L-streptamine, 2-hydroxybutanoyl]-2-deoxy-D-streptamine,

4000 5ee the information section on general monographs (cover pages)

 EUROPEAN PHARMACOPOEIA 8.2 Arginine

HO
Results: the principal spot in the chromatogram obtained

H2N~~O' 1Y ~'-/ '",

with the test solution is similar in position, colour and size
to the principal spot in the chromatogram obtained with
H~ HN'
the reference solution.

OH
o OH~<'
HO--
H 'OH
E. Dissolve about 25 mg in 2 mL of water R. Add 1 mL
of a-naphthol solution R and 2 mL of a mixture of
equal volumes of strong sodium hypochlorite solution R and
HO \
NH 2 O NH, water R. A red colour develops.

H. 6-0-(3-amino-3-deoxy-0-D-glucopyranosyl)-1-N- [(2S)-
4-amino-2-hydroxybutanoyl]-4-0-(2,6-diamino-2,6-
dideoxy -o -D-glucopyranosyl) -2- deoxy -D-streptamine,
1. (2S)-4-amino-2-hydroxybutanoic acid.
0712014:0806
ARGININE
Argininum
C6H14N402 M r 174.2 Solution A: water R or a sample preparation buffer suitable
[74-79-3]
DEFINITION
(2S)-2-Amino-5-guanidinopentanoic acid.
Fermentation product, extraet or hydrolysate of protein.
Content: 98.5 per cent to 101.0 per eent (dried substance).
CHARACTERS
Appearance: white or almost white, crystalline powder or
colourless crystals, hygroscopic.
Solubility: freely soluble in water, very slightly soluble in
ethanol (96 per cent).
IDENTIFICATION
First identification: A, C.
Seeond identification: A, B, D, E.
A. Specific optical rotation (see Tests).
B. Solution S (see Tests) is strongly alkaline (2.2.4).
C. Infrared absorption spectrophotometry (2.2.24).
l!II!i
Comparison: arginine CRS.
lf the spectra obtained show differences, dry the substance System suitability: reference solution (d):
to be examined and the reference substance in an oven at
105 oC and record new spectra.
D. Thin-Iayer chromatography (2.2.27).
Test solution. Dissolve 10 mg of the substance to be
examined in a 10.3 giL solution of hydroehloric aeid R and
dilute to 50 mL with the same solution.
Reference solution. Dissolve 10 mg of arginine CRS in a
10.3 giL solution of hydrochlorie acid R and dilute to 50 mL
with the same solution.
Plate: TLC si/ica gel plate R.
Mobile phase: cancentrated ammonia R, 2-propanol R
(30:70 V/V).
Application: 5 f-lL.
Development: over 2/3 of the plateo
Drying: at 105 oC until the ammonia disappears completely. The thresholds indicated under Related substances
Deteetion: spray with ninhydrin solution R and heat at
105 oC for 15 mino
TESTS
Solution S. Dissolve 2.5 g in distilled water R and dilute to
50 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solution BY6 (2.2.2,
Method JI).
Specific optical rotation (2.2.7): + 25.5 to + 28.5 (dried
substance).
Dissolve 2.00 g in hydrochloric acid Rl and dilute to 25.0 mL
with the same acid.
Ninhydrin-positive substances. Amino acid analysis
(2.2.56). For analysis, use Method 1.
The concentrations of the test solution and the reference
solutions may be adapted according to the sensitivity of the
equipment used. The concentrations of all solutions are
adjusted so that the system suitability requirements described
in general chapter 2.2.46 are fulfilled, keeping the ratios of
concentrations between all solutions as described.
for the apparatus used.
Test solution. Dissolve 30.0 mg of the substance to be
examined in solution A and dilute to 50.0 mL with solution A.
Referenee solution (a). Dilute 1.0 mL of the test solution to
100.0 mL with solution A. Dilute 2.0 mL of this solution to
10.0 mL with solution A.
Reference solution (b). Dissolve 30.0 mg of pro/ine R in
solution A and dilute to 100.0 mL with solution A. Dilute
1.0 mL of the solution to 250.0 mL with solution A.
Referenee solution (e). Dilute 6.0 mL of ammonium standard
solution (lOO ppm NH.J R to 50.0 mL with solution A. Dilute
1.0 mL of this solution to 100.0 mL with solution A.
Reference solution (d). Dissolve 30 mg of isoleucine R and
30 mg of leucine R in solution A and dilute to 50.0 mL with
solution A. Dilute 1.0 mL of the solution to 200.0 mL with
solution A.
Blank solution: solution A.
Inject suitable, equal amounts of the test, blank and reference
solutions into the amino acid analyser. Run a program suitable
for the determination of physiological amino acids.
- resolution: minimum 1.5 between the peaks due to
isoleucine and leucine.
Calculation of percentage cantents:
- for any ninhydrin-positive substance detected at 570 nm,
use the concentration of arginine in reference solution (a);
- for any ninhydrin-positive substance detected at 440 nm,
use the concentration of proline in reference solution (b); if
a peak is aboye the reporting threshold at both wavelengths,
use the result obtained at 570 nm for quantification.
Limits:
- any ninhydrin-positive substanee: for each impurity,
maximum 0.2 per cent;
- total: maximum 0.5 per eent;
- reporting threshold: 0.05 per eent.
(Table 2034.-1) in the general monograph Substances for
pharmaeeutical use (2034) do 110t apply.

General Notices (1) apply to all monographs and other texts 4001
Arginine hydrochloride EUROPEAN PHARMACOPOEIA 8.2

Chlorides (2.4.4): maximum 200 ppm. 07/2014:0805

To 5 mL of solution S add 0.5 mL of dilute nitric acid R and
dilute to 15 mL with water R. ARGININE HYDROCHLORIDE
Sulfates (2.4.13): maximum 300 ppm.
To 10 mL of solution S, add 1.7 mL of dilute hydrochloric Arginini hydrochloridum
acid R and dilute to 15 mL with distilled water R.
Ammonium. Amino acid analysis (2.2.56) as described in H H .NHz
the test for ninhydrin-positive substances with the following HzN'v'N~ ,HCI
11 COzH
modifications. NH
Injection: test solution, reference solution (c) and blank
C6HlsCIN402 M r 210.7
solution. [1119-34-2]
Limit:
- ammonium at 570 nm: not more than the area of the DEFINITION
corresponding peak in the chromatogram obtained with (2S) -2-Amino-5-guanidinopentanoic acid hydrochloride.
reference solution (c) (0.02 per cent), taking into account Fermentation product, extract or hydrolysate of protein.
the peak due to ammonium in the chromatogram obtained
Content: 98.5 per cent to 101.0 per cent (dried substance).
with the blank solution.
Iron (2.4.9): maximum 10 ppm. CHARACTERS
In a separating funnel, dissolve 1.0 g in 10 mL of dilute Appearance: white or almost white, crystalline powder or
hydrochloric acid R. Shake with 3 quantities, each of 10 mL, of colourless crystals.
methyl isobutyl ketone R1, shaking for 3 min each time. To the Solubility: freely soluble in water, very slightly soluble in
combined organic layers add 10 mL of water R and shake for ethanol (96 per cent).
3 mino Use the aqueous layer.
IDENTIFICATION
Heavy metals (2.4.8): maximum 10 ppm.
First identification: A, B, E.
Dissolve 2.0 g in water R and dilute to 20 mL with the same
solvento 12 mL of the solution complies with test A. Prepare Second identification: A, C, D, E.
the reference solution using lead standard solution (1 ppm A. Specific optical rotation (see Tests).
Pb)R. B. Infrared absorption spectrophotometry (2.2.24).
Loss on drying (2.2.32): maximum 0.5 per cent, determined •
on 1.000 g by drying in an oven at 105 0e. Comparison: arginine hydrochloride CRS.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on e. Thin-Iayer chromatography (2.2.27).
1.0 g. Test solution. Dissolve 10 mg of the substance to be
examined in water R and dilute to 50 mL with the same
ASSAY solvento
Dissolve 0.150 g in 50 mL of water R. Titrate with Reference solution. Dissolve 10 mg of arginine
0.1 M hydrochloric acid, determining the end-point hydrochloride CRS in water R and dilute to 50 mL with the
potentiometrically (2.2.20). same solvent.
1 mL of 0.1 M hydrochloric acid is equivalent to 17.42 mg of Plate: TLC silica gel plate R.
C6H14N402' Mobile phase: concentrated ammonia R, 2-propanol R
STORAGE (30:70 V/V).
In an airtight container, protected from light. Application: 5 flL
Development: over 2/3 of the plateo
IMPURITIES Drying: at 105 oC until the ammonia disappears completely.
Other detectable impurities (the following substances would, Detection: spray with ninhydrin solution R and heat at
if present at a sufficient leve!, be detected by one or other of 105 oC for 15 mino
the tests in the monograph. They are limited by the general
Results: the principal spot in the chromatogram obtained
acceptance criterion for other/unspecified impurities. It with the test solution is similar in position, colour and size
is therefore not necessary to identify these impurities for
to the principal spot in the chromatogram obtained with
demonstration of compliance. See also 5.10. Control of the reference solution.
impurities in substances for pharmaceutical use): A, B, C.
D. Dissolve about 25 mg in 2 mL of water R. Add 1 mL
of a-naphthol solution R and 2 mL of a mixture of
equal volumes of strong sodium hypochlorite solution R and
water R. A red colour develops.
A. (2S)-2,6-diaminohexanoic acid (lysine), E. It gives reaction (a) of chlorides (2.3.1).

H H ,NHz TESTS
HzN'v'N~ Solution S. Dissolve 2.5 g in distilled water R and dilute to
11 COzH
o 50 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
B. (2S)-2-amino-5-(carbamoylamino )pentanoic acid more intensely coloured than reference solution BY6 (2.2.2,
(citrulline), Method II).
Specific optical rotation (2.2.7): + 21.0 to + 23.5 (dried
substance).
Dissolve 2.00 g in hydrochloric acid R1 and dilute to 25.0 mL
e. (2S)-2,5-diaminopentanoic acid (ornithine). with the same acid.

4002 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
Ninhydrin-positive substances. Amino acid analysis
(2.2.56). Por analysis, use Method 1.
The concentrations of the test solution and the reference
solutions may be adapted according to the sensitivity of the
equipment used. The eoncentrations of al! solutions are
adjusted so that the system suitability requirements described
in general ehapter 2.2.46 are fulfilled, keeping the ratios of
concentrations between all solutions as deseribed.
Solution A: water R 01' a sample preparation buffer suitable
for the apparatus used.
Test solution. Dissolve 30.0 mg of the substance to be
examined in solution A and dilute to 50.0 mL with solution A.
Rejerence solution (a). Dilute 1.0 mL of the test solution to
100.0 mL with solution A. DiIute 2.0 mL of this solution to
10.0 mL with solution A.
Rejerence solution (b). DissoIve 30.0 mg of proline R in
solution A and dilute to 100.0 mL with solution A. Dilute
1.0 mL of the solution to 250.0 mL with solution A.
Rejerenee solution (e). Dilute 6.0 mL of ammonium standard
solution (lOO ppm NHJ R to 50.0 mL with solution A. Dilute
1.0 mL of this solution to 100.0 mL with solution A.
Rejerence solution (d). Dissolve 30 mg of isoleucine R and
30 mg of leucine R in solution A and dilute to 50.0 mL with
solution A. Dilute 1.0 mL of the solution to 200.0 mL with
solution A.
Blank solution: solution A.
Inject suitable, equal amounts of the test, blank and referenee
solutions into the amino aeid analyser. Run a program suitable
for the determination of physiological amino acids.
System suitability: reference solution (d):
- resolution: mínimum 1.5 between the peaks due to
isoleucine and leucine.
Calculation of percentage contents:
- for any ninhydrin-positive substance deteeted at 570 nm,
use the concentration of arginine in referenee solution (a);
- for any ninhydrin-positive substance deteeted at 440 nm,
use the eoneentration of proline in referenee solution (b) ; if
a peak is aboye the reporting threshold at both wavelengths,
use the result obtained at 570 nm for quantifieation.
Limits:
- any ninhydrin-positive substance: for eaeh impurity,
maximum 0.2 per eent;
- total: maximum 0.5 per cent;
- reporting threshold: 0.05 per cent.
The thresholds indieated under Related substances
(Table 2034.-1) in the general monograph Substances jor
pharmaceutical use (2034) do not apply.
Sulfates (2.4.13): maximum 300 ppm.
Dilute 10 mL of solution S to 15 mL with distilled water R.
Ammonium. Amino acid analysis (2.2.56) as deseribed in
the test for ninhydrin-positive substances with the following
modifieations.
Injection: test solution, reference solution (e) and blank
solution.
General Notiees (1) apply to all monographs and other texts
Arginine hydrochloride
Limit:
- ammonium at 570 nm: not more than the are a of the
eorresponding peak in the chromatogram obtained with
referenee solution (e) (0.02 per eent), taking into aeeount
the peak due to ammonium in the ehromatogram obtained
with the blank solution.
lron (2.4.9): maximum 10 ppm.
In a separating funnel, dissolve LO g in 10 mL of dílute
hydrochloric aeid R. Shake with 3 quantities, eaeh of 10 mL, of
methyl isobutyl ketone Rl, shaking for 3 min eaeh time. To the
eombined organie layers add 10 mL of water R and shake for
3 mino Use the aqueous layer.
Heavy metals (2.4.8): maximum 10 ppm.
Dissolve 2.0 g in water R and dilute to 20 mL with the same
solvento 12 mL of the solution eomplies with test A. Prepare
the referenee solution using lead standard solution (1 ppm
Pb) R.
Loss Oil drying (2.2.32): maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 105 0e.
Sulfaied ash (2.4.14): maximum 0.1 per eent, determined on
1.0 g.
ASSAY
Dissolve 0.180 g in 3 mL of anhydrous jormic acid R. Add
30 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric
acid, determining the end-point potentiometrically (2.2.20).
1 mL of 0.1 M perchloric acid is equivalent to 21.07 mg of
C6HlsCIN402'
STORAGE
Proteeted from light.
IMPURITIES
Other detectable impurities (the following substanees would,
if present at a suffieient leve!, be detected by one or other of
the tests in the monograph. They are limited by the general
aeeeptance eriterion for other/unspeeified impurities. 1t
is therefore not neeessary to identify these impurities for
demol1stration of eompliance. See also 5.10. Controloj
impurities in substances jor pharmaceutical use): A, B, C.
H NH 2
H2N~C02H
A. (2S)-2,6-diaminohexanoic acid (Iysine),
B. (2S)- 2-amino-5-( carbamoylamino )pentanoic acid
(citrulline),
H NH 2
H N '-.'
2 ~C02H
e. (2S)-2,5-diaminopentanoic acid (ornithine).
4003
 EUROPEAN PHARMACOPOEIA 8.2

4004 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2

B
Brimonidine tartrate .............................................................. 4007

General Notices (1) apply to all monographs and other texts 4005
 EUROPEAN PHARMACOPOEIA 8.2

4006 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 Brimonidine tartrate

07/2014:2760 System suitability: reference solution (b):

- resolution: minimum 1.5 between the peaks due to
BRIMONIDINE TARTRATE impurity E and brimonidine.
Calcu/ation of percentage contents:
Brimonidini tartras - for each impurity, use the concentratíon of brimonidine in
reference solution (a).
Limits:
- unspecified impurities: for each impurity, maximum
0.10 per cent;
- total: maximum 0.2 per cent;
- reporting threshold: 0.05 per cent.
ClsH16BrNs06 M r 442.2 L oss on d ' (2.2.32) : maximum 0.5 per cent, d etermine d
[70359-46-5] rymg
on 1.000 g by drying in an oven at 105 oC for 3 h.
DEFINITION Sulfated ash (2.4.14): maximum 0.2 per cent, determined on
5-Bromo -N- (imidazolidin -2 -ylidene )quinoxalin -6-amine 1.0 g.
(2R,3R)-2,3-dihydroxybutanedioate.
ASSAY
Content: 99.0 per cent to 101.0 per cent (dried substance).
Dissolve 0.350 g in 70 mL of anhydrous acetic acid R using
CHARACTERS
sonication until complete dissolution. Titrate with 0.1 M
perch/oric acid, determining the end-point potentiometrically
Appearanee: white or slightly yellowish or slightly brownish (2.2.20).
powder.
1 mL of 0.1 M perch/orie acid is equivalent to 44.22 mg of
Solubility: soluble in water, practically insoluble in anhydrous ClsHI6BrNs06'
ethanol and in toluene.
IMPURITIES
IDENTIFICATION Other detectable impurities (the following substances would,
A. Speciflc optical rotation (see Tests). if present at a sufficient level, be detected by one or other of
B. Infrared absorption spectrophotometry (2.2.24). the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecifled impurities and/or
Comparison: brimonidine tartrate CRS. by the general monograph Substanees for pharmaceutical
use (2034). It is therefore not necessary to identify these
TESTS
impurities for demonstration of compliance. See also 5.10,
Spedfic optical rotation (2.2.7): + 9.0 to + 10.5 (dried Control of impurities in substances for pharmaeeutieal use):
substance). A, B, C, D, E, F, G.
Dissolve 0.50 g in water R and dilute to 50.0 mL with the same
r
solvento
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 65.0 mg of the substance to be
NONANHN)
~
N

/' I

H
examined in water R and dilute to 50.0 mL with the same
solvent. A. N-(imidazolidin-2-ylidene)quinoxalin-6-amine,
Reference solution (a). Dilute 1.0 mL of the test solution to
100.0 mL with water R. Dilute 1.0 mL of this solution to
10.0 mL with water R.
Reference solution (b). Dissolve the contents of a vial of
brimonidine for system suitability CRS (containing impurity E)
in 1.0 mL of water R.
B. 5-bromoquinoxalin-6-amine,
Column:
- size: 1= 0.25 m, 0 = 4.6 mm;
- stationary phase: end-capped octadecylsilyl si/ica gel for
chromatography R (5 fim);
- tempera tu re : 30 0e.
Mobile phase: dissolve 2.6 g of sodium heptanesulfonate R in e. quinoxalin-6-amine,
310 mL of methanol R, add 2.5 mL of triethylamine R and
7.5 mL of glacial acetic acid R, and dilute to 1000 mL with
water R. Use a freshly prepared mixture.
Flow rate: 1.0 mL/min.
Deteetion: spectrophotometer at 264 nm.
Injection: 20 fiL.
D. 1-( 5-bromoquinoxalin-6-yl)thiourea,
Run time: 3 times the retention time of brimonidine.
Identificatíon of impuríties: use the chromatogram supplied
with brimonidine for system suitability CRS and the r N

N~Br NH
chromatogram obtained with reference solution (b) to identify 2

the peak due to impurity E. U A N NH2

Relative retention with reference to brimonidine (retention
time = about 19 min): impurity E = about 0.9. E. 2-(5-bromoquinoxalin-6-yl)guanidine,

General Notices (1) apply to all monographs and other texts 4007
Brimonidine tartrate EUROPEAN PHARMACOPOEIA 8.2

r
NOBr N

I o
~ N
)l N~NH2
H H

F. 5-bromo-N-(lH-imidazol-2-yl)quinoxalin-6-amine, G. 1-(2-aminoethyl)-3-(5-bromoquinoxalin -6-yl)urea.

4008 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

e
Chlormadinone acetate ............... .............. ..... ........................ 4011 Cilastatin sodium .................................................................... 4013
Cholesterol. .............................................................................. 4012 Cyanocobalamin ..................................................................... 4016

General Natices (1) apply ta all managraphs and other texts 4009
 EUROPEAN PHARMACOPOEIA 8.2

4010 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2 Chlormadinone acetate

07/2014:2702 Flow rate: 1.0 mLlmin.

Detection: speetrophotometer at 236 nm.
CHLORMADINONE ACETATE Injection: 10 I1L of test solution (a) and referenee solutions (a),
(b) and (e).
Chlormadinoni acetas Identificatíon of impuritíes: use the chromatogram supplied
with chlormadinone acetate for system suitability CRS and
the chromatogram obtained with reference solution (a) to
identify the peaks due to impurities A, B, E and K; use the
chromatogram obtained with reference solution (c) to identify
the peak due to impurity G.
Relative retention with reference to chlormadinone acetate
(retention time = about 15 min): impurity K = about 0.75;
impurity G = about 0.80; impurity A = about 0.95;
C23H29CI04 M r 404.9 impurity E = about 1.04; impurity B = about 1.2.
[302-22-7]
System suitability:
DEFINITION - signal-to-noise ratio: minimum 35 for the principal peak in
6-Chloro-3,20-dioxopregna -4,6-dien -17 -yl aeetate. the chromatogram obtained with reference solution (b);
Content: 97.5 per eent to 102.0 per cent (dried substanee). - peak-to-valley ratio: mínimum 1.6, where H p = height
above the baseline of the peak due to impurity E and
CHARACTERS H v = height aboye the baseline of the lowest point of
Appearance: white or almost white, erystalline powder. the curve separating this peak from the peak due to
Solubility: practically insoluble in water, soluble in aeetonitrile, chlormadinone acetate in the chromatogram obtained with
slightly soluble in ethanol (96 per eent). reference solution (a).
Calculation of percentage contents:
IDENTIFICATION
- correction factor: multiply the peak area of impurity K by
Infrared absorption speetrophotometry (2.2.24). 1.7 ;
Comparison: chlormadinone acetate CRS.
- for impurities E, B and K, use the concentration of
TESTS chlormadinone acetate in referenee solution (b) ;
Specific optical rotatlon (2.2.7): - 14.0 to - 10.0 (dried - for impurities other than E, B and K, use the eoncentration
substanee) . of impurity G in reference solution (c).
Dissolve 0.200 g in acetonitrile R and dilute to 10.0 mL with Limits:
the same solvento - impurity B: maximum 0.2 per cent;
Rdated substances. Liquid chromatography (2.2.29). - impurities A, E, G, K: for each impurity, maximum 0.15 per
Test solution (a). Dissolve 20 mg of the substance to be cent;
examined in mobile phase B and dilute to 10.0 mL with mobile - unspecified impurities: for each impurity, maximum
phase B. 0.10 per cent;
Test solution (b). Dissolve 10.0 mg of the substanee to be
- total: maximum 0.5 per cent;
examined in mobile phase B and dilute to 20.0 mL with mobile
phase B. - reportíng threshold: 0.05 per cent.
Reference solution (a). Dissolve 4 mg of chlormadinone acetate Loss on drying (2.2.32): maximum 0.5 per cent, determined
for system suitability CRS (containing impurities A, B, E and K) on 1.000 g by drying in an oven at 105 oc.
in mobile phase B and dilute to 2.0 mL with mobile phase B. Sulfated ash (2.4.14): maximum 0.1 per cent, determined Oil
Reference solution (b). Dilute 1.0 mL of test solution (a) to 1.0 g.
100.0 mL with mobile phase B. Dilute 1.0 mL of this solution
to 10.0 mL with mobile phase B. ASSAY
Reference solution (e). Dissolve 5.0 mg of chlormadinone Liquid chromatography (2.2.29) as described in the test for
acetate impurity G CRS in mobile phase B and dilute to related substances with the following modifications.
50.0 mL with mobile phase B. Dilute 1.0 mL of the solution to
50.0 mL with mobile phase B. Mobile phase: mobile phase B, mobile phase A (45:55 V/V).
Reference solution (d). Dissolve 10.0 mg of chlormadinone Injection: test solution (b) and reference solution (d).
acetate CRS in mobile phase B and dilute to 20.0 mL with Run time: twice the retention time of chlormadinone acetate.
mobile phase B. Retentíon time: chlormadinone acetate = about 12 mino
Column:
Calculate the percentage content of C23 H 29 CIO 4 taking into
- size: 1= 0.15 m, 0 = 3.0 mm; aceount the assigned content of chlormadinone acetate CRS.
- stationary phase: end-capped extra-dense bonded
octadecylsilyl si/ica gel for chromatography R (3.5 11m). IMPURITIES
Mobile phase: Specified impurities: A, B, E, G, K.
- mobile phase A: water R; Other detectable impurities (the following substances would,
- mobile phase B: acetonitrile R; if present at a sufficient level, be detected by one or other of
Time Mobile phase A Mobile phase B the tests in the monograph. They are limited by the general
(min) (per cent V/V) (per cent V/V) acceptance criterion for other/unspeeified impurities and/or
0-8 60 40 by the general monograph Substances for pharmaceutical
use (2034). It is therefore not necessary to identify these
8 - 30 60 -7 5 40 -7 95 impurities for demonstration of compliance. See also 5.10.
30 - 33 5 95
Control of impurities in substances for pharmaceutical use):
C, D, F, H, I, J, L.

General Notices (1) apply to all monographs and other texts 4011
Cholesterol EUROPEAN PHARMACOPOEIA 8.2

H. 3-methoxy-20-oxopregna -3,5 -dien -17 -yl acetate,

A. 6a-chloro-3,20-dioxopregn-4-en-17 -yl acetate,

Br

el
a
el 1. 6-chloro-3-ethoxy-20-oxopregna-3,5-dien-17 -yl acetate,

B. 2-bromo-6-chloro-3,20-dioxopregna -1,4,6-trien -17 -yl

acetate,

a
el

J. 6-chloro-17 -hydroxypregna-4,6-diene-3,20-dione,
a
el

C. 6~-chloro- 2~ -methyl-3,20-dioxopregn -4-en -17 -yl acetate,

a
a
K. 3,20-dioxopregna -4,6-dien -17 -yl acetate,

a
el

D. 6-chloro-3,20-dioxopregna -1,4,6-trien -17 -yl acetate,

a

L. 6~-chloro-3,20-dioxopregn-4-en-17 -yl acetate.

07/2014:0993

a CHOLESTEROL
Br

E. 6-bromo-3,20-dioxopregna-4,6-dien-17 -yl acetate, Cholesterolum

a

a Ha
C27H 46 0 M r 386.7
[57-88-5]
F. 6~-methyl-3,20-dioxopregn-4-en-17 -yl acetate,
DEFINITION
a Cholest-5-en-3~-01.
Content:
- cholesterol: minimum 95.0 per cent (dried substance);
- total sterols: 97.0 per cent to 103.0 per cent (dried
substance).
a
CHARACTERS
G. 3,20-dioxopregn-4-en-17-yl acetate, Appearance: white or almost white, crystalline powder.

4012 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 Cilastatin sodium

Solubility: practically insoluble in water, sparingly soluble in Split ratio: 1:25.

acetone and in ethanol (96 per cent). Temperature:
It is sensitive to light. - column: 275 oC;
IDENTIFICATION - injection port: 285 oC;
A. Melting point (2.2.14): 147 oC to 150 oc. - detector: 300 oc.
B. Thin-Iayer chromatography (2.2.27). Prepare the solutions Detection: flame íonisation.
immediately before use. Injection: 1.0 1lL.
Test solution. Dissolve 10 mg of the substance to be System suitabi/ity: reference solution:
examined in ethylene chloride R and dilute to 5 mL with - resolution: minimum 10.0 between the peaks due to
the same solvent. pregnenolone isobutyrate and cholesterol;
Reference solution. Dissolve 10 mg of eholesterol CRS in - symmetry factor: mínimum 0.6 for the peak due to
ethylene ehloride R and dilute to 5 mL with the same solvent. cholesterol.
Plate: TLC si/ica gel G plate R. Calculate the percentage content of cholesterol taking into
Mobile phase: ethyl aceta te R, toluene R (33:66 V/V). account the assigned content of cholesterol CRS. Calculate
the percentage content of total sterols by adding together the
Application: 20 flL.
contents of cholesterol and other substances with a retention
Development: immediately, protected from light, over a time less than or equal to 1.5 times the retention time of
path of 15 cm. cholesterol. Disregard the peaks due to the internal standard
Drying: in airo and the solvento
Deteetion: spray 3 times with antimony trichloride
STORAGE
solution R; examine within 3-4 mino
Protected from light.
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size LABELLING
to the principal spot in the chromatogram obtained with
The labe! states the source material for the production of
the reference solution.
cholesterol (for example bovine brain and spinal cord, wool
C. Dissolve about 5 mg in 2 mL of methylene chloride R. Add fat or chicken eggs).
1 mL of acetic anhydride R, 0.01 mL of sulfuric acid R and
shake. A pink colour is produced which rapidly changes to IMPURITIES
red, then to blue and finally to brilliant green.
TESTS
Solubility in ethanol (96 per (ent). In a stoppered flask,
dissolve 0.5 g in 50 mL of ethanol (96 per cent) R at 50 oc.
Allow to stand for 2 h. No deposit or turbidity is formed.
Addity. Dissolve 1.0 g in 10 mL of ether R, add 10.0 mL of
0.1 M sodium hydroxide and shake for about 1 mino Heat
gently to eliminate ether and then boíl for 5 mino Cool, add A. 5a-cholest-7 -en -3~-01 (lathosterol),
10 mL of water R and 0.1 mL of phenolphthalein solution R as
indicator and titrate with 0.1 M hydrochloric acid until the
pink colour just disappears, stirring the solution vigorously
throughout the titration. Carry out a blank titration. The
difference between the volumes of 0.1 M hydrochloric acid
required to change the colour of the indicator in the blank
and in the test is not more than 0.3 mL. HO
L058 on drying (2.2.32): maximum 0.3 per cent, determined
B. cholesta-5,24-dien-3~-ol (desmosterol),
on 1.000 g by drying in vacuo at 60 oC for 4 h.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Gas chromatography (2.2.28).
Internal standard solution. Dissolve 0.100 g of pregnenolone
isobutyrate CRS in heptane R and dilute to 100.0 mL with the
same solvent. C. 5a-cholesta-7,24-dien-3~-ol.
Test solution. Dissolve 25.0 mg of the substance to be
examined in the internal standard solution and dilute to
07/2014:1408
25.0 mL with the same solution.
Reference solution. Dissolve 25.0 mg of cholesterol CRS in
the internal standard solution and dilute to 25.0 mL with the
CILASTATIN SODIUM
same solution.
Column:
Cilastatinum natricum
- material: fused silica;
- size: 1 = 30 m, 0 = 0.25 mm;
- stationary phase: poly(dimethyl)siloxane R (film thickness
0.25 flm).
Carrier gas: helium for chromatography R. C16H2SN2NaOsS M,380.4
Flow rate: 2 mLlmin. [81129-83-1]

General Notices (1) apply to all monographs and other texts 4013
Cilastatin sodium
DEFINITION
Sodium (2)-7- [[ (2R)- 2-amino-2-carboxyethyl] sulfanyl]-2-
[[ [( lS) -2,2-dimethylcyclopropyl] carbonyl] amino] hept -2-
enoate.
Content: 98.0 per cent to 101.5 per cent (anhydrous substance).
CHARACTERS
Appearance: white or light yellow, amorphous, hygroscopic
powder.
Solubility: very soluble in water and in methanol, slightly
soluble in anhydrous ethanol, very slightly soluble in dimethyl
sulfoxide, practically insoluble in acetone and in methylene
chloride.
IDENTIFICATION
A. Specific optical rotation (see Tests).
B. Infrared absorption spectrophotometry (2.2.24).
Comparison: cilastatin sodium CRS.
e. It gives reaction (a) of sodium (2.3.1).
TESTS
Solution S. Dissolve 1.0 g in carbon dioxide-free water R and
dilute to 100 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solution Y6 (2.2.2,
Method II).
pH (2.2.3): 6.5 to 7.5 for solution S.
Specific optical rotation (2.2.7): + 41.5 to + 44.5 (anhydrous
substance).
Dissolve 0.250 g in a mixture of 1 volume of hydroehloric
acid R and 120 volumes of methanol R, then dilute to 25.0 mL
with the same mixture of solvents.
Rdated substances. Liquid chromatography (2.2.29). Prepare
the solutions immediately before use.
Test solution. Dissolve 32 mg of the substance to be examined
in water R and dilute to 20.0 mL with the same solvent.
Referenee solution (a). Dilute 1.0 mL of the test solution to
100.0 mL with water R. Dilute 1.0 mL of this solution to
10.0 mL with water R.
Reference solution (b). Dissolve 3 mg of cilastatin for system
suitability 1 CRS (containing impurities A, B, E, F, G (epimer 2)
and H) in water R and dilute to 2.0 mL with the same solvent.
Reference solution (e). Dissolve 3 mg of cilastatin for system
suitability 2 CRS (containing impurities C and G (epimer 1))
in water R and dilute to 2.0 mL with the same solvento
Reference solution (d). Dissolve 32 mg of mesityl oxide R
(impurity D) in 100.0 mL of water R. Dilute 1.0 mL ofthe
solution to 50.0 mL with water R.
Column:
- size: 1 = 0.25 m, 0 = 4.6 mm;
- stationary phase: end-eapped oetadecylsilyl siliea gel for
ehromatography compatible with 100 per cent aqueous
mobile phases R (5 11m);
- temperature: 50 De.
Mobile phase:
- mobile phase A: phosphate buffer solution pH 3.25 R;
4014
EUROPEAN PHARMACOPOEIA 8.2
- mobile phase B: acetonitrile Rl, phosphate buffer solution
pH 3.25 R (50:50 V/V);
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0-3 100 O
3 - 28 100 -7 90 0-7 10
28 - 38 90 10
38 - 63 90 -7 50 10 -7 50
63 - 78 50 -7 30 50 -770
78 - 88 30 70
Flow rate: 2.0 mL/min.
Deteetion: spectrophotometer at 210 nm.
Injeetion: 20 flL.
Identificatíon of impurities: use the chromatogram
supplied with cilastatin for system suitability 1 CRS and
the chromatogram obtained with reference solution (b) to
identify the peaks due to impurities A, B, E, F, G (epimer 2)
and H; use the chromatogram supplied with eilastatin for
system suitability 2 CRS and the chromatogram obtained with
reference solution (c) to identify the peaks due to impurities
C and G (epimer 1); use the chromatogram obtained with
reference solution (d) to identify the peak due to impurity n
Relative retention with reference to cilastatin (retention
time = about 50 min): impurity E = about 0.2; impurity A
(epimer 1) = about 0.60; impurity A (epimer 2) = about 0.62;
impurity D = about 0.9; impurity F = about 0.98; impurity G
(epimer 1) = about l.02; impurity G (epimer 2) = about l.05;
impurity H = about 1.06; impurity B = about 1.17;
impurity e = about 1.23.
System suitability:
- peak-to-valley ratio: minimum 10, where Hp = height
aboye the baseline of the peak due to impurity F and
H v = height aboye the baseline of the lowest point of the
curve separating this peak from the peak due to cilastatin
in the chromatogram obtained with reference solution (b);
- peak-to-valley ratio: minimum 2.5, where Hp = height aboye
the baseline of the peak due to impurity G (epimer 1) and
H v = height above the baseline of the lowest point of the
curve separating this peak from the peak due to cilastatin
in the chromatogram obtained with reference solution (e).
Calculation of pereentage contents:
- for all impurities, use the concentration of cilastatin in
reference solution (a);
- correction faetors: multiply the peak afeas of the following
impurities by the corresponding correction factor:
impurity C = 1.3; impurity E = 3.3; impurity G (epimer 1)
and impurity G (epimer 2) = 1.6.
Limits:
- impurities A (sum of the epimers): maximum 0.5 per cent;
- impurity C: maximum 0.4 per cent;
- impuríties E: maximum 0.3 per cent;
- impurities B, F, H: for each impurity, maximum 0.1 per
cent;
- impurity G: for each epimer, maximum 0.1 per cent;
- unspecified impurities: for each impurity, maximum
0.05 per cent;
- total: maximum 1.0 per cent;
reporting threshold: 0.03 per cent; disregard any peak
due to impurity D in the chromatogram obtained with
reference solution (d).
Impurity D, acetone and methanol. Gas chromatography
(2.2.28).
Internal standard solution. Dissolve 0.5 mL of propanol R in
water R and dilute to 1000 mL with the same solvento
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2 Cilastatin sodium

Test solution. Dissolve 0.200 g of the substance to be examined 1 mL of 0.1 M sodium hydroxide is equivalent to 19.02 mg
in water R, add 2.0 mL of the internal standard solution and of CI6H2SN2NaOsS.
dilute to 10.0 mL with water R.
Reference solution. Dissolve 2.0 mL of acetone R, 0.5 mL of
STORAGE
methanol R and 0.5 mL of mesityl oxide R (impurity D) in In an airtight container, at a temperature of 2 oC to 8 oC If the
water R and dilute to 1000 mL with the same solvent. To substance is sterile, store in a sterile, airtight, tamper-proof
2.0 mL of this solution add 2.0 mL of the internal standard container.
solution and dilute to 10.0 mL with water R. This solution
contains 316 flg of acetone, 79 flg of methanol and 86 flg of IMPURITIES
impurity D per millilitre. Specified impurities: A, B, C, D, E, F, G, H.
Column:
- material: fused silica;
- size: 1= 30 m, 0 = 0.53 mm;
- stationary phase: macrogol20 000 R (film thickness 1.0 flm).
Carrier gas: helium for chromatography R.
Flow rate: 9 mL/min. A. (2)-7- [(RS)- [(2R)-2-amino-2-carboxyethyl] sulfinyl]-2-
[[ [( lS)- 2,2-dimethylcyclopropyl] carbonyl] amino] hept -2-
Temperature: enoic acid,
Time Temperature
(min) (oC)
Column 0-2.5 50

2.5 - 5 50 -¿ 70

5 - 5.5 70

Injection port 160

B. (2)-7-[[(2R)-2-carboxy-2-[[(lRS)-1-methyl-3-
Detector 220 oxobutyl]amino] ethyl] sulfanyl]-2- [[[ (lS)-2,2-
dimethylcyclopropyl]carbonyl] amino ]hept-2-enoic acid,
Deteetíon: flame ionisation.
Injeetion: 1 flL.
Calculate the percentage contents of acetone, methanol and
impurity D using the following expression:

(~) (~:)X

e (2)-7 -[[(2R)-2-carboxy-2-[(1,l-dimethyl-3-
C concentration of the solvent in the reference oxobutyl)amino] ethyl]sulfanyl]-2- [[ [( lS)-2,2-
solution, in flg/mL; dimethylcyclopropyl] carbonyl] amino] hept -2-enoic acid,
W quantity of cilastatin sodium in the test solution,
in milligrams;
Ru ratio of the are a of the solvent peak to the area of
the propanol peak in the chromatogram obtained
with the test solution;
Rs ratio of the are a of the solvent peak to the area of D. 4-methylpent-3-en-2-one (mesityl oxide),
the propanol peak in the chromatogram obtained
with the reference solution. H02CTs~C02H

Limits: H NH 2 o
- aeetone: maximum 1.0 per cent m/m; E. 7- [[ (2R) - 2-amino-2-carboxyethyl] sulfanyl]-2-oxoheptanoic
- methanol: maximum 0.5 per cent m/m; acid,
- impurity D: maximum 0.4 per cent m/m.
H02CTs~C02H
Heavy metals (2.4.8): maximum 10 ppm.
Solvent: methanol R. H NH 2 HNyO CH
1.0 g complies with test H. Prepare the reference solution
using 1 mL of lead standard solution (lO ppm Pb) R. H3C~ 2

CH 3
Water (2.5.12): maximum 2.0 per cent, determined on 0.500 g.
Bacterial endotoxins (2.6.14): less than 0.17 IU/mg, if F. (2)-7- [[ (2R)-2-amino-2-carboxyethyl] sulfanyl]-2- [(2,3-
intended for use in the manufacture of parenteral preparations dimethylbut -3-enoyl)amino ]hept -2-enoic acid,
without a further appropriate procedure for the removal of
bacterial endotoxins.

ASSAY
Dissolve 0.100 g in 30 mL of methanol R and add 5 mL of
water R. Add 0.1 M hydrochloric acid to a pH of about 3.0.
Carry out a potentiometric titration (2.2.20), using 0.1 M
sodium hydroxide. Three jumps of potential are observed. G. (E)-(2RS)-7 - [[ (2R)-2-amino-2-carboxyethyl] sulfanyl]-2-
Read the volume added between the 1st and the 3rd point of [[ [( lS)-2,2-dimethylcyclopropyl] carbonyl] amino ]hept-3-
inflexion. enoic acid,

General Notices (1) apply to all monographs and other texts 4015
Cyanocobalamin EUROPEAN PHARMACOPOEIA 8.2

Mobile phase: dilute ammonia Rl, methanol R, methylene

H. (Z)-7 - [(2-aminoethyl)sulfanyl]-2- [[ [( lS)- 2,2-dimethyl-
cyclopropyl] carbonyl] amino ]hept -2-enoic acid.
07/2014:0547
CYANOCOBALAMIN
Cyanocobalaminum
C63HssCoNl4014P M r 1355
[68-19-9]
DEFINITION
a-(5,6- Dimethylbenzimidazol-1-yl)cobamide cyanide.
Content: 96.0 per cent to 102.0 per cent (dried substance).
This monograph applies to cyanocobalamin produced by
fermentation.
CHARACTERS
Appearanee: dark red, crystalline powder or dark red crystals.
Solubility: sparingly soluble in water and in ethanol (96 per
cent), practically insoluble in acetone.
The anhydrous substance is very hygroscopic.
IDENTIFICATION
A. Ultraviolet and visible absorption spectrophotometry
(2.2.25).
Test solution. Dissolve 2.5 mg in water R and dilute to
100.0 mL with the same solvento
Speetral range: 260-610 nm.
Absorption maxima: at 278 nm, 361 nm and from 547 nm
to 559 nm.
Absorbanee ratio:
- A361 I AS47-SS9 = 3.15 to 3.45;
- A361 I A278 = 1.70 to 1.90.
B. Thin-layer chromatography (2.2.27). Carry out the test
proteeted from light.
Test solution. Dissolve 2 mg of the substance to be
examined in 1 mL of a mixture of equal volumes of ethanol maximum at 361 nm.
(96 per eent) R and water R.
Referenee solution. Dissolve 2 mg of eyanoeobalamin CRS
in 1 mL of a mixture of equal volumes of ethanol (96 per
eent) R and water R.
Plate: TLC siliea gel G plate R.
ehloride R (9:30:45 V/V/V).
Applieation: 10 ¡..tL.
Development: in an unsaturated tank, over 2/3 of the plateo
Drying: in airo
Deteetion: examine in daylight.
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size
to the principal spot in the chromatogram obtained with
the reference solution.
TESTS
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 10.0 mg of the substance to be
examined in the mobile phase and dilute to 10.0 mL with the
mobile phase. Use within 1 h.
Referenee solution (a). Dilute 3.0 mL of the test solution to
100.0 mL with the mobile phase. Use within 1 h.
Referenee solution (b). Dilute 5.0 mL of the test solution to
50.0 mL with the mobile phase. Dilute 1.0 mL of this solution
to 100.0 mL with the mobile phase. Use within 1 h.
Referenee solution (e). Dissolve 25 mg of the substance to be
examined in 10 mL of water R, warming if necessary. Allow
to cool and add 5 mL of a 1.0 giL solution of ehloramine R
and 0.5 mL of 0.05 M hydroehlorie acid, then dilute to 25 mL
with water R. Shake and allow to stand for 5 mino Dilute 1 mL
of this solution to 10 mL with the mobile phase and inject
immediately.
Column:
- size: 1= 0.25 m, 0 = 4 mm;
- stationary phase: oetylsilyl si/ica gel for ehromatography R
(5 ¡..tm).
Mobile phase: mix 26.5 volumes of methanol R and
73.5 volumes of a 10 giL solution of disodium hydrogen
phosphate R adjusted to pH 3.5 with phosphorie acid R and
use within 2 days.
Flow rate: 0.8 mL/min.
Deteetion: spectrophotometer at 361 nm.
Injeetion: 20 ¡..tL.
Run time: 3 times the retention time of cyanocobalamin.
System suitability:
- the chromatogram obtained with reference solution (c)
shows 2 principal peaks;
- resolution: minimum 2.5 between the 2 principal peaks in
the chromatogram obtained with reference solution (c);
- signal-to-noise ratio: minimum 5 for the principal peak in
the chromatogram obtained with reference solution (b).
Limits:
- total: not more than the area of the principal peak in the
chromatogram obtained with reference solution (a) (3 per
cent) ;
- disregard limit: the area of the principal peak in the
chromatogram obtained with reference solution (b) (0.1 per
cent).
L088 on drying (2.2.32) : maximum 12.0 per cent, determined
on 40.00 mg by drying in vacuo at 105 oC for 2 h.
ASSAY
Dissolve 100.0 mg in water R and dilute to 500.0 mL with the
same solvento Dilute 25.0 mL of the solution to 200.0 mL with
water R. Measure the absorbance (2.2.25) at the absorption
Calculate the content of C63HssCoNl4014P taking the specific
absorbance to be 207.
STORAGE
In an airtight container, protected from light.

4016 See the information seetion on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2

D
Diclofenac potassium ... """ .. " ................................................ 4019 Dutasteride ......... ,................................... ,... ,........ " .................. 4022
Diclofenac sodium .. ,..... " .... ,................... ,......................... ,..... 4020

General Notices (1) apply to all monographs and other texts 4017
 EUROPEAN PHARMACOPOEIA 8.2

4018 See the information section on general monographs (cover pages)

 EUROPEAN PHARMACOPOEIA 8.2
0712014:1508
DICLOFENAC POTASSIUM
Diclofenacum kalicum
C 14 HlQC1 2KN0 2 M,334.2
[15307-81-0]
DEFINITION
Potassium [2- [(2,6-dichlorophenyl)amino 1phenyl] acetate.
Content: 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance: white or slightly yellowish, slightly hygroscopic,
crystalline powder.
Solubility: sparingly soluble in water, freely soluble in
methanol, soluble in ethanol (96 per cent), slightly soluble
in acetone.
IDENTIFICATION
First identification: A, D.
Second identification: B, C, D.
A. Infrared absorption spectrophotometry (2.2.24).
III!IIII!
Comparison: diclofenac potassium CRS.
B. Thin-layer chromatography (2.2.27).
Test solution. Dissolve 25 mg of the substance to be
examined in methanol R and dilute to 5 mL with the same
solvento
Reference solution (a)' Dissolve 25 mg of diclofenac
potassium CRS in methanol R and dilute to 5 mL with the
same solvent.
Reference solution (b). Dissolve 10 mg of indometacin R
in reference solution (a) and dilute to 2 mL with the same
solution.
Plate: TLC silica gel GF254 plate R.
Mobile phase: concentrated ammonia R, methanol R, ethyl
acetate R (10:10:80 V/V/V).
Application: 5 ¡.ti.
Development: over 1/2 of the plateo
Drying: in airo
Detection: examine in ultraviolet light at 254 nm.
System suitability: reference solution (b):
- the chromatogram shows 2 clearly separated spots.
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position and size to
the principal spot in the chromatogram obtained with
reference solution (a).
C. Dissolve about 10 mg in 10 mL of ethanol (96 per eent) R.
To 1 mL of this solution add 0.2 mL of a mixture, prepared L085 on drying (2.2.32): maximum 0.5 per cent, determined
immediately befo re use, of equal volumes of a 6 giL solution on l.000 g by drying in an oven at 105 oC for 3 h.
of potassium ferricyanide R and a 9 giL solution of ferric
chloride R. Allow to stand protected from light for 5 mino
Add 3 mL of a 10 giL solution of hydrochloric acid R. Allow Dissolve 0.250 g in 60 mL of anhydrous acetic acid R. Titrate
to stand protected from light for 15 mino A blue colour
develops and a precipitate is formed.
D. Suspend 0.5 g in 10 mL of water R. Stir and add water R
until the substance is dissolved. Add 2 mL of hydroehloric
acid Rl, stir for 1 h and filter with the aid of vacuum.
Neutralise with sodium hydroxide solution R. The solution
gives reaction (b) of potassium (2.3.1).
General Notices (1) apply ta all monographs and other texts
Didofenac potassium
TESTS
Appearance of solntion. The solution is clear (2.2.1) and its
absorbance (2.2.25) at 440 nm is not greater than 0.05.
Dissolve 1.25 g in methanol R and dilute to 25.0 mL with the
same solvent.
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 50.0 mg of the substance to be
examined in the mobile phase and dilute to 50.0 mL with the
mobile phase.
Referenee solution (a). Dilute 2.0 mL of the test solution to
100.0 mL with the mobile phase. Dilute 1.0 mL of this solution
to 10.0 mL with the mobile phase.
Reference solution (b). Dissolve the contents of a vial of
diclofenac for system suitability CRS (containing impurities A
and F) in 1.0 mL of the mobile phase.
Column:
- size: 1 = 0.25 m, 0 = 4.6 mm;
- stationary phase: end-eapped octadecylsilyl si/iea gel for
chromatography R (5 flm).
Mobile phase: mix 34 volumes of a solution containing
0.5 giL of phosphoric acid R and 0.8 giL of sodium dihydrogen
phosphate R, previously adjusted to pH 2.5 with phosphoric
aeid R, and 66 volumes of methanol R.
Flow rate: 1.0 mL/min.
Detection: spectrophotometer at 254 nm.
Injection: 20 ¡.tL.
Run time: 1.6 times the retention time of diclofenac.
Identification of impurities: use the chromatogram
supplied with diclofenac for system suitability CRS and the
chromatogram obtained with reference solution (b) to identify
the peaks due to impurities A and F.
Relative retention with reference to diclofenac
(retention time = about 25 min): impurity A = about 0.4;
impurity F = about 0.8.
System suitability: reference solution (b):
- resolution: mínimum 4.0 between the peaks due to
impurity F and diclofenac.
Calculation of percentage contents:
- correctian factors: multiply the peak areas of the following
impurities by the corresponding correction factor:
impurity A = 0.7; impurity F = 0.3;
- for each impurity, use the concentration of didofenac in
reference solution (a).
Limits:
- impurities A, F: for each impurity, maximum 0.15 per cent;
- unspecified impurities: for each impurity, maximum
0.10 per cent;
- total: maximum 0.4 per cent;
- reporting threshold: 0.05 per cent.
Heavy metals (2.4.8): maximum 10 ppm.
Dissolve 2.0 g in 20 mL of methanol R. The solution complies
with test H. Prepare the reference solution using lead standard
solution (1 ppm Pb) obtained by diluting lead standard
solution (100 ppm Pb) R with methanol R.
ASSAY
with 0.1 M perchloric acid, determining the end-point
potentiometrically (2.2.20).
1 mL of 0.1 M perchloric acid is equivalent to 33.42 mg
of C 14HlQCI 2 KN0 2 •
STORAGE
In an airtight container, protected from light.
4019
Didofenac sodium EUROPEAN PHARMACOPOEIA 8.2

IMPURITIES 07/2014:1002
Specified impurities: A, F.
DICLOFENAC SODIUlVI
Other detectable impurities (the Íollowing substances would,
iÍ present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general Didofenacum natricum
acceptance criterio n for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical use
(2034). It is therefore not necessary to identiíy these impurities
Íor demonstration of compliance. See also 5.10. Controlof
impurities in substances for pharmaceutical use): B, C, D, E.

~o C 14H lO C1 2 NNa0 2 M,318.1

~-oNN¡-~e! [15307-79-6]

el DEFINITION
~ # Sodium [2- [(2,6-dichlorophenyl)amino ]phenyl]acetate.
Content: 99.0 per cent to 101.0 per cent (dried substance).
A. 1- (2,6-dichlorophenyl) -1 ,3-dihydro- 2H- indol-2-one,
CHARACTERS

ryeHo Appearance: white or slightly yellowish, slightly hygroscopic,

crystalline powder.
Solubility: sparingly soluble in water, freely soluble in
~NH methanol, soluble in ethanol (96 per cent), slightly soluble
in acetone.
el,&el
mp: about 280 oC, with decomposition.
IDENTIFICATION
B. 2- [(2,6-dichlorophenyl)amino ]benzaldehyde, First identification: A, D.
Second identification: B, C, D.
A. Infrared absorption spectrophotometry (2.2.24).

Comparison: diclofenac sodium CRS.

B. Thin-Iayer chromatography (2.2.27).
Test solution. Dissolve 25 mg of the substance to be
examined in methanol R and dilute to 5 mL with the same
solvent.
e. [2- [(2,6-dichlorophenyl)amino] phenyl] methanol, Reference so/ution (a). Dissolve 25 mg of diclofenae
sodium CRS in methanol R and dilute to 5 mL with the
same solvent.
Reference solution (b). Dissolve 10 mg of indometacin R in
reference solution (a) and dilute to 2 mL with reference
solution (a).
Plate: TLC si/ica gel GF254 plate R.
Mobile phase: concentrated ammonia R, methanol R, ethyl
aceta te R 00:10:80 V/V/V).
Applícation: 5 ¡.tL.
D. [2- [(2-bromo-6-chlorophenyl)amino ]phenyl] acetic acid,
Development: over 1/2 of the plateo
Drying: in airo
Deteetion: examine in ultraviolet light at 254 nm.
~o
~N¡- System suitabi/ity: reference solution (b):
H - the chromatogram shows 2 dearly separated spots.
Results: the principal spot in the chromatogram obtained
E. 1,3-dihydro-2H-indol-2-one, with the test solution is similar in position and size to
the principal spot in the chromatogram obtained with
reÍerence solution (a).
(Y el e. Dissolve about 10 mg in 10 mL of ethanol (96 per cent) R.
To 1 mL of this solution add 0.2 mL oí a mixture, prepared
HN~ immediately before use, of equal volumes of a 6 giL solution

c~~" "
of potassium ferricyanide R and a 9 giL solution of ferric
ch/oride R. Allow to stand protected from light Íor 5 mino
Add 3 mL of a 10 giL solution oí hydrochloric acid R. Allow

U to stand, protected from light, for 15 mino A blue colour

develops and a precipitate is formed.
D. Dissolve 60 mg in 0.5 mL of methanol R and add 0.5 mL of
F. N-( 4-chlorophenyl)-2-(2,6-dichlorophenyl)acetamide. water R. The solution gives reaction (b) of sodium (2.3.1).

4020 See the informatíon section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 Didofenac sodium

TESTS 1 mL of 0.1 M perchloric acid is equivalent to 31.81 mg

Appearance of solution. The solution is clear (2.2.1) and its of C 14HlQC1 2 NNa0 2 •
absorbance (2.2.25) at 440 nm is not greater than 0.05.
STORAGE
Dissolve 1.25 g in methanol R and dilute to 25.0 mL with the
same solvento In an airtight container, protected from light.
Related substances. Liquid chromatography (2.2.29). IMPURITIES
Test solution. Dissolve 50.0 mg of the substance to be Specified impurities: A, F.
examined in the mobile phase and dilute to 50.0 mL with the
mobile phase. Other detectable impurities (the following substances would,
if present at a sufficient leve!, be detected by one or other of
Reference solution (a). Dilute 2.0 mL ofthe test solution to the tests in the monograph. They are limited by the general
100.0 mL with the mobile phase. Dilute l.0 mL of this solution acceptance criterion for other/unspecified impurities and/or
to 10.0 mL with the mobile phase. by the general monograph Substances for pharmaceutical use
Reference solution (b). Dissolve the contents of a vial of (2034). It is therefore not necessary to identify these impurities
diclofenae for system suitability CRS (containing impurities A for demonstration of compliance. See also 5.10. Controlof
and F) in l.0 mL of the mobile phase. impuritíes in substances for pharmaeeutical use): B, C, D, E.
Column:
- size: 1 = 0.25 m, 0 = 4.6 mm;
- stationary phase: end-capped octadecylsilyl silica gel for
chromatography R (5 flm).
Mobile phase: mix 34 volumes of a solution containing
0.5 giL of phosphoric acid R and 0.8 giL of sodium dihydrogen
phosphate R, previously adjusted to pH 2.5 with phosphoric
acid R, and 66 volumes of methanol R. A. 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one,
Flow rate: 1.0 mL/min.
Deteetion: spectrophotometer at 254 nm.
Injection: 20 flL.
(XI
~
CHO

NH

Run time: 1.6 times the retention time of diclofenac. CI~CI

Identification of impurities: use the chromatogram
supplied with diclofenac for system suitability CRS and the U
chromatogram obtained with reference solution (b) to identify
the peaks due to impurities A and F. B. 2- [(2,6-dichlorophenyl)amino ]benzaldehyde,

Relative retention with reference to diclofenac (retention

time = about 25 min): impurity A = about 0.4;
impurity F = about 0.8.
System suitability: reference solution (b):
- resolutiol1: minimum 4.0 between the peaks due to
impurity F and diclofenac.
Calculation of percentage contents:
C. [2- [(2,6-dichlorophenyl)amino ]phenyl]methanol,
- correction factors: multiply the peak areas of the following
impurities by the corresponding correction factor:
impurity A = 0.7; impurity F = 0.3;
- for each impurity, use the concentration of diclofenac in
reference solution (a).
Limits:
- impuríty A: maximum 0.2 per cent;
- impurity F: maximum 0.15 per cent; D. [2- [(2-bromo-6-chlorophenyl)amino ] phenyl]acetic acid,
- unspeeified impurities: for each impurity, maximum
0.10 per cent;
- total: maximum 0.4 per cent; ~O
~N/
- reporting threshold: 0.05 per cent. H

Heavy metals (2.4.8): maximum 10 ppm. E. l,3-dihydro-2H-indol-2-one,

Dissolve 2.0 g in 20 mL of methanol R. The solution complies
with test H. Prepare the reference solution using lead standard
solution (1 ppm Pb) obtained by diluting lead standard (YCI

HN~
solution (100 ppm Pb) R with methanol R.
Loss on drying (2.2.32): maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 105 oC for 3 h.
c~~ e
ASSAY
Dissolve 0.250 g in 60 mL of anhydrous aeetic acid R. Titrate
with 0.1 M perchloric acid, determining the end-point
U
potentiometrically (2.2.20). F. N- (4-chlorophenyl)-2- (2,6-dichlorophenyl)acetamide.

General Notices (1) apply to all monographs and other texts 4021
Dutasteride EUROPEAN PHARMACOPOEIA 8.2

01/2014:2641 Identifieation of impurities: use the chromatogram

corrected 8.2 supplied with dutasteride for system suitability CRS and
the chromatogram obtained with reference solution (b) to
DUTASTERIDE identify the peaks due to impurities A, B, C, E, F and G.
Relative retention with reference to dutasteride (retention
Dutasteridum time = about 36 min): impurity A = about 0.10;
o H
CH 3
y
--H
N
CF3

~ /¡
impurity B = about 0.11; impurity C = about 0.4;
impurity E = about 0.9; impurity F = about 1.1;
impurity G = about 1.2.
System suitability:
- resolution: minimum 1.5 between the peaks due
F3C to impurity E and dutasteride and minimum 1.5
o N between the peaks due to impurities A and B in the
H H chromatogram obtained with reference solution (b);
C27H30F6N202 M r 528.5 - signal-to-noise ratio: minimum 30 for the peak due
[164656-23-9] to dutasteride in the chromatogram obtained with
DEFINITION
reference solution (a).
N - [2,5 -Bis( trifluoromethyl)phenyl]-3-oxo-4-aza-Su-androst-
Caleulation of pereentage eontents:
1-ene-17~-carboxamide. - eorreetion faetors: multiply the peak areas of the
Content: 97.0 per cent to 102.0 per cent (anhydrous substance). following impurities by the corresponding correction
factor: impurity B = 0.7; impurity F = 3.0;
CHARACTERS - for each impurity, use the concentration of dutasteride
Appearanee: white or pale yellow powder. in reference solution (a).
Solubility: practically insoluble in water, freely soluble in Limits:
methylene chloride, soluble or sparingly soluble in anhydrous - impurity F: maximum 0.4 per cent;
ethanol. - impurities E, G: for each impurity, maximum 0.3 per
IDENTIFICATION
cent;
A. Specific optical rotation (see Tests). - impurities A, C: for each impurity, maximum 0.2 per
cent;
B. Infrared absorption spectrophotometry (2.2.24).
- impurity B: maximum 0.15 per cent;
Comparison: dutasteride CRS.
- unspeeified impurities: for each impurity, maximum
TESTS 0.10 per cent;
Specific optical rotation (2.2.7): + 33.0 to + 39.0 (anhydrous - reporting threshold: 0.05 per cent.
substance). E. Liquid chromatography (2.2.29) as described in test A for
Dissolve 0.100 g in anhydrous ethanol R and dilute to 20.0 mL related substances with the following modifications.
with the same solvent. Column:
Related substances - size: 1= 0.15 m, 0 = 4.6 mm;
A. Liquid chromatography (2.2.29). - stationary phase: phenylsilyl silica gel for
Solvent mixture: water for ehromatography R, aeetonitrile Rl ehromatography R (5 flm).
(40:60 V/V). Mobile phase: water for ehromatography R, aeetonitrile Rl
Test solution. Dissolve 50.0 mg of the substance to be (20:80 V/V).
examined in the solvent mixture and dilute to 100.0 mL Injeetion: 10 flL of the test solution and reference
with the solvent mixture. solutions (a) and (b).
Referenee solution (a). Dilute 1.0 mL of the test solution to Run time: 5 times the retention time of dutasteride.
100.0 mL with the solvent mixture. Dilute 1.0 mL of this Identification of impurities: use the chromatogram
solution to 10.0 mL with the solvent mixture. supplied with dutasteride for system suitability CRS and
Referenee solution (b). Dissolve 5 mg of dutasteride for the chromatogram obtained with reference solution (b) to
system suitability CRS (containing impurities A, B, C, E, identify the peaks due to impurities H and 1.
F, G, H and 1) in the solvent mixture and dilute to 10 mL
Relative retention with reference to dutasteride
with the solvent mixture. (retention time = about 4 min) : impurity H = about 3.4;
Referenee solution (e). Dissolve 50.0 mg of dutasteride CRS impurity 1 = about 3.9.
in the solvent mixture and dilute to 100.0 mL with the
System suitability: reference solution (b):
solvent mixture.
- resolution: minimum 2.0 between the peaks due to
Column:
impurities H and 1.
- size: 1= 0.25 m, 0 = 4.6 mm;
Caleulation of pereentage eontents:
- stationary phase: end-eapped oetadeeylsilyl silica gel for
ehromatography R (5 flm); - for each impurity, use the concentration of dutasteride
in reference solution (a).
- temperature: 35 oc.
Limits:
Mobile phase: mix 0.25 volumes of trifluoroaeetie
acid R, 480 volumes of water for ehromatography R and - impurity I: maximum 0.5 per cent;
520 volumes of aeetonitrile Rl. - impurity H: maximum 0.3 per cent;
Flow rate: 1.0 mL/min. - unspeeified impurities eluting afier dutasteride: for each
Deteetion: spectrophotometer at 220 nm. impurity, maximum 0.10 per cent;
Injeetion: 20 flL of the test solution and reference - reporting threshold: 0.05 per cent.
solutions (a) and (b). Limit:
Run time: 1.6 times the retention time of dutasteride. - total for tests A and B: maximum 1.5 per cent.

4022 See the information seetion on general monographs (eover pages)

EUROPEAN PHARMACOPOEIA 8.2 Dutasteride

Water (2.5.32): maximum 0.2 per cent, determined

using the evaporation teehnique:
- temperature: 180 oC;
- heating time: 4 mino
011 0.100 g

~
" "C"~~;~~'
5 .. y H H F3 C
Sulfated ash (2.4.14): maximum 0.1 per eent, determined on o N:
H H
1.0 g in a platinum crucible.
E. N- [2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5a-
ASSAY androst -1-ene-17 a-carboxamide,
Liquid chromatography (2.2.29) as deseribed in test A for
related substances with the following modification.

CH~rH~r\3
Injection: 10 IlL ofthe test solution and referenee so!ution (e).
Calculate the percentage content of C27 H JO F6N202 taking into
aceount the assigned content of dutasteride CRS. y
F3C
IMPURITIES
o
Specified impurities: A, B, C, E, F, G, H, I.
Other detectable impurities (the following substances would,
F. N- [2,5-bis(trifluoromethyl)phenyl]-la-chloro-3-oxo-4-aza-
if present at a sufficient leve!, be detected by one OI other of
5a-androstane-17~-carboxamide,
the tests in the monograph. They are limited by the general
acceptanee criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical
use (2034). It is therefore not necessary to identify these
impurities for demonstration of compliance. See also 5.10.
Control of impurities in substances for pharmaceutical use): D.

CH 3 C0 2 H

CH3~'H
~ H H G. N- [2,5-bis( trifluoromethyl)phenyl]-3 -oxo-4-azaandrost-
1,5-diene-17~-carboxamide,
o N:
H H

A. 3-oxo-4-aza-5a-androst-l-ene-17~-carboxylic acid,

o N
H H

B. N,N-dimethyl-3-oxo-4-aza -5a-androst -1-ene-17~­ o N

carboxamide, H H

H. N- [2,5-bis( trifluoromethyl)phenyl]- 3 -oxo-4- [3-oxo-4-aza-

o 5u-androst -1-ene-17 u -carbonyl]-4-aza -5u-androst -l-ene-
17~-carboxamide (dutasteride dimer 1),

o N
H H

C. ethyl 3-oxo-4-aza-5u-androst -1-ene-17~-carboxylate,

o N
H H
o N
H
1. N- [2,5-bis( trifluoromethyl)phenyl]-3-oxo-4- [3-oxo-4-aza-
D. N- [2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost- Su -androst -1-ene-17~-carbonyl]-4-aza -5a-androst -l-ene-
1,5-diene-17 u -carboxamide, 17~-carboxamide (dutasteride dimer 2).

General Notices (1) apply to all monographs and other texts 4023
 EUROPEAN PHARMACOPOEIA 8.2

4024 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2

E
Esomeprazole magnesium dihydrate ................................... 4027 Esomeprazole magnesium trihydrate ................................... 4028

General Natices (1) apply ta all monographs and other texts 4025
 EUROPEAN PHARMACOPOEIA 8.2

4026 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2
07/2014:2787
ESOMEPRAZOLE MAGNESIUM
DIHYDRATE
Esomeprazolum magnesicum dihydricum
. 2 H2 0
C34H36MgN606S2,2H20 M r 749.2
[217087-10-0]
DEFINITION
Magnesium bis[ 5-methoxy-2- [(5)- [( 4-methoxy-3,5-
dimethylpyridin-2-yl)methyl]sulfinyl]-lH-benzimidazol-l-
ide] dihydrate.
Content: 98.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance: white or slightly coloured powder, slightly
hygroscopic.
Solubility: slightly soluble in water, soluble in methanol,
practically insoluble in heptane.
It shows polymorphism (5.9).
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24).
Comparison: esomeprazole magnesium dihydrate CRS.
lf the spectra obtained in the solid state show differences,
dissolve the substance to be examined and the reference
substance separately in methanol R, evaporate to dryness and
record new spectra using the residues.
B. Enantiomeric purity (see Tests).
C. Ignite about 0.5 g of the substance to be examined
according to the procedure for the sulfated ash test (2.4.14).
Dissolve the residue in 10 mL of water R. 2 mL of this
solution gives the reaction of magnesium (2.3.1).
D. Water (see Tests).
TESTS
Absorbance (2.2.25): maximum 0.20 at 440 nm.
Dissolve 0.500 g in methanol R and dilute to 25.0 mL with
the same solvent. Filter through a membrane filter (nominal
pore size 0.45 11m).
Enantiomeric purity. Liquid chromatography (2.2.29): use
the normalisation procedure.
Buffer solution pH 6.0. Mix 20 mL of a 179.1 giL solution
of disodium hydrogen phosphate R and 70 mL of a 156.0 giL
solution of sodium dihydrogen phosphate R, then dilute to
1000 mL with water R. Dilute 250 mL of this solution to
1000 mL with water R.
Buffer solution pH 11.0. Mix 11 mL of a 95.0 giL solution of
trisodium phosphate dodeeahydrate R and 22 mL of a 179.1 giL
solution of disodium hydrogen phosphate R, then dilute to
1000 mL with water R.
Test solution. Dissolve 40 mg of the substance to be examined
in 5 mL of methanol R and dilute to 50.0 mL with buffer
solution pH 1l.0. Dilute 1.0 mL of this solution to 25.0 mL
with buffer solution pH 11.0.
Referenee solution. Dissolve 2 mg of omeprazole CRS in buffer
solution pH 1l.0 and dilute to 50.0 mL with the same buffer
solution. Dilute 1.0 mL of the solution to 10.0 mL with buffer
solution pH 1l.0.
General Notices (1) apply to all monographs and other texts
Esomeprazole magnesium dihydrate
Column:
- size: 1= 0.1 m, 0 = 4.0 mm;
- stationary phase: a¡-acid-glycoprotein silica gel for chiral
separation R (5 11m).
Mobile phase: acetonitríle R, buffer solution pH 6.0
(13:87 V/V).
Flow rate: 0.6 mLlmin.
Detection: spectrophotometer at 302 nm.
Injection: 20 11L.
Relative retention with reference to esomeprazole (retention
time = about 5 min): impurity F = about 0.7.
5ystem suitabi/ity: reference solution:
- resolution: minimum 3.0 between the peaks due to
impurity F and esomeprazole.
Limit:
- impurity F: maximum 0.6 per cent; disregard any peak
other than impurity F and esomeprazole.
Related substances. Liquid chromatography (2.2.29): use the
normalisation procedure. Prepare the solutions immediately
befare use.
Test solution. Dissolve 14 mg of the substance to be examined
in the mobile phase and dilute to 100.0 mL with the mobile
phase.
Referenee solution (a). Dissolve 1 mg of omeprazole CRS and
1 mg of omeprazole impurity D CRS in the mobile phase and
dilute to 10.0 mL with the mobile phase.
Reference solution (b). Dissolve 3 mg of omeprazole for peak
identification CRS (containing impurity E) in the mobile phase
and dilute to 20.0 mL with the mobile phase.
Reference solution (e). Dilute 1.0 mL of the test solution to
100.0 mL with the mobile phase. Dilute 1.0 mL of this solution
to 10.0 mL with the mobile phase.
Column:
- size: 1= 0.125 m, 0 = 4.6 mm;
- stationary phase: oetylsi/yl si/ica gel for ehromatography R
(5 11m).
Mobi/e phase: mix 27 volumes of acetonitrile R and 73 volumes
of a 1.4 giL solution of disodium hydrogen phosphate R
previously adjusted to pH 7.6 with phosphoric acid R.
Flow rate: 1 mLlmin.
Detection: spectrophotometer at 280 nm.
Injection: 40 11L.
Run time: 4 times the retention time of esomeprazole.
Identification of impurities: use the chromatogram supplied
with omeprazole for peak identification CRS and the
chromatogram obtained with reference solution (b) to
identify the peak due to impurity E; use the chromatogram
obtained with reference solution (a) to identify the peak due
to impurity D.
Relative retention with reference to esomeprazole
(retention time = about 9 min): impurity E = about 0.4;
impurity D = about 0.7.
System suitability: reference solution (a):
- resolution: minimum 3.0 between the peaks due to
impurity D and omeprazole.
Limits:
- impurities D, E: for each impurity, maximum 0.15 per cent;
- unspecified impurities: for each impurity, maximum
0.10 per cent;
- total: maximum 0.3 per cent;
- disregard limit: 0.5 times the area of the principal peak in
the chromatogram obtained with reference solution (c)
(0.05 per cent).
4027
Esomeprazole magnesium trihydrate EUROPEAN PHARMACOPOEIA 8.2

Magnesium: 3.30 per cent to 3.55 per cent (anhydrous

substance).
Dissolve 0.400 g in 25 mL of methanol R, sonicate until
dissolution is complete. Add 25 mL of water R, 10 mL of
eoneentrated ammonia R, 20.000 mL of 0.05 M sodium edetate
and about 50 mg of mordant black 11 triturate R. Titrate the B. 2- [(RS)- [( 3,5-dimethylpyridin·-2-yl)methyl] sulfinyl]-5-
excess of sodium edetate with 0.05 M zinc sulfate until the methoxy-lH-benzimidazole,
colour changes from full blue to violet. Carry out a blank
titration. H3CO~NH CH 3
1 mL of 0.05 M sodium edetate corresponds to 1.21525 mg
ofMg.
NAs~OCH3
Water (2.5.12): 4.5 per cent to 6.1 per cent, determined on ~~CH3
0.200 g.
C. 5-methoxy-2- [[ (4-methoxy-3,5-dimethylpyridin-2-
yl)methyl] sulfanyl]-lH-benzimidazole (ufiprazole),
ASSAY
Liquid chromatography (2.2.29). H3c0 0 N H CH 3
Buffer solution pH 11.0. Mix 11 mL of a 95.0 giL solution of
trisodium phosphate dodecahydrate R and 22 mL of a 179.1 giL
'L(NAs~OCH3
o °
11\\ 1
solution of disodium hydrogen phosphate R, then dilute to CH
N Y
3
100.0 mL with water R.
Test solution. Dissolve 10.0 mg of the substance to be D. 5-methoxy-2- [[ (4-methoxy-3,5-dimethylpyridin-2-
examined in about 10 mL of methanol R, add 10 mL ofbuffer yl)methyl] sulfonyl]-lH-benzimidazole (omeprazole
solution pH ll.O and dilute to 200.0 mL with water R. sulfone),

Reference solution. Dissolve 10.0 mg of omeprazole CRS in H3C0 0 N H CH 3

about 10 mL of methanol R, add 10 mL of buffer solution
pH 11.0 and dilute to 200.0 mL with water R. 'L(NAS)(x0CH3
11 1

Column: o ...,-N y
and enantiomer o CH 3
- size: 1 = 0.125 m, 0 = 4 mm;
E. 4-methoxy-2-[ [(RS)-(5-methoxy-lH-benzimidazol-2-
- stationary phase: octylsilyl si/ica gel for ehromatography R yl)sulfinyl]methyl]-3,5-dimethylpyridine l-oxide,
(5 flm).
Mobile phase: mix 35 volumes of acetonitrile R and 65 volumes H3CO~NH CH 3
of a 1.4 giL solution of disodium hydrogen phosphate R
CH3
previously adjusted to pH 7.6 with phosphoric acid R. NA~ U 1 O
o N y
Flow rate: 1 mL/min. CH 3

Deteetion: spectrophotometer at 280 nm. F. 5-methoxy-2- [(R)- [( 4-methoxy-3,5-dimethylpyridin-2-

Injection: 20 flL. yl)methyl] sulfinyl]-lH-benzimidazole ((R)-omeprazole).
Run time: 1.5 times the retention time of esomeprazole. 07/2014:2372
Retention time: esomeprazole = about 4 mino
Calculate the percentage content of CJ4H36MgN606S2 taldng ESOMEPRAZOLE MAGNESIUM
into account the assigned content of omeprazole CRS. TRIHYDRATE
1 g of omeprazole is equivalent to 1.032 g of esomeprazole
magnesium. Esomeprazolum magnesicum trihydricum
STORAGE
In an airtight container, protected from light.
, 3 H2 0
IMPURITIES
Specified impurities: D, E, F.
Other detectable impurities (the following substances would, M r 767.2
if present at a sufficient leve!, be detected by one or other of
the tests in the monograph. They are limited by the general [217087 -09-7]
acceptance criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical use DEFINITION
(2034). It is therefore not necessary to identify these impurities Magnesium bis[5-methoxy-2- [(S)- [( 4-methoxy-3,5-
for demonstration of compliance. See also 5.10. Control of dimethylpyridin -2-yl)methyl] sulfinyl]-lH-benzimidazol-l-
impurities in substances for pharmaceutical use): A, B, C. ide] trihydrate.
Content: 98.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance: white or slightly coloured powder, slightly
hygroscopic.
Solubility: slightly soluble in water, soluble in methanol,
A. 5-methoxy -lH-benzimidazole-2-thio!, practically insoluble in heptane.

4028 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24).
Comparison: esomeprazole magnesium trihydrate CRS.
B. Enantiomeric purity (see Tests).
C. Ignite about 0.5 g of the substance to be examined
according to the procedure for the sulfated ash test (2.4.14).
Dissolve the residue in 10 mL of water R. 2 mL of this
solution gives the reaction ofmagnesium (2.3.1).
D. Water (see Tests).
TESTS
Absorbance (2.2.25): maximum 0.20 at 440 nm.
Dissolve 0.500 g in methanol R and dilute to 25.0 mL with
the same solvent. Filter through a membrane filter (nominal
pore size 0.45 [lm).
Enantiomeric purity. Liquid chromatography (2.2.29) : use
the normalisation procedure.
Buffer solution pH 6.0. Mix 20 mL of a 179.1 giL solution
of disodium hydrogen phosphate R and 70 mL of a 156.0 giL
solution of sodium dihydrogen phosphate R, then dHute to
1000 mL with water R. Dilute 250 mL of this solution to
1000 mL with water R.
Buffer so/uíion pH 11.0. Mix 11 mL of a 95.0 giL solution of
trisodium phosphate dodecahydrate R and 22 mL of a 179.1 giL
solution of disodium hydrogen phosphate R, then dilute to
1000 mL with water R.
Test solution. Dissolve 40 mg of the substance to be examined
in 5 mL of methanol R and dilute to 50.0 mL with buffer
solution pH 11.0. Dilute 1.0 mL of this solution to 25.0 mL
with buffer solution pH 11.0.
Reference solution. Dissolve 2 mg of omeprazole CRS in buffer
solution pH 11.0 and dHute to 50.0 mL with the same buffer
solution. Dilute 1.0 mL of the solution to 10.0 mL with buffer substance).
solution pH ll.O.
Column:
- size: 1 = 0.1 m, 0 = 4.0 mm;
- stationary phase: aj-acid-glycoprotein silica gel for chiral and about 50 mg of mordant black 11 triturate R. Titrate the
separation R (5 [lm).
Mobile phase: acetonitrile R, buffer solution pH 6.0
(13:87 V/V).
Flow rate: 0.6 mL/min.
Detection: spectrophotometer at 302 nm.
Injection: 20 [lL.
Relative retention with reference to esomeprazole (retention
time = about 5 min): impurity F = about 0.7.
System suitability: reference solution:
- resolution: minimum 3.0 between the peaks due to
impurity F and esomeprazole.
Limit:
- impurity F: maximum 0.2 per cent; disregard any peak
other than impurity F and esomeprazole.
Related substances. Liquid chromatography (2.2.29) : use the solution pH 11.0 and dilute to 200.0 mL with water R.
normalisation procedure. Prepare the solutions immediately
before use.
Test solution. Dissolve 14 mg of the substance to be examined pH ll.O and dilute to 200.0 mL with water R.
in the mobile phase and dilute to 100.0 mL with the mobile
phase.
Reference solution (a). Dissolve 1 mg of omeprazole CRS and
1 mg of omeprazole impurity D CRS in the mobile phase and
dHute to 10.0 mL with the mobile phase.
Reference solution (b). Dissolve 3 mg of omeprazole for peak
identification CRS (containing impurity E) in the mobile phase of a 1.4 giL solution of disodium hydrogen phosphate R
and dilute to 20.0 mL with the mobile phase.
Reference solution (e). Dilute 1.0 mL ofthe test solution to
100.0 mL with the mobile phase. Dilute 1.0 mL of this solution Detection: spectrophotometer at 280 nm.
to 10.0 mL with the mobile phase.
General Notices (1) apply to all monographs and other texts
Esomeprazole magnesium trihydrate
Column:
- size: l = 0.125 m, 0 = 4.6 mm;
- stationary phase: octylsilyl si/ica gel for chromatography R
(5 [lm).
Mobile phase: mix 27 volumes of acetonitrile R and 73 volumes
of a lA giL solution of disodium hydrogen phosphate R
previously adjusted to pH 7.6 with phosphoric aeid R.
Flow rate: 1 mL/min.
Detection: spectrophotometer at 280 nm.
Injeetion: 40 fiL.
Run time: 4 times the retention time of esomeprazole.
Identification of impurities: use the chromatogram supplied
with omeprazole for peak identification CRS and the
chromatogram obtained with reference solution (b) to
identify the peak due to impurity E; use the chromatogram
obtained with reference solution (a) to identify the peak due
to impurity D.
Relative retention with reference to esomeprazole
(retention time = about 9 min): impurity E = about 0.4;
impurity D = about 0.7.
System suitability: reference solution (a):
- resolution: minimum 3.0 between the peaks due to
impurity D and omeprazole.
Limits:
- impurities D, E: for each impurity, maximum 0.15 per cent;
- unspecified impurities: for each impurity, maximum
0.10 per cent;
- total: maximum 0.3 per cent;
- disregard limit: 0.5 times the area of the principal peak in
the chromatogram obtained with reference solution (c)
(0.05 per cent).
Magnesium: 3.30 per cent to 3.55 per cent (anhydrous
Dissolve 0.400 g in 25 111L of methanol R, sonicate until
dissolution is complete. Add 25 mL of water R, 10 mL of
eoncentrated ammonia R, 20.000 mL of 0.05 M sodium edetate
excess of sodium edetate with 0.05 M zinc sulfate until the
colour changes fr0111 full blue to violet. Carry out a blank
titration.
1 mL of 0.05 M sodium edetate corresponds to 1.21525 mg
ofMg.
Water (2.5.12): 6.2 per cent to 8.0 per cent, determined on
0.200 g.
ASSAY
Liquid chromatography (2.2.29).
Buffer solution pH 11.0. Mix 11 mL of a 95.0 giL solution of
trisodium phosphate dodecahydrate R and 22 mL of a 179.1 giL
solution of disodium hydrogen phosphate R, then dilute to
100.0 mL with water R.
Test solution. Dissolve 10.0 mg of the substance to be
examined in about 10 mL of methanol R, add 10 mL ofbuffer
Reference solution. Dissolve 10.0 mg of omeprazole CRS in
about 10 mL of methanol R, add 10 mL of buffer solution
Column:
- size: 1 = 0.125 m, 0 = 4 mm;
- stationary phase: oetylsilyl siliea gel for chromatography R
(5 [lm).
Mobile phase: mix 35 volumes of acetonitrile R and 65 volumes
previously adjusted to pH 7.6 with phosphoric acid R.
Flow rate: 1 mL/min.
Injection: 20 ¡..tL.
4029
Esomeprazole magnesium trihydrate EUROPEAN PHARMACOPOElA 8.2

Run time: 1.5 times the retention time of esomeprazole.

Retention time: esomeprazole = about 4 mino
Calculate the percentage content of C34H36MgN606S2 taking
into account the assigned content of omeprazole CRS.
1 g of omeprazole is equivalent to 1.032 g of esomeprazole
magnesium. C. 5-methoxy-2- [ [(4-methoxy-3,5-dimethylpyridin -2-
yl)methyl]sulfanyl]-lH-benzimidazole (ufiprazole),
STORAGE
In an airtight container, protected from light.
H3C0-0--NH CH 3
IMPURITIES
Specified impurities: D, E, F.
~NAs:D:0CH3
I 11\\
o o N #
Other detectable impurities (the following substances would, CH 3
if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general D. 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-
acceptance criterio n for other/unspecified impurities and/or yl)methyl] sulfonyl]-lH-benzimidazole (omeprazole
by the general monograph Substances for pharmaceutical use sulfone),
(2034). It is therefore not necessary to identify these impurities
for demonstration of compliance. See also 5.10. Controlof H3C0-0--NH CH 3
impurities in substances for pharmaceutical use): A, B, C.
~NAsnOCH3
I 11

H3CO - Q N H
o ..... N #
and enantiomer o CH 3
NASH
E. 4-methoxy-2-[[(RS)-(5-methoxy-lH-benzimidazol-2-
A. 5-methoxy-lH-benzimidazole-2-thiol, yl)sulfinyl]methyl]-3,5-dimethylpyridine l-oxide,

H3 CO - Q N H CH3 H3C0-0--NH CH 3

NAs~
I 11
~NAsí):0CH3
I 11
and enantiomer o N # CH 3 o N #
CH 3

B. 2-[(RS)-[(3,5-dimethylpyridin-2-yl)methyl]sulfinyl]-5- F. 5-methoxy-2- [(R)- [( 4-methoxy-3,5-dimethylpyridin -2-

methoxy-lH-benzimidazole, yl)methyl] sulfinyl]-lH-benzimidazole ((R)-omeprazole).

4030 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

F
Fenticonazole nitrate .............................................................. 4033 Fulvestrant.. ............................................................................. 4035
Fibrin sealant kit.. ................................................................... 4034

General Natices (1) apply ta all managraphs and ather texts 4031
 EUROPEAN PHARMACOPOEIA 8.2

4032 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 Fenticonazole nitraíe

07/2014:1211 Mobile phase: mix 70 volumes of acetonitrile Rl and

30 volumes of a phosphate buffer solution prepared by
FENTICONAZOLE NITRATE dissolving 3.4 g of potassium dihydrogen phosphate R in
900 mL of water R, adjusting to pH 3.0 with phosphoric aeid R
and diluting to 1000 mL with water R.
Fenticonazoli nitras
Flow rate: 1.0 mLJmin.
CI Detection: speetrophotometer at 229 nm.

CI~ Injection: 10 11L.

Run time: 5.5 times the retention time of fenticonazole,

o~AJ ~o\
, HN0 3
N impurity D and fenticonazole in the chromatogram
S and enantiomer l ~
C24H21C12N304S
[73151-29-8]
DEFINITION
1- [(2RS)- 2-(2,4-Dichlorophenyl) -2- [[ 4- (phenylsulfanyl)-
benzyl] oxy]ethyl]-IH-imidazole nitrate.
Content: 99,0 per cent to 101.0 per eent (dried substanee).
CHARACTERS
Appearance: white or almost white, erystalline powder.
Solubility: practically insoluble in water, freely soluble in
dimethylformamide and in methanol, sparingly soluble in
anhydrous ethano!.
ID ENTIFICATION
First identification: C, D.
Second identification: A, B, D.
A. Melting point (2.2.14): 134 oC to 137 0e.
B. Ultraviolet and visible absorption speetrophotometry
(2.2.25).
Test so/ution. Dissolve 20.0 mg in anhydrous ethanol R and
dilute to 100.0 mL with the same solvento Dilute 1.0 mL of
this solution to 10.0 mL with anhydrous ethanol R.
Spectral range: 230-350 nm.
Absorption maximum: at 252 nm.
Shoulder: at about 270 nm.
Absorption minimum: at 236 nm.
Specific absorbanee at the absorption maximum: 260 to 280.
e. Infrared absorption spectrophotometry (2.2,24).
Comparison: fenticonazole nitrate CRS.
D. It gives the reaction of nitrates (2.3.1).
TESTS
Optical rotation (2.2.7): - 0.10° to + 0.10°.
Dissolve 0.10 g in methanol R and dilute to 10.0 mL with the
same solvent.
Related substances. Liquid chromatography (2.2.29).
Test so/uNon. Dissolve 25.0 mg of the substance to be
examined in the mobile phase and dilute to 25.0 mL with the
mobile phase.
Reference solution (a). Dilute 1.0 mL of the test solution to
200.0 mL with the mobile phase.
Reference solution (b). DiIute 10.0 mL of reference solntion (a)
to 25.0 mL with the mobile phase.
Reference solution (e). Dilute 1.0 mL of reference solution (a)
to 10.0 mL with the mobile phase.
Reference solution (d). Dilute 1.0 mL ofthe test solution to
100.0 mL with the mobile phase, Dissolve the contents of a
vial of fenticonazole impurity D CRS in 1.0 mL of this solution.
Column:
- size: 1 == 0.25 m, 0 == 4 mm;
- stationary phase: oetadeeylsi/yl si/iea gel for
chromatography R (5-10 flm).
System suitability:
- reso/ution: minimum 2.0 between the peaks dne to
obtained with referenee solution (d);
- signal-to-noise ratio: minimum 5 for the principal peak in
M r 518.4 the ehromatogram obtained with referenee solution (e).
Limits:
- impurities A, B, C, D, E: for eaeh impurity, not more
than the are a of the principal peak in the chromatogram
obtained with reference solution (b) (0.2 per cent);
- total: not more than the are a of the principal peak in the
chromatogram obtained with reference solution (a) (0.5 per
cent) ;
- disregard limit: the are a of the principal peak in the
chromatogram obtained with reference solution (e)
(0.05 per cent); disregard the peak due to the nitric ion
(whieh corresponds to the dead volume ofthe column).
Toluene. Head-space gas chromatography (2.2.28) : use the
standard additions method.
Test solution. Disperse 0.2 g of the substance to be examined
in a 10 mL vial with 5 mL of water R.
Referenee solution. Mix 4 mg of toluene R with water R and
dilute to 1000 mL with the same solvent. Place 5 mL of this
solution in a 10 mL vial.
Column:
- size: 1 == 25 m, 0 == 0.32 mm;
- stationary phase: poly(cyanopropyl)(7) (phenyl)(7)-
(methyl)(86)siloxane R (film thickness 1.2 11m).
Carrier gas: helium for chromatography R.
Split ratio: 1:25.
Column head pressure: 40 kPa.
Static head-space conditions which may be used:
- equilibration temperature: 90 oC;
- equilibration time: 1 h.
Temperature:
- column: 80 oC;
- injection port: 180 oC;
- detector: 220 0e.
Detection: flame ionisation.
Injection: 1 mL of the gaseous phase.
Limit:
- toluene: maximum 100 ppm,
Loss on drying (2.2.32) : maximum 0.5 per cent, determined
011 1.000 g by drying in vacuo at 60 De.
Sulfated ash (2.4,14): maximum 0.1 per cent, determined 011
1.0 g.
ASSAY
Dissolve 0.450 g in 50 mL of a mixture of equal volumes of
anhydrous aeetic acid R and methyl ethyl ketone R. Titrate
with 0,1 M perch/oric acid, determining the end-point
potentiometrieally (2.2.20).
1 mL of 0.1 M perchloric acid is equivalent to 51.84 mg
of C24H21CI2NP4S,
STORAGE
Protected from light.

General Notices (1) apply to all monographs and other texts 4033
Fibrin sealant kit EVROPEAN PHARMACOPOEIA 8.2

IMPVRITIES formed when the 2 thawed or reconstituted components are

Specified impurities: A, B, C, D, E. mixed. Other ingredients (for example, human coagulation
el factor XIII, a fibrinolysis inhibitor or calcium ions) and
stabilisers (for example, Human albumin solution (0255)) may
el~ be added.
Human constituents are obtained from plasma that
HO~ N
and enantiomer complies with the monograph on Human plasma for
fractionation (0853).
When thawed or reconstituted as stated on the label,
LJ component 1 contains not less than 40 gil of dottable protein;
the thrombin activity of component 2 varies over a wide range
A. (RS)-1-(2,4-dichlorophenyl)-2-(lH-imidazol-1-yl)ethanol, (approximately 4-1000 IV/mL).
el PRODVCTION

el~H ,
The method of preparation is designed to maintain functional
integrity of the components. It indudes a step or steps that

o ~o~
~.~ N
and enantiomer have been shown to remove or to inactivate known agents of
infection; if substances are used for inactivation of viruses
during production, the subsequent purification procedure
o* ('LN) must be validated to demonstrate that the concentration of
these substances is reduced to a suitable level and any residues
are such as not to compromise the safety of the preparation
B. 1-[(2RS)-2-(2,4-dichlorophenyl)-2-[[4-(benzenesulfinyl)- for patients.
benzyl] oxy] ethyl]-lH-imidazole,
The constituents or mixtures of constituents are dissolved in
el a suitable liquido No antimicrobial preservative or antibiotic

el~ is added. Constituents or mixtures of constituents are passed

through a bacteria-retentive filter and distributed aseptically

o ~o~ and enantiomer

into sterile containers. Containers of freeze-dried constituents
are dosed under vacuum or filled with a suitable inert gas,
such as oxygen-free nitrogen, before being do sed.
~~ N
"S,\ ( ) If the human coagulation factor XIII content in component 1
o o 'LN is greater than 10 IV/mL, the assay of human coagulation
factor XIII is carried out.
C. 1- [(2RS) - 2- (2,4-dichlorophenyl) -2- [ [4- (benzenesulfonyl)-
benzyl] oxy] ethyl]-lH-imidazole, CHARACTERS

~
el

HO~
n el

and enantiomer
Appearance:
- freeze-dried constituents: white or pale yellow, hygroscopic
powder or friable solid,
- frozen constituents: colourless or pale yellow, opaque solid,
- liquid constituents: colourless or pale yellow liquido

(~ (YS~
Por the freeze-dried or frozen constituents, reconstitute or
thaw as stated on the label immediately before carrying out the
N~ V identification and the tests, except those for solubility and water.
D. (RS)-1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]-3- [4-
(phenylsulfanyl) benzyl] imidazolium nitrate, Component 1 (fibrinogen concentrate)
el IDENTIFICATION

el~ A. It complies with the limits of the assay of fibrinogen.

B. It complies with the limits of the assay of human

Q~O~ "0, coagulation factor XIII (where applicable).

TESTS
# S~ (~(YSY') Solubility. Freeze-dried concentrates dissolve within 20 min
and enantiomer N~ V in the volume of liquid and at the temperature stated on the
label, forming an almost colourless, dear or slight1y turbid
E. (RS)-1-[2-(2,4-dichlorophenyl)-2-[4-(phenylsulfanyl)- solution.
benzyloxy] ethyl]-3-[4- (phenylsulfanyl) benzyl] imidazolium
nitrate. pH (2.2.3): 6.5 to 8.0.
Stability of solution. No gel formation appears at
07/2014:0903 room temperature during 120 min following thawing or
reconstitution.
FIBRIN SEALANT KIT Water. Determined by a suitable method, such as semi-micro
determination of water (2.5.12), loss on drying (2.2.32) or
Fibrini glutinum near-infrared spectroscopy (2.2.40), the water content is
within the limits approved by the competent authority.
DEFINITION Sterility (2.6.1). It complies with the test.
Sterile, freeze-dried, frozen or liquid preparation of plasma
protein fractions containing essentially 2 components, namely ASSAY
fibrinogen concentrate (component 1), a protein fraction Fibrinogen (clottable protein). Mix 0.2 mL of the
containing human fibrinogen, and a preparation containing reconstituted concentrate with 2 mL of a suitable buffer
human thrombin (component 2). A fibrin dot is rapidly solution (pH 6.6-7.4) containing sufficient human thrombin R

4034 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
(approximately 3 IU/mL) and calcium (0.05 mol/L). Maintain
at 37 oC for 20 min, separate the precipitate by centrifugation
at 5000 g for 20 min, wash thoroughly with a 9 giL solution of
sodium chloride R and determine the protein as nitro gen by
sulfuric acid digestion (2.5.9). Calculate the clottable protein
content by multiplying the result by 6.0. The estimated content
in milligrams of clottable protein is not less than 70 per cent
and not more than 130 per cent of the stated contento lf for
a particular preparation this method cannot be applied, use
another validated method for determination of fibrinogen.
Human coagulation factor XIII. Use a reference plasma
calibrated against the International Standard for blood
coagulation factor XIII in plasma. Where the ¡abel indicates
that the human coagulation factor XIII potency is greater than
10 IU/mL, the estimated potency is not less than 80 per cent
and not more than 120 per cent of the stated potency.
Make at least 3 suitable dilutions of thawed or reconstituted
concentrate and of the reference preparation using human
coagulation factor XIIl-deficient plasma or another suitable
diluent. Coagulation factors V, VIII, XI and XIII plasma BRP
is suitable for use as a reference preparation. Add to each
dilution suitable amounts of the following reagents:
- activator reagent, containing bovine or human thrombin,
a suitable buffer, calcium chloride and a suitable inhibitor
such as Gly-Pro-Arg-Pro-Ala-NH 2 which inhibits clotting
of the sample but do es 110t prevent human coagulation
factor XIII activation by thrombin;
- detection reagent, containing a suitable factor XlIIa -specific
peptide substrate, such as Leu-Gly-Pro-Gly-Glu-Ser-Lys-
Val-Ile-Gly-NH2 and glycine ethyl ester as 2nd substrate in a
suitable buffer solution;
- NADH reagent, containing glutamate dehydrogenase,
a-ketoglutarate and NADH in a suitable buffer solution.
After mixing, the absorbance changes (t..A/min) are measured
at a wavelength of 340 nm, after the linear phase of the
-
reaction is reachedo
Calculate the potency of the test preparation by the usual
statistical methods (5.3, for example). The confidence limits
(P = 0.95) are not less than 80 per cent and not more than
125 per cent of the estimated potency.
Component 2 (thrombin preparation)
IDENTIFICATION
It complies with the limits of the assay of thrombin.
TESTS
Solubility. Freeze-dried preparations dissolve within 5 min in
the volume of liquid stated on the label, forming a colourless,
clear or slightly turbid solution.
pH (2.2.3): 5.0 to 800.
Water. Determined by a suitab1e method, such as semi-micro
determination of water (2.5.12), 10ss on drying (2.2.32) or
near-infrared spectroscopy (2.2.40), the water content is
within the limits approved by the competent authority.
Sterility (2.6.1). It complies with the test.
ASSAY
Thrombin. If necessary, dilute the reconstituted preparation
to be examined to approximately 2-20 IU of thrombin
per millilitre using as diluent a suitable buffer solution
(pH 7.3-7.5), such as imidazole buffer solution pH 7.3 R
containing 10 giL of human albumin R or bovine albumin R
To a suitable volume of the dilution, add a suitable volume
of fibrinogen solution (1 giL of clottable protein) warmed to
37 oC and start measurement of the clotting time immediatelyo
General Notices (1) apply to all monographs and other texts
Fulvestrant
Repeat the procedure with each of at least 3 dilutions, in the
range stated aboye, of a reference preparation of thrombin,
calibrated in International Units.
Calculate the activity of the test preparation by the usual
statistical methods (5.3, for example). The estimated activity
is not less than 80 per cent and not more than 125 per cent
of the stated activity. The confidence limits (P = 0.95) are
not less than 80 per cent and not more than 125 per cent of
the estimated activity.
STORAGE
Protected from light and, for freeze-dried components, in an
airtight container.
LABELLING
The label states:
- the amount of fibrinogen (milligrams of dottable protein),
thrombin (International Units) per container, and of
human coagulation factor XIII, lf the latter is greater than
10 IU/mL,
- where applicable, the name and volume of liquid to be used
to reconstitute the components.
07/2014:2443
FULVESTRANT
Fulvestrantum
•
~CH30HH
H and epimer at S
~ 1: : OFF
H H 11\/
HO~ o-~S~CF
H 3
C32 H 47 F5 0 3S
[129453-61-8]
DEFINITION
M r 607
7a -[9- [(RS)-( 4,4,5,5,5-Pentafluoropentyl)sulfinyl] nonyl] estra-
1,3,5( 10)-triene-3,17~-diol.
Content: 97.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance: white or almost white powder.
Solubility: practically insoluble in water, freely soluble in
ethano1 (96 per cent) and in methylene chloride.
IDENTIFlCATION
Carry out either tests A, B or tests B, e.
A. Specific optical rotation (2.2.7): + 108 to + 115 (anhydrous
substance), measured at 365 nm at a temperature of 25 0e.
Dissolve 0.50 g in methanol R and dilute to 25.0 mL with
the same solvent.
B. lnfrared absorption spectrophotometry (2.2.24).
Comparison: fulvestrant CRS.
e. Stereochemical purity (see Tests).
TESTS
Appearance of solution. The solution is clear (2.2.1).
Dissolve 0.1 g in ethanol (96 per cent) R and dilute to 10 mL
with the same solvent.
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 50.0 mg of the substance to be
examined in methanol Rl and dilute to 5.0 mL with the same
solvento
Reference solution (a). Dissolve 50.0 mg of fulvestrant CRS in
methanol Rl and dilute to 5.0 mL with the same solvent.
4035
Fulvestrant EUROPEAN PHARMACOPOElA 8.2

Rejerence solution (b J. Dissolve 10 mg of julvestrant jor system Stereochemical purity. Liquid chromatography (2.2.29) : use
suitabílity CRS (containing impurities A, B, C, D and F) in the normalisation procedure.
1.0 mL of methanol Rl. Test solution. Dissolve 20.0 mg of the substanee to be
Rejerence solution (ej. Dilute 1.0 mL of the test solution to examined in the mobile phase and dilute to 20.0 mL with the
100.0 mL with methanol R1. Dilute LO mL ofthis solution mobile phase.
to 10.0 mL with methanol Rl. Rejerence solution. Dissolve 5 mg of julvestrant CRS in the
Column: mobile phase and dilute to 5.0 mL with the mobile phase.
- size: 1 == 0.15 m, 0 == 4.6 mm; Column:
- stationary phase: end-capped octylsilyl silica gel jor size: 1== 0.25 m, 0 == 4.6 mm;
ehromatography R (3.5 11m); - stationary phase: silica gel AD jor chiral separation R
- temperature: 40 oc. (10 [lm);
Mobile phase: - tempera tu re: 40 oc.
- mobile phase A: methanol R2, acetonitrile R1, water jor Mobile phase: anhydrous ethanolR, 2-methylpentane R
ehromatography R (27:32:41 V/V/V); (12:88 V/V).
- mobile phase B: water jor chromatography R, methanol R2, Flow rate: 1 mLlmin.
acetonitríle Rl (10:41:49 V/V/V);
Deteetion: speetrophotometer at 280 nm.
Time Mobile phase A Mobile phase B Injeetion: 10 IlL
(min) (per cent V/V) (per cent V/V)
Run time: 1.75 times the retention time of fulvestrant
0-25 100 O
epimer B.
25 - 55 100 -7 O O -7 100
Identification of peaks: use the chromatogram supplied with
55 - 65 O 100 julvestrant CRS and the ehromatogram obtained with the
reference solution to identify the peaks due to fulvestrant
Flow rate: 2 mL/min. epimers A and B.
Deteetion: speetrophotometer at 225 nm. Relative retention with reference to fulvestrant
epimer B (retention time == about 26 min): fulvestrant
Injeetion: 10 IlL of the test solution and referenee solutions (b)
epimer A == about 1.1.
and (e).
Identification oj impurities: use the ehromatogram System suitability: reference solution:
supplied with julvestrant jor system suitability CRS and the - resoluNon: minimum 1.3 between the peaks due to
ehromatogram obtained with referenee solution (b) to identify fulvestrant epimer B and fulvestrant epimer A.
the peaks due to impurities A, B, C, D and F. Limit:
Relative retention with referenee to fulvestrant (retention - julvestrant epimer A/julvestrant epimer B ratio:
time == about 23 min): impurity F == about 0.4; 42:58 to 48:52.
impurity A == about 1.1; impurity B == about 1.2;
impurity C == about 1.7; impurity D == about 1.9. Heavy metals (2.4.8): maximum 20 ppm.
System suitability: reference solution (b) : Solvent: ethanol (96 per eentJ R.
- resolution: minimum 1.5 between the peaks due to 0.250 g complíes with test H. Prepare the reference solution
fulvestrant and impurity A. using 0.5 mL of lead standard solution (10 ppm PbJ R.
Limits: Water (2.5.32) : maximum 0.5 per cent, determined on 50 mg.
- correction jaetors: for the ealculation of content, multiply Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
the peak are as of the following impurities by the 1.0 g in a platinum crucible.
eorresponding correction factor: impurity D == 0.7; Bacterial endotoxins (2.6.14): less than 1.25 IU/mg, if
impurity F == 0.3; intended for use in the manufacture of parenteral preparations
- impurity D: not more than 6 times the are a of the principal without a further appropriate proeedure for the removal of
peak in the chromatogram obtained with reference bacterial endotoxins.
solution (e) (0.6 per cent); Test solution. Dissolve 0.1 g of the substance to be examined
- impurity C: not more than 3 times the are a of the principal in 1 mL of ethanol (96 per cent) R and dilute to 80 mL with
peak in the ehromatogram obtained with referenee water for BET.
solution (c) (0.3 per cent);
ASSAY
- impurity B: not more than twice the are a of the principal
peak in the ehromatogram obtained with reference Liquid chromatography (2.2.29) as deseribed in the test for
solution (e) (0.2 per cent); related substanees with the following modification.
- impurity F: not more than 1.5 times the area of the principal Injection: test solution and referenee solution (a).
peak in the ehromatogram obtained with reference Calculate the percentage eontent of C32H47Fs03S from the
solution (e) (0.15 per eent); declared content of julvestrant CRS.
- unspecified impurities: for each impurity, not more than the
area of the principal peak in the ehromatogram obtained STORAGE
with reference solution (e) (0.10 per eent); Proteeted from light at a temperature of 2 oC to 8 oc. lf the
- total: not more than 10 times the are a of the principal peak substanee is sterile, store in a sterile, airtight, tamper-proof
in the ehromatogram obtained with reference solution (c) container.
(1.0 per cent);
- disregard limit: 0.5 times the area of the principal peak in LABELLING
the ehromatogram obtained with reference solution (e) The label states, where applicable, that the substance is suitable
(0.05 per eent). for use in the manufacture of parenteral preparations.

4036 See the injormation section on general monographs (cover pagesJ

EUROPEAN PHARMACOPOEIA 8.2 Fulvestrant

IMPURITIES
Specified impurities: B, C, D, F.

Other detectable impurities (the following substances would,

if present at a sufficient level, be detected by one or other of HO
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecifled impurities and/or
by the general monograph Substances for pharmaceutical use
(2034). 1t is therefore not necessary to identiÍy these impurities
for demonstration oí compliance. See also 5.10. Control of C. 7- [9- [[9- [( 4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-
impurities in substances for pharmaceutical use): A, E. sulfinyl] nonyl] estra-1,3,5( 1O)-triene-3, 17~-diol,
HO 9H3
H

HO OH
and epimer at S

OFF

HO
~~ CF 3
D. 7,7' -nonane-l,9-diylbis [estra-l,3,5(1O)-triene-3,17~-diol],

A. 7~- [9- [(RS) -( 4,4,5,5,5-pentafluoropentyl)sulfinyl] nonyl]-

estra-l,3,5( lO)-triene-3,17p-diol (7~-fulvestrant),
HO

E. 7- [9- [( 4,4,5,5,5-pentafluoropentyl)sulfinyl] nonyl] estra-

1,3,5( 10),6-tetraene-3,17~-diol (M-fulvestrant),

~I~
•"
H
C",o,~
H
,,~S~CF3
o o

\\//
"

\! OFF
11 '\/
HO
H
HO ~~CF3
O

B. 7Q- [9- [( 4,4,5,5,5-pentafluoropentyl)sulfonyl] nonyl] estra- F. 7- [9- [( 4,4,5,5,5-pentaf1uoropentyl)sulfinyl]nonyll-3,17~­

l,3,5(1O)-triene-3,17~-diol, dihydroxyestra-l,3,5( 10)-trien-6-one (6-keto-fulvestrant).

General Notices (1) apply to all monographs and other texts 4037
 EUROPEAN PHARMACOPOEIA 8.2

4038 See the ínformatíon section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2

H
Histidine .................................................................................. 4041
Histidine hydrochloride monohydrate ................................ 4042
Human coagulation factor IX (rDNA) concentrated
solution ....................................................................... " ......... 4043
Human plasma (pooled and treated for virus
inactivation) .......................................................................... 4048
Hydroxypropylbetadex ........................................................... 4050

General Natices (1) apply ta all monographs and other texts 4039
 EUROPEAN PHARMACOPOEIA 8.2

4040 See the information section on general monographs (ca ver pages)
 EUROPEAN PHARMACOPOEIA 8.2
07/2014:09H
HISTIDINE
Histidinum
C6H 9NP2 M,155.2 for the apparatus used.
[71-00-1]
DEFINITION
(2S)-2-Amino-3-(lH-imidazol-4-yl)propanoic acid.
Fermentation produet, extraet or hydrolysate of protein.
Content: 98.5 per eent to 101.0 per cent (dried substance).
CHARACTERS
Appearanee: white or almost white, erystalline powder or
eolourless crystals.
Solubility: soluble in water, very slight1y soluble in ethanol
(96 per eent).
IDENTIFICATION
First identification: A, B,
Seeond identification: A, C, D.
A. Specific optical rotation (see Tests).
B. Infrared absorption spectrophotometry (2.2.24).
llIIII
Comparison: histidíne CRS.
If the spectra obtained show differences, dissolve the
substanee to be examined and the reference substance
separately in the minimum volume of water R, evaporate to
dryness at 60 oC and record new spectra using the residues.
C. Thin-layer chromatography (2.2.27).
Test solution. Dissolve 10 mg of the substance to be
exal11ined in water R and dilute to 50 l11L with the same
solvent.
Reference solution. Dissolve 10 mg of histidine CRS in
water R and dilute to 50 mL with the same solvent.
Piafe: TLC siliea gel plate R.
Mobile phase: glacial acetic acid R, water R, butanol R
(20:20:60 V/V/V).
Applieation: 5 ¡..tL.
Development: over 2/3 of the plateo
Drying: in airo
Deteetíon: spray with ninhydrin solution R and heat at
105 oC for 15 mino
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size Chlorides (2.4.4): maximum 200 ppm.
to the principal spot in the chromatogram obtained with
the reference solution.
D. Dissolve 0.1 g in 7 mL of water R and add 3 mL of a
200 giL solution of sodium hydroxide R. Dissolve 50 l11g
of sulfanilic aeid R in a mixture of 0.1 mL of hydrochloric
aeid R and 10 mL of water R and add 0.1 mL of sodium
nitrite solution R. Add the second solution to the first and
mix. An orange-red colour develops.
TESTS
Solution S. Dissolve 2.5 g in distilled water R, heating in a
water-bath, and dilute to 50 mL with the same solvent.
Appearance oí solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solutioll BY? (2.2.2,
Method IJ).
Spedfic optical rotation (2.2.7): + 11.4 to + 12.4 (dried
substance).
Dissolve 2.75 g in 12.0 mL of hydroehlorie acid Rl and dilute
to 25.0 mL with water R.
General Notiees (1) apply to all monographs and other texts
Histidine
Ninhydrin-positive substances. Amino acid analysis
(2.2.56). For analysis, use Method lo
The concentrations of the test solution and the reference
solutions may be adapted according to the sensitivity of the
equipment used. The eoncentrations of aH solutions are
adjusted so that the system suitability requirements described
in general chapter 2.2.46 are fulfilled, keeping the ratio s of
eoncentrations between al! solutions as described.
So/ution A: water R 01' a sample preparation buffer suitable
Test so/ution. Dissolve 30.0 mg of the substanee to be
examined in solution A and dilute to 50.0 mL with solution A.
Reference solution (a). Dilute 1.0 mL of the test solution to
100.0 mL with solution A. Dilute 2.0 mL of this solution to
10.0 mL with solution A.
Reference so/ution (b). Dissolve 30.0 mg of proline R in
solution A and dilute to 100.0 mL with solution A. Dilute
1.0 mL of the solution to 250.0 mL with solution A.
Referenee solution (e). Dilute 6.0 mL of ammonium standard
solution (100 ppm NHJ R to 50.0 mL with solution A. Dilute
1.0 mL of this solution to 100.0 mL with solution A.
Reference solution (d). Dissolve 30 mg of isoleucine R and
30 mg of leucine R in solution A and dilute to 50.0 mL with
solution A. DiIute 1.0 mL of the solution to 200.0 mL with
solution A.
Blank solution: solution A.
Inject suitable, equal amounts of the test, blank and reference
solutions into the amino acid analyser. Run a program suitable
for the determination of physiological amino acids.
System suitability: re fe rene e solution (d):
- resolution: minimum 1.5 between the peaks due to
isoleucine and leucine.
Calculation of percentage contents:
- for any ninhydrin-positive substanee detected at 570 nm,
use the concentration of histidine in reference solution (a);
- for any ninhydrin-positive substance detected at 440 nm,
use the concentration of proline in reference solution (b); if
a peak is aboye the reporting threshold at both wavelengths,
use the result obtained at 570 nm for quantification.
Limits:
- any ninhydrin-positive substance: for each impurity,
maxil11um 0.2 per cent;
- total: maximum 0.5 per cent;
- reporting threshold: 0.05 per cent.
The thresholds indicated under Re!ated substances
(Table 2034.-1) in the general monograph Substances for
pharmaceutical use (2034) do 110t apply.
Dilute 5 mL of solution S to 15 mL with water R.
Sulfates (2.4.13): maximum 300 ppm.
Dilute 10 mL of solution S to 15 mL with distilled water R.
Ammonium. Amino acid analysis (2.2.56) as described in
the test for ninhydrin-positive substanees with the following
l110difications.
Injection: test solution, reference solution (e) and blank
solution.
Limit:
- ammonium at 570 nm: not more than the area of the
eorresponding peak in the chromatogram obtained with
reference solution (e) (0.02 per cent), taking into account
the peak due to al11monium in the chromatogram obtained
with the blank solution.
Iron (2.4.9): maximum 10 ppm.
In a separating funnel, dissolve 1.0 g in 10 mL of dilute
hydrochloric acid R. Shake with 3 quantities, eaeh of 10 mL, of
methyl isobutyl ketone Rl, shaking for 3 min each time. To the
4041
Histidine hydrochloride monohydrate
combined organic layers add 10 mL of water R and shake fOI
3 mino Use the aqueous layer.
Heavy metals (2.4.8): maximum 10 ppm.
Dissolve 2.0 g in a mixture of 3 mL of dilute hydroehlorie
acid R and 15 mL of water R, with gentle warming if necessary,
and dilute to 20 mL with water R. 12 mL of the solution
complies with test A. Prepare the reference solution using lead
standard solution (1 ppm Pb) R.
Loss on drying (2.2.32): maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 105 0e.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Dissolve 0.130 g in 50 mL of water R. Titrate with
0.1 M hydroehlorie acid, determining the end-point
potentiometrically (2.2.20).
1 mL of 0.1 M hydroehlorie aeid is equivalent to 15.52 mg of
C6H 9N 30Z'
STORAGE
Protected from light.
IMPURITIES
Other detectable impurities (the following substances would,
if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities. It
is therefore not necessary to identify these impurities for
demonstration of compliance. See also 5.10. Control of
impurities in substanees for pharmaeeutieal use): A.
A. (2S)-2-amino-3-( 4-hydroxyphenyl)propanoic acid
(tyrosine) .
07/2014:0910
HISTIDINE HYDROCHLORIDE
MONOHYDRATE
Histidini hydrochloridum monohydricum Ninhydrin-positive
j=N H NHz
HN~ • HCI • HzO
COzH
C6HIOCINpz,HzO M r 209.6 adjusted so that the system suitability requirements described
[5934-29-2]
DEFINITION
(2S)-2-Amino-3-(lH-imidazol-4-yl)propanoic acid
hydrochloride monohydrate.
Fermentation product, extract or hydrolysate of protein.
Content: 98.5 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearanee: white or almost white, crystalline powder OI
colourless crystals.
Solubility: freely soluble in water, slightly soluble in ethanol
(96 per cent).
IDENTIFICATION
First identifieation: A, B, C, F.
Second identifieation: A, B, D, E, F.
A. Specific optical rotation (see Tests).
B. pH (see Tests).
e. Infrared absorption spectrophotometry (2.2.24).
4042 See the information seetion on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Comparison: histidine hydroehloride monohydrate CRS.
D. Thin-Iayer chromatography (2.2.27).
-
Test solution. Dissolve 10 mg of the substance to be
examined in water R and dilute to 50 mL with the same
solvento
Referenee solution. Dissolve 10 mg of histidine hydroehloride
monohydrate CRS in water R and dilute to 50 mL with the
same solvento
Plate: TIC silica gel plate R.
Mobile phase: glacial aeetie acid R, water R, butanol R
(20:20:60 V/VlV).
Applieation: 5 flL.
Development: over 2/3 of the plateo
Drying: in airo
Deteetion: spray with ninhydrin solution R and heat at
105 oC for 15 mino
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size
to the principal spot in the chromatogram obtained with
the reference solution.
E. Dissolve 0.1 g in 7 mL of water R and add 3 mL of a
200 g/L solution of sodium hydroxide R. Dissolve 50 mg
of sulfanilie acid R in a mixture of 0.1 mL of hydroehlorie
acid R and 10 mL of water R and add 0.1 mL of sodium
nitrite solution R. Add the second solution to the first and
mix. An orange-red colour develops.
F. About 20 mg gives reaction (a) of chlorides (2.3.1).
TESTS
Solution S. Dissolve 2.5 g in earbon dioxide-free water R
prepared from distilled water R and dilute to 50 mL with the
same solvento
Appearance of solution. Solution S is clear (2.2.1) and
not more intensely coloured than reference solution BY6
(2.2.2, Method II).
pH (2.2.3): 3.0 to 5.0 for solution S.
Specific optical rotation (2.2.7): + 9.2 to + 10.6 (dried
substance).
Dissolve 2.75 g in 12.0 mL of hydroehlorie acid R1 and dilute
to 25.0 mL with water R.
substances. Amino acid analysis
(2.2.56). For analysis, use Method 1.
The concentrations of the test solution and the reference
solutions may be adapted according to the sensitivity of the
equipment used. The concentrations of all solutions are
in general chapter 2.2.46 are fulfilled, keeping the ratios of
concentrations between all solutions as described.
Solution A: water R or a sample preparation buffer suitable
fOI the apparatus used.
Test solution. Dissolve 30.0 mg of the substance to be
examined in solution A and dilute to 50.0 mL with solution A.
Referenee solution (a). Dilute 1.0 mL of the test solution to
100.0 mL with solution A. Dilute 2.0 mL of this solution to
10.0 mL with solution A.
Reference solution (b). Dissolve 30.0 mg of proline R in
solution A and dilute to 100.0 mL with solution A. Dilute
1.0 mL of the solution to 250.0 mL with solution A.
Referenee solution (e). Dilute 6.0 mL of ammonium standard
solution (lOO ppm NH,J R to 50.0 mL with solution A. Dilute
1.0 mL ofthis solution to 100.0 mL with solution A.
Referenee solution (d). Dissolve 30 mg of isoleueine R and
30 mg of leucine R in solution A and dilute to 50.0 mL with
solution A. Dilute 1.0 mL of the solution to 200.0 mL with
solution A.
Blank solution: solution A.
EUROPEAN PHARMACOPOEIA 8.2 Human coagulation factor IX (rDNA) concentraíed solution

Inject suitable, equal amounts of the test, blank and reference

solutions into the amino acid analyser. Run a program suitable
for the determination of physiological amino acids.
System suitability: reference solution (d): A. (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid
- reso/ution: minimum 1.5 between the peaks due to (tyrosine).
isoleucine and leucine.
Calculation of percentage contents:
0712014:2522
- for any ninhydrin-positive substance detected at 570 nm,
use the concentration of histidine in reference solution (a);
- for any ninhydrin-positive substance detected at 440 nm,
HUMAN COAGULATION FACTOR IX
use the concentration of proline in reference solution (b); if (rDNA) CONCENTRATED SOLUTION
a peak is aboye the reporting threshold at both wavelengths,
use the result obtained at 570 nm for quantiflcation. Factoris IX coagulationis humani (ADNr)
LimUs: solutio concentrata
- any ninhydrin-positive substance: for each impurity,
maximum 0.2 per cent; - - VFENTERTTE
YNSGKLEEFV QGNL¡;:R¡;:CM¡;: EKCSFEEARE
-
40
- total: maximum 0.5 per cent; FWKQYVDGDQ CESNPCLNGG SCKIJDINSYE CWCPFGFEGK 80

- reporting threshold: 0.05 per cent. NCELDVTCNI KNGRCEQFCK NSADNKVVCS CTEGYRLAEN 120
QKSCEPAVPF PCGRVSVSQT SKLTRAEAVF PDVD2:VNSTE 160
The thresholds indicated under Related substances
(Table 2034.-1) in the general monograph Substances for AETILDNITQ STQSFNDFTR VVGGEDAKPG QFPWQVVLNG 200

pharmaceutical use (2034) do not apply. KVDAFCGGSI VNEKWIVTAA HCVETGVKIT VVAGEHNIEE 240
TEHTEQKRNV IRIIPHHNYN AAINKYNHDI ALLELDEPLV 280
Sulfates (2.4.13): maximum 300 ppm.
LNSYVTPICI ADKEYTNIFL KFGSGYVSGW GRVFHKGRSA 320
Dilute 10 mL of solution S to 15 mL with distilled water R.
LVLQYLRVPL VDRATCLRST KFTIYNNMFC AGFHEGGRDS 360
Ammonium. Amino acid analysis (2.2.56) as described in CQGDSGGPHV TEVEGTSFLT GIISWGEECA MKGKYGIYTK 400
the test for ninhydrin-positive substances with the following VSRYVNWIKE KTKLT 415
modifications.
disulfide bridges:
Injection: test solution, referenee solution (e) and blank 18-23,51-62,56-71,73-82,88-99,95-109,111-124,132-289,
solution. 206-222,336-350,361-389
Limit: glycosylation sites:
Ser-53, Ser-61, Asn-157, Thr-159, Asn-167. Thr-169
- ammonium at 570 nm: not more than the are a of the
corresponding peak in the chromatogram obtained with modified residues:
referenee solution (c) (0.02 per cent), taking into account ¡;: (4-carboxyGlu): 7, 8, 15, 17, 20. 21, 26. 27. 30, 33, 36, 40
the peak due to ammonium in the chromatogram obtained Q ((3R)-3-hydroxyAsp): 64
with the blank solution. i2. (03-phosphoSer): 68. 158
y: (04-sulloTyr): 155
Iron (2.4.9): maximum 10 ppm.
H ,NH2

X X'C0 H
In a separating funnel, dissolve 1.0 g in 10 mL of dilute H02C H NH 2 H0 2C,
hydrochloric acid R. Shake with 3 quantities, each of 10 mL, of
H02C~\(C02H
2

methyl isobutyl ketone Rl, shaking for 3 min each time. To the HO H

combined organic layers add 10 mL of water R and shake for ¡;: = 4-carboxyGlu Q = (3R)-3-hydroxyAsp
3 mino Use the aqueous ¡ayer. H NH 2
O,,"p/00 COH
H03S/0~ H.....NH 2
Heavy metals (2.4.8): maximum 10 ppm.
Dissolve 2.0 g in water R and dilute to 20 mL with the same HO
( \
OH
2
V J C02H
solvent. 12 mL of the solution complíes with test A. Prepare i2. = (03-phosphoSer) y: = (04-sulloTyr)
the reference solution using lead standard solution (1 ppm
Pb) R. M r approx. 55 000

Loss on drying (2.2.32): 7.0 per cent to 10.0 per cent,
determined 011 1.000 g by drying in an oven at 145-150 oc.
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Dissolve 0.160 g in 50 mL of carbon dioxide-free water R.
Titrate with 0.1 M sodium hydroxide, determining the
end-point potentiometrically (2.2.20).
1 mL of 0.1 M sodium hydroxide is equivalent to 19.16 mg
of C6 H lO CINP2'
STORAGE
Protected from light.
IMPURITIES
Other detectable impurities (the following substances would,
if present at a sufficient leve!, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities. It
is therefore not necessary to identify these impurities for
demonstration of compliance. See also 5.10. Control of
impurities in substances for pharmaceutical use): A.
DEFINITION
Solution containing closely related glycoproteins, which
have the same amino acid sequence (415 amino acids)
as the naturally occurring Ala 148 allelic form analogue
(plasma-derived coagulation factor IX). It is a single-chain
glycoprotein with structural and functional characteristics
similar to those of the endogenous factor IX. It may contain
buffer salts and/or non-proteinaceous stabilisers.
Content: minimum 150 IU per millilitre.
Potency: 200 to 360 IU per milligram of protein.
PRODUCTION
Human coagulation factor IX (rDNA) is produced in
mammalian cells by a method based on recombinant DNA
technology (rDNA). The method of preparation is designed to
maintain the functional integrity of factor IX, and to minimise
the activation of human coagulation factor IX (rDNA) (to
minimise potential thrombogenicity).
No antibiotic or antimicrobial preservative is added.
Prior to release, the following tests are carried out on ea eh batch
of the final bulk product, unless exemption has been granted by
the competent authority.

General Notices (1) apply to all monographs and other texts 4043
Human coagulation factor IX (rDNA) concentrated solution EUROPEAN PHARMACOPOElA 8.2

Host-cell-derived proteins. The limit is approved by the Injection: 20 flL, using an automatic injector maintained at
competent authority. 2-8 oc.
Host-cell- and vector-derived DNA. The limit is approved If carry-over of material is observed, running a blank gradient
by the competent authority after each injection may be appropriate.
Glycan analysis. Use a suitable method developed according Identification of peak groups: use the chromatogram in
to general chapter 2.2.59. Glycan analysis of glycoproteins, Figure 2522.-1 to identify the 5 groups of oligosaccharides
Section 2-3. corresponding to PO neutral, PI mono-, P2 di-, P3 tri- and P4
tetrasialylated oligosaccharides. Record the retention times of
- Release the glycans using one of the agents described the most prominent peaks in groups PO to P4. Calculate the
in Table 2.2.59.-1, for example peptide N-glycosidase F relative retentions of the most prominent peaks in groups PO
(PNGase F). to P3 with reference to the most prominent peak in group P4.
- Label the released glycans with one of the fluorescent Calculate the tetrasialylated peak area ratio for the test
labelling agents described in Table 2.2.59.-2, for example solution using the following expression:
2-aminobenzamide.
A p4
- Analyse the labelled glycans by liquid chromatography
(2.2.29) using a high-pH-resistant column with fluorescence ~T=oApi
detection.
The following indications are given as an example. Ap4 peak area of group P4;
Test solution. Dilute the preparation to be examined with Api peak area of groups PO to P3.
the formulation buffer (see Tests) to obtain a concentration System suitability:
of about 2 mg/mL. Use 50 flL of this solution to proceed to
glycan release and labelling. Resuspend or dilute the labelled - the chromatogram obtained with reference solution (a)
glycans in 200 flL of water R. is qualitatively similar to the chromatogram supplied
with human coagulation factor IX (rDNA) CRS;
Reference solution (a). Dilute human coagulation factor IX 5 groups of oligosaccharide peaks corresponding to PO
(rDNA) CRS with the formulation buffer to obtain a neutral, PI mono-, P2 di-, P3 tri- and P4 tetrasialylated
concentration of about 2 mg/mL. Use 50 flL of this solution to oligosaccharides are present; group P4 indudes the highest
proceed to glycan release and labelling. Resuspend or dilute peak, and P3 the second-highest peak;
the labelled glycans in 200 flL of water R.
- no significant peaks are observed in regions PO to P4 in the
Reference solution (b). Use a suitable human coagulation chromatogram obtained with the blank solution.
factor IX (rDNA) in-house reference preparation shown to
Results:
be representative of batches tested dinically and batches
used to demonstrate consistency of production. Dilute with - the profile of the chromatogram obtained with the test
the formulation buffer to obtain a concentration of about solution corresponds to that of the chromatogram obtained
2 mg/mL. Use 50 flL of this solution to proceed to glycan with reference solution (b);
release and labelling. Resuspend or dilute the labelled glycans - the relative retentions of the most prominent peaks in
in 200 flL of water R. groups PO to P3 in the chromatogram obtained with the
Blank solution. Use 50 flL of the formulation buffer to proceed test solution correspond to those in the chromatogram
to glycan release and labelling. obtained with reference solution (b);
Analyse the labelled glycans by liquid chromatography - the tetrasialylated peak area ratio for the test solution is
(2.2.29). within the limits authorised by the competent authority.
Precolumn: CHARACTERS
- size: 1 = 0.01 m, 0 = 4.6 mm; Appearance: dear, colourless liquido
- stationary phase: polyamine grafted poly(vinyl alcohol) IDENTIFICATION
copolymer R.
A. It forms a dot when examined in the conditions described
Column: under Assay (Potency).
- size: 1 = 0.25 m, 0 = 4.6 mm; B. Peptide mapping (2.2.55).
- stationary phase: polyamine grafted poly(vinyl alcohol) SELECTIVE CLEA VAGE OF THE PEPTIDE BONDS
copolymer R (5 flm). Solution A. Dissolve 143.3 g of guanidine hydrochloride R,
- temperature: 50 oc. 9.086 g of tris(hydroxymethyl)aminomethane R and 0.931 g
Mobile phase: of sodium edetate R in 250 mL of water R and adjust to
pH 8.0 ± 0.1 with hydrochloric acid R.
- mobile phase A: water R, glacial acetic acid R, acetonitrile R
(1:2:97 V/V/V); Test solution. Dilute the preparation to be examined with
the formulation buffer (see Tests) to obtain a concentration
- mobile phase B: concentrated ammonia R, glacial acetic
of about 1.5 mg/mL.
acid R, water R (1:3:96 V/V/V);
Reference solution. Prepare at the same time and in the
Time Mobile phase A Mobile phase B same manner as for the test solution but using human
(min) (per cent V/V) (per cent V/V) coagulation factor IX (rDNA) CRS instead of the preparation
0-2 70 30 to be examined.
2 - 67 70 -7 O 30 -7 100 Reduction and alkylation. To 67 flL of the test solution
add 28 flL of water R, 100 flL of solution A, then 5 flL
67 - 70 O 100 of a 30.85 gIL solution of dithiothreitol R, mix well and
70 - 70.1 0-770 100 -7 30 centrifuge briefly. Overlay with nitrogen. Incubate in
a water-bath at 40 oC for 1 h. Add 6.6 flL of a freshly
70.1 - 95 70 30 prepared 115.04 gIL solution of iodoacetic acid R, mix well
and centrifuge briefly. Overlay with nitro gen. Incubate at
Flow rate: 0.5 mL/min. room temperature for 1 h protected from light. Add 5.3 flL
Detection: fluorimeter at 330 nm for excitation and 420 nm of a 30.85 gIL of solution of dithiothreitol R and mix well.
for emission. Add 188.1 flL of water R.

4044 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 Human coagulation factor IX (rDNA) concentraíed solution

P3

~
I

P2
P1

o 20 40 60 80 min

Figure 2522.-1. - Chromatogram for the test for g/yean analysis of human coagu/ation factor IX (rDNA)

Digestion. To the reduced solution prepared previously, TiTIle Mobile puase A Mobile puase B
add 10 [lL of a freshly prepared 3.4 U/mL solution of lysy/ (min) (per cent V/V) (per cent V/V)
endopeptidase R, mix well and centrifuge briefiy. Overiay 0-5 97 3
with nitrogen. Incubate at 30 oC for 4 h. Mix 90 [lL of the
5 - 35 97 -?- 85 3 -?- 15
digested solution and 180 [lL of a 33.22 giL solution of
sodium edetate R. 35 - 60 85 -?- 81 15 -?- 19

60 - 81 81 -?- 74 19 -?- 26
Carry out the reduction/alkylation and digestion steps for
the reference solution in the same manner as for the test 81 - 101 74 -?- 71 26 -?- 29
solution. 101 - 135 71 -?- 60 29 -?- 40

135 - 140 60 -?- O 40 -?- 100

CHROMATOGRAPHIC SEPARA TION Liquid
chromatography (2.2.29). 140 - 150 O 100

150 - 150.01 O -?- 97 100 -?- 3

Co/umn:
150.01 - 190 97 3

- size: l = 0.25 m, 0 = 2.1 mm; 190 - 191 97 -?- 50 3 -?- 50

- stationary phase: octadecylsilyl silica gel for
chromatography R (5 [lm) with a pore size of 30 nm;
- temperature: 25 oc.
Mobile phase:
mobile phase A: add 0.5 mL of trifluoroacetic acid R to
1000 mL of water R and degas;
- mobile phase B: mix 0.5 mL of trifluoroacetic acid R,
50 mL of water R and 950 mL of acetonitrile for
chromatography R and degas;
191 - 251 50 50
Flow rate: 025 mLlmin.
Detection: spectrophotometer at 214 nm.
Injection: 240 [lL, using an automatic injector maintained
at 2-8 oc.
System suitability:
- the chromatogram obtained with the reference solution
is qualitatively similar to the chromatogram supplied
with human coagulation factor IX (rDNA) CRS;
- all peaks identined in the chromatogram supplied with
human coagulation factor IX (rDNA) CRS are visible in
the chromatogram obtained with the reference solution.

General Notices (1) apply to all monographs and other texts 4045
Humau coagulation factor IX (rDNA) concentrated solution
Results:
- the profile of the chromatogram obtained with the
test solution corresponds to that of the chromatogram
obtained with the reference solution;
- no new major peaks are observed in the chromatogram
obtained with the test solution in comparison to the
chromatogram obtained with the reference solution.
e. Polyacrylamide gel electrophoresis (2.2.31).
Examine the electropherograms obtained in the test for
impurities with molecular masses differing from that of
human coagulation factor IX (rDNA).
Calculate the relative mobility (in per cent) of the main
band in the electropherogram obtained with the test
solution with reference to the mobility of the main band in
the electropherogram obtained with reference solution (a),
using the following expression:
MI molecular mass of the main band in the
electropherogram obtained with the test
solution;
M2 molecular mas s of the main band in the
electropheragram obtained with reference
solution (a).
Results:
the electropherogram obtained with the test solution is
similar to the electropherogram obtained with reference
solution (a);
- the mobility of the main band in the electropherogram
obtained with the test solution is within 10 per cent of
that of the main band in the electropherogram obtained
with reference solution (a).
TESTS
Formulation buffer. Dissolve 19.53 g of glyeine R, 1.55 g of
histidine R and 10.00 g of sucrose R in 1000 mL of water R.
Add 50 flL of polysorbate 80 R and adjust to pH 6.8 with
hydrochloric aeid R.
Gamma-carboxyglutamic acid (Gla). Liquid
chromatography (2.2.29) : use the normalisation procedure.
Test solution. Dilute the preparation to be examined with
the formulation buffer to obtain a concentration of about
1 mg/mL.
Reference solution. Prepare in the same manner as for the test
solution but using human coagulation factor IX (rDNA) CRS
instead of the preparation to be examined.
Blank solution. The formulation buffer.
Column:
- size: 1 = 0.05 m, el = 5 mm;
- stationary phase: strongly-basic anion exchange resin for
chromatography R (10 flm).
Mobile phase:
- mobile phase A: solution containing 2.42 giL of
tris(hydroxymethyl)aminomethane R, adjusted to pH 9.0
with hydrochloric acid R;
4046
EUROPEAN PHARMACOPOElA 8.2
- mobile phase B: solution containing 2.42 giL of
tris(hydroxymethyl)aminomethane R and 58.45 giL of
sodium chloride R, adjusted to pH 9.0 with hydrochloric
aeid R;
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent VIV)
0-40 70 .¿ 60 30.¿ 40
40 - 49 60.¿ O 40.¿ 100
49 - 50 O.¿ 70 100 .¿ 30
50 - 71 70 30
Flow rate: 0.75 mL/min.
Detection: spectrophotometer at 214 nm.
Injection: 50 flL; perform at least 3 injections using an
automatic injector maintained at 2-8 0e.
Relative retention with reference to human coagulation
factor IX (rDNA) containing 12 Gla residues per molecule
(12 Gla, retention time = about 25 min): 9Gla = 0.60;
lOGIa = 0.75; 11Gla = 0.85. NOTE: molecular species
containing 9 or fewer Gla residues per molecule of human
coagulation factor IX (rDNA) may not be present in the
preparation.
System suitability: reference solution:
- repeatability: maximum relative standard deviation of 3 per
cent for the total area of the peak due to human coagulation
factor IX (rDNA), determined on 3 injections performed
immediately before the mn;
- the lOGIa peak is visible and is similar to the corresponding
peak in the chromatogram supplied with human
coagulation factor IX (rDNA) CRS;
- peak-to-valley ratio: minimum 1.2, where l!,
= height aboye
the baseline of the peak due to 11 Gla, and H v = height aboye
the baseline of the lowest point of the curve separating this
peak fram the peak due to 12Gla.
Results:
- repeatability: maximum relative standard deviation of 3 per
cent for the total area of the peak due to human coagulation
factor IX (rDNA), determined on 3 injections of the test
solution;
- the profile of the chramatogram obtained with the test
solution corresponds to that of the chromatogram obtained
with the reference solution.
Calculate the total Gla content using the following expression:
12
~ ___A.. .:.P. .:. . i_ _
L... X z. GZ a.moZ-l
i=9 totaZ peak area
- A p¡: area ofthe concerned peak (9Gla, lOGIa, 11Gla or
12Gla); any shoulder appearing on the descending part of
the 12Gla peak is included in the area of the 12Gla peak;
- total peak area: sum ofthe areas ofpeaks 9Gla to 12Gla;
- i Gla.mol- 1 : 9, 10, 11 or 12, corresponding to the theoretical
number of Gla residues per mole of human coagulation
factor IX (rDNA) for the concerned peak.
Limit:
- 1l.0 to 12.0 moles of Gla per mole ofhuman coagulation
factor IX (rDNA).
Related proteins and impurities. Liquid chromatography
(2.2.29).
Test solution. Dilute the preparation to be examined with
the formulation buffer to obtain a concentration of about
0.5 mg/mL.
Reference solution. Prepare in the same manner as for the test
solution but using human coagulation factor IX (rDNA) CRS
instead of the preparation to be examined.
Column:
- size: 1 = 0.10 m, el = 4.6 mm;
See the information section on general monographs (caver pages)
EUROPEAN PHARMACOPOEIA 8,2 Human coagulation factor IX (rDNA) concenírated solution

- stationary phase: styrene-divinylbenzene copolymer R - 72 volumes of water R;

(lO flm) with a pore size of 400 nm; - 2 volumes of a 100 giL solution of sodium dodecyl sulfate R;
- temperature: 37 oC 1 volume of a 0,04 mg/mL solution of putrescine R;
Mobile phase: - 2 volumes of a 15 mg/mL solution of ammonium
- mobile phase A: add 1 mL of trifluoroacetic acid R to persulfate R
1000 mL of water R; Prepare a 15 per eent acrylamide solution by mixing:
- mobile phase B: mix 1 mL of trifluoroacetic aeid R, 200 mL 50 volumes of 30 per cent acrylamide/bisacrylamide (365: 1)
of water R and 800 mL of acetonitrile for chromatography R solution R;
Time Mobile phase A Mobile phase B - 13 volumes of 3 M tris-hydrochloride buffer solution
(min) (per cen! V/V) (per cent V/V) pH 8,8 R;
0-0,5 75 25 - 15 volumes of water R;
0,5 - 30 75 -7 20 25 -7 80 - 17 volumes of an 855,8 giL solution of sucrose R;
30 - 31 20 -7 O 80 -7 100
- 2 volumes of a 100 giL solution of sodium dodeeyl sulfate R;
- 1 volume of a 0,04 mg/mL solution of putrescine R;
31 - 33 O 100
- 2 volumes of a 15 mg/mL solution of ammonium
Flow rate: 2,0 mL/min, persulfate R
Deteetion: speetrophotometer at 214 nm, Load the compartments of the gradient -forming apparatus
with the acrylamide solutions and proceed as per the
Injection: 100 flL; perform at least 3 injections using an instructions of the equipment supplier to obtain the
automatic injector, polymerised gradient gel,
Relative retention with referenee to the 2 nd peak of the double After polymerisation is completed, rinse the gradient gel with
peak (retention time = about 12-14 min) due to human water R Remove any excess liquid, Pour the staeking gel
coagulation factor IX (rDNA): related protein A = about 0,75; solution into the equipment, insert a clean eomb and allow
related protein B = about 0,78; related protein C = about 0,80; for polymerisation,
related protein D = about 0,85; related protein E = about 0,93,
Alternatively, eommercially available gradient gels may be
System suitability: reference solution: used,
- the chromatogram obtained is qualitatively similar to the Test solution, Dilute the preparation to be examined with
chromatogram supplied with human coagulation factor IX the formulation buffer to obtain a concentration of about
(rDNA) CRS; 1 mg/mL
- repeatability: maximum relative standard deviation of 3 per Reference solution (a), Dilute human coagulationfactor IX
cent for the total area of the peak due to human coagulation (rDNA) CRS with the formulation buffer to obtain a
factor IX after 3 injeetions performed immediately concentration of about 1 mg/mL
before the run;
Reference solution (b), 0,01 mg/mL solution of bovine
- peak-to-valley ratio: minimum L5, where H = height albumin R in the formulatiol1 buffer,
aboye the baseline of the peak due to related protein E and
H" = height above the baseline of the lowest point of the Reference solution (e) A solution of molecular mass markers
curve separating this peak from the peak due to human suitable for ealibrating SDS-polyacrylamide gel s in the range
coagulation factor IX (rDNA), of 5-200 kDa,
Report individual relative peak are as eonsidering the peak Sample buffer, Concentrated SDS-PAGE sample buffer for
are a of the entire ehromatogram, Individual relative per eent reducing conditions R containing dithiothreitol R as reducing
peak are as are ealculated as the average of the 3 injeetions of agent
the test solution, Sample treatment: ineubate in a water-bath for 5 min,
Results: Application: 35 flL
- the profile of the chromatogram obtained with the test Use SDS-PAGE running buffer R for running the gel,
solution corresponds to that of the chromatogram obtained For eaeh gel, run 1 lane with reference solution (b), 2 ¡anes
with the referenee solution, except that minor peaks, whieh with referenee solution (e), 21anes with the incubated reducing
are due to impurities, may be absent in the chromatogram buffer (as blank) and at least 1 lane with redueed reference
obtained with the test solution, SOlUtiOll (a); use the remaining lanes for reduced test solutions,

Limits: Detection: by Coomassie staining,

- related protein C: maximum 0,6 per (ent;
- total impurities (all peaks not eluted at the positions expected has an approximate molecular mass of 55 kDa, and related
for human coagulation factor IX (rDNA) and its related
proteins): maximum LO per cent,
Impurities with molecular masses differing from that of
human coagulation factor IX (rDNA), Polyacrylamide gel
electrophoresis (22,31) using a gradient geL
Gradient gels (resolving gels) are prepared with an increasing
concentration of aerylamide from the lop to the bottom,
Preparation of gradient gels requires a gradient-forming
apparatus,
Prepare a 3-15 per eent acrylamide gradient geL
Prepare a 3 per cent acrylamide solution by mixing:
- 10 volumes of 30 per eent aerylamide/bisacrylamide (365: 1)
solution R;
13 volumes of 3 M tris-hydrochloride buffer solution
pH 8,8 R;
Identification of bands: human eoagulation factor IX (rDNA)
protein bands with molecular masses of approximately 54 kDa,
44 kDa, 29-32 kDa, 27 kDa and 14 kDa are present,
System suitability:
- a clear background is obtained after destaining;
- the band in the eleetropherogram obtained with reference
solution (b) is clearly visible;
- al! expected bands in the electropherogram obtained with
referenee solution (c) are visible;
- the bands in the electropherogram obtained with reference
solution (e) are clearly separated;
- no band is visible in the blank lanes,
Results:
- the electropherogram obtained with the test solution is
similar to the eleetropherogram obtained with reference
solution (a);

General Notices (1) apply to all monographs and other texts 4047
Human plasma (pooled and treated for virus inactivation) EUROPEAN PHARMACOPOEIA 8.2

- no new band in the electropherogram obtained with the test ASSAY

solution has an intensity greater than that of the band in
the electropherogram obtained with reference solution (b). before the addition of any protein stabiliser.
Impurities with molecular masses greater than that of
human coagulation factor IX (rDNA). Size-exclusion
chromatography (2.2.30) : use the normalisation procedure.
Test solution. Dilute the preparation to be examined with
the formulation buffer to obtain a concentration of about
400 flg/mL.
Reference solution. Dilute human coagulation factor IX
(rDNA) CRS with the formulation buffer to obtain a
concentration of about 400 flg/mL.
Resolution solution. Incubate a volume of the reference
solution at 50 oC for 120 min in an HPLC vial. After
incubation, place the vial immediately in the autosampler.
Start the chromatographic run immediately afterwards.
Blank solution. The formulation buffer.
Precolumn:
- size: 1= 0.04 m, 0 = 6 mm;
- stationary phase: hydrophilic si/ica gel for chromatography R
(5 flm) of a grade suitable for the fractionation of globular
proteins in the relative molecular mass range of 10 000 to
500000.
Column:
- size: 1= 0.30 m, 0 = 7.8 mm;
- stationary phase: hydrophi/ic si/ica gel for chromatography R than 125 per cent of the stated potency. The confidence limits
(5 flm) of a grade suitable for the fractionation of globular (P = 0.95) are not les s than 80 per cent and not more than
proteins in the relative molecular mas s range of 10 000 to
500000.
Mobi/e phase. Dissolve 7.80 g of sodium dihydrogen
phosphate R and 8.77 g of sodium chloride R in 1000 mL of
water R. Adjust to pH 7.00 ± 0.05 with phosphoric acid R.
Flow rate: 1.0 mL/min.
Detection: spectrophotometer at 214 nm.
Injection: 50 flL; perform 3 injections using an automatic
injector maintained at 2-8 oc.
Retention time: human coagulation factor IX (rDNA) = about
9 mino
System suitabi/ity:
- the chromatogram obtained with the reference solution is
qualitatively similar to the chromatogram supplied with
human coagulationfactor IX (rDNA) CRS;
- peak-to-valley ratio: minimum 1.5, where Hp = height
aboye the baseline of the peak due to the high molecular
mass species and H v = height aboye the baseline of the
lowest point of the curve separating this peak from the
peak due to human coagulation factor IX (rDNA) in the
chromatogram obtained with the resolution solution.
Calculate the relative area (in per cent) of the sum of the peaks a frozen or freeze-dried, sterile, non-pyrogenic preparation
with retention times less than that of human coagulation
factor IX (rDNA), with reference to the area ofthe peak due to to the same ABO blood group. The preparation is thawed or
human coagulation factor IX (rDNA). Any shoulder appearing reconstituted before use to give a solution for infusion.
on the descending part of the peak due to human coagulation
factor IX (rDNA) is included in its area.
Result:
- the profile of the chromatogram obtained with the test
solution corresponds to that of the chromatogram obtained The units of plasma to be used are cooled to - 30 oC or lower
with the reference solution.
Limit:
- sum of the peaks eluted before the principal peak: maximum
1.3 per cent.
Microbial contamination (2.6.12): maximum 10 CFU/mL.
Bacterial endotoxins (2.6.14): less than 1 IU per 100 IU of
factor IX activity.
The specific biological activity of the substance is determined
Protein. Size-exclusion chromatography (2.2.30) as described
in the test for impurities with molecular masses greater
than that ofhuman coagulation factor IX (rDNA) with the
following modifications.
Prepare triplicate dilutions of the test solution.
Reference solutions. Dilute human coagulation factor IX
(rDNA) CRS with the formulation buffer to obtain a
concentration of 1 mg/mL. Further dilute this solution to
prepare a standard curve with concentrations in the range
of 100-800 flg/mL (5 concentrations, typically 100 flg/mL,
200 flg/mL, 400 flg/mL, 600 flg/mL, 800 flg/mL).
Plot peak areas versus injected protein content and perform
linear regression to create a standard curve.
System suitabi/ity (in addition to those described in the test for
impurities with molecular masses greater than that of human
coagulation factor IX (rDNA»:
- the correlation coefficient (r) calculated for the standard
curve is not less than 0.995.
Calculate the protein concentration of each replicate of the
preparation to be examined using the standard curve and the
assigned content in human coagulation factor IX (rDNA) CRS.
Potency. Assay ofhuman coagulation factor IX (2.7.11). The
estimated potency is not less than 80 per cent and not more
120 per cent of the estimated potency.
Human coagulation factor IX concentrate BRP is suitable for
use as a reference preparation.
STORAGE
In an airtight container, under approved conditions.
LABELLING
The label states the factor IX content in International Units per
millilitre and in International Units per milligram of protein.
07/2014:1646
HUMAN PLASMA (POOLED AND
TREATED FOR VIRUS INACTIVATION)
Plasma humanum coagmentatum
conditumque ad exstinguendum virum
DEFINITION
Human plasma (pooled and treated for virus inactivation) is
obtained from human plasma derived from donors belonging
The human plasma used complies with the monograph
Human plasma for jractionation (0853).
PRODUCTION
within 6 h of separation of cells and always within 24 h of
collection.
The pool is prepared by mixing units of plasma belonging to
the same ABO blood group.
The pool of plasma is tested for hepatitis B surface antigen
(HBsAg) and for HIV antibodies using test methods of
suitable sensitivity and specificity; the pool must give negative
results in these tests.

4048 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
Hepatitis A virus RNA. The plasma pool is tested using a
validated nucleic acid amplification technique (2.6.21). A
positive control with 1.0 x 10 2 IU of hepatitis A virus RNA
per millilitre and, to test for inhibitors, an internal control
prepared by addition of a suitable marker to a sample of the
plasma pool are included in the test. The test is invalid if
the positive control is non-reactive or if the result obtained
with the internal control indicates the presence of inhibitors.
The pool complies with the test if it is found non-reactive for
hepatitis A virus RNA.
Hepatitis C virus RNA. The plasma pool is tested using a
validated nucleic acid amplification technique (2.6.21). A
positive control with 1.0 x 10 2 IU of hepatitis C virus RNA
per millilitre and, to test for inhibitors, an internal control
prepared by addition of a suitable marker to a sample of the
plasma pool are included in the test. The test is invalid if
the positive control is non-reactive or if the result obtained
with the internal control indicates the presence of inhibitors.
The pool complies with the test if it is found non-reactive for
hepatitis C virus RNA.
Hepatitis C virus RNA for NAT testing BRP is suitable for use
as a positive control.
To limit the potential burden of B 19 virus in plasma pools,
the plasma pool is also tested for Bl9 virus using a validated
nucleic acid amplification technique (2.6.21).
B19 virus DNA. The plasma pool contains not more than
10.0 IU IflL.
A positive control with 10.0 IU of B19 virus DNA per
microlitre and, to test for inhibitors, an internal control
prepared by addition of a suitable marker to a sample of the
plasma pool are included in the test. The test is invalid if the
positive control is non-reactive or if the result obtained with
the internal control indicates the presence of inhibitors.
B19 virus DNAfor NAT testing BRP is suitable for use as a
positive control.
The method of preparation is designed to minimise
activation of any coagulation factor (to minimise potential
thrombogenicity) and includes a step or steps that have been
shown to inactivate known agents of infection; if substances
are used for the inactivation of virus es during production,
the subsequent purification procedure must be validated to
demonstrate that the concentration of these substances is
reduced to a suitable leve! and that any residues are such as
not to compromise the safety of the preparation for patients.
Inactivation process. The solvent -detergent process, which
is one of the methods used to inactivate enveloped viruses,
uses treatment with a combination of tributyl phosphate and
octoxinollO; these reagents are subsequently removed by oil
extraction or by solid phase extraction so that the amount in
the final product is less than 2 flg/mL for tributyl phosphate
and less than 5 flg/mL for octoxinol 10.
No antimicrobial preservative is added.
The solution is passed through a bacteria -retentive filter,
distributed aseptically into the final containers and
immediately frozen; it may subsequently be freeze-dried.
Plastic containers comply with the requirements for sterile
plastic containers for human blood and blood components
(3.2.3).
Glass container s comply with the requirements for glass
containers for pharmaceutical use (3.2.1).
CHARACTERS
Frozen preparation: clear or slightly opalescent liquid, free
from solid and gelatinous particles after thawing.
Freeze-dried preparation: almost white or slightly yellow
powder ar friable solido
Thaw or reconstitute the preparation to be examined as stated
on the ¡abe! immediately befare carrying out the identification,
tests and assay.
General Notices (1) apply to all monographs and other texts
Human plasma (pooled and treated for virus inactivation)
IDENT1FICAT10N
A. Examine by electrophoresis (2.2.31) comparing with
normal human plasma. The electropherograms show the
same bands.
B. 1t complies with the test for anti-A and anti-B
haemagglutinins (see Tests).
TESTS
pH (2.2.3): 6.5 to 7.6.
Osmolality (2.2.35) : mínimum 240 mosmol/kg.
Total pro te in : mínimum 45 giL.
Dilute if necessary with a 9 giL solution of sodium chloride R
to obtain a protein concentration of about 7.5 mg/mL. Place
2.0 mL of this solution in a round-bottomed centrifuge tube
and add 2 mL of a 75 giL solution of sodium molybdate R and
2 mL of a mixture of 1 volume of nitrogen-free sulfuric acid R
and 30 volumes of water R. Shake, centrifuge for 5 min, decant
the supernatant and allow the inverted tube to drain on filter
papero Determine the nitro gen in the residue by the method
of sulfuric acid digestion (2.5.9) and ca!culate the quantity of
protein by multiplying the result by 6.25.
Activated coagulation factors (2.6.22). It complies with
the test for activated coagulation factors. Carry out the test
with 0.1 mL of the preparation to be examined instead of
10-fold and 100-fold dilutians. The coagulation time for the
preparation to be examined is not less than 150 S.
Anti-A and anti-B haemagglutinins (2.6.20, Method A). The
presence of haemagglutinins (anti -A or anti -B) corresponds
to the bIoad group stated on the label.
Hepatitis A virus antibodies: minimum 1.0 IU/mL,
determined by a suitable immunochemical method (2.7.1).
Human hepatitis A immunoglobulin BRP is suitable for use as
a rderence preparation.
Irregular erythrocyte antibodies. The preparation to be
examined does not show the presence of irregular erythrocyte
antibodies when examined without dilution by an indirect
antiglobulin test.
Citrate. Liquid chromatography (2.2.29).
Test solution. Dilute the preparation to be examined with an
equal volume of a 9 giL salution of sodium chloride R. Filter
the solution using a filter with 0.45 flm pares.
Reference solution. Dissolve 0.300 g of sodium cifrate R in
water R and dilute to 100.0 mL with the same solvent.
Column:
- size: 1= 0.3 m, 0 = 7.8 mm;
- stationary phase: cation-exchange resin R (9 flm).
Mobile phase: 0.51 giL solution of sulfuric acid R.
Flow rate: 0.5 mLlmin.
Detection: spectrophotometer at 215 nm.
Equilibration: 15 mino
Injection: 10 flL.
Retention time: citrate = about 10 mino
Limit:
- citrate: maximum 25 mmol/L.
Cakium: maximum 5.0 mmol!L.
Atomic absorption spectrometry (2.2.23, Method I).
Source: ca!cium hollow-cathode lamp using a transmission
band preferably of 0.5 nm.
Wavelength: 622 nm.
Atomisation device: air-acetylene or acetylene-propane flameo
Potassium: maximum 5.0 mmo1!L.
Atomic emission spectrametry (2.2.22, Method I).
Wavelength: 766.5 nm.
4049
Hydroxypropylbetadex EUROPEAN PHARMACOPOElA 8.2

Sodium: maximum 200 mmol/L.
Atomic emission spectrometry (2.2.22, Method 1).
Wavelength: 589 nm.
Water: determined by a suitable method, such as the
semi-micro determination of water (2.5.12), loss on drying
(2.2.32) or near-infrared spectroscopy (2.2.40), the water
content is within the limits approved by the competent
authority (freeze-dried product).
Sterility (2.6.1). It complies with the test.
Pyrogens (2.6.8) or Bacterial endotoxins (2.6.14). It complies 1 unit of human plasmin inhibitor is equal to the activity
with the test for pyrogens or, preferably and where justified of 1 mL of human normal plasma. Human normal plasma
and authorised, with a validated in vitro test such as the
bacterial endotoxin test.
For the pyrogen test, inject 3 mL per kilogram of the rabbit's
mass.
Where the bacterial endotoxin test is used, the preparation
to be examined contains less than 0.1 IU of endotoxin per
millilitre.
ASSAY
Assay ofhuman coagulation factor VIII (2.7.4). Use a
reference plasma calibrated against the International Standard
for blood coagulation factor VIII in plasma.
The estimated potency is not less than 0.5 IU/mL. The
confidence limits (P = 0.95) are not less than 80 per cent and
not more than 120 per cent of the estimated potency.
Assay ofhuman coagulation factor V. Carry out the assay of
human coagulation factor V described below using a reference
plasma calibrated against the International Standard for blood
coagulation factor V in plasma.
Using imidazole buffer solution pH 7.3 R, prepare at least
3 twofold dilutions of the preparation to be examined,
preferably in duplicate, from 1 in 10 to 1 in 40. Test each
dilution as follows: mix 1 volume of plasma substrate deficient
in factor V R, 1 volume of the dilution to be examined,
1 volume of thromboplastin R and 1 volume of a 3.5 gIL
solution of calcium chloride R; measure the coagulation
times, i.e. the interval between the moment at which the
calcium chloride solution is added and the 1sI indication of
the formation of fibrin, which may be observed visually or by
means of a suitable apparatus.
In the same manner, determine the coagulation time of
4 twofold dilutions (1 in 10 to 1 in 80) ofhuman normal
plasma in imidazole buffer solution pH 7.3 R.
Check the validity of the assay and calculate the potency of the
test preparation by the usual statistical methods (for example,
5.3).
The estimated potency is not les s than 0.5 IU/mL. The
confidence limits (P = 0.95) are not less than 80 per cent and
not more than 120 per cent of the estimated potency.
Assay ofhuman coagulation factor XI (2.7.22). Use a
Assay ofhuman protein S (2.7.31). Use a reference plasma
calibrated against the International Standard for human
protein S in plasma.
The estimated potency is within the limits approved for the
particular product. The confidence limits (P = 0.95) are not
les s than 80 per cent and not more than 120 per cent of the
estimated potency.
Assay ofhuman plasmin inhibitor (2.7.25) (uz-antiplasmin).
Use a reference plasma calibrated against human normal
plasma.
is prepared by pooling plasma units from not fewer than
30 donors and storing at - 30 oC or lower.
The estimated potency is not less than 0.2 units/mL. The
confidence limits (P = 0.95) are not less than 80 per cent and
not more than 120 per cent of the estimated potency.
Activated partia! thromboplastin time (APTT). Use an
apparatus suitable for measurement of coagulation times
or perform the assay with incubation tubes maintained
in a water-bath at 37 oc. Place in each tube 0.1 mL of the
preparation to be examined and 0.1 mL of a suitable APTT
reagent (containing phospholipid and contact activator), both
previously heated to 37 oC, and incubate the mixture for a
recommended time at 37 oc. To each tube add 0.1 mL of a
3.7 gIL solution of calcium chloride R previously heated to
37 oc. Using a timer, measure the coagulation time, i.e. the
interval between the moment of the addition of the calcium
chloride and the 1sI indication of the formation of fibrin, which
may be observed visually or by means of a suitable apparatus.
The volumes given aboye may be adapted to the APTT reagent
and apparatus used. The coagulation time complies with the
agreed specification for the product.
LABELLING
The label states:
- the ABO blood group;
- the method used for virus inactivation.
07/2013:1804
corrected 8.2
HYDROXYPROPYLBETADEX
Hydroxypropylbetadexurn
OR RO
R O ' , ' C \ ' O " y :,OR
R0(:r:
O' O

OR
RO
O

RO
p"O
'O

"OR

reference plasma calibrated against the International Standard RO" D

O
O ' OR RO "OR
O
for blood coagulation factor XI in plasma.
The estimated potency is not less than 0.5 IU/mL. The
confidence limits (P = 0.95) are not less than 80 per cent and
not more than 125 per cent of the estimated potency.
RO

RO
•••• : <;:>POR
y OR

Coagulation factors V; VIII, XI and XIII plasma BRP is suitable RO OR

for use as a reference preparation in the aboye assays. R = -[CH 2-CH(CH 3)-0ln-H n = O, 1, 2 ...
Assay ofhuman protein C (2.7.30). Use a reference plasma
calibrated against the International Standard for human C42H7003S(C3H60)x with x = 7 MS
protein C in plasma. DEFINITION
The estimated potency is not less than 0.7 IU/mL. The Hydroxypropylbetadex (~-cyclodextrin, 2-hydroxypropyl
confidence limits (P = 0.95) are not less than 80 per cent and ether) is a partially substituted poly(hydroxypropyl) ether of
not more than 120 per cent of the estimated potency. betadex.

4050 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
Content:
- hydroxypropyl groups per anhydroglucose unit, expressed as
molar substitution (MS): 0.40 to 1.50 and content within
10 per cent of the value stated on the labe!'
CHARACTERS
Appearance: white or almost white, amorphous or crystalline
powder.
Solubility: freely soluble in water and in propylene glycol.
IDENTIFICATI ON
A. Infrared absorption spectrophotometry (22.24).
Comparison: hydroxypropylbetadex CRS.
Results: the spectrum obtained with the substance to
be examined shows the same absorption bands as the
spectrum obtained with hydroxypropylbetadex CRS. Due
to differences in the substitution of the substance, the
intensity of sorne absorption bands can vary.
B. Appearance of solution (see Tests).
TESTS
Soluti.on S. Dissolve 5.0 g in carbon dioxide-free water R
prepared from distilled water R and dilute to 50.0 mL with
the same solvent.
Appearance oí solution. The solution is clear (2.2.1) and
colourless (22.2, Method II), and remains so after cooling to
room temperature.
Dissolve 5.0 g in 10.0 mL of water R, with heating.
Conductivity (2.2.38): maximum 200 ¡.tS.cm o1 •
Measure the conductivity of solution S, while gently stirring
with a magnetic stirrer.
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 0.600 g of the substance to be examined Internal standard solution. To 62.5 mg oí ethylene glyeol R,
in water R and dilute to 10.0 mL with the same solvent.
Reference so/ution (a). Dissolve 60.0 mg of betadex CRS
(impurity A) in water R and dilute to 50.0 mL with the same
solvent.
Reference solutions (b), (e), (d), (e), (j). Dilute reference
solution (a) with water R to obtain 5 reference solutions
containing respectively 0.03 mg/mL, 0.09 mg/mL, 0.45 mg/mL, ethanol (96 per cent) R.
0.90 mg/mL and 1.20 mg/mL of betadex CRS.
Referenee solution (g). Dissolve 0.15 g of hydroxypropyl-
betadex CRS (containing impurity A) in water R and dilute to with the same solvent. Dilute 1.0 mL of the solution to 10.0 mL
10 mL with the same solvento
Column:
- size: 1", 0.25 m, 0 '" 4.0 mm;
stationary phase: 4-nitrophenylcarbamidesilyl si/ica gel for - material: fused silica;
chromatography R (5 ¡.tm);
- tempera tu re: 30 oc.
Mobile phase:
- mobile phase A: water for chromatography R;
- mobile phase B: water for ehromatography R, methanol R
(10:90 V/V);
Time Mohile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0-5 52 48
5 - 15 52 -7 O 48 -7 100
15 - 20 O 100
Flow rate: 1.0 mLlmin.
General Notices (1) apply to all monographs and other texts
Hydroxypropylbetadex
Detection: evaporative light-scattering detector; the following
settings have been found to be suitable; if the detector has
different setting parameters, adjust the detector settings
so as to comply with the system suitability criteria. The
use of a 2-port/6-way valve is advisable for 'heart-cutting'
hydroxypropylbetadex peaks to save the detector from the
huge amount of injected hydroxypropylbetadex:
carrier gas: nitrogen R;
- J70w rate: 1.5 L/min;
- evaporator temperature: 70 oc.
Injection: 20 ¡.tL.
Retention time: impurity A", about 4.2 min.
Hydroxypropylbetadex elutes as a very wide peak or as several
peaks after impurity A. Gther typical impurities elute together
as a wide peak or as a group of several peaks before impurity A.
System suitability:
- resolution: minimum 2.0 between the peak due to
impurity A and the 1st peak due to hydroxypropylbetadex
in the chromatogram obtained with reference solution (g);
if necessary, adjust the column temperature (decreasing the
temperature improves the resolution);
- plot a curve representing the logarithm of the concentration
ofimpurity A in reference solutions (b), (c), (d), (e) and
(f) as the abscissa and the logarithm of the corresponding
peak afeas as ordinates taking the assigned content of
betadex CRS into account; the coefficient of correlation
is not less than 0.950.
Calculate the percentage content of impurities with reference
to the dried substance using the curve.
Limits:
- impurity A: maximum 1.5 per cent;
- sum of impurities other than A: maximum 1.0 per cent;
- reporting threshold: 0.05 per cent; disregard any peak
eluting after impurity A.
Impurity B. Gas chromatography (2.2.28).
add ethanol (96 per cent) R and dilute to 10.0 mL with the
same solvent. Dilute 1.0 mL of the solution to 50.0 mL with
ethanol (96 per cent) R.
Test solution. Dissolve 50.0 mg of the substance to be
examined in ethanol (96 per cent) R and dilute to 10.0 mL
with the same solvent. To 1.0 mL of the solution, add 1.0 mL
of the internal standard solution and dilute to 10.0 mL with
Reference solution. Dissolve 62.5 mg of propylene glyeol CRS
(impurity B) in ethanol (96 per cent) R and dilute to 50.0 mL
with ethanol (96 per cent) R. To 1.0 mL of this solution, add
1.0 mL of the internal standard solution and dilute to 10.0 mL
with ethanol (96 per cent) R.
Column:
- size: 1", 30 m, 0 '" 0.32 mm;
- stationary phase: macrogol20 000 R (film thickness 1 ¡.tm).
Carrier gas: helium for chromatography R.
Flow rate: 1.4 mL/min.
Split ratio: 1:35.
Temperature:
Time Temperature
(min) (oC)
Column 0-10 150 -7 200
la - 11 200 -7 240
Injection port 220
Detector 240
Detection: flame ionisation.
4051
Hydroxypropylbetadex
Injection: 2 I1L; wash the syringe thoroughly with ethanol
(96 per cent) R to avoid occlusion in the needle.
Relative retention with reference to ethylene glycol (retention
time = about 7.5 min): impurity B = about 0.9.
System suitability: reference solution:
- resolution: minimum 4.0 between the peaks due to
impurity B and ethylene glycol;
- symmetry factor: maximum 2.0 for the peak due to
propylene glycol.
Calculation of percentage contents: use the internal standard
method.
Limit:
- impurity B: maximum 2.5 per cent.
Heavy metals (2.4.8): maximum 20 ppm.
12 mL of solution S complies with test A. Prepare the reference
solution using lead standard solution (2 ppm Pb) R.
Loss on drying (2.2.32): maximum 10.0 per cent, determined
on 1.000 g by drying in an oven at 120 oC for 2 h.
Microbial contamination
If intended for use in the manufacture of parenteral
preparations :
- TAMC: acceptance criterion 102 CFU/g (2.6.12).
If not intended for use in the manufacture of parenteral
preparations:
- TAMC: acceptance criterion 103 CFU/g (2.6.12);
- TYMC: acceptance criterion 102 CFU/g (2.6.12);
- absence of Escherichia colí (2.6.13);
- absence of Salmonella (2.6.13).
Bacterial endotoxins (2.6.14): less than 10 IU/ g, if intended
for use in the manufacture of parenteral preparations without
a further appropriate procedure for the removal of bacterial
endotoxins.
ASSAY
Nuclear magnetic resonance spectrometry (2.2.33).
The molar substitution (MS) is calculated from the ratio
between the signal from the 3 protons of the methyl group
that is part of the hydroxypropyl group and the signal from
the proton attached to the C1 carbon (glycosidic proton) of
the anhydroglucose units.
Test solution. Introduce not less than the equivalent of
10.0 mg ofthe substance to be examined, previously dried,
into a 5 mm NMR tube equipped with a spinner in order to
record the spectrum in rotation. Add approximately 0.75 mL
of deuterium oxide Rl. Cap the tube, mix thoroughly and
adapt the spinner.
Apparatus: FT-NMR spectrometer operating at minimum
250 MHz, suited to record a proton spectrum and to carry out
quantitative analysis, at a temperature of at least 25 oC.
Acquisition opH NMR spectra. Use the appropriate instrument
settings (frequency, gain, digital resolution, sample rotation,
shims, probe tuning, resolution/data point, receiver gain, etc.)
so as to obtain a suitable spectrum for quantitative analysis
(good FID (Free Induction Decay), no distortion of the
spectrum after Fourier transform and phase corrections). The
relaxation delay must be adapted to the pulse angle in order
to ha,:e sufficient relaxation of the protons of interest between
2 pulses (for example: 10 s for a 90° pulse).
Record the FID signal with at least 8 scans so as to obtain
a spectral window comprised, at least, between O ppm and
+ 6.2 ppm, referring to the signal of exchangeable protons
(solvent) at + 4.8 ppm (25 OC).
Make a zero filling at least 3-fold in size relative to the
acquisition data file and transform the FID to the spectrum
without any correction ofGaussian broadening factor (GB = O)
and with a line broadening factor not greater than 0.2 Hz
(LB:::; 0.2).
4052
EUROPEAN PHARMACOPOEIA 8.2
Call the integration sub-routine after phase corrections and
baseline correction between + 0.5 ppm and + 6.2 ppm.
Measure the peak areas of the doublet from the methyl groups
at + 1.2 ppm (Al)' and of the signals of the glycosidic protons
between + 5 ppm and + 5.4 ppm (AJ.
Calculate the molar substitution (MS) using the following
expression:
Al area of the signal due to the 3 protons of the methyl
groups that are part of the hydroxypropyl groups;
A2 area of the signals due to the glycosidic protons
(protons attached to the C1 carbon) of the
anhydroglucose units.
The degree of substitution is the number of hydroxypropyl
groups per molecule of ~-cyclodextrin and is obtained by
multiplying the MS by 7.
LABELLING
The label states:
- the molar substitution (MS);
- where applicable, that the substance is suitable for use in
the manufacture of parenteral preparations.
IMPURITIES
A. cycloheptakis-(l ~4)-(a-D-glucopyranosyl) (betadex or
cyclomaltoheptaose or ~-cyclodextrin),
H OH
~OH and enantiomer
H3C
B. (2RS)-propane-1,2-diol (propylene glycol).
FUNCTIONALITY -RELATED CHARACTERISTICS
This section provides information on characteristics that are
recognised as being relevant control parameters for one or
more functions of the substance when used as an excipient
(see chapter 5.15). Some of the characteristics described in
the Functionality-related characteristics section may also be
present in the mandatory part of the monograph since they
also represent mandatory quality criteria. In such cases, a
cross-reference to the tests described in the mandatory part is
included in the Functionalíty-related characteristics section.
Control of the characteristics can contribute to the quality
of a medicinal product by improving the consistency of the
manufacturing process and the performance of the medicinal
product during use. Where control methods are cited, theyare
recognised as being suitable for the purpose, but other methods
can also be used. Wherever results for a particular characteristic
are reported, the control method must be indicated.
The following characteristic may be relevant for
hydroxypropylbetadex used as solubility-increasing agent.
Degree of substitution (see Assay).
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2

1
Indometacin .............. ,. ..... ,. ..................................................... 4055 Interferon gamma-lb concentrated solution ...................... 4056

General NaNces (1) apply ta all managraphs and ather texts 4053
 EUROPEAN PHARMACOPOEIA 8.2

4054 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 Indometacin

0712014:0092 Reference solution (a). Dilute LO mL of the test solution to

100.0 mL with the solvent mixture. Dilute l.0 mL of this
INDOMETACIN solution to 10.0 mL with the solvent mixture.
Reference solution (b). Dissolve the contents of a vial of
Indometacinum indometacin impurity mixture CRS (impurities 1 and J) in
1.0 mL of the solvent mixture.
Column:
- size: 1= 0.15 m, 0 = 4.6 mm;
- stationary phase: end-capped phenylhexylsilyl si/ica gel for
chromatography R (3 flm);
- temperature: 40 0e.
Mobile phase:
C19H16CIN04 M r 357.8
- mobile phase A: 10 giL solution of acetic acid R;
[53-86-1]
- mobile phase B: acetonitrile R;
DEFINITION
Time Mobile pnase A MocHe pnase B
[1-( 4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3- (min) (per cení V/V) (per cent V/V)
yl] acetic acid. 0-2 70 30
Content: 98.5 per cent to 100.5 per cent (dried substance).
2 - 11 70 -'7 50 30 -'7 50
CHARACTERS
11 - 12 50 50
Appearance: white or yellow, crystalline powder.
12 50 -'7 70 50 -'7 30
Solubility: practically insoluble in water, sparingly soluble in
ethanol (96 per cent). 12 - 21 70 -'7 30 30 -'7 70
It shows polymorphism (5.9). 21 - 27 30 70

IDENTIFICATION
First identification: A, C.
Second identification: A, B, D, E.
A. Melting point (2.2.14): 158 oC to 162 0e.
B. Ultraviolet and visible absorption spectrophotometry
(2.2.25).
Test solution. Dissolve 25 mg in a mixture of 1 volume
of 1 M hydrochloríc acid and 9 volumes of methanol R
and dilute to 100.0 mL with the same mixture of solvents.
Dilute 10.0 mL of the solution to 100.0 mL with a mixture
of 1 vo!ume of 1 M hydrochloric acid and 9 volumes of
methanol R.
Spectral range: 300-350 nm.
Absorption maximum: at 318 nm.
Specific absorbance at the absorption maximum: 170 to 190.
e. Infrared absorption spectrophotometry (2.2.24), without
recrystallisation.
Comparison: indometacin CRS.
D. Dissolve 0.1 g in 10 mL of ethanol (96 per cent) R, heating
slightly if necessary. To 0.1 mL of the solution add 2 mL
of a freshly prepared mixture of 1 volume of a 250 giL
solution of hydroxylamine hydrochloride R and 3 volumes
of dilute sodium hydroxide solution R. Add 2 mL of dilute
hydrochloric acid R and 1 mL of ferric chloride solution R2
and mix. A violet-pink colour develops.
E. To 0.5 mL of the solution in ethanol (96 per cent)
prepared in identification test D, add 0.5 mL of
dimethylaminobenzaldehyde solution R2. A precipitate is
formed that dissolves on shaking. Heat on a water-bath.
A bluish-green colour is produced. Continue to heat for
5 min and cool in iced water for 2 mino A precipitate is
formed and the colour changes to light greyish-green. Add ASSAY
3 mL of ethanol (96 per cent) R. The solution is clear and Dissolve 0.300 g in 75 mL of acetone R, through which
violet-pink in colour.
TESTS
Related substances. Liquid chromatography (2.2.29).
Solvent mixture: acetonitrile R, water for chromatography R
(50:50 V/V).
Test solution. Dissolve 25.0 mg of the substance to be
examined in the solvent mixture and dilute to 25.0 mL with
the solvent mixture.
Flow rate: 1.0 mL/min.
Detection: spectrophotometer at 254 nm.
Injection: 20 f.lL.
Identification of impurities: use the chromatogram
supplied with indometacin impurity mixture CRS and the
chromatogram obtained with reference solution (b) to identify
the peaks due to impurities 1 and J.
Relative retention with reference to indometacin
(retention time = about 18 min): impurity 1 = about 1.3;
impurity J = about lA.
System suitability: reference solution (b):
- resolution: mínimum 1.5 between the peaks due to
impurities I and J.
Calculatíon of percentage con ten ts :
- for each impurity, use the concentration of indometacin in
reference solution (a).
LimUs:
- unspecified impurities: for each impurity, maximum 0.10 per
cent;
- total: maximum 0.3 per cent;
- reporting threshoId : 0.05 per cent.
Heavy meíals (2.4.8): maximum 20 ppm.
2.0 g complies with test e. Prepare the reference solution using
4 mL of lead standard solution (10 ppm Pb) R.
Loss on drying (2.2.32): maximum 0.5 per cent, determined
on LODO g by drying in an oven at 105 0e.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
LO g.
nitrogen R, free from carbon dioxide, has been passed for
15 mino Maintain a constant stream of nitro gen through the
solution. Add 0.1 mL of phenolphthalein so/ution R. Titrate
with 0.1 M sodium hydroxide. Carry out a blank titration.
1 mL of 0.1 M sodium hydroxíde is equivalent to 35.78 mg
of C19H16CIN04'
STORAGE
Protected from light.

General Notices (1) apply to all monographs and other texts 4055
Interferon gamma-lb concentrated solution EVROPEAN PHARMACOPOEIA 8.2

IMPVRITIES
Other detectable impurities (the following substances would,
if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical
use (2034). It is therefore not necessary to identify these
H. methyl [1-( 4-chlorobenzoyl)-5-methoxy-2-methyl-1H-
impurities for demonstration of compliance. See aIso 5.10.
Control of impurities in substances for pharmaceutical use): A,
indol-3-yI] acetate,
B, C, D, E, F, G, H, 1, J.
~C02H

C:~
A. 4-chlorobenzoic acid,
H3 C
1. ethyI [1-( 4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-
H N Y 'C02H 3 -yI] acetate,

Q OCH 3

B. (5-methoxy-2-methyI-1H-indol-3-yl)acetic acid,
o

c,dyA J. 4-chIoro-N' -[[ 1-( 4-chlorobenzoyl)-5-methoxy-2-

methyl-lH-indol- 3-yl] acetyl]- N-( 4-methoxyphenyl)-
benzohydrazide.
OCH 3
07/2014:1440
C. 4-chloro- N- (4-methoxyphenyl) benzamide,
INTERFERON GAMMA-lb
CONCENTRATED SOLUTION
Interferoni gamma -1 b solutio concentrata
M, 16465
D. [1-(2-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-
yI] acetic acid, DEFINITION
InterÍeron gamma-lb concentrated solution is a solution oí
the N-terminal methionyI form of interÍeron gamma, a protein
which is produced and secreted by human antigen-stimulated
T lymphocytes in response to viral inÍections and various
other inducers. It has specific immunomodulatory properties,
such as potent phagocyte-activating effects. The protein
consists of non-covalent dimers of two identical monomers.
The formula of the monomer is as follows:
E. [1-(3-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3- M
yI] acetic acid, QDPYVKEAEN LKKYFNAGHS DVADNGTLFL GILKNWKEES
DRKIMQSQIV SFYFKLFKNF KDDQSIQKSV ETIKEDMNVK
FFNSNKKKRD DFEKLTNYSV TDLNVQRKAI HELIQVMAEL
SPAAKTGKRK RSQMLFRGR
The potency of interferon gamma -1 b is not less than
20 x 106 IV per milligram of protein. Interferon gamma-1 b
concentrated solution contains not less than 30 x 10 6 IV of
OCH 3
interferon gamma -1 b per millilitre.
PRODVCTION
F. 4-chloro-N' -( 4-chlorobenzoyl)-N-( 4-methoxyphenyl)-
benzohydrazide, InterÍeron gamma -1 b concentrated solution is produced by
a method based on recombinant DNA technology, using
bacteria as host-cells. It is produced under conditions
designed to minimise microbial contamination.
Interferon gamma-lb concentrated solution complies with the
following additional requirements.
Host-ceU derived proteins. The limit is approved by the
competent authority.
G. [1-(3,4-dichlorobenzoyl)-5-methoxy-2-methyl-lH-indol- Host-cell- and vector-derived DNA. The limit is approved
3-yl]acetic acid, by the competent authority.

4056 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2
CHARACTERS
A clear, colourless or slightly yellowish liquido
IDENTIFICATION
A. It shows the expected biological activity when tested as
prescribed in the assay.
B. Examine the electropherograms obtained in the test
for impurities of molecular mas ses differing Írom
that oí interferon gamma -1 b. The principal bands in
the electropherogram obtained with the test solution
correspond in position to the principal bands in the
electropherogram obtained with reÍerence solution (a).
e. Examine by peptide mapping.
Solution A. Prepare a solution containing 1.2 giL oí
trís(hydroxyrnethyl)arninornethane R, 8.2 giL of anhydrous
sodiurn acetate R, 0.02 giL of calciurn chloride R and adjust
to pH 8.3 with dilute acetic acid R. Add polysorbate 20 R to
a concentration of 0.1 per cent V/V.
Test solution. Desalt a volume of the preparation to
be examined containing 1 mg of protein by a suitable
procedure. For example, filter in a microcentrifuge tube
and reconstitute with 500 I1L of solution A. Add 10 I1L of
a freshly prepared 1 mg/mL solution of trypsin for peptide
rnapping R in water R and mix gently by inversion. Incubate
at 30 oC to 37 oC for 24 h, add 100 I1L of phosphoric acid R
per millilitre of digested sample and mix by inversion.
Reference solution. Dilute interferon garnrna-l b CRS in
water R to obtain a concentration of 1 mg/mL. Prepare
as for the test solution, ensuring that al! procedures are
carried out simultaneously and under identical conditions.
Examine liquid chromatography (2.2.29).
The chromatographic procedure may be carried out using: mobile phase to a protein concentration of 0.1 mg/mL.
- a stainless steel column, 0.15 m long and 4.6 mm in
internal diameter packed with octadecylsilyl silica gel for the mobile phase to a protein concentration of O. 1 mg/mL.
R (lO 11m),
at a flow rate oí 1.0 mLlmin:
Mobile phase A (0.05 M sodium phosphate buffer solution
pH 3.3). Solution 1: dissolve 7.80 g of sodiurn dihydrogen
phosphate R in water R and dilute to 1000.0 mL with the
same solvent. Solution II: dilute 0.33 mL of phosphoric
acid R to 100.0 mL with water R. Mix 920 mL of solution 1
and 80 mL of solution n. Adjust the pH if necessary,
Mobile phase B. Acetonitrile for chrornatography R, with the
following elution conditions (if necessary, the gradient may
be modified to improve the separation of the digest):
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0-30 100 -7 80 0-720
30 - 50 80 -7 60 20 -7 40
50 - 51 60 -7 30 40 -7 70
51 - 59 30 70
- as detector a spectrophotometer set at 214 nm,
maintaining the temperature of the column at 40 0e.
Equilibrate the column for at least 15 min at the initial
elution composition. Carry out a blank run using the
above-mentioned gradient.
Inject 100 I1L of the test solution and 100 ¡.tL of the reference between the retention time of trypsinogen and lysozyme in
solution. The test is not valid unless the chromatogram
obtained with each solutiol1 is qualitatively similar
to the chromatogram of interferon gamma -1 b digest
supplied with interferon garnma-l b CRS. The profile of the shoulders or peaks in the chromatogram obtained with the
chromatogram obtained with the test solution corresponds test solution compared with the chromatogram obtained with
to that oí the chromatogram obtained with the reference
solution.
D. Examine by N-terminal sequence analysis.
General Notices (1) apply to all rnonographs and other texts
Interferon gamma-l b concentrated solution
Use an automated solid-phase sequencer, operated in
accordance with the manufacturer's instructions.
Equilibrate by a suitable procedure the equivalent of 100 Ilg
ofinterferon gamma-lb in a 10 giL solution of arnrnonium
hydrogen carbonate R, pH 9.0.
IdentiÍy the phenylthiohydantoin (PTH)-amino acids
released at each sequencing cycle by reverse-phase
liquid chromatography. The procedure may be carried
out using the column and reagents recommended by
the manufacturer of the sequencing equipment for the
separation of PTH -amino acids.
The separation procedure is calibrated using:
- the mixture of PTH -amino acids provided by the
manufacturer, with the gradient conditions adjusted as
indicated to achieve optimum resolution of aH amino
acids,
- a sample from a blank sequencing cycle, obtained as
recommended by the equipment manufacturero
The first fifteen amino acids are:
Met-Gln -Asp-Pro-Tyr-Val-Lys-Glu-Ala-Glu- Asn -Leu-Lys-
Lys-Tyr.
TESTS
Appearance. The preparation to be examined is clear (2.2.1)
and not more intensely coloured than reference solution Y7
(2.2.2, Method II).
pH (2.2.3). The pH of the preparation to be examined is 4.5
to S.S.
Covalent dimers and oligomers. Not greater than 2 per cent,
determined by size-exclusion chromatography (2.2.30).
Test solution. Dilute the preparation to be examined with the
Reference solution (a). Dilute interferon gamrna-l b CRS with
Reference solution (b). Prepare a mixture of the following
molecular mass standards: bovine albumin, ovalbumin,
trypsinogen, lysozyme, at a concentration of 0.1 mg/mL to
0.2 mg/mL for each standard.
The chromatographic procedure may be carried out using:
- a stainless steel column 0.3 m long and 7.8 mm in
internal diameter packed with hydrophilic si/ica gel for
chrornatography R, of a grade suitable for fractionation of
globular proteins in the molecular weight range of 10000 to
500 000 (5 11m),
- as mobile phase at a flow rate of 1.0 mL/min a mixture
prepared as follows (0.2 M sodium phosphate buffer
solution pH 6.8). Solution I: dissolve 31.2 g oí sodiurn
dihydrogen phosphate R and 1.0 g of sodiurn dodecyl
sulfate R in water R and dilute to 1000.0 mL with the same
solvent. Solution Ir: dissolve 28.4 g of anhydrous disodium
hydrogen phosphate R and 1.0 g of sodiurn dodecyl sulfate R
in water R and dilute to 1000.0 mL with the same solvento
Mix 450 mL of solution 1 and 550 mL of solution n. Adjust
the pH if necessary,
- as detector a spectrophotometer set at 210 nm to 214 nm.
Inject 200 f-lL oí each solution. The test is not valid unless:
the molecular mass standard s in reference solution (b) are
well separated; the retention time of the principal peak in
the chromatogram obtained with reference solution (a) is
the chromatogram obtained with reference solution (b).
Compare the chromatograms obtained with the test solution
and with reference solution (a). There are no additional
reference solution (a).
Calculate the percentage content of covalent dimers and
oligomers.
4057
Interferon gamma-l b concentrated solution
Monomer and aggregates. Examine by size-exclusion
chromatography (2.2.30). The content of monomer and
aggregates is not greater than 2 per cent.
Solution A. Prepare a solution of the following composition:
0.59 giL of succinic acid R and 40 giL of mannitol R, adjusted
to pH 5.0 with sodium hydroxide solution R.
Test solution. Dilute the preparation to be examined with
solution A to a protein concentration of 1 mg/mL.
Reference solution. Dilute interferon gamma-l b CRS with
solution A to a protein concentration of 1 mg/mL.
Resolution solution. Prepare 500 f!L of a mixture consisting of - as detector a spectrophotometer set at 280 nm,
0.04 mg/mL of bovine albumin R and 0.2 mg/mL of interferon
gamma-l b CRS in solution A. Use this solution within 24 h of
preparation.
The chromatographic procedure may be carried out using:
- a stainless steel column 0.3 m long and 7.8 mm in
internal diameter packed with hydrophilic silica gel for
chromatography R, of a grade suitable for fractionation of
globular proteins in the molecular weight range of 10 000 - separating the two peaks, is at least 1.2.
300 000 (5 f!m),
- as mobile phase at a flow rate of 0.8 mL/min a 89.5 giL
solution of potassium chloride R (1.2 M),
- as detector a spectrophotometer set at 214 nm.
Inject 20 f!L of the resolution solution. In the chromatogram
obtained, the retention time of the principal peak,
corresponding to the native interferon gamma-lb dimer, is
about 10 mino Bovine albumin elutes at a relative retention
time of about 0.85, relative to the main peak. The test is not interferon gamma-lb. Examine by polyacrylamide gel
valid unless the resolution between the peaks due to bovine
albumin and interferon gamma-lb is at least 1.5.
Inject 20 f!L of the test solution and 20 f!L of the reference method.
solution. The chromatograms obtained show principal peaks
with identical retention times. Calculate the percentage
content of monomer and aggregates from the peak area of the sulfate R and 0.100 g of bromophenol blue R in water R. Add
monomer peak and of peaks which elute prior to the native
interferon gamma-lb peak in the chromatogram obtained
with the test solution, by the normalisation procedure,
disregarding any peak due to the solvent.
Deamidated and oxidised forms and heterodimers.
Examine by liquid chromatography (2.2.29). The content of
deamidated and oxidised forms is not greater than 10 per cent. 50.0 mL of glyeerol R and dilute to 80 mL with water R. Adjust
The content of heterodimers is not greater than 3 per cent.
Test solution. Dilute the preparation to be examined with
water R to a protein concentration of 1 mg/mL.
Reference solution (a). Dilute interferon gamma-lb CRS with
water R to a protein concentration of 1 mg/mL.
Reference solution (b). Dissolve the contents of a vial of
interferon gamma-l b for system suitability CRS in water R to
obtain a protein concentration of about 1 mg/mL.
The chromatographic procedure may be carried out using:
- a stainless steel column 0.075 m long and 7.5 mm in
internal diameter packed with an appropriate hydrophilic
polymethacrylate, strong cation-exchange gel (10 f!m,
100 nm),
- as mobile phase at a flow rate of 1.2 mL/min:
Mobile phase A (0.05 M ammonium acetate buffer pH 6.5).
A 3.86 giL solution of ammonium acetate R, adjusted to
pH 6.5 with dilute acetic acid R,
4058
EUROPEAN PHARMACOPOEIA 8.2
Mobile phase B (1.2 M ammonium acetate buffer pH 6.5).
A 92.5 giL solution of ammonium acetate R, adjusted to
pH 6.5 with dilute acetic acid R,
with the following elution conditions (if necessary, the slope
of the gradient may be modified to improve the separation).
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0- 1 100 O
2 - 30 100 ~ O O ~ 100
31 - 35 O 100
maintaining the temperature of the column at 35 oc.
Inject 25 f!L of reference solution (b). In the chromatogram
obtained, the retention time of the principal peak is about
26 mino Deamidated and oxidised forms co-elute at a relative
retention time of about 0.95, relative to the principal peak.
The test is not valid unless the resolution, defined by the ratio
of the height of the peak corresponding to the deamidated and
oxidised forms to the height aboye the baseline of the valley
Inject 25 f!L of the test solution and 25 f!L of reference
solution (a). The chromatograms obtained show principal
peaks with identical retention times. Calculate the percentage
content of deamidated and oxidised interferon gamma -1 b
as a percentage of the area of the main peak. Heterodimers
have relative retention times of 0.7 and 0.85 relative to the
main peak. Calculate the percentage of heterodimers as a
percentage of the sum of the areas of all peaks.
Impurities of molecular masses differing from that of
electrophoresis (2.2.31). The test is performed under both
reducing and non-reducing conditions, using resolving gels of
15 per cent acrylamide and silver staining as the detection
Sample buffer (non-reducing conditions). Dissolve 3.78 g of
tris(hydroxymethyl)aminomethane R, 10.0 g of sodium dodecyl
50.0 mL of glycerol R and dilute to 80 mL with water R. Adjust
the pH to 6.8 with hydrochloric acid R and dilute to 100 mL
with water R.
Sample buffer (reducing conditions). Dissolve 3.78 g of
tris(hydroxymethyl)aminomethane R, 10.0 g of sodium dodecyl
sulfate R and 0.100 g of bromophenol blue R in water R. Add
the pH to 6.8 with hydroehlorie acid R and dilute to 100 mL
with water R. Immediately before use, add dithiothreitol R to a
final concentration of 250 mM.
Test solution. Dilute the preparation to be examined in
water R to a protein concentration of 1 mg/mL. Dilute 150 f!L
of the solution with 38 f!L of sample buffer.
Referenee solution (a). Prepare in the same manner as for the
test solution, but using interferon gamma-l b CRS instead of
the preparation to be examined.
Referenee solution (b) (5 ng control). Mix 50 f!L of a
0.01 mg/mL solution of bovine albumin R with 2000 f!L of
water R and 450 f!L of sample buffer.
Referenee solution (e) (2 ng control). Mix 20 f!L of a 0.01 mg/mL
solution of bovine albumin R with 2000 f!L of water R and
450 f!L of sample buffer.
Referenee solution (d). Use a solution of molecular mass
standards suitable for calibrating SDS-polyacrylamide gels in
the range of 10 kDa to 70 kDa.
Leave each solution, contained in a test tube, at ambient
temperature for 15 min, then store on ice.
See the information seetion on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Apply 25 flL of each solution to the stacking gel wells. Perform
the electrophoresis under the conditions recommended by the
manufacturer of the equipment. Detect proteins in the gel
by silver staining.
The test is not valid unless: the validation criteria are met
(2.2.31); a band is seen in the electropherograms obtained
with reference solutions (b) and (c).
The principal band in the electropherogram obtained with
the test solution is similar in intensity to the principal band
in the electropherogram obtained with reference solution (a).
In the electropherogram obtained with the test solution,
no significant bands are observed that are not present in
the electropherogram obtained with reference solution (a)
(0.01 per cent). A significant band is defined as any band
whose intensity is greater than or equal to that of the band in Inject 50 flL of each solution.
the electropherogram obtained with reference solution (c).
Nodeudne. Not more than 0.2 mole of norleucine per mole
of interferon gamma -1 b, determined by amino acid analysis.
Test solution. Add 2.5 mL of the preparation to be examined
onto a column suitable for the desalting of proteins previously per mole ofinterferon gamma-lb) from the peak afeas of
equilibrated with 25 mL of a 10 per cent V/V solution of
acetic acid R. Elute the sample with another 2.5 mL of a
10 per cent V/V solution of acetic acid R. Determine the
protein content by measuring the absorbance of this solution
as described under Protein, in the Assay section. Pipette
a volume containing the equivalent of 100 flg of interferon
gamma -1 b into each of three reaction vials. Evaporate to
dryness under reduced pressure.
Perform the hydrolysis of the three samples as follows. Add
to each reaction vial 200 ~lL of a 50 per cent V/V solution of
hydrochloric acid R containing 1 per cent V/V of phenol R,
evacuate the samples, purge with nitro gen and hydrolyse in
the gas phase. Heat the reaction vials at 110 oC for 22 h. After 316 nm. Calculate the concentration of interferon gamma-lb
hydrolysis evaporate to dryness under reduced pressure.
Perform the derivatisation of the samples as follows. Prepare
immediately before use a mixture consisting of two volumes
of ethanol R, one volume of water R and one volume of
triethylamine R. Add 50 flL of this solution to each reaction
vial and shake Iightly. Evaporate to dryness under reduced
pressure. Add to each vial 50 flL of a mixture consisting of
7 volumes of ethanol R, one volume of water R, one volume
of triethylamine R and one volume of phenyl isothiocyanate R. International Units.
Shake lightly and allow to stand at room temperature for
about 15 mino Evaporate to dryness under reduced pressure.
Reconstitute the samples in 250 flL of mobile phase A.
Norleucine stock solution. Prepare a 250 nmol/mL solution of
DL-norleucine R in 0.01 M hydrochloric acid. This solution may Carry out the assay by a suitable method, based on the
be kept for two months at 4 oc.
Leucine stock solution. Prepare a 250 nmol/mL solutiol1 of
leucine R in 0.01 M hydrochloric acid. This solution may be
kept at 4 oC for two months.
Reference solution. Mix 10 flL of norleucine stock solution
with 100 flL of leucine stock solution in each of the three
reaction vials. Evaporate to dryness under reduced pressure.
Perform the derivatisation of the samples as described for the to be tested onto the plate and carry out a series of twofold
preparation of the test solution.
Examine by liquid chromatography (2.2.29).
The chromatographic procedure may be carried out using:
- a stainless steel column 0.l5 m long and 3.9 mm in diameter fix cells to the plateo Add an antibody able to detect HLA-DR
packed with octadecylsilyl si/ica gel for chromatography R
(4 ¡.un),
- as mobile phase at a flow rate of 1.0 mL/min:
Mobile phase A. Mix 70 volumes of a 19 giL solution
of sodium acetate R containing 0.05 per cent V/V of
triethylamine R and adjusted to pH 6.4 with dilute acetic
acid R and 30 volumes of mobile phase B,
General Notices (1) apply to all monographs and other texts
Interferon gamma-l b concentrated solution
Mobile phase B. Mix 40 volumes of water R and 60 volumes
of acetonitrile R,
Time Mobile phase A Mobile phase B Comment
(min) (per cent V/V) (per cent V/V)
0-7 100 O isocratic
7 - 7.1 100 -7 O O -7 100 linear gradient
7.1 - 10 O 100 washing step
10 - 10.1 O -7 100 100 -7 O linear gradient
10.1 - 15 100 O re-eqnilibration
- as detector a spectrophotometer set at 254 nm,
maintaining the temperature of the column at 43 oc.
In the chromatograms obtained with the test solution, identify
the peaks corresponding to leucine and norleucine. The
retention time of norleucine is 6.2 min to 7 mino
Calculate the content of norleucine (in moles of norleucine
leucine and 110rleucine in the chromatograms obtained with
the reference and test solutions, considering that there are
10 moles of leucine per mole of interferon gamma -1 b.
Bacterial endotoxins (2.6.14): less than 5 IU in the volume
that contains 20 x 106 IU of interferon gamma-lb.
ASSAY
Pro te in (2.2.25). Dilute the substance to be examined in
water R to obtain a concentration of 1 mg/mL. Record the
absorbance spectrum between 220 nm and 340 nm. Measure
the value at the absorbance maximum of 280 nm, after
correction for any light scattering due to turbidity measured at
using a specific absorbance value of 7.5.
Potency. The potency of interferan gamma -1 b is
estimated by evaluating the increase of the expression of
human -Ieukocyte-antigen -D R (HLA -D R) dne to the interferon
gamma-lb present in test solutions during cultivation ofthe
cells, and comparing this increase with the same effect of the
appropriate International Standard of human recombinant
interferon gamma or of a reference preparation calibrated in
The International Unit is the activity contained in a stated
amount of the appropriate International Standard. The
equivalence in International Units of the International
Standard is stated by the World Health Organizatioll.
following designo
Use COLO 205 cells under standard culture conditions.
Trypsinise a 3- to 5-day-old flask of COLO 205 cells
and prepare a cel! suspension at a concentration of
l.0 x 10 6 cells/mL
Add 100 flL of the dilution medium to all wells of a 96-well
microtitre plateo Add an additional 100 flL of this solution to
the wells designed for the blanks. Add 100 flL of each solution
dilution steps in order to obtain a standard curve. Then add
100 flL of the ceH suspension to a11 wells and incubate the plate
under appropriate conditions for ceH cultivation.
After cultivation remove the grawth medium and wash and
expressed due to the presence of interferon gamma -1 b and
incubate under appropriate conditiol1s. After washing the
plate, incubate with an antibody conjugated to a marker
enzyme which is able to detect the anti-HLA-DR antibody.
After this incubation step, wash the plate and add an
appropriate substrate solution. Stop the reaction. Measure the
absorbance of the solution and calculate the potency of the
preparation to be examined by the usual statistical methods.
4059
Interfenm gamma-l b concentrated solution EUROPEAN PHARMACOPOEIA 8.2

The estimated specific activity is not less than 80 per cent STORAGE
and 110t more than 125 per cent of the stated potency. The
confidence limits (P = 0.95) are not less than 70 per cent and Store in an airtight container, protected from light and at a
not more than 140 per cent of the estimated potency. temperature of - 70 oc.

4060 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

L
Levocabastine hydrochloride ................................................ 4063 Linseed oil, virgin ................................................................... 4065

General Notices (1) apply to all monographs and other texts 4061
 EUROPEA N PHARMACOPOEIA 8.2

4062 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 Levocabastine hydrochloride

07/2014:1484 - mobile phase B: acetonitrile R1;

Time Mobile phase A Mobile pitase B
LEVOCABASTINE HYDROCHLORIDE (min) (per cent V/V) (per cent V/V)
O - 0.5 95

Levocabastini hydrochloridum 0.5 - 3.5 95 -7 90 5 -7 10

3.5 - 6.0 90 -7 85 10 -7 15

6.0 - !l.0 85 -7 70 15 -7 30

11.0 14.5 70 -7 20 30 -7 80
, Hel
14.5 - 15.5 20 80

Flow rate: 0.45 mLlmin.

C26H30CIFN202 M,457.0 D
[79547 -78-7J
DEFINITION
(3SAR)-l- [cis-4-Cyano-4-( 4-fluorophenyl)cyclohexyl]-3-
methyl-4-phenylpiperidine-4-carboxylic acid hydrochloride.
Content: 98.5 per cent to 101.5 per cent (dried substance).
CHARACTERS
Appearance: white or almost white powder.
Solubility: practically insoluble in water, sparingly soluble in
methanol, slightly soluble in ethanol (96 per cent) and in a
2 giL solution of sodium hydroxide.
IDENTIFICATION
A. Specific optical rotation (see Tests).
B. Infrared absorption spectrophotometry (2.2.24).
: levocabastine hydrochloride CRS.
e. Dissolve 50 mg in a mixture of 0.4 mL of ammonia R
and 2 mL of water R. Mix, allow to stand for 5 min and
filter. the filtrate with dihtte nitric acid R. 1t gives
chlorides (2.3.
TESTS
Solution S. Dissolve 0.250 g in methanol R and dilute to
25.0 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solution (2.2.2,
Method II).
Spedfic optical rotation (2.2.7): - 106 to - 102 (dried
substance), determined on solution S.
Related substances. Liquid chromatography (2.2.29). Carry
out the test protected from light.
Test solution. Dissolve 50 mg of the substance to be examined
in methanol R1 and dilute to 10.0 mL with the same solvento
Reference solution (a). Dissolve the contents of a vial
of levocabastine for system suitability 1 CRS (containing
impurities A, B, E, J and K) in 1.0 mL of methanol R1.
Reference solution (b). Dilute 1.0 mL ofthe test solution to
20.0 mL with methanol Rl. Dilute 1.0 mL of this solution to
10.0 mL with methanol R1,
Column:
- size: 1=o 0.10 m, (O =o 2.1 mm;
- stationary phase: end-capped phenylsilyl silica gel for
chromatography R (1.7 [.lm);
- tempera tu re: 60 0e.
Mobile phase:
- mobile phase A: 17 giL solution of tetrabutylammonium
hydrogen sulfate R;
'
etectlOn: spectrop h otometer at 214 nm.
Injection: 2.0 ~lL.
Identification of impurities: use the chromatogram supplied
with levocabastine for system suitability 1 CRS and the
chromatogram obtained with reference solution (a) to identify
the peaks due to impurities A, B, E, J and K.
Relative retention with reference to levocabastine (retention
time =o about 6.5 min): impurity A =o about 0.85;
impurity J =o about 0.86; impurity B =o about 0.90;
impurity E =o about 0.94; impurity K =o about 1.07.
System suitability: reference solution (a):
- peak-to-valley ratio: minimum 2.9, where Hp =o height aboye
the baseline of the peak due to impurity K and H" =o height
aboye the baseline of the lowest point of the curve
separating this peak from the peak due to levocabastine;
mínimum 5.0, where Hp =o height aboye the baseline of the
peak due to impurity J and H v =o height above the baseline
of the lowest point of the curve separating this peak from
the peak due to impurity A.
Calculation of percentage contents:
- for each impurity, use the concentration of levocabastine in
reference solution (b).
Limits:
- impurity E: maximum 0.4 per cent;
- impurity A: maximum 0.2 per cent;
- impurity B: maximum 0.15 per cent;
- unspecified impurities: for each impurity, maximum
0,10 per cent;
- total: maximum 0.6 per cent;
- reporting threshold: 0.05 per cent.
Impurity e. Liquid chromatography (2.2.29). Carry out the
test protected from light.
Test solution. Dissolve 50 mg of the substance to be examined
in methanol Rl and dilute to 10.0 mL with the same solvento
Reference solution (a). Dissolve the contents of a vial
of levocabastine for system suitability 2 CRS (containing
impurity e) in 1.0 mL of methanol Rl.
Reference solutiol1 (b J. Dilute 1.0 mL of the test solution to
20.0 mL with methanol Rl. Dilute l.0 mL of this solution to
10.0 mL with methanol Rl.
Column:
- size: 1=o 0.15 m, (O =o 2.1 mm;
- stationary phase: end-capped octadecylsilyl silica gel for
chromatography R (1.8 [.lm);
- temperature: 35 De.
Mobile phase:
- mobile phase A: 17 giL solution of tetrabutylammonium
hydrogen sulfate R;

General Notices (1) apply to all monographs and other texts 4063
Levocabastine hydrochloride EUROPEAN PHARMACOPOEIA 8.2

- mobile phase B: acetonítrile R1 ;

Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0-0.5 90 10

0.5 - 15.5 90 -7 80 10 -7 20

15.5 - 20.5 80 -7 50 20 -7 50 B. (3S,4R)-1- [cis-4-cyano-4-(2-fluorophenyl)cyclohexyl]-3-

methyl-4-phenylpiperidine-4-carboxylic acid,
Flow rate: 0.30 mL!min.
Detection: spectrophotometer at 214 nm.
Injection: 2.0 flL.
Identification of impuríties: use the chromatogram supplied
with levocabastine for system suitability 2 CRS and the
chromatogram obtained with reference solution (a) to identify
the peak due to impurity e.
Relative retention with reference to levocabastine (retention
e. (3S,4R)-1-[cis-4-cyano-4-(3-fluorophenyl)cyclohexyl]-3-
methyl-4-phenylpiperidine-4-carboxylic acid,
time = about 16 min): impurity C = about 0.98.
System suitability: reference solution (a):
- peak-to-valley ratio: minimum 10.0, where H p = height
aboye the baseline of the peak due to impurity C and
H v = height aboye the baseline of the lowest point of
thecurve separating this peak from the peak due to
levocabastine.
Calculation of percentage content: D. 1- [cis-4-cyano-4-( 4-fluorophenyl)cyclohexyl]-4-
phenylpiperidine-4-carboxylic acid,
- for impurity C, use the concentration of levocabastine in
reference solution (b).
Limit:
- impurity C: maximum 0.3 per cent.
Loss on drying (2.2.32): maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 105 0e.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
E. (3S,4R)-1- [trans-4-cyano-4-( 4-fluorophenyl)cyclohexyl]-3-
1.0 g in a platinum crucible.
methyl-4-phenylpiperidine-4-carboxylic acid,
ASSAY
H CH 3
Dissolve 0.175 g in 50 mL of ethanol (96 per cent) R, previously
neutralised to phenol red solution R, and add 5.0 mL of
water R. Carry out a potentiometric titration (2.2.20), using
0.1 M sodium hydroxide. Read the volume at the 2nd point of
inflexion.
HéfO
F. (3S,4R)-3- methyl-4-phenylpiperidine-4-carboxylic acid,
1 mL of 0.1 M sodium hydroxide is equivalent to 22.85 mg
of C26H30ClFNzÜ2'

STORAGE
Protected from light.

IMPURITIES
Specified impuríties: A, B, C, E.
Other detectable impurities (the following substances would, G. (3S,4R)-l- [cis-4-carbamoyl-4-( 4-fluorophenyl)cyclohexyl]-
if present at a sufficient level, be detected by one or other of 3-methyl-4-phenylpiperidine-4-carboxylic acid,
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical
use (2034). It is therefore not necessary to identify these
impurities for demonstration of compliance. See also 5.10.
Control of impurities in substances for pharmaceutical use): D,
F, G, H, 1, f, K, L. H. 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile,

A. (3S,4R)-1-(cis-4-cyano-4-phenylcyclohexyl)-3-methyl-4- 1. (3S,4S)-1- [cis-4-cyano-4-( 4-fluorophenyl)cyclohexyl]-3-

phenylpiperidine-4-carboxylic acid, methyl-4-phenylpiperidine-4-carboxylic acid,

4064 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2 Linseed oH, virgin

Relative density: about 0.93l.

Refraetive index: about 1.480.

IDENTIFICATION
First identifieation: B, e
Second identifieation: A, B.
J, (3S,4R)-l- [cis-4-cyano-4-( 4-f1uorophenyl)cyclohexyl]-4-(3-
hydroxyphenyl)-3-methylpiperidine-4-carboxylic acid, A. Identification of fatty oils by thin-layer chromatography
(2.32).
Results: the chromatogram obtained is similar to the
corresponding chromatogram shown in Figure 2.3.2.-l.
F I ~ B. Iodine value (see Tests).
~D·WÉ
V ... H
C. Composition of fatty acids (see Tests).
NC
TESTS
K. 1- [eis-4-cyano-4-( 4-f1uorophenyl)cyclohexyl]- 3-methyl- Add value (2.5.1): maximum 4.5.
4-phenylpyridinium, Iodine value (2.5.4): 160 to 200.
Peroxide value (2.5.5, Method A): maximum 15.0.
Saponification value (2.5.6): 188 to 195; carry out the
saponification for 1 h.
Unsaponifiable matter (2.5.7): maximum 1.5 per cent,
determined on 5.0 g.
L. (3S,4R)-l- [eis-4-cyano-4-( 4-f1uorophenyl)cyclohexyl]-3- Composition of faUy acids. Gas chromatography (2.4.22,
methyl-4-phenylpiperidine-4-carboxylic acid l-oxide. Method e). Use the calibration mixture in Table 2.4.22.-3.
Composition of the fatty-acid fraction of the oil:
fatty aeids with a chain length less than maximum
1.0 per cent,
07/2014: 1908
- palmitic acid: 3.0 per cent to 8.0 per cent,
LINSEED OIL, VIRGIN - palmito/eie acid: maximum l.0 per cent,
- stearie acid: 2.0 per cent to 8.0 per cent,
Lini oleum virginale - oleie aeid: 11.0 per cent to 35.0 per cent,
- Iino/eie acid: 11.0 per cent to 24.0 per cent,
DEFINITION
- linolenic acid: 35.0 per cent to 65.0 per cent,
Fatty oil obtained by cold expression from ripe seeds of Linum
- araehidic acid: maximum 1.0 per cent.
usitatissimum L. A suitable antioxidant may be added.
Cadmium: maximum 0.5 ppm, determined as described in
CHARACTERS general method 2.4.27. Heavy metals in herbal drugs and
Appearance: clear, yellow or brownish -yellow liquid, on herbal drug preparations.
exposure to air turning dark and gradually thickening. When Water (2.5.32): maximum 0.1 per cent, determined 011 1.00 g.
cooled, it becomes a 50ft mass at about - 20 oc.
Solubility: very slightly soluble in ethanol (96 per cent), STORAGE
miscible with light petroleum. In an airtight container, protected fram light.

General Notiees (1) apply to all monographs and other texts 4065
 EUROPEAN PHARMACOPOEIA 8.2

4066 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

M
Macrogol stearate .................................................................... 4069 Manganese gluconate ............................................................. 4071
Magaldrate ............................................................................... 4069 MannitoL ................................................................................. 4072
Magnesium gluconate ............................................................ 4070

General Notices (1) apply to all monographs and other texts 4067
 EUROPEAN PHARMACOPOEIA 8.2

4068 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2 Magaldrate

07/2014:1234 Ethylene oxide and dioxan (2.4.25): maximum 1 ppm of

ethylene oxide and 10 ppm of dioxan.
MACRO GOL STEARATE Heavy metals (2.4.8): maximum 10 ppm.
2.0 g complíes with test C. Prepare the reference solution using
Macrogoli stearas 2 mL of lead standard solution (10 ppm Pb) R.
Water (2,5,12): maximum 3.0 per cent, determined on 0.50 g,
DEFINITION Use as the solvent a mixture of equal volumes of anhydrous
Mixture of monoesters and diesters of mainly stearic methanol R and methylene chloride R,
(octadecanoic) acid and/or palmitic (hexadecanoic) acid Total ash (2.4.16): maximum 0.3 per cent, determined on
and macrogols. It may be obtained by ethoxylation or by LO g.
esterification of macrogols with stearic acid 50 (type 1) or
stearic acid 95 (type II) (see Stearic acid (1474)). 1t may contain STORAGE
free macrogols, The average polymer length is equivalent to 6 In an airtight container.
to 100 ethylene oxide units per molecule (nominal value),
LABELLING
CHARACTERS
The labe! states:
Appearance: white or slíghtly yellowish waxy mass,
- the number of ethylene oxide units per molecule (nominal
Solubility: soluble in ethanol (96 per cent) and in 2-propanol. value),
Macrogol stearate corresponding to a product with 6 to 9 units
of ethylene oxide per molecule is practically insoluble, but - the type of macro gol stearate.
freely dispersible in water and miscible with fatty oils and with
waxes. Macrogol stearate corresponding to a product with 20
to 100 units of ethylene oxide per molecule is soluble in water 07/2013:1539
and practically insoluble in fatty oils and in waxes. corrected 8.2

IDENTIFICATION
MAGALDRATE
A Saponification value (see Tests).
B. Composition of fatty acids (see Tests). Magaldratum
TESTS
AlsMglO(OH)3¡(SO'¡)2,xHzÜ M r 1097 (anhydrous substance)
Alkalinity. Dissolve 2.0 g in alcohol R and dilute to 20 mL [74978-16-8]
with the same solvent. To 2 mL of this solution add 0,05 mL
of phenol red solution R. The solution is not red. DEFINITION
MeHing poini: (2.2.15). See Table 1234,-1. Magaldrate is composed of aluminium and magnesium
Melt about 10 g at 80-90 oc. Introduce a sufficient amount hydroxides and sulfates, Its composition corresponds
of the substance into the tube by capillary action to form a approximately to the formula AI sMg lO (OH)3¡(S04)2,xHp.
column of the prescribed height. Allow to stand at Ooc for 2 h. Content: 90,0 per cent to 105.0 per cent (dried substance).
Add value (2.5.1): maximum 2.0, determined on 2.0 g. It contains a variable quantity of water.
Hydroxyl vallle (2.5.3, Method A). See Table 1234.-1. CHARACTERS
Jodine value Appearance: white 01' almost white, crystalline powder.
Saponification value (2,5,6). See Table 1234.-1. Solubility: practically insoluble in water and in ethanol (96 per
cent), It is soluble in dilute mineral acids,
Table 1234.-1
Ethy!ene oxide units Melting point Hydroxyl Sapollificaüoll IDENTIFICATION
per moleeule (oC) value value A, Dissolve 0,6 g in 20 mL of 3 M hydrochloric acid R, add
(nominal value)
about 30 mL of water R and heat to boiling. Adjust to
6 90 - 110 85 - 105
pH 6.2 with dilute ammonia R1, continue boiling fol' a
8 -9 26 - 35 80 - 105 88 - 100 further 2 min, filter and retain the precipitate and the
filtrate. To 2 mL of the filtrate add 2 mL of ammonium
20 33 - 40 50 - 62 46 - 56
chloride solution R and neutralise with a solution prepared
40 - 50 38 - 52 23 - 40 20 - 35 by dissolving 2 g of ammonium carbonate R and 2 mL of
dilute ammonia Rl in 20 mL of water R; no precipitate is
100 48 - 60 15 - 30 5 - 20
produced, Add disodium hydrogen phosphate solution R;
a white, crystalline precipitate is produced which does not
Composition of fatty acids. Gas chromatography (2.4.22, dissolve in dilute ammonia Rl,
Method C), B, The precipitate retained in identification test A gives the
Composition of the fatty aeid fraetion of the substance:
reaction of aluminium (2,3,1).
e. The filtrate retained in id entificatio n test A gives
Type of faHy Composition of fatty acids reaction (a) of sulfates (2.3,1).
acid used
Macrogol stearate Stearic acid 50 Stearic acid: 40,0 per cent to TESTS
type 1 60,0 per cent,
cantents ofpalmi/ic and Soluble chlorides: maximum 3.5 per cent.
acids: not less than 90.0 per To 0,5 g add 25 mL of dilute nitric acid R and shake ul1til
cent.
completely dissolved, Add 10.0 mL of 0,1 M silver nitrate and
Macrogol stearate Stearic acid 95 Stearic acid: 90.0 per cent to 2 mL of ferrie ammonium sulfate solution R2 as indicator,
type II 99,0 per cent,
Titrate with 0.1 M ammonium thiocyanate, shaking vigorously
Sum afthe cantents ofpalmitic and
stearie acids: not les s than 96,0 per until a persistent brownish-red colour is obtained,
cent. 1 mL of 0,1 M si/ver nitrate is equivalent to 3.545 mg of Cl.

General Notices (1) apply to all monographs and other texts 4069
Magnesium gluconate
Soluble sulfates: maximum 1.9 per cent.
Disperse 0.5 g in 25 mL of water R, boil for 5 min, cool, dilute
to 25.0 mL with water R, mix and filter. To 2.5 mL of the
filtrate, add 30 mL of water R, neutralise to blue litmus paper R
with hydrochloric acid R, add 3 mL of 1 M hydrochloric acid,
3 mL of a 120 gIL solution of barium chloride R and dilute to
50 mL with water R. Mix and allow to stand for 10 mino Any
opalescence in the solution is not more intense than that in a
standard prepared at the same time in the same manner using
1 mL of O. 01 M sulfuric acid instead of 2.5 mL of filtrate.
Sulfates: 16.0 per cent to 21.0 per cent (dried substance).
Dissolve 0.875 g in a mixture of 5 mL of glacial acetic acid R
and 10 mL of water R and dilute to 25.0 mL with water R.
Prepare a chromatographic column of 1 cm in internal
diameter containing 15 mL of cation-exchange resin R
(150-300 ¡.tm), previously washed with 30 mL of water R.
Transfer 5.0 mL of the solution to be examined to the column
and elute with 15 mL of water R. To the eluate add 5 mL of a
53.6 gIL solution of magnesium acetate R, 32 mL of methanol R
and 0.2 mL of alizarin S solution R. Add from a burette about
4.0 mL of 0.05 M barium chloride, add a further 0.2 mL of
alizarin S solution R and slowly complete the titration until
the yellow colour disappears and a violet-red tinge is visible.
1 mL of 0.05 M barium chloride is equivalent to 4.803 mg
ofS0 4·
Aluminium hydroxide: 32.1 per cent to 45.9 per cent (dried 2,3,4,5,6-pentahydroxyhexanoate] (anhydrous or hydrated
substance).
Dissolve 0.800 g in 10 mL of dilute hydrochloric acid R,
heating on a water-bath. Cool and dilute to 50.0 mL with
water R. To 10.0 mL of this solution, add dilute ammonia R1
until a precipitate begins to appear. Add the smallest
quantity of dilute hydrochloric acid R needed to dissolve the
precipitate and dilute to 20 mL with water R. Carry out the
complexometric titration of aluminium (2.5.11).
1 mL of 0.1 M sodium edetate is equivalent to 7.80 mg
of Al(OH)y
Magnesium hydroxide: 49.2 per cent to 66.6 per cent (dried
substance).
Dissolve 0.100 g in 2 mL of dilute hydrochloric acid R and
transfer to a 500 mL conical flask with the aid of water R.
Dilute to 200 mL with water R, add 20 mL of triethanolamine R
with shaking, 10 mL of ammonium chloride buffer solution
pH 10.0 R and about 50 mg of mordant black 11 triturate R.
Titrate with 0.1 M sodium edetate until the colour changes
from violet to pure blue.
1 mL of 0.1 M sodium edetate is equivalent to 5.832 mg of
Mg(OH)z·
Sodium: maximum 0.10 per cent.
Atomic absorption spectrometry (2.2.23, Method 1).
Test solution. Weigh 2.00 g into a 100 mL volumetric flask,
place in an ice-bath, add 5 mL of nitric acid R and swirl to mix.
Allow to warm to room temperature and dilute to 100 mL
with water R. Filter, if necessary, to obtain a clear solution.
Dilute 10.0 mL of the filtrate to 100.0 mL with water R.
Reference solutions. Prepare the reference solutions using
sodium standard solution (200 ppm Na) R, diluted as necessary
with dilute nitric acid R.
Source: sodium hollow-cathode lampo
Wavelength: 589 nm.
Atomisation device: air-acetylene flameo
Heavy metals (2.4.8): maximum 30 ppm.
Dissolve 2.0 g in 30 mL of hydrochloric acid R1 and shake with
50 mL of methyl isobutyl ketone R for 2 mino Allow to stand,
then separate and evaporate the aqueous layer to dryness.
Dissolve the residue in 30 mL of water R. 12 mL of the solution Appearance of solution. Solution S is clear (2.2.1) and not
complies with test A. Prepare the reference solution using lead more intensely coloured than reference solution Y7 (2.2.2,
standard solution (2 ppm Pb) R.
4070
EUROPEAN PHARMACOPOEIA 8.2
Loss on drying (2.2.32): 10.0 per cent to 20.0 per cent,
determined on 1.000 g by drying in an oven at 200 oC for 4 h.
ASSAY
To 1.500 g add 50.0 mL of 1 M hydrochloric acid. Titrate the
excess hydrochloric acid with 1 M sodium hydroxide to pH 3.0,
determining the end-point potentiometrically (2.2.20). Carry
out a blank titration.
1 mL of 1 M hydrochloric acid is equivalent to 35.40 mg
of AlsMg¡o(OH)3¡(S04)z.
07/2014:2161
MAGNESIUM GLUCONATE
Magnesii gluconas
M r 414.6 (anhydrous substance)
DEFINITION
Anhydrous or hydrated magnesium bis[(2R,3S,4R,5R)-
magnesium di(D-gluconate)).
Content: 98.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance: white or almost white, amorphous, hygroscopic,
crystalline or granular powder.
Solubility: freely soluble in water, slightly soluble in ethanol
(96 per cent), very slightly soluble in methylene chloride.
IDENTIFICATION
A. Thin-layer chromatography (2.2.27).
Test solution. Dissolve 20 mg of the substance to be
examined in 1 mL of water R.
Reference solution. Dissolve 20 mg of calcium gluconate CRS
in 1 mL of water R, heating if necessary in a water-bath
at 60 oc.
Plate: TLC silica gel plate R (5-40 ¡.tm) [or TLC silica gel
plate R (2-10 ¡.tm)].
Mobile phase: concentrated ammonia R, ethyl acetate R,
water R, ethanol (96 per cent) R (10:10:30:50 V/V/V/V).
Application: 1 ¡.tL.
Development: over 3/4 of the plateo
Drying: at 105 oC for 20 min, then allow to cool to room
temperature.
Detection: spray with a solution containing 25 gIL of
ammonium molybdate R and 10 gIL of cerium sulfate R in
dilute sulfuric acid R, then heat at 105 oC for about 10 mino
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size
to the principal spot in the chromatogram obtained with
the reference solution.
B. To 10 mL of solution S (see Tests) add 3 mL of ammonium
chloride solution R. A slight opalescence may be observed.
Add 10 mL of disodium hydrogen phosphate solution R. A
white precipitate is formed that do es not dissolve upon the
addition of 2 mL of dilute ammonia R1.
TESTS
Solution S. Dissolve 1.0 g in water R and dilute to 50 mL with
the same solvent.
Method II).
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Sucrose and redudng sugars. Dissolve 0.5 g in a mixture of
2 mL of hydrochloric acid Rl and 10 mL of water R. Boil for
5 min, allow to cool, add 10 mL of sodium carbonate solution R
and allow to stand for 10 mino Dilute to 25 mL with water R
and filter. To 5 mL of the filtrate add 2 mL of cupri-tartaric
solution R and boíl for 1 mino Allow to stand for 2 mino No
red precipitate is formed.
Chlorides (2.4.4): maximum 500 ppm.
Dilute 5 mL of solution S to 15 mL with water R.
Sulfates (2.4.13): maximum 500 ppm.
Dissolve 2.0 g in a mixture of 10 mL of acetic acid R and 90 mL
of distilled water R.
Heavy metals (2.4.8): maximum 10 ppm.
Dissolve 2.0 g in 20 mL of water R. 12 mL of the solution
complies with test A. Prepare the reference solution using lead
standard solution (1 ppm Pb) R.
Water (2.5.32): maximum 12.0 per cent, determined on 80 mg.
Microbial contamination
TAMC: acceptance criterion 10 3 CFU/g (2.6.12).
TYMC: acceptance criterion 10 2 CFU/g (2.6.12).
ASSAY
Dissolve 0.350 g in 100 mL of water R and carry out the
complexometric titration of magnesium (2.5.11).
1 mL of 0.1 M sodium edetate is equivalent to 41.46 mg
of C 12 H 22 Mg014'
STORAGE
In an airtight container.
07/2014:2162
MANGANESE GLUCONATE
Mangani gluconas
M r 445.2 (anhydrous substance)
DEFINITION
Anhydrous or hydrated manganese(II) bis[(2R,3SAR,5R)-
2,3,4,5,6-pentahydroxyhexanoate] (anhydrous or hydrated
manganese(II) di(D-gluconate)).
Content: 98.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance: white or pale pink, slightly hygroscopic,
crystalline powder.
Solubility: soluble in water, practically insoluble in anhydrous
ethanol, insoluble in methylene chloride.
IDENTIFICATION
A. Thin-layer chromatography (2.2.27).
Test solution. Dissolve 20 mg of the substance to be
examined in 1 mL of water R.
Reference solution. Dissolve 20 mg of calcium gluconate CRS
in 1 mL of water R, heating if necessary in a water-bath
at 60 oc.
PIate: TLC silica gel plate R (5-40 flm) [or TLC silica gel
plate R (2-10 flm)].
General Notices (1) apply to all monographs and other texts
Manganese gluconate
Mobile phase: concentrated ammonia R, ethyl acetate R,
water R, ethanol (96 per cent) R (10:10:30:50 V/V/V/V).
Application: 1 flL.
DeveIopment: over 3/4 of the plateo
Drying: at 105 oC for 20 min, then allow to cool to room
temperature.
Detection: spray with a solution containing 25 giL of
ammonium molybdate R and 10 giL of cerium sulfate R in
dilute sulfuric acid R, and heat at 105 oC for about 10 mh
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size
to the principal spot in the chromatogram obtained with
the reference solution.
B. Dissolve 50 mg in 5 mL of water R. Add 0.5 mL of
ammonium sulfide solution R. A palIO pink precipitate is
formed that dissolves upon the addition of 1 mL of glacial
acetic acid R.
TESTS
Solution S. Dissolve 1.0 g in water R and dilute to 50 mL with
the same solvent.
Appearance of solution. Solution S is not more opalescent
than reference suspension II (2.2.1) and not more intensely
coloured than intensity 6 of the range of reference solutions of
the most appropriate colour (2.2.2, Method II).
Sucrose and redudng sugars. Dissolve 0.5 g in a mixture of
2 mL of hydrochloric acid R1 and 10 mL of water R. Boil for
5 min, allow to cool, add 10 mL of sodium carbonate solution R
and allow to stand for 10 mino Dilute to 25 mL with water R
and filter. To 5 mL of the filtrate add 2 mL of cupri-tartaric
solution R and boíl for 1 mino Allow to stand for 2 mino No
red precipitate is formed.
Chlorides (2.4.4): maximum 500 ppm.
Dilute 5 mL of solution S to 15 mL with water R.
Sulfates (2.4.13): maximum 500 ppm.
Dissolve 2.0 g in a mixture of 10 mL of acetic acid R and 90 mL
of distilled water R.
Zinc: maximum 50 ppm.
To 10 mL of solution S add 1 mL of sulfuric acid R and
0.1 mL of potassium ferrocyanide so/ution R. After 30 s, any
opalescence in the solution is not more intense than that
in a mixture of 1.0 mL of zinc standard so/ution (lO ppm
Zn) R, 9 mL of water R, 1 mL of sulfuric acid R and 0.1 mL of
potassium ferrocyanide solution R.
Heavy metals (2.4.8): maximum 10 ppm.
Dissolve 2.0 g in 20 mL of water R, heating in a water-bath at
60 oc. 12 mL of the solution complies with test A. Prepare the
reference solution using lead standard solution (1 ppm Pb) R.
Water (2.5.32): maximum 9.0 per cent, determined on 80 mg.
Microbial contamination
TAMC: acceptance criterion 10 3 CFU/g (2.6.12).
TYMC: acceptance criterion 10 2 CFU/g (2.6.12).
ASSAY
Dissolve 0.400 g in 50 mL of water R. Add 10 mg of ascorbic
acid R, 20 mL of ammonium chloride buffer solution pH 10.0 R
and 0.2 mL of a 2 giL solution of mordant black 11 R in
triethanolamine R. Titrate with 0.1 M sodium edetate until the
colour changes from violet to pure blue.
1 mL of 0.1 M sodium edetate is equivalent to 44.52 mg
of C12H22Mn0l4'
STORAGE
In a non-metallic, airtight container.
4071
Mannitol EUROPEAN PHARMACOPOEIA 8.2

01/2014:0559 Deteetion: spray with 4-aminobenzoie aeid solution R and

corrected 8.2 dry in a current of cold air until the acetone is removed;
heat at 100 oC for 15 min, allow to cool then spray with a
2 giL solution of sodium periodate R; dry in a current of
MANNITOVlJ cold air and heat at 100 oC for 15 mino
System suitability: reference solution (b):
Mannitolum - the chromatogram shows 2 clearly separated spots.
Results: the principal spot in the chromatogram obtained
OH
~~~
OH
with the test solution is similar in position, colour and size
H '
to the principal spot in the chromatogram obtained with
HO" ' ..
reference solution (a).O
HO H
HO
TESTS
C6H 140 6 M r 182.2 Appearance of solution. The solution is clear (2.2.1) and
[69-65-8]
colourless (2.2.2, Method II).
DEFINITION Dissolve 5.0 g in water R and dilute to 50 mL with the same
solvent.
D-Mannitol.
Conductivity (2.2.38): maximum 20 flS.cm - l.
Content: 97.0 per cent to 102.0 per cent (dried substance).
Dissolve 20.0 g in earbon dioxide-free water R prepared from
• CHARACTERS distilled water R by heating at 40-50 oC and dilute to 100.0 mL
with the same solvent. After cooling, measure the conductivity
Appearanee: white or almost white crystals or powder.
of the solution while gently stirring with a magnetic stirrer.
Solubility: freely soluble in water, practically insoluble in
ethanol (96 per cent). Melting point (2.2.14): 165 oC to 170 0e.
It shows polymorphism (5.9) .• Reducing sugars: maximum 0.1 per cent (calculated as
glucose equivalent).
IDENTIFICATION To 7.0 g add 13 mL of water R. Boil gently with 40 mL of
First identifieation: C. eupri-tartarie solution R for 3 min, and allow to stand for
2 mino A precipitate is formed. Filter through a sintered-glass
0Seeond identification: A, B, D. filter (16) (2.1.2) coated with diatomaeeous earth R or
A. Specific optical rotation (2.2.7): + 23 to + 25 (dried a sintered-glass filter (10) (2.1.2). Wash the precipitate
substance). with hot water R (about 50-60 oC) until the washing is no
Dissolve 2.00 g of the substance to be examined and 2.6 g of longer alkaline, and filter the washings through the same
disodium tetraborate R in about 20 mL of water R at 30 oC; sintered-glass filter. Discard the filtrate. Immediately dissolve
shake continuously for 15-30 min without further heating. the precipitate in 20 mL of ferrie sulfate solution R, filter
Dilute the resulting clear solution to 25.0 mL with water R. through the same sintered-glass filter, and wash the filter with
15-20 mL of water R. Combine the washings and the filtrate,
B. Melting point (see Tests).O heat to 80 oC, and titrate with 0.02 M potassium permanganate.
e. Infrared absorption spectrophotometry (2.2.24). Not more than 3.2 mL is required to change the colour of the
Comparison: mannitol CRS. solution from green to pink so that the colour persists for at
least 10 s.
If the spectra obtained in the solid state show differences,
dissolve separately in 2 glass vials 25 mg of the substance Related substances. Liquid chromatography (2.2.29).
to be examined and 25 mg of the reference substance in Test solution. Dissolve 0.50 g of the substance to be examined
0.25 mL of distilled water R without heating. The solutions in 2.5 mL of water R and dilute to 10.0 mL with the same
obtained are clear. Evaporate to dryness by heating in solvento
a microwave oven with a power range of 600-700 W Referenee solution (a). Dissolve 0.50 g of mannitol CRS in
for 20 min or by heating in an oven at 100 oC for 1 h 2.5 mL of water R and dilute to 10.0 mL with the same solvento
then gradually applying vacuum until a dry residue is
obtained. Non-sticky, white or slightly yellowish powders Referenee solution (b). Dilute 2.0 mL of the test solution to
are obtained. Record new spectra using the residues. 100.0 mL with water R.
Referenee solution (e). Dilute 0.5 mL ofreference solution (b)
OD. Thin-layer chromatography (2.2.27).
to 20.0 mL with water R.
Test solution. Dissolve 25 mg of the substance to be Referenee solution (d). Dissolve 0.25 g of mannitol R and
examined in water R and dilute to 10 mL with the same
0.25 g of sorbitol R (impurity A) in 5 mL of water R and dilute
solvent.
to 10.0 mL with the same solvento
Referenee solution (a). Dissolve 25 mg of mannitol CRS in Referenee solution (e). Dissolve 0.5 g of maltitol R (impurity B)
water R and dilute to 10 mL with the same solvento and 0.5 g of isomalt R (impurity C) in 5 mL of water R and
Referenee solution (b). Dissolve 25 mg of mannitol R and dilute to 100 mL with the same solvent. Dilute 2 mL ofthe
25 mg of sorbitol R in water R and dilute to 10 mL with solution to 10 mL with water R.
the same solvent. Column:
Plate: TLC si/ica gel plate R. - size: 1= 0.3 m, 0 = 7.8 mm;
Mobile phase: water R, ethyl aeetate R, propanol R - stationary phase: strong cation-exehange resin (ealcium
(10:20:70 V/V/V). form) R (9 flm);
Applieation: 2 flL. - temperature: 85 ± 2 0e.
Development: over 2/3 of the plateo Mobile phase: degassed water R.
Drying: in airo Flow rate: 0.5 mL!min.

(1) This monograph has undergone pharmacopoeial harmonisation. See chapter 5.8. Pharmacopoeial harmonisation.

4072 See the information seetion on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2
Detectíon: refracto meter maintained at a constant temperature
(40 oC for example).
Injectíon: 20 ¡..tL of the test solution and reference solutions (b),
(c), (d) and (e).
Run tíme: 1.5 times the retention time of mannitol.
Identificatíon of impurities: use the chromatogram obtained
with reference solution (d) to identify the peak due to
impurity A and the chromatogram obtained with reference
solution (e) to identify the peaks due to impurities B and C.
Relative retention with reference to mannitol (retention
time = about 20 min): impurity C (l sI peak) = about 0.6;
impurity B = about 0.7; impurity C (2 nd peak) = about 0.73;
impurity A = about 1.2. Impurity C elutes in 2 peaks.
Coelution of impurity B and the 2nd peak due to impurity C
may be observed.
System suitability: reference solution (d):
- resolution: minimum 2.0 between the peaks due to
mannitol and impurity A.
Limits:
- impurity A: not more than the area of the principal peak
in the chromatogram obtained with reference solution (b)
(2.0 per cent);
- sum of impurities B and C: not more than the area of
the principal peak in the chromatogram obtained with
reference solution (b) (2.0 per cent);
- unspecified impurities: for each impurity, not more than
twice the are a of the principal peak in the chromatogram
obtained with reference solution (c) (0.10 per cent);
- total: not more than the are a of the principal peak in the
chromatogram obtained with reference solution (b) (2.0 per
cent) ;
- disregard limit: the are a of the principal peak in the
chromatogram obtained with reference solution (c)
(0.05 per cent).
Nickel (2.4.15): maximum 1 ppm.
Suspend 10.0 g in 30.0 mL of dilute acetic acid R and dilute to
100.0 mL with water R. Use water-saturated methyl isobutyl
ketone R.
Heavy metal,,: maximum 5 ppm.
Test solution. Introduce 5.0 g into a 50 mL colour comparison
tube and dissolve with 40 mL of water R. Add 2 mL of dilute
acetic acid Rl and dilute to 50 mL with water R.
Reference solution. Introduce 2.5 mL of lead standard solution
(10 ppm Pb) R into a 50 mL colour comparison tube, add 2 mL
of dilute acetic acid Rl and dilute to 50 mL with water R.
Add about 50 ¡..tL of sodium sulfide solution Rl to each of the
test solution and the reference solution, mix thoroughly, and
allow to stand for 5 mino Examine the solutions by viewing
the tubes vertically or horizontaly against a white background.
The test solution is not more intensely coloured than the
reference solution.
Loss on drying (2.2.32): maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 105 oC for 4 h.
Microbial contamination. If intended for use in the
manufacture of parenteral preparations:
- TAMC: acceptance criterion 102 CFU/g (2.6.12).
If not intended for use in the manufacture of parenteral
preparations:
- TAMC: acceptance criterion 10 3 CFU/g (2.6.12);
- TYMC: acceptance criterion 102 CFU/g (2.6.12);
- absence of Escherichia coli (2.6.13);
L absence of Salmonella (2.6.13).0
+Bacterial endotoxins (2.6.14). Ifintended for use in the
manufacture of parenteral preparations without a further
appropriate procedure for the removal of bacterial endotoxins:
- less than 4 IU/g for parenteral preparations having a
concentration of 100 giL or less of mannitol;
General Notices (1) apply to al/ monographs and other texts
Mannitol
- less than 2.5 IU/g for parenteral preparations having a
concentration of more than 100 giL of mannitol. +
ASSAY
Liquid chromatography (2.2.29) as described in the test for
related substances with the following modification.
Injection: test solution and reference solution (a).
Calculate the percentage content of D-mannitol taking into
account the assigned content of mannitol CRS.
LABELLING
The label states:
- where applicable, the maximum concentration of bacterial
endotoxins;
- where applicable, that the substance is suitable for use in
the manufacture of parenteral preparations.
IMPURITIES
Specified impurities: A, B, C.
OH
~
OH
H.. " ··OH
HO .. H
HO HO H
A. D-glucitol (D-sorbitol),
HO~:A0Hp~
OH H
HO o" ~~
HO H-~
HO I
OH
B. 4-0-a-D-glucopyranosyl-D-glucitol (D-maltitol),
C. mixture of 6-0-a-D-glucopyranosyl-D-glucitol and
1-0-a-D-glucopyranosyl-D-mannitol (isomalt).
FUNCTIONALITY -RELATED CHARACTERISTICS
This section provides information on characteristics that are
recognised as beíng relevant control parameters for one or
more functions of the substance when used as an excipient
(see chapter 5.15). Sorne of the characteristics described in
the Functionality-related characteristics section may also be
present in the mandatory part of the monograph since they
also represent mandatory quality criteria. In such cases, a
cross-reference to the tests described in the mandatory part is
included in the Functionality-related characteristics section.
Control of the characteristics can contribute to the quality
of a medicinal product by improving the consistency of the
manufacturing process and the performance of the medicinal
product during use. Where control methods are cUed, they are
recognised as beíng suitable for the purpose, but other methods
can also be used. Wherever results for a particular characteristic
are reported, the control method must be indícated.
The following characteristics may be relevant for mannitol used
as filler in tablets and capsules.
Partide-size distribution (2.9.31 or 2.9.38).
Powder f1.ow (2.9.36).
4073
 EUROPEAN PHARMACOPOEIA 8.2

4074 See the information section on general monographs (cover pages)

EUROPEAl'~ PHARMACOPOEIA 8.2

Neostigmine bromide ............................................................. 4077 Neostigmine metilsulfate ....................................................... 4078

General Notices (1) apply to all monographs and other texts 4075
 EUROPEAN PHARMACOPOEIA 8.2

4076 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
07/2014:0046
NEOSTIGMINE BROMIDE
Neostigmini bromidum
8r
Cl2Hl9BrN202 303.2
[114-80-7]
DEFINITION
3- [(Dimethylcarbamoyl)oxy]- N,N,N- trimethylanilinium
bromide.
Content: 98.5 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance: white or almost white, crystalline powder or
colourless crystals, hygroscopic.
Solubility: very soluble in water, freely soluble in ethanol
(96 per cent).
IDENTIFICATION
First identificatían: B, D.
Secand identificatian: A, C, D.
A. Ultraviolet and visible absorption spectrophotometry
(2.2.25).
Test solutian. Dissolve 20 mg in 0.5 M sulfuric acid and
dilute to 100 mL with the same acid.
Spectral range: 230-350 nm.
Absarptian maxima: at 260 nm and 266 nm.
Specific absorbance at the absarptian maxima:
- at 260 nm: about 16;
- at 266 nm: about 14.
B. Infrared absorption spectrophotometry (2.2.24).
Comparison: neostigmine bromide CRS.
e. To 50 mg add 0.4 g of potassium hydroxide R and 2 mL of on 1.000 g by drying in an oven at 105 De.
ethanol (96 per cent) R and heat on a water-bath for 3 min, Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
replacing the evaporated ethanol (96 per cent). Cool and
add 2 mL of water R and 2 mL of diazobenzenesulfonic acid
solution Rl. An orange-red colour develops.
D. It gives the reactions ofbromides (2.3.1).
TESTS
Solution S. Dissolve 2.5 g in distilled water R and dilute to 1 mL of 0.1 M perchlorie acid is equivalent to 30.32 mg
50 mL with the same solvento
Appearance of solution. Solution S is clear (2.2.1) and
colourless (2.2.2, Method II).
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 50 mg of the substance to be examined
in the mobile phase and dilute to 50.0 mL with the mobile
phase.
Reference solutian (a). Dilute 1.0 mL ofthe test solution to
100.0 mL with the mobile phase. Dilute 1.0 mL of this solution
to 10.0 mL with the mobile phase.
Reference solutian (b). Dissolve the contents of a vial of
neostigmine impurity mixture CRS (impurities A and B) in
1.0 mL of the mobile phase.
Reference solution (e). Mix 1.0 mL of the mobile phase and
1.0 mL of reference solution (a).
Column:
- size: 1= 0.25 m, 0 = 4.0 mm;
- stationary phase: base-deactivated end-capped octylsi/yl
silica gel for chromatography R (5 ¡.tm);
General Notices (1) apply to all monographs and other texts
Neostigmine bromide
- temperature: 30 De.
Mobile phase: to 710 mL of a 3.6 giL solution of sodium
dihydrogen phosphate R previously adjusted to pH 3.2 with
phosphoric acid R, add 4.3 g of sodium dodeeyl sulfate R and
290 mL of acetonitrile Rl.
Flow rate: 1.6 mL/min.
Deteetion: spectrophotometer at 220 nm.
Injection: 50 11L.
Run time: twice the retention time of neostigmine.
Identification of impurities: use the chromatogram supplied
with neostigmine impurity mixture CRS and the chromatogram
obtained with reference solution (b) to identify the peaks due
to impurities A and B.
Relative retention with reference to neostigmine (retention
time = about 20 min): impurity B = about 0.56;
impurity A = about 0.61.
System suítability:
- resolution: minimum 1.5 between the peaks due to
impurities B and A in the chromatogram obtained with
reference solution (b);
- signal-to-noise ratio: mínimum 25 for the principal peak in
the chromatogram obtained with reference solution (e).
Calculation of percentage contents:
- for each impurity, use the concentration of neostigmine in
reference solution (a);
- eorrection factor: multiply the peak area of impurity B
by 0.5.
Limits:
- impurity B: maximum 0.01 per cent;
- unspecified impurities: for each impurity, maximum
0.10 per cent;
- total: maximum 0.3 per cent;
- reporting threshold: 0.05 per eent; disregard the peak due
to impurity B.
Sulfates (2.4.13): maximum 200 ppm, determined on
solution S.
L05s on drying (2.2.32) : maximum l.0 per cent, determined
1.0 g.
ASSAY
Dissolve 0.225 g in 2 mL of anhydrous formic acid R. Add
50 mL of acetie anhydride R. Titrate with 0.1 M perchlarie
acid, determining the end-point potentiometrically (2.2.20).
of C12H19BrN202'
STORAGE
In an airtight container, protected from hght.
IMPURITIES
Speeified impurities: B.
Other detectable impurities (the following substances would,
if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical use
(2034). It is therefore not necessary to identify these impurities
for demonstration of compliance. See also 5.10. Contralof
impurities in substances for pharmaceutical use): A, C.
A. 3-hydroxy-N,N,N-trimethylanilinium,
4077
Neostigmine metilsulfate
HO D ~
[
N/
I
CH 3
CH
3
C. 3-( dimethylamino )phenyl dimethylcarbamate.
07/2014:0626
NEOSTIGMINE METILSULFATE
Neostigmini metilsulfas
C13H22N206S M r 334.4 dihydrogen phosphate R previously adjusted to pH 3.2 with
[51-60-5]
DEFINITION
3 - [(Dimethylcarbamoyl)oxy]- N,N, N- trimethylanilinium
methyl sulfate.
Content: 98.5 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance: white or almost white, crystalline powder or
colourless crystals, hygroseopic.
Solubility: very soluble in water, freely soluble in ethanol
(96 per cent).
IDENTIFICATION
First identification: A, C.
Second identification: A, B, D, E.
A. Melting point (2.2.14): 144 oC to 149 oc.
B. Ultraviolet and visible absorption spectrophotometry
(2.2.25).
Test solution. Dissolve 50 mg in 0.5 M sulfuric acid and
dilute to 100 mL with the same acid.
Spectral range: 230-350 nm.
Absorption maxima: at 261 nm and 267 nm.
Resolution (2.2.25): minimum 1.9 for the absorbance ratio.
Absorbance ratio: A 267 I A 261 =o 0.84 to 0.87.
-
C. Infrared absorption speetrophotometry (2.2.24).
Comparison: neostigmine metí/sulfate CRS.
D. To 50 mg add 004 g of potassium hydroxide R and 2 mL of - unspecified impurities: for eaeh impurity, maximum
ethanol (96 per cent) R and heat on a water-bath for 3 min,
replacing the evaporated ethanol (96 per eent). Cool and
add 2 mL of water R and 2 mL of diazobenzenesulfonic acid
solution R1. An orange-red colour develops.
E. Dissolve 0.1 g in 5 mL of distilled water R and add 1 mL of
barium chloride solution Rl. No precipitate is formed. Add
2 mL of hydrochlorie acid R and heat in a water-bath for
10 mino A fine, white precipitate is formed.
TESTS
Solution S. Dissolve 2.5 g in distilled water R and dilute to
50 mL with the same solvent.
Appearance of solution. Solution S is dear (2.2.1) and
colourless (2.2.2, Method JI).
Acidity or alkalinity. To 4.0 mL of solution S add 6.0 mL
of water R and 0.1 mL of phenolphthalein solution R1. The
solution is colourless. Add 0.3 mL of O. 01 M sodium hydroxide;
4078
EUROPEAN PHARMACOPOEIA 8.2
the solution becomes red. Add 0.4 mL of 0.01 M hydrochloríc
acid; the solution beeomes eolourless. Add 0.1 mL of methyl
red so/ution R; the solution beeomes red or yellowish-red.
Related substances. Liquid ehromatography (2.2.29).
Test so/ution. Dissolve 50 mg of the substanee to be examined
in the mobile phase and dilute to 50.0 mL with the mobile
phase.
ReÍerence solution (aJ. Dilute l.0 mL of the test solution to
100.0 mL with the mobile phase. Dilute l.0 mL of this solutiol1
to 10.0 mL with the mobile phase.
ReÍerence solution (b). Dissolve the contents of a vial of
neostigmine impurity mixture CRS (impurities A and B) in
l.0 mL of the mobile phase.
ReÍerence solution (e). Mix 1.0 mL ofthe mobile phase and
1.0 mL of referenee solution (a).
Column:
- size: 1 =o 0.25 m, 0 =o 4.0 mm;
- stationary phase: base-deaetivated end-capped octylsilyl
silica gel Íor chromatography R (5 flm);
- temperature: 30 oc.
Mobile phase: to 710 mL of a 3.6 giL solution of sodium
phosphoric acid R, add 4.3 g of sodium dodecyl sulfate R and
290 mL of acetonitrile Rl.
Flow rate: 1.6 mLlmin.
Deteetion: spectrophotometer at 220 nm.
Injection: 50 flL.
Run time: twice the retention time of neostigmine.
Identificatían oÍ impurities: use the chromatogram supplied
with neostigmine impurity mixture CRS and the chromatogram
obtained with reference solution (b) to identify the peaks due
to impurities A and B.
Relative retention with reference to neostigmine (retention
time =o about 20 min): impurity B =o about 0.56;
impurity A =o about 0.6lo
System suitability:
- resolution: mínimum 1.5 between the peaks dne to
impurities B and A in the ehromatogram obtained with
reference solntion (b);
- signal-to-noise ratio: minimum 25 for the principal peak in
the chromatogram obtained with reference solution (e).
Calculation oÍ percentage cantents:
- for eaeh impurity, use the eoneentration of neostigmine in
referenee solution (a);
- correetion Íactor: multiply the peak area of impurity B
by 0.5.
Limits:
- impurity B: maximum 0.01 per cent;
0.10 per eent;
- total: maximum 0.2 per eent;
- reporting threshold: 0.05 per cent; disregard the peak dne
to impurity B.
Sulfates (2.4.13): maximum 200 ppm, determined on
solution S.
Loss on drying (2.2.32): maximum 0.5 per eent, determined
on 1.000 g by drying in an oven at 105 oc.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Dissolve 0.300 g in 150 mL of water R and add 100 mL of
dilute sodium hydroxide so/ution R. Distil, collecting the
distillate in 40 mL of a 40 giL solution of boric acid R until the
total volume in the colleeting vessel is about 250 mL. Titrate
See the inÍormation section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2 Neostigmine metHsulfate

the solution in the collecting vessel with 0.1 M hydrochloric

acid, using 0.25 mL of methyl red mixed solution R as indicator.
Carry out a blank test. HO
V+/H3
N
é CH3
CH 3

1 mL of 0.1 M hydrochloric acíd is equivalent to 33.44 mg of

C13H22N206S. A. 3-hydroxy -N,N,N -trimethylanilinium,
STORAGE
In an airtight container, protected from Iight.
IMPURITIES
Speciíied impurities: B.
Other detectable impurities (the following substances would, B. 3-( dimethylal11ino )phenol,
if present at a sufficient leve!, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities and/or
by the generall11onograph Substances for pharmaceutical use
(2034). It is therefore not necessary to identify these impurities
for del11onstration of compliance. See also 5.10. Control of
impurities in substances fDr pharmaceutical use): A, C. C. 3-( dimethylamino )phenyl dimethylcarbal11ate.

General Notices (1) apply to all monographs and other texts 4079
 EUROPEAN PHARMACOPOEIA 8.2

4080 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

p
Pancreas powder..................................................................... 4083 Phenylalanine .......................................................................... 4085

General Natices (1) apply ta all managraphs and ather texts 4081
 EUROPEAN PHARMACOPOEIA 8.2

4082 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
07/2014:0350
PAN CREAS POWD ER
Pancreatis pulvis
DEFINITION
Pan creas powder is prepared from the fresh 01' fl'ozen
pancreases of mammals. 1t contains various enzymes having
proteolytic, lipolytic and amylolytic activities.
1 mg of pancreas powder contains not less than 1.0 Ph. Eur. U.
of total proteolytic activity, 15 Ph. Eur. U. oflipolytie activity Enterokinase so/uNon. Dissolve 50 mg of enterokínase BRP in
and 12 Ph. Eur. U. of amylolytic activity.
PRODUCTION
The animals from whieh pancreas powder is derived must
fulfil the requirements for the health of animals suitable for
human consumption.
CHARACTERS
Appearance: slightly brown, amorphous powder.
So/ubí/ity: partly soluble in water, practically insoluble in
ethanol (96 per cent).
IDENTIFICATION
A. Triturate 0.5 g with 10 mL of water R and adjust to
pH 8 with 0.1 M sadium hydroxide, using 0.1 mL of
cresol red so/ution R as indicator. Divide the suspension
into 2 equal parts (suspension (a) and suspension (b)).
Boil suspension (a). To each suspension add 10 mg of
fíbrin congo red R, heat to 38-40 oC and maintain at this
temperature Íor 1 h. Suspension (a) is colourless or slightly without the addition of enterokinase so as to obtain a known
pink and suspension (b) is distinctly more red.
B. Triturate 0.25 g with 10 mL of water R and adjust to
pH 8 with 0.1 M sodium hydroxide, using 0.1 mL of
cresol red solutíon R as indicator. Divide the suspension
into 2 equal parts (suspension (a) and suspension (b)).
Boil suspension (a). Dissolve 0.1 g of soluble starch R
in 100 mL of boiling water R, boil for 2 min, cool and
dilute to 150 mL with water R. To 75 mL oí the starch
solution add suspension (a) and to the remaining 75 mL
add suspension (b). Heat each mixture to 38-40 oC and
maintain at this temperature for 5 mino
To 1 mL of each mixture add 10 mL of iodíne so/ution R2.
The mixture obtained with suspension (a) has an
intense blue-violet colour; the mixture obtained with
suspension (b) has the colour of the iodine solution.
TESTS
Fa! conten!: maximum 5.0 per cent.
In an extractiol1 apparatus, treat 1.0 g with /ight petro/eum Rl 35 ± 0.5 oc. Place a glass rod in each tube. When temperature
for 3 h. Evaporate the solvent and dry the residue at 100-105 oC equilibrium is reached, add 2.0 mL of the casein solution to
fol' 2 h. The residue weighs a maximum of 50 mg.
Loss on drying (2.2.32): maximum 5.0 per cent, determined
on 0.50 g by drying at 60 oC at a pressure not exceeding 670 Pa
for 4 h.
Microbial contamination
TAMC: acceptance criterion 104 CFU/g (2.6.12).
TYMC: acceptance criterion 10 2 CFU/g (2.6.12).
Absence of Escheríchia co/í (2.6.13).
Absence of Sa/monella (2.6.13).
ASSAY
Total proteolytic activity. The total proteolytic activity of
pancreas powder is determined by comparing the quantity of filtrate, measured at 275 nm using unfiltered triehloroacetic
peptides non-precipitable by a 50 giL solution of trichloroacetic acid solution as the compensation liquid, is les s than 0.04.
Genera/ Notices (1) apply to all monagraphs and other texts
Pan creas powder
acid R released per minute from a substrate of easein solution
with the quantity of sueh peptides released by pancreas powder
(pro tease) BRP from the same substrate in the same conditions.
Casein so/ution. Suspend a quantity of casein BRP equivalent
to 1.25 g of dried substance in 5 mL of water R, add 10 mL
of 0.1 M sodium hydroxide and stir for 1 mino (Determine
the water content of casein BRP prior to the test by heating at
60 oC in vacuo for 4 h.) Add 60 mL of water R and stir with a
magnetic stirrer until the solution is practically cIear. Adjust
to pH 8.0 with 0.1 M sodium hydroxide or 0.1 M hydroch/oríc
acid. Dilute to 100.0 mL with water R. Use the solution on
the day of preparation.
0.02 M ca/cium ch/oríde so/ution R and dilute to 50.0 mL with
the same solvento Use the solution on the day of preparation.
1'0 avoid absorptíon of water formed by condensatíon, allow
the preparatíon to be examined and the reference preparation
fo reach room temperature before opening the containers.
For the test suspension and the reference suspension, prepare
the suspension and carry out the dilutíon at 0-4 oc.
Test suspensíon Triturate 0.100 g of the substance to be
examined for 5 min adding gradually 25 mL of 0.02 M ca/cium
ch/oríde solutíon R. Transfer completely to a volumetric flask
and dilute to 100.0 mL with 0.02 M calcium ch/oríde so/ution R.
To 10.0 mL of this suspension add 10.0 mL of the enterokinase
solution and heat on a water-bath at 35 ± 0.5 oC for 15 mino
Coo! and dilute with borate buffer so/u tia n pH 7.5 R at 5 ± 3 oC
to a final concentration of about 0.065 Ph. Eur. U. of total
proteo!ytic activity per millilitre calculated on the basis of the
stated activity.
Reference suspension. Prepare a suspension of pancreas
powder (protease) BRP as described "eH the test suspension but
final eoncentration of about 0.065 Ph. Eur. U. per millilitre
calculated on the basis of the stated activity.
Designate tubes in duplicate T, TI>' SI' SIl>' S2' S3' S31>;
designate a tube B.
Add borate buffer so/ution pH 7.5 R to the tubes as follows:
B: 3.0 mL,
S¡ and S¡b: 2.0 mL,
S2' T and . 1.0 mL.
Add the reference suspension to the tubes as follows:
S¡ and S¡b: 1.0 mL,
S2 and S2b: 2.0 mL,
S3 and S3b: 3.0 mL.
Add 2.0 mL of the test suspension to tubes T and T b'
Add 5.0 mL of a 50 giL solution of trich/oroacetic acid R to
tubes B, Su" S2b' S31> and T b. Mix by shaking.
Place the tubes and the casein solution in a water-bath at
tubes B, Slb' S2b' S3b and T b· Mix. At time zero, add 2.0 mL of
easein solution successively and at intervals of 30 s to tubes
SI' S2' S3 and T. Mix immediately after each addition. Exactly
30 min after addition of the easein solution, taking into
aceount the regular interval adopted, add 5.0 mL of a 50 giL
solut'Jl1 of trichloroacetic acid R to tubes SI' S2' S3 and T. Mix.
Withdraw the tubes from the water-bath and allow to stand at
room temperature for 20 mino
Filter the contents of each tube twice through the same
suitable filter paper previously washed with a 50 giL solution
of trich/oroacetic acid R, then with water R and dried.
A suitable filter paper complies with the following test: filter
5 mL of a 50 giL solution of trichloroacetic acíd R on a 7 cm
dise of white filter paper; the absorbance (2.2.25) of the
4083
Pancreas powder EUROPEAN PHARMACOPOEIA 8.2

A schematic presentation of the aboye operations is shown Olive oil emulsiono For 10 determinations, mix the following
in Table 0350.-l. solutions in the order indicated: 100 mL of the stock emulsion,
80 mL of tris(hydroxymethyl)aminomethane solution R1,
Table 0350.-1 20 mL of a freshly prepared 80 gIL of sodium taurocholate BRP
and 95 mL of water R. Use on the day of preparation.
Tubes
Apparatus. Use a reaction vessel of about 50 mL capacity
S¡ S¡b S, S'b S3 S3b T Tb B provided with:
Buffer solution 2 2 3 - a device that will maintain a temperature of 37 ± 0.5 oC;
Reference suspension 2 2 3 3 - a magnetic stirrer;
Test suspension 2 2 - a lid with holes for the insertion of electrodes, the tip of
Trichloroacetic acid solution 5 5 5 5 5 a burette, a tube for the admission of nitro gen and the
introduction of reagents.
Mix + + + + +
An automatic or manual titration apparatus may be used.
Water-bath 35 oC + + + + + + + + +
In the latter case, the burette is graduated in 0.005 mL
Casein solution 2 2 2 2 2 and the pH-meter is provided with a wide reading scale
and glass-calomel or glass-silver-silver chloride electrodes.
Mix + + + + +
After each test the reaction vessel is evacuated by suction
Casein solution 2 2 2 2 and washed several times with water R, the washings being
removed each time by suction.
Mix + + + +

+ + + + + +
Water-bath 35 oC 30 min
Trichloroacetic acid solution 5 5 5 5
Mix + + + +
Room temperature + + + + + +
20 min
Filter + + + + + +
Measure the absorbance (2.2.25) of the filtrates at 275 nm
using the filtrate obtained from tube B as the compensation
liquido
Correct the average absorbance values for the filtrates obtained solution. Keep the flask containing the test suspension in iced
from tubes SI' S2 and S3 by subtracting the average values
obtained for the filtrates from tubes S¡b' S2b and S3b respectively. Reference suspension. Prepare a suspension of pan creas powder
Draw a calibration curve of the corrected values against the
volume of reference suspension used.
Determine the activity of the substance to be examined using
the corrected absorbance for the test suspension (T - T b) and
the calibration curve and taking into account the dilution
factors.
The test is not valid unless the corrected absorbance values are
between 0.15 and 0.60.
Lipolytic activity. The lipolytic activity is determined
by comparing the rate at which a suspension of pancreas
powder hydrolyses a substrate of olive oil emulsion with the
rate at which a suspension of pan creas powder (lipase) BRP
hydrolyses the same substrate under the same conditions. The
test is carried out under nitrogen.
Olive oil stock emulsiono In an 800 mL beaker 9 cm in diameter,
place 40 mL of olive oil R, 330 mL of acacia solution R and
30 mL of water R. Place an electric mixer at the bottom of
the beaker. Place the beaker in a vessel containing ethanol
(96 per cent) R and a sufficient quantity of ice as a cooling
mixture. Emulsify using the mixer at an average speed of
1000-2000 r/min. Cool to 5-10 oc. Increase the mixing speed
to 8000 r/min. Mix for 30 min keeping the temperature below
25 oC by the continuous addition of crushed ice into the
cooling mixture. (A mixture of calcium chloride and crushed
ice is also suitable). Store the stock emulsion in a refrigerator
and use within 14 days. The emulsion must not separate into
2 distinct layers. Check the diameter of the globules of the
emulsion under a microscope. At least 90 per cent have a
diameter below 3 ¡..tm and none has a diameter greater than
10 ¡..tm. Shake the emulsion thoroughly before preparing the
emulsion substrate.
+ + +
To avoid absorption of water formed by condensation, allow
the preparation to be examined and the reference preparation
to reach room temperature before opening the containers.
For the test suspension and the reference suspension, prepare
+ + + the suspension and carry out the dilution at 0-4 oc.
Test suspension. In a small mortar cooled to 0-4 oC, triturate
+ + +
carefullya quantity of the substance to be examined equivalent
to about 2500 Ph. Eur. U. of lipolytic activity with 1 mL of
maleate buffer solution pH 7.0 R (lipase solvent) until a very
fine suspension is obtained. Dilute the suspension with
maleate buffer solution pH 7.0 R, transfer quantitatively to
a volumetric flask and dilute to 100.0 mL with the buffer
water during the titration.
(lipase) BRP as described for the test suspension using a
quantity equivalent to about 2500 Ph. Eur. U.
Carry out the titrations immediately after preparation of the
test suspension and the reference suspension. Place 29.5 mL
of olive oil emulsion in the reaction vessel equilibrated at
37 ± 0.5 oc. Fit the vessel with the electrodes, a stirrer and the
burette (the tip being immersed in the olive oil emulsion).
Put the lid in place and switch on the apparatus. Carefully
add 0.1 M sodium hydroxide with stirring to adjust to pH 9.2.
Using a rapid-flow graduated pipette transfer about 0.5 mL of
the previously homogenised reference suspension, start the
chronometer and add continuously 0.1 M sodium hydroxide to
maintain the pH at 9.0. After exactIy 1 min, note the volume
of 0.1 M sodium hydroxide used. Carry out the measurement
a further 4 times. Discard the first reading and determine the
average of the 4 others (S¡). Make 2 further determinations (S2
and S3). Calculate the average of the values SI' S2 and S3. The
average volume of 0.1 M sodium hydroxide used should be
about 0.12 mL per minute with limits ofO.08 mL to 0.16 mL.
Carry out 3 determinations in the same manner for the test
suspension (TI' T2 and T3). If the quantity of 0.1 M sodium
hydroxide used is outside the limits of 0.08 mL to 0.16 mL per
minute, the assay is repeated with a quantity of test suspension
that is more suitable but situated between 0.4 mL and 0.6 mL.
Otherwise the quantity of the substance to be examined is
adjusted to comply with the conditions of the test. Calculate
the average of the values TI' T 2 and T3.
Calculate the activity in European Pharmacopoeia Units per
milligram using the following expression:
n x mI x A
nI x m

4084 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
n average volume of 0.1 M sodium hydroxide used per
minute during the titration of the test suspension,
in millilitres;
11] average volume of 0.1 M sodium hydroxide used
per minute during the titration of the reference
suspension, in millilitres;
m mass of the substance to be examined, in
milligrams;
m] mass of the reference preparation, in milligrams;
A activity of pancreas powder (lipase) BRP, in
European Pharmacopoeia Units per milligram.
Amylolytk activity. The amylolytic activity is determined by
comparing the rate at which a suspension of pancreas powder A
hydrolyses a substrate of starch solution with the rate at which
a suspension of pancreas powder (amylase) BRP hydrolyses
the same substrate under the same conditions.
Starch solution. 1'0 a quantity of starch BRP equivalent to
2.0 g of the dried substance add 10 mL of water R and mix.
(Determine the water content of starch BRP prior to the test
by heating at 120 oC for 4 h). Add this suspension, whilst
stirring continuously, to 160 mL of boiling water R. Wash
the container several times with successive quantities, each
of 10 mL, of water R and add the washings to the hot starch
solution. Heat to boiling, stirring continuously. Cool to room
temperature and dilute to 200 mL with water R. Use the
solution on the day of preparation.
To avoid absorption of water formed by condensation, allow
the preparation to be examined and the reference preparation
to reach room temperature before opening the containers.
For the test suspension and the reference suspension, prepare
the and carry out the di/ution at 0-4 oc.
Test suspension. Triturate a quantity of the substance to be
examined equivalent to about 1500 Ph. Eur. U. of amylolytic
activity with 60 mL of phosphate buffer solution pH 6.8 Rl
for 15 mino Transfer quantitatively to a volumetric flask and
dilute to 100.0 mL with phosphate buffer solution pH 6.8 Rl.
Reference suspension. Prepare a suspension of pancreas powder
BRP as described for the test suspension, using a
quantity equivalent to about 1500 Ph. Eur. U.
In a test-tube 200 mm long and 22 mm in diameter, fitted
with a ground-glass stopper, place 25.0 mL of starch solution, IDENTIFICATION
10.0 mL of phosphate buffer solution pH 6.8 R1 and 1.0 mL
of an 11.7 giL solution of sodium chloride R. Close the tube,
shake and place in a water-bath at 25.0 ± 0.1 De. When the
temperature equilibrium has been reached, add 1.0 mL of the B. Infrared absorption spectrophotometry (2.2.24).
test suspension and start the chronometer. Mix and place
the tube in the water-bath. After exactly 10 min, add 2 mL
of 1 M hydroehloric aeid. Transfer the mixture quantitatively
to a 300 mL conical flask fitted with a ground-glass stopper.
Whilst shaking continuously, add 10.0 mL of 0.05 M iodine
immediately followed by 45 mL of 0.1 M sodium hydroxide.
Allow to stand in the dark at a temperature between 15 oC and
25 oC for 15 mino Add 4 mL of a mixture of 1 volume of sulfuric
acid R and 4 volumes of water R. Titrate the excess of iodine
with 0.1 M sodium thiosulfate using a microburette. Carry out
a blank titration adding the 2 mL of 1 M hydrochloric acid
before introducing the test suspension. Carry out the titration
of the reference suspension in the same manner.
The test is not valid unless both n I_ n and n I]_n] are between
1.9 mL and 3.6 mL.
Calculate the amylolytic activity in European Pharmacopoeia
Units per milligram using the following expression:
(n' -n)m1 A Deteetion: spray with ninhydrin solution R and heat at
( n I - )
1 n1 m,
X 105 oC for 15 mino
General Notices (1) apply lo all monographs and other texts
Phenylalanine
n volume of 0.1 M sodium thiosulfate used in the
titration of the test suspension, in millilitres;
n] volume of 0.1 M sodium thiosulfate used in the
titration of the reference suspension, in millilitres;
ni volume of 0.1 M sodium thiosulfate used in the
blank titration of the test suspension, in millilitres;
ni) volume of 0.1 M sodium thiosulfate used in the
blank titration of the reference suspension, in
millilitres;
m mass of the substance to be examined, in
milligrams;
m] mass of the reference preparation, in milligrams;
activity of pancreas powder (amylase) BRP, in
European Pharmacopoeia Units per milligram.
STORAGE
In an airtight container.
0712014:0782
PHENYLALANINE
Phenylalaninum
C 9H]]N0 2 M r 165.2
[63-91-2]
DEFINITION
(2S)-2- Amino-3-phenylpropanoic aeid.
Fermentation product, extract or hydrolysate of protein.
Content: 98.5 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance: white or almost white, crystalline powder, or
shiny, white flakes.
Solubility: sparingly soluble in water, very slightly soluble in
ethanol (96 per cent). 1t dissolves in dilute mineral aeids and
in dilute solutions of alkali hydroxides.
First identification: A, B.
Second identification: A, C, D.
A. Specific optical rotation (see Tests).
Comparison: phenylalanine CRS.
e. Thin-layer chromatography (2.2.27).
Test solution. Dissolve 10 mg of the substance to be
examined in a mixture of equal volumes of glacial acetic
aeid R and water R and dilute to 50 mL with the same
mixture of solvents.
Reference solution. Dissolve 10 mg of phenylalanine CRS
in a mixture of equal volumes of glacial acetie aeid R and
water R and dilute to 50 mL with the same mixture of
solvents.
Plate: TLC silica gel plate R.
Mobile phase: glacial acetic acid R, water R, butanol R
(20:20:60 V/V/V).
Application: 5 I~L.
Development: over 2/3 of the plateo
Drying: in airo
4085
Phenylalanine
Results: the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size
to the principal spot in the chromatogram obtained with
the reference solution.
D. To about 10 mg add 0.5 g of potassium nitrate R and 2 mL
of sulfuric acid R. Heat on a water-bath for 20 mino Allow
to coo1. Add 5 mL of a 50 giL solution of hydroxylamine
hydrochloride R and allow to stand in iced water for
10 mino Add 9 mL of strong sodium hydroxide solution R.
A violet-red or violet-brown colour develops.
TESTS
Appearance of solution. The solution is clear (2.2.1) and not
more intensely coloured than reference solution BY 6 (2.2.2,
Method II).
Dissolve 0.5 g in a 103 giL solution of hydrochloric acid R and
dilute to 10 mL with the same solution.
Spedfic optkal rotation (2.2.7): - 35.5 to - 33.0 (dried
substance) . Limit:
Dissolve 0.50 g in water R and dilute to 25.0 mL with the same - ammonium at 570 nm: not more than the area of the
solvent.
Ninhydrin-positive substances. Amino acid analysis
(2.2.56). For analysis, use Method 1.
The concentrations of the test solution and the reference
solutions may be adapted according to the sensitivity of the
equipment used. The concentrations of all solutions are
adjusted so that the system suitability requirements described
in general chapter 2.2,46 are fulfilled, keeping the ratios of
concentrations between al! solutions as described.
Solution A: dilute hydrochloric acid Rl or a sample preparation
buffer suitable for the apparatus used.
Test solution. Dissolve 30.0 mg of the substanee to be
examined in solution A and dilute to 50.0 mL with solution A.
Reference solution (a). Dilute l.0 mL of the test solution to
100.0 mL with solution A. Dilute 2.0 mL of this solution to
10.0 mL with solution A.
Reference solution (b). Dissolve 30.0 mg of proline R in
solution A and dilute to 100.0 mL with solution A. Dilute
l.0 mL of the solution to 250.0 mL with solution A.
Reference solution (e). Dilute 6.0 mL of ammonium standard
solution (lOO ppm NH,J R to 50.0 mL with solution A. Dilute
1.0 mL of this solution to 100.0 mL with solution A.
Reference solution (d). Dissolve 30 mg of isoleucine R and
30 mg of leucine R in solution A and dilute to 50.0 mL with
solution A. Dilute 1.0 mL of the solution to 200.0 mL with
solution A.
Blank solution: solution A.
Inject suitable, equal amounts of the test, blank and referenee
solutions into the amino acid analyser. Run a program suitable
for the determination of physiological amino acids.
System suitability: referenee solution (d):
- resolution: minimum 1.5 between the peaks due to
isoleucine and leucine.
Calculation of percentage contents:
- for any ninhydrin-positive substanee deteeted at 570 nm,
use the eoneentration of phenylalanine in referenee
solution (a);
- for any ninhydrin-positive substance detected at 440 nm,
use the eoncentration of proline in reference solution (b) ; if
a peak is aboye the reporting threshold at both wavelengths, A. (2S)-2-amino-4-methylpentanoic acid (leucine),
use the result obtained at 570 nm for quantification.
Limits:
- any ninhydrin-positive substance: for eaeh impurity,
maximum 0.2 per cent;
- total: maximum 0.5 per cent;
4086
EUROPEAN PHARMACOPOEIA 8.2
- reporting threshold: 0.05 per cent.
The thresholds indicated under Related substances
(Table 2034.-1) in the general monograph Substances for
pharmaceutical use (2034) do not apply.
Chlorides (2.4.4): maximum 200 ppm.
Dissolve 0.25 g in 3 mL of dilute nitric acid R and dilute to
15 mL with water R. The solution, without further addition of
nitric acid, complies with the test.
Sulfates (2.4.13): maximum 300 ppm.
Dissolve 0.5 g in a mixture of 5 volumes of dilute hydrochloric
acid R and 25 volumes of distilled water R and dilute to 15 mL
with the same mixture of solvents.
Ammonium. Amino acid analysis (2.2.56) as described in
the test for ninhydrin-positive substanees with the following
modifications.
Injection: test solution, referenee solution (e) and blank
solution.
eorresponding peak in the chromatogram obtained with
referenee solution (e) (0.02 per cent), taking into account
the peak due to ammonium in the ehromatogram obtained
with the blank solution.
Iron (2.4.9) : maximum 10 ppm.
In a separating funnel, dissolve l.0 g in 10 mL of dilute
hydrochloric acid R. Shake with 3 quantities, each of 10 mL, of
methyl isobutyl ketone Rl, shaking for 3 min eaeh time. To the
combined organic layers add 10 mL of water R and shake for
3 mino Use the aqueous layer.
Heavy metals (2.4,8): maximum 10 ppm.
2.0 g complies with test D. Prepare the reference solution
using 2 mL of lead standard solution (lO ppm Pb) R.
Loss on drying (2.2.32) : maximum 0.5 per eent, determined
on 1.000 g by drying in an oven at 105 oc.
Sulfated ash (2.4.14): maximum 0.1 per eent, determined on
1.0 g.
ASSAY
Dissolve 0.100 g in 3 mL of anhydrous formic acid R. Add
30 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric
acid, determining the end-point potentiometrically (2.2.20).
1 mL of 0.1 M perchloric acid is equivalent to 16.52 mg of
C9H ll N0 2 •
STORAGE
Protected from light.
IMPURITIES
Other detectable impurities (the following substances wouid,
if present at a suffieient leve!, be deteeted by one or other of
the tests in the monograph. They are limited by the general
acceptanee eriterion for other/unspecified impurities. It
is therefore not necessary to identify these impurities for
demonstration of complianee. See also 5.10. Control of
impurities in substances for pharmaceutical use): A, B, C, D.
B. (2S)-2-amino-4-(methylsuifanyl)butanoic acid
(methionine),
See the information section on general monographs (caver pages)
EUROPEAN PHARMACOPOEIA 8.2 Phenylalanine

C. (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid
(tyrosine), D. (2S)-2-amino-3-methylbutanoic acid (valine).

General Notices (1) apply to all monographs and other texts 4087
 EUROPEAN PHARMACOPOEIA 8.2

4088 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

Q
Quetiapine fumarate .............................................. ................. 4091

General Notíces (1) apply to all monographs and other texts 4089
 EUROPEAN PHARMACOPOEIA 8.2

4090 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 Quetiapine fumarate

07/2014:2541 - mobile phase B: acetonitrile R;

Time Mobile phase A Mobile phase B
(min)
QUETIAPINE FUMARATE (per cent V/V) (per cent V/V)
0-8 80 20

8 - 14.50 80 -¿ 60 20 -¿ 40
Quetiapini fumaras
14.50 - 22.60 60 -¿ 50 40 -¿ 50

22.60 - 26 50 -¿ 30 50 -¿ 70
~ rN~o~OH
'" N.J
QNÓ s ::7 \
26 - 29

29 - 30

Flow rate: 0.5 mUmin.

30 -¿ 10

10
70 -¿ 90

90

""--- Detection: spectrophotometer at 240 nm.

C 46 H S4N 6 0 gS2 M,883
[111974-72-2J
DEFINITION
Bis[2- [2- [4-( dibenzo [bJl [1,4Jthiazepin-ll-yl)piperazin-l-
ylJethoxyJ ethanolJ (2E)-but -2-enedioate.
Content:
- quetiapine fumarate (C46Hs4N60SS2; M r 883): 99.0 per cent
to 101.0 per cent (dried substance);
- fumaric acid (C 4H 4 0 4 ; M, 116.1): 12.5 per cent to 13.8 per
cent (dried substance).
CHARACTERS
Appearance: white or almost white powder.
Solubility: slightly soluble in water, in anhydrous ethanol and
in methanol.
It shows polymorphism (5.9).
IDENTIFICATION
Infrared absorption spt:crror)!1()wmeu (2.2.24).
Comparison: quetiapine fumarate CRS.
lf the spectra obtained in the solid state show differences,
dissolve the substance to be examined and the reference
substance separately in methanol R, evaporate to dryness and
record new spectra using the residues.
TESTS
Related substances. Liquid chromatography (2.2.29).
Solvent mixture: acetonitrile R, water R (50:50 V/V).
Test solution. Dissolve 50 mg of the substance to be examined
in the solvent mixture and dilute to 25.0 mL with the solvent
mixture.
Rejerence solution (a). Dissolve the contents of a vial of
quetiapine jor system suitability CRS (containing impurities G
and N) in 1.0 mL of the solvent mixture.
Reference solution (b). Dilute 1.0 mL ofthe test solution to
100.0 mL with the solvent mixture. Dilute 1.0 mL of this
solution to 10.0 mL with the solvent mixture.
Column:
- size: 1= 0.10 m, 0 = 2.1 mm;
- stationary phase: end-capped phenylsilyl siliea gel for
chromatography R (1.7 ¡.un);
- tempera tu re: 50 oc.
Mobile phase:
- mobile phase A: mix 10 volumes of methanol R and
90 volumes of a 3.85 giL solution of ammonium acetate R,
previously adjusted to pH 9.0 with ammonia R;
Injection: 3.0 flL.
Identification of impurities: use the chromatogram
supplied with quetiapine for system suitability CRS and the
chromatogram obtained with reference solution (a) to identify
the peaks due to impurities G and N.
Relative retention with reference to quetiapine (retention
time = about 13 min) : fumaric acid = about 0.05;
impurity G = about 0.5; impurity N = about 1.04.
System suitability:
- signal-to-noise ratio: minimum 40 for the principal peak in
the chromatogram obtained with reference solution (b);
- peak-to-valley ratio: minimum 5.0, where H p = height
above the baseline of the peak due to impurity N and
H" = height above the baseline of the lowest point of the
curve separating this peak from the peak due to quetiapine
in the chromatogram obtained with reference solution (a).
Calculation oj percentage contents:
- correction jaetors: multiply the peak are as of the following
impurities by the corresponding correction factor:
impurity G = 0.5; impurity N = 2.0;
- for each impurity, use the concentration of quetiapine in
reference solution (b).
Limits:
- impurities G, N: for each impurity, maximum 0.15 per cent;
- unspecified impurities: for each impurity, maximum
0.10 per cent;
- total: maximum 0.5 per cent;
- reporting threshold: 0.05 per cent; disregard any peak due
to fumaric acid.
Heavy metals (2.4.8): maximum 10 ppm.
Solvent mixture: methanol R, water R (50:50 V/V).
0.25 g complies with test H. Prepare the reference solution
using 0.25 mL of lead standard solution (lO ppm Pb) R.
Loss 011 drying (2.2.32): maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 105 oc.
Sulfaíed ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Quetiapine fumarate. Dissolve 0.170 g in 40 mL of anhydrous
acetic acid R. Titrate with 0.1 M perchlorie acid, determining
the end-point potentiometrically (2.2.20).
1 mL of 0.1 M perchloric acid is equivalent to 22.08 mg of
C46Hs4N60SS2·
Fumaric add. Dissolve 0.350 g in 70 mL of a mixture of equal
volumes of methanol R and water R. Titrate with 0.1 M sodium
hydroxide, determining the end-point potentiometrically
(2.2.20).
1 mL of 0.1 M sodium hydroxide is equivalent to 5.804 mg
ofC,¡H 40 4 ·
STORAGE
Protected from light.

General Notíces (1) apply to all monographs and other texts 4091
Quetiapine fumarate EUROPEAN PHARMACOPOEIA 8.2

IMPURITIES
Specified impurities: G, N.
Other detectable impurities (the following substances would,
if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterio n for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical F. [2- [(2-aminophenyl)sulfanyl]phenyl] [4- [2-(2-
use (2034). It is therefore not necessary to identify these hydroxyethoxy) ethyl] piperazin -1-yl] methanone,
impurities for demonstration of compliance. See also 5.10.
Control of impurities in substances for pharmaceutical use): A,
~C~EBRLl~L~EQ~IU~W

G. dibenzo[bJ] [1,4]thiazepin-11(10H)-one,
o
~ r~~O~OH

A. 2-[2- [4-(dibenzo[bJ] [1,4]thiazepin-11-yl)piperazin-1-

Q-¿)N""N~ S f'" ~
yl] ethoxy] ethyl acetate, ""-

H. 2- [2- [4-( dibenzo[bJ] [1,4]thiazepin-11-yl)-1-

oxidopiperazin -1-yl] ethoxy] ethanol,
~ rN~OH

Q-¿)N""N~ S f'" ~
B. 1l-(piperazin-1-yl)dibenzo[bJ] [l,4]thiazepine, ""-

1. 2- [4-(dibenzo[bJ] [1,4]thiazepin-11-yl)piperazin-1-
yl]ethanol,
~ rN~O~O~O~OH

Q-¿)N""N~ S f'" ~
""-

J. 2- [2- [2- [2- [4-(dibenzo[bJ] [1,4]thiazepin-11-yl)piperazin-

C. 2-[2-[4-( dibenzo[bJ] [1,4]thiazepin-11-yl)piperazin- 1-yl] ethoxy] ethoxy] ethoxy] ethanol,
1-yl]ethoxy]ethyl 2- [4-(dibenzo[bJ] [l,4]thiazepin-ll-
O rN~O~OH
yl)piperazin -1-yl] acetate,
HC)lNH úON~
3

~S~I
U ~
K. N- [2- [[2- [[ 4- [2-(2-hydroxyethoxy)ethyl]piperazin -1-
yl]carbonyl] phenyl] sulfanyl]phenyl] acetamide,

A-¿)NO~O~OH
D. 11,11' -(piperazine-1,4-diyl)bis( dibenzo-
V<""f'" S ~
[bJ] [l,4]thiazepine), ""-

L. 2-[2-[4-(9-chlorodibenzo[bJ] [1,4]thiazepin-11-
yl)piperazin -l-yl] ethoxy] ethanol,

rN~O~Nl
N"" N~
Q-¿)
~ j
~N~ o~OH
S f'" ~
""-

N. 2-[2-[4-[2-[2-[4-(dibenzo[bJ] [l,4]thiazepin-
E. 11,11'- [ethylenebis( oxyethylenepiperazine-4, 1- 11-yl)piperazin-1-yl]ethoxy]ethyl]piperazin-1-
diyl)]bis(dibenzo[bJ] [l,4]thiazepine), yl] ethoxy] ethanol,

4092 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2 Quetiapine fumarate

T. 11-(morpholin-4-yl)dibenzo[bJ] [l,4]thiazepine,

O. 11- [4- [2- [2-(triphenylmethoxy)ethoxy]ethyl]piperazin-1-

yl]dibenzo[bJ] [1,4]thiazepine,
rN~CH3
N NJ
Qú
'" /¡
S
'"
,f" ~
U. dibenzo[bJ] [1,4]thiazepin-ll-amine,

""--

P. 11-( 4-ethylpiperazin-1-yl)dibenzo[bJ] [lA]thiazepine,

O~OH

r¿~O~O"
0_

Q_N NJ
S
"ú,
,f" ~
V. 2- [2- [4-(phenanthridin-6-yl)piperazin-1-
yl]ethoxy] ethanol,

""--

Q. 4-( dibenzo[bJ] [1,4]thiazepin-11-yl)-1, l-bis[2-(2-

hydroxyethoxy) ethyl] piperazin -1-ium,

Q N NJ
'" /¡
liS

o
o
'"
,f"
""--
rN~O~OH

~
W. 11-(4- [2- [2-( dibenzo[ bJ] [1 A]thiazepin-ll-
S. 2-[2- [4-(S-oxidodibenzo[bJ] [lA]thiazepin-l1- yloxy)ethoxy] ethyl]piperazin -1-yl)dibenzo-
yl)piperazin-l-yl]ethoxy]ethanol, [bd] [1,4]thiazepine.

General Natices (1) apply ta all managraphs and ather texts 4093
 EUROPEAN PHARMACOPOElA 8.2

4094 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2

R
Rifamycin sodium ................................................................... 4097

General Notices (1) apply to all monographs and other texts 4095
 EUROPEAN PHARMACOPOEIA 8.2

4096 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2
0712014:0432
RIFAMYCIN SODIUM
Rifamycinum natricum
C37H46NNaOl2 M r 720 Reference so/ution (b). Dissolve 25 mg of the substance to be
[14897-39-3]
DEFINITION
Sodium (25,122, 14E,165, 175, 18R, 19 R,20R,21 5,22R,235,24E)-
2l-(acetyloxy)-6,9, 17, 19-tetrahydroxy-23-methoxy-
2,4,12, 16,18,20,22-heptamethyl-l, 11-dioxo-1,2-dihydro-2,7-
(epoxypentadeca[ 1, 11,13]trienimino )naphtho[2,1-b ]furan-
5-olate.
Monosodium salt of rifamycin Sv, obtained by chemical
transformation of rifamycin B, which is produced during
the growth of certain strains of Amyco/atopsis mediterranei.
Rifamycin SV may also be obtained directly from certain
A. mediterranei mutants.
Potency: mínimum 900 IU/mg (anhydrous substanee).
PRODUCTION
It is produced by methods of manufacture designed to
minimise or eliminate substances lowering blood pressure.
The manufacturing process is validated to demonstrate that
the product, if tested, would eomply with the following test.
Abnormal toxidty (2.6.9). Inject into eaeh mouse 4 mg
dissolved in 0.5 mL of water for injections R.
CHARACTERS
Appearance: fine or slightly granular, red powder.
So/ubility: soluble in water, freely soluble in anhydrous
ethanol.
IDENTIFICATION
A. Infrared absorptíon spectrophotometry (2.2.24).
Preparation: dises of potassium bromide R.
Comparison: rifamycin sodium CRS.
B. Suspend 70 mg of the substance to be examined in 0.5 mL
of water R. Add 1.5 mL of methoxypheny/acetic reagent R
to obtain a clear red solution. Cool in ice-water for
30 mino A precipitate is formed. Place in water at 20 oC
and stir fOI 5 mino The precipitate does 110t disappear.
Add 1 mL of dilute ammonia Rl. The precipitate dissolves
completely. Add 1 mL of ammonium carbonate solution R.
No precipitate is formed.
TESTS
pH (2.2.3): 6.5 to 8.0.
Dissolve 0.5 g in carbon dioxide-free water R and dilute to
10 mL with the same solvent.
Absorbance (2.2.25). Dissolve 20.0 mg in 5 mL of methano/ R
and dilute to 100.0 mL with freshly prepared phosphate buffer
so/ution pH 7.0 Rl to which 1 giL of ascorbic acid R has
been added immediately before use. Dilute 5.0 mL of this
solution to 50.0 mL with the same phosphate buffer solution
containing ascorbic acid. Allow to stand for 30 mino The
Genera/ Notices (1) app/y to al! monographs and other texts
Rifamycin sodium
solution shows an absorption maximum at 445 nm. The
specific absorbance at this absorption maximum is 190 to 210
(anhydrous substance).
Related substances. Liquid chromatography (2.2.29). Prepare
the so/utions immediate/y before use.
So/vent mixture. Mix 50 volumes of acetonitrile R and
50 volumes of a 3.9 giL solution of sodium dihydrogen
phosphate R previously adjusted to pH 3.0 with phosphoric
acid R.
Test so/ution. Dissolve 50.0 mg of the substance to be
examined in the solvent mixture and dilute to 50.0 mL with
the solvent mixture.
Reference so/ution (a). Dissolve 10.0 mg of rifamycin B CRS
(impurity A) and 40.0 mg of rifamycin S CR5 (impurity B) in
the solvent mixture and dilute to 200.0 mL with the solvent
mixture. Dilute 5.0 mL of this solution to 50.0 mL with the
solvent mixture.
examined and 8 mg of rifamycin 5 CRS in the solvent mixture
and dilute to 250.0 mL with the solvent mixture.
Column:
- size: l = 0.25 m, 0 = 4.6 mm;
- stationary phase: octadecylsily/ si/ica gel for
chromatography R (5 !-un).
Mobile phase:
- mobi/e phase A: mix 10 volumes of acetonitrile R and
90 volumes of a 3.9 giL solution of sodium dihydrogen
phosphate R adjusted to pH 7.5 with dílute sodium
hydroxide so/ution R;
- mabi/e phase B: mix 30 volumes of a 3.9 giL solution of
sodium dihydrogen phosphate R adjusted to pH 7.5 with
di/ute sodium hydroxide salution R and 70 volumes of
acetonitrile R;
- temperature: minimum 20 oC;
Time Mobile ph.ase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0-40 80 -7 20 20 -7 80
40 - 45 20 80
45 - 47 20 -7 80 80 -7 20
Flow rate: 1 mL!min.
Deteetion: spectrophotometer at 254 nm.
Injeetion: 20 flL.
E/ution order: impurity A, rifamycin SV, impurity B.
System suitabi/ity: reference solution (b):
- reso/ution: minimum 5.0 between the peaks due to
rifamycin SV and impurity B.
Limits:
- impurity B: not more than the area of the corresponding
peak in the chromatogram obtained with reference
solution (a) (2 per cent);
- impurity A: not more than the are a of the corresponding
peak in the chromatogram obtained with reference
solution (a) (0.5 per cent);
- sum of impurities other than A and B: not more than the
area of the peak due to impurity B in the chromatogram
obtained with reference solution (a) (2 per cent);
- disregard limit: 0.05 times the are a of the peak due to
impurity B in the chromatogram obtained with reference
solution (a) (0.1 per cent).
Heavy metals (2.4.8): maximum 10 ppm.
2.0 g complies with test C. Prepare the reference solution using
2 mL of lead standard so/utian (la ppm Pb) R.
Water (2.5.12): 12.0 per cent to 17.0 per cent, determined on
0.200 g.
4097
Rifamydn sodium EUROPEAN PHARMACOPOEIA 8.2

Bacterial endotoxins (2.6.14): less than 0.50 IU/mg, if

intended for use in the manufacture of parenteral preparations
without a further appropriate procedure for removal of
bacterial endotoxins.
ASSAY
Carry out the microbiological assay of antibiotics (2.7.2).
STORAGE
In an airtight container, protected from light at a temperature
of 2 oC to 8 oc. lf the substance is sterile, sto re in a sterile,
airtight, tamper-proof container. and epimer al C*

IMPURITIES
Specified impurities: A, B. B. rifamycin S,
Other detectable impurities (the following substances would,
if present at a sufficient leve!, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterio n for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical
use (2034). 1t is therefore not necessary to identify these
impurities for demonstration of compliance. See also 5.10.
Control of impurities in substances for pharmaceutical use): C. ''---+--0
o
'" <?H3
.
l

and epimer at C*
H

A. rifamycin B, C. rifamycin O.

4098 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2

s
Selegiline hydrochloride ........................................................ 4101

General Notices (1) apply to all monographs and other texts 4099
 EUROPEAN PHARMACOPOEIA 8.2

4100 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
07/2014:1260
SELEGILINE HYDROCHLORIDE
Selegilini hydrochloridum
CJ3H 1SCIN M,223.7
[14611-52-0]
DEFINITION
N- Methyl- N- [( lR)-I-methyl-2-phenylethyl]prop-2-yn-l-
amine hydrochloride.
Content: 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance: white or almost white, crystalline powder.
Solubility: freely soluble in water and in methanol, slightly
soluble in acetone and in ethyl acetate.
mp: about 143 oc.
IDENTIFICATION
Carry out either tests A, B, D ol' tests B, C, D.
A. Speciflc optical rotation (2.2.7): - 12.0 to - 10.0 (drieJ
substance) .
Dissolve 2.00 g in earbon dioxide-free water R and dilute to
20.0 mL with the same solvent.
B. Infrared absorption spectrophotometry (2.224).
Comparison: selegiline hydrochloride CRS.
C. Enantiomeric purity (see Tests).
D. It gives l'eaction (a) of chlorides
TESTS
pH (2.2.3): 3.5 to 4.5.
Dissolve 0.20 g in carbon dioxide-free water R and dilute to
10 mL with the same solvent.
Enantiomeric purity. Liquid chromatography (2.2.29).
Test so/ution. Dissolve 20.0 mg of the substance to be
examined in a mixture of 10 flL of butylamine R and 1 mL of
2-propanol R and dHute to 10.0 mL with the mobile phase.
Reference solution (a). Dissolve 8.0 mg of (RS)-selegiline
hydrochloride CRS in a mixture of 10 IlL oE butylamine R and
1 mL of 2-propanol R and dilute to 10.0 mL with the mobile
phase.
Referenee solution (b). Dilute 0.5 mL of reference solution (a)
to 20.0 mL with the mobile phase.
Column:
- size: 1= 0.25 m, (3 = 4.6 mm;
- stationary phase: eellulose derivative of siliea gel for ehiral
separation R.
Mobile phase: 2-propanol R, eyclohexane R (0.2:99.8 V/V).
Flow rate: 1 mL/min.
Deteetion: spectrophotometer at 220 11m.
Injeetion: 20 flL.
Relative retention with reference to (R)-selegiline (retention
time = about 6 min): impurity E = about 0.9.
System suitability: reference solution (a):
- resolution: minimum 1.5 between the peaks due to
impurity E and (R)-selegiline; if necessary, adjust the
concentration of 2-propanol in the mobile phase.
Limit:
- impurity E: not more than the are a of the corresponding
peak in the chromatogram obtained with reference
solution (b) (0.5 per cent).
General Notices (1) apply to all monographs and other texts
Selegiline hydrochloride
Related substances. Liquid chromatography (2.2.29).
Butylammonium acetate buffer solution. Dilute 4 mL of
buty/amine R in 900 mL of water R, adjust to pH 6.5 with
acetic aeid R and dilute to 1000.0 mL with water R.
Test solution. Dissolve 20 mg of the substance to be examined
in the mobile phase and dilute to 10.0 mL with the mobile
phase.
Reference so/ution (aJ. Dissolve 50 mg of the substance to be
examined and 10 mg of butyl parahydroxybenzoate R in the
mobile phase alld dilute to 50.0 mL with the mobile phase.
Dilute 1.0 mL of the solution to 20.0 mL with the mobile phase.
Referenee solution (b). Dilute 1.0 mL of the test solution to
100.0 mL with the mobile phase. Dilute 1.0 mL of this solution
to 10.0 mL with the mobile phase.
Column:
- size: 1 = 0.25 m, (3 = 4.6 mm;
- stationary phase: end-eapped octylsilyl siliea gel for
chromatography R (5 flm).
Mobile phase: acetonitrile R1, butylammonium acetate buffer
solution (50:50 V/V).
Flow rate: 1 mLlmin.
Deteetion: spectrophotometer at 215 11m.
Injeetion: 20 flL.
Run time: 1.7 times the retention time of selegiline.
Relative retention with reference to selegiline (retention
time = about 14min): butyl parahydroxybenzoate = about 0.8.
System suitability: reference solution (a):
- resolution: minimum 3.0 between the peaks due to butyl
parahydroxybenzoate and selegiline.
Limits:
- unspecified impurities: for each impurity, not more than the
area of the principal peak in the chromatogram obtained
with reference solution (b) (0.10 per cent);
- total: not more than 5 times the area of the principal peak
in the chromatogram obtained with reference solution (b)
(0.5 per cent);
- disregard limit: 0.5 times the area of the principal peak in
the chromatogram obtained with reference solution (b)
(0.05 per cent).
Heavy melals (2.4.8): maximum 20 ppm.
Dissolve 2.0 g in water R and dilute to 20 mL with the same
solvent. 12 mL of the solution complies with test A. Prepare
the reference solution using lead standard solution (2 ppm
Pb) R.
Loss on drying (2.2.32): maximum 0.5 per cent, determined
on 1.000 g by drying at 60 oC at a pressure not exceeding
0.5 kPa fOI 3 h.
Sulfaied ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Dissolve 0.180 g in 50 mL of acetie anhydride R. Titrate
with 0.1 M perehlorie aeid, determining the end-point
potentiometl'ically (2.2.20).
1 mL of 0.1 M perchlorie aeid is equivalent to 22.37 mg
of C 13 H 1S ClN.
STORAGE
Protected from light.
IMPURITIES
Speeified impurities: E.
Other detectable impurities (the following substances would,
if present at a sufflcient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecifled impurities al1d/or
by the general monograph Substances for pharmaceutical use
4101
Selegiline hydrochloride EUROPEAN PHARMACOPOEIA 8.2

(2034). It is therefore not necessary to identify these impurities

for demonstration of compliance. See also 5.10. Controlof
impurities in substances for pharmaceutical use): A, B, C, D, G.
H
~ N 'CH 3 and enantiomer
D. N- [(lR)-1-methyl-2-phenylethyl]prop-2-yn-l-amine
V H' CH 3
(desmethylselegiline),
CH 3
/~JCH
()?
A. (2RS)-N-methyl-l-phenylpropan-2-amine
((RS)- metamfetamine),
~
I ,,\ H CH 3
~NH2
V H"CH 3
E. N-methyl-N- [(lS)-1-methyl-2-phenylethyl]prop-2-yn-1-
amine,
B. (2R)-1-phenylpropan-2-amine (amfetamine),

~
H .. OHNH
/' I /\ 2 and enantiomer and enantiomer
~ H CH 3

C. (lRS,2SR)-2-amino-l-phenylpropan-l-ol G. (2EZ)-3-chloro-N-methyl-N- [( 1RS)-1-methyl-2-

(phenylpropanolamine) , phenylethyl] prop-2-en -l-amine.

4102 See the informatíon section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2

T
Tyrosine ................................................................................... 4105

General Notices (1) apply to all monographs and other texts 4103
 EUROPEAN PHARMACOPOEIA 8.2

4104 See the information section on general monographs (cover pages)

 EUROPEAN PHARMACOPOEIA 8.2
0712014:1161
TYROSINE
Tyrosinum
C9 H 11 N0 3 M,181.2 adjusted so that the system suitability requirements described
[60-18-4]
DEFINITION
(2S)- 2-Amino- 3- (4-hydroxyphenyl)propanoic add.
Fermentation product, extraet or hydrolysate of protein.
Content: 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance: white or almost white, crystalline powder or
colourless crystals.
Solubility: very slightly soluble in water, practically insoluble solution A. Dilute 1.0 mL of the solution to 250.0 mL with
in ethanol (96 per cent). It dissolves in dilute mineral acids
and in dilute solutions of alkali hydroxides.
IDENTIFICATION
First identification: A, B.
Second identification : A, C, D, E.
A. Specific optical rotation (see Tests).
B. Infrared absorption spectrop;10tometry (2.2.24).
lliiI
Comparison: CRS.
C. Thin-layer chromatography (2.2.27).
Test solution. Dissolve 10 mg of the substance to be
examined in 1 mL of dilule ammonia R2 and dilute to
50 mL with water R.
Reference so/ution. Dissolve 10 mg of tyrosine CRS in 1 mL
of dilute ammonia R2 and dilute to 50 mL with water R.
Plate: TLC silica gel plate R.
lVIobile phase: concentrated ammonia Rl, propanol R
(30:70 V/V).
Application: 5 1lL.
Development: over 2/3 of the plateo
Drying: in airo
Deteetion: spray with ninhydrin solution R and heat at
105 oC for 15 mino
Results: the principal spot in the ehromatogram obtained
with the test solution is similar in position, eolour and size
to the principal spot in the chromatogram obtained with
the referenee solution.
D. To about 50 mg add 1 mL of dilute nitric aeid R. A dark red - any ninhydrin-positive substance: for each impurity,
colour is produeed within 15 mino
E. Dissolve about 30 mg in 2 mL of dilute sodium hydroxide
solution R. Add 3 mL of a freshly prepared mixture of
equal volumes of a 100 giL solution of sodium nitrite R
and a solution of 0.5 g of sulfanilic acid R in a mixture of
6 mL of hydrochloric acid Rl and 94 mL of water R. An
orange-red eolour is produeed.
TESTS
Appearance of solution. The solution is clear (2.2,1) and not 15 mL with water R. The solution, without further addition of
more intensely coloured than referenee solution Y7 (2.2.2,
Method II).
Dissolve 0.5 g in dilute hydrochloric acid R and dilute to 20 mL Dissolve, with gentle heating, 0.5 g in 5 mL of dilute
with the same acid.
General Notiees (1) apply to all monographs and other texts
Tyrosine
Spedfic optical rotation (2.2.7): - 12.3 to - ll.O (dried
substance).
Dissolve 1.25 g in a mixture of equal volumes of dilute
hydrochlorie acid R and water R and dilute to 25.0 mL with
the same mixture of solvents.
Ninhyddn-positive substances. Amino acid analysis
(2.2.56). For analysis, use Method l.
The coneentrations of the test solution and the reference
solutions may be adapted according to the sensitivity of the
equipment used. The eoneentrations of al! solutions are
in general ehapter 2.2.46 are fulfilled, keeping the ratios of
eoneentrations between al! solutions as deseribed.
Solution A: dilute hydroehloric acid Rl or a sample preparation
buffer suitable for the apparatus used.
Test solution. Dissolve 30.0 mg of the substance to be
examined in solution A and dilute to 50.0 mL with solution A.
Reference solutian (a). Dilute 1.0 mL ofthe test solution to
100,0 mL with solution A. Dilute 2.0 mL of this solution to
10.0 mL with solution A.
Reference solution (b). Dissolve 30.0 mg of phenylalanine R
(impurity A) in solution A and dilute to 100.0 mL with
solution A.
Reference solution (e). Dissolve 30.0 mg of proline R in
solution A and dilute to 100.0 mL with solution A. Dilute
1.0 mL of the solution to 250.0 mL with solution A.
Reference solution (d). Dilute 6.0 mL of ammonium standard
solution (lOO ppm NHJ R to 50,0 mL with solution A. Dilute
1.0 mL of this solution to 100.0 mL with solution A.
Reference solution (e). Dissolve 30 mg of isoleucine R and
30 mg of leueine R in solution A and dilute to 50.0 mL with
solution A. Dilute 1.0 mL of the solution to 200.0 mL with
solution A.
Blank solution: solution A.
Inject suitable, equal amounts of the test, blank and referenee
solutions into the muino acid analyser. Run a program suitable
for the determination of physiological amino acids.
System suitability: reference solutiol1
- resolution: minimum 1.5 between the peaks due to
isoleucine and leucine.
Calculation of percentage contents:
- for impurity A, use the eoncentration of impurity A in
reference solution (b);
- for any ninhydrin-positive substanee detected at 570 nm,
use the coneentration of tyrosine in referenee solutiol1 (a);
- for any ninhydrin-positive substance detected at 440 nm,
use the coneentratiol1 of proline in referenee solution (e); if
a peak is aboye the reporting threshold at both wavelengths,
use the result obtained at 570 nm for quantification.
LimUs:
- impurity A at 570 nm: maximum 0.5 per eent;
maximum 0.2 per cent;
- total: maximum 0.6 per eent;
- reporting threshold: 0.05 per eent.
The thresholds indieated under Related substanees
(Table 2034.-1) in the general monograph Substances for
pharmaceutical use (2034) do not apply.
Chlorides (2.4.4): maximum 200 ppm.
Dissolve 0.25 g in 3 mL of dilute nitric aeid R and dilute to
nitric acid, eomplies with the test.
Sulfates (2.4.13): maximum 300 ppm.
hydrochloric acid R and dilute to 15 mL with distilled water R.
4105
Tyrosine EUROPEAN PHARMACOPOEIA 8.2

Ammonium. Amino acid analysis (2.2.56) as described in
the test for ninhydrin-positive substances with the following
modifications.
Injection: test solution, reference solution (d) and blank
solution.
Limit:
- ammonium at 570 nm: not more than the area of the
corresponding peak in the chromatogram obtained with
reference solution (d) (0.02 per cent), taking into account
the peak due to ammonium in the chromatogram obtained
with the blank solution.
Iron (2.4.9): maximum 10 ppm.
In a separating funnel, dissolve 1.0 g in 10 mL of dilute
hydrochloric acid R. Shake with 3 quantities, each of 10 mL, of impurities in substances Íor pharmaceutical use): B, C.
methyl isobutyl ketone R1, shaking for 3 min each time. To the
combined organic layers add 10 mL of water R and shake for
3 mino Use the aqueous layer.
1 mL of 0.1 M perchloric acid is equivalent to 18.12 mg of
C9H ll N0 3 •
STORAGE
Protected from light.
IMPURITIES
Specified impurities: A.
Other detectable impurities (the following substances would,
if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities. It
is therefore not necessary to identify these impurities for
demonstration of compliance. See also 5.10. Control oÍ
o~C02HH.,'NH 2

Heavy metal s (2.4.8): maximum 10 ppm.

A. (2S)-2-amino-3-phenylpropanoic acid (phenylalanine),
0.5 g complíes with test G. Prepare the reference solution
using 0.5 mL of lead standard solution (la ppm Pb) R. ¡; NH 2

Loss on drying (2.2.32): maximum 0.5 per cent, determined H2N~C02H

on 1.000 g by drying in an oven at 105 oc.
B. (2S)-2,6-diaminohexanoic acid (lysine),
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.

ASSAY
Dissolve 0.150 g in 5 mL oí anhydrous Íormic acid R. Add
30 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric C. 3,3'-disulfanediylbis((2R)-2-aminopropanoic acid]
acid, determining the end-point potentiometrically (2.2.20). (cystine).

4106 See the inÍormation section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2

v
Valaciclovir hydrochloride, hydrated ... ,..................... "",."., 4109 Vardenafil hydrochloride trihydrate ......... " ..... " ........ " ......... 4111

General Notices (1) apply to all monographs and other texts 4107
 EUROPEAN PHARMACOPOEIA 8.2

4108 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2
0712014:2751
VALACICLOVIR HYDROCHLORIDE,
HYDRATED
Valacidoviri hydrochloridum hydricum
DEFIN1TION
2- [(2-Amino-6-oxo-1 ,6-dihydro-9H-purin -9-yl)methoxy]-
ethyl L-valinate hydroehloride.
Content: 95.0 per cent to 102.0 per cent (anhydrous substance).
1t contains a variable quantity of water.
CHARACTERS
Appearance: white or almost white powder, hygroscopic.
Solubility: freely soluble in water, very slightly soluble in
anhydrous ethanol, practically insoluble in acetonitrile.
It shows polymorphism (5.9).
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24).
Preparation: dissolve the substance to be examined in the
minimum volume of water R, evaporate to dryness at room
temperature and record the spectrum using the residue.
Comparison: repeat the operations using anhydrous
valaciclovir hydrochloride CRS.
B. It complies with the limit for impurity R (see test A for
related substances).
e. Water (see Tests).
D. It gives reaction (a) of ehlorides (2.3.1).
TESTS
Impurities G and S. Thin-layer chromatography (2.2.27).
Test solution. Dissolve 0.250 g of the substanee to be examined
in 2 mL of water R and dilute to 5.0 mL with ethanol (96 per
cent) R.
Reference solution. Dissolve 5.0 mg of valaciclovir
impurity G CRS and 5.0 mg of valaciclovír impurity S CRS in a
mixture of 2 mL of water R and 6 mL of ethanol (96 per cent) R
and dilute to 10.0 mL with ethanol (96 per cent) R. Dilute
0.5 mL of the solution to 10.0 mL with ethanol (96 per cent) R.
Plate: TLC sílica gel F254 plate R (2-10 11m).
Pretreatment: wash the plate with methanol R until the solvent
front has migrated over at least 4/5 oí the plate; allow to dry
in airo
Mobile phase: concentrated ammonia R, tetrahydrofuran R,
methanol R, methylene chloride R (3:12:34:54 V/V/V/V); use
freshly prepared mobile phase.
Applieation: 4 1lL.
Development: over 4/5 of the plateo
Drying: in a current of airo
Deteetion: examine in ultraviolet light at 254 nm.
Retardation factors: valaeiclovir = about 0.3;
impurity S = about 0.7; impurity G = about 0.8.
System suitability: the chromatogram obtained with the
referenee solution shows 2 clearly separated spots due to
impurities S and G.
General Notices (1) apply to all monographs and other texts
Valaddovir hydrochloride, hydrated
Limits:
- impurity G: any spot due to impurity G is not more intense
than the corresponding spot in the ehromatogram obtained
with the referenee solution (0.05 per cent);
- impurity S: any spot due to impurity S is not more intense
than the eorresponding spot in the ehromatogram obtained
with the referenee solution (0.05 per eent).
Related substances
A. Liquid ehromatography (2.2.29): use the normalisation
proeedure.
Test solution. Dissolve 50.0 mg of the substanee to be
examined in a 0.5 per cent V/V solution of hydrochloric
acid R and dilute to 100.0 mL with the same solution.
Referenee solution (a). Dissolve 2.5 mg of valaciclovir for
system suitability CRS (eontaining impurities A, B, C, D,
H, M and R) in a 0.5 per eent V/V solution of hydrochlorie
acid R and dilute to 5.0 mL with the same solution.
Reference solution (b). Dissolve 50.0 mg of anhydrous
valaciclovir hydrochloride CRS in a 0.5 per eent V/V
solution of hydroehlorie aeid R and dilute to 100.0 mL with
the same solution.
Referenee solution (e). Dilute 3.0 mL ofthe test solution to
100.0 mL with a 0.5 per cent V/V solution of hydroehloric
aeid R. Dilute 1.0 mL of this solution to 100.0 mL with a
0.5 per cent V/V solution of hydrochloric acid R.
Column:
- size: 1= 0.15 m, 0 = 4.0 mm;
- stationary phase: crown-ether silica gel for
chromatography R (5 11m);
- temperature: 10 De.
Mobile phase: perchloric acid R, methanol R, water R
(0.5:5:95 V/V/V).
Flow rate: 0.75 mL/min.
Deteetion: speetrophotometer at 254 nm.
Injection: 10 IlL of the test solution and referenee
solutions (a) and (e).
Run time: 1.5 times the retention time of valacidovir.
Identification of impurities: use the chromatogram
supplied with valaciclovir for system suitability CRS and
the ehromatogram obtained with referenee solution (a) to
identify the peaks due to impurities A + B, C + R, D and M.
Relative retention with referenee to valaciclovir (retention
time = about 17 min): impurities A and B = about 0.2;
impurities C and R = about 0.6; impurity D = about 0.7;
impurity M = about 1.3.
System suitability: rderenee solution (a):
peak-to-valley ratio: minimum 1.5, where H p = height
aboye the baseline of the peak due to impurity D and
H v = height aboye the baseline of the lowest point of
the curve separating this peak from the peak due to
impurities C and R.
Limits:
- correction factor: for the ealculation of eontent, multiply
the peak afea of impurities A and B by 0.7;
impurity R: maximum 3.0 per cent; for the ealculation,
subtraet the content of impurity C as determined in
test B for related substances from the eontent of the
coeluting impurities C and R as determined in this test;
sum of ímpuríties A and B: maximum 2.0 per cent;
disregard limit: the afea of the principal peak in the
ehromatogram obtained with referenee solution (e)
(0.03 per cent); disregard any peaks due to impurities
other than A + B and C + R.
B. Liquid ehromatography (2.2.29): use the normalisation
proeedure. Use the solutions within 24 h of preparation.
Solvent mixture: ethanol (96 per cent) R, water R
(20:80 V/V).
4109
Valaddovir hydrochloride, hydrated EUROPEAN PHARMACOPOEIA 8.2

Test solution. Dissolve 80 mg of the substance to be Palladium: maximum 10 ppm.

examined in the solvent mixture and dilute to 100.0 mL Inductive!y coupled plasma-atomic emission spectrometry
with the solvent mixture. (2.2.57).
Reference solution (a). Dissolve 1.6 mg of valaciclovir for
Test solution. Dissolve 0.1 g in a 2 per cent V/V solution
system suitability CRS (containing impurities A, B, C, D,
of hydrochloric acid R in dimethyl sulfoxide R and dilute to
H, M and R) in the solvent mixture and dilute to 2.0 mL 10.0 mL with the same solution.
with the solvent mixture.
Reference solutions. Prepare the reference solutions using a
Reference solution (b). Dilute 1.0 mL of the test solution to
solution containing 1000 of Pd per millilitre, diluted as
100.0 mL with the solvent mixture. Dilute 1.0 mL of this
necessary with a 2 per cent solution of hydrochloric acid R
solution to 20.0 mL with the solvent mixture.
in dimethyl sulfoxide R.
Reference solution (ej. Dissolve 2 mg of valaciclovir
Wavelength: 340.5 nm.
impurity P CRS in the solvent mixture and dilute to 25.0 mL
with the solvent mixture. Dilute 1.0 mL of the solution to Heavy metals (2.4.8): maximum 20 ppm.
100.0 mL with the solvent mixture. Dissolve 2.0 g in water R and dilute to 20 mL with the same
Column: solvento 12 mL of the solution complies with test A. Prepare
- síze: 1= 0.25 m, 0 = 4.6 mm; the reference solution using 10 mL of lead standard solution
(2 ppm Pb) R.
- stationary phase: end-capped phenylhexylsilyl silica gel
for chromatography R (5 [1m); Water (2.5.12): 4.5 per cent to 11.0 per cent, determined on
0.100 g.
- temperature: 15 oc.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
Mobile phase:
1.0 g.
- mobile phase A: trifluoroacetic acid R, water R
(0.2:100 V/V); ASSAY
- mobile phase B: trifluoroacetic acid R, methanol R2 Liquid chromatography (2.2.29) as described in test A for
(0.2:100 V/V); related substances with the following modification.
Time Mobile phase A Mobile phase B Injection: test solution and reference solution (b).
(min) (per cent V/V) (per cent V/V)
Calculate the percentage content of C13H2lCIN604 taking
O- 5 90 10 into account the assigned content of anhydrous valaciclovir
5 - 35 90 -7 60 10 -7 40 hydrochloride CRS.
35 - 45 60 40 STORAGE
Flow rate: 0.8 mUmin. In an airtight container.
Detection: spectrophotometer at 254 nm. IMPURITIES
Injection: 10 [1L.
Specified impurities: A, B, C, D, G, H, M, P, R, S.
Identification of impurities: use the chromatogram
Other detectable impurities following substances would,
supplied with valaciclovir for system suitability CRS and
if present at a sufficient leve!, be detected by one or other of
the chromatogram obtained with reference solution (a) to
the tests in the monograph. They are limited by the general
identify the peaks due to impurities A, B, C, D, H and M;
acceptance criterion for other/unspecified impurities and/or
use the chromatogram obtained with reference solution (c)
by the general monograph Substances for pharmaceutical use
to identify the peak due to impurity P.
(2034). 1t is therefore not necessary to identify these impurities
Relative retention with reference to valaciclovir (retention for demonstration of compliance. See also 5.10. Controlof
time = about 20 min): impurity A = about 0.3; impurities in substances for pharmaceutical use): I, J, N.
impurity B = about 0.4; impurity H = about 0.5;
impurity C = about 1.06; impurity D = about 1.2;
impurity M = about 1.6; impurity P = about 2.0.
System suitability: reference solution (a):
- peak-to-valley ratio: minimum 2.0, where H p = height
aboye the baseline of the peak due to impurity C and
H v = height aboye the baseline of the lowest point of A. 2-amino-1,9-dihydro-6H-purin-6-one (guanine),
the curve separating this peak from the peak due to
valaciclovir.
LimUs:
- impurity M: maximum 0.6 per cent;
- impurity D: maximum 0.3 per cent;
- impurity C: maximum 0.2 per cent;
- impurities H, P: for each impurity, maximum 0.1 per B. 2-amino-9- [(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-
cent; purin-6-one (aciclovir),
- unspecified impurities: for each impurity, maximum
0.05 per cent;
- disregard limit: 0.6 times the area of the principal peak in
the chromatogram obtained with reference solution (b)
(0.03 per cent); disregard the peaks due to impurities
A and B.
Limit: C. 2- [(2-amino-6-oxo-1,6-dihydro-9H-purin -9-
- total for tests A and B: maximum 4.0 per cent. yl)methoxy] ethyl N- methyl- L- valinate,

4110 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2 Vardenafil hydrochloride trihydrate

R. 2- [(2-amino-6-oxo-1,6-dihydro-9H-purin-9-
D. 2- [(2-amino-6-oxo-l,6-dihydro-9H-purin-9-
yl)methoxy]ethyl D-valinate,
yl)methoxy] ethyl N-ethyl-L-valinate,
CH 3 O

O H3C~0)lNH
~ H3C H ..J--<CH 3

~ L~
G. N,N-dimethylpyridin-4-amine,
HN
2
N N
LO
r o-{ O
CH 3

S. 2- [(2-amino-6-oxo-l ,6-dihydro-9H-purin-9-
0 :t.NH2
yl)methoxy] ethyl N- [( 1, 1-dimethylethoxy)carbonyl]-L-
] :N . CH 3 valinate.
~ I l O
HN
2
N N
Le!~ O
07/2014:2782

H. 2- [(2-amino-6-oxo-1,6-dihydro-9H-purin-9- VARDENAFIL HYDROCHLORIDE

yl)methoxy]ethyl L-alaninate,
TRIHYDRATE
Vardenafili hydrochloridum trihydricum

1. 2- [(2-amino-6-oxo-1,6-dihydro-9H-purin-9-
yl)methoxy]ethy! acetate,

C23H33CIN604S,3H20 579.1
[330808-88-3]
DEFINITION
2- [2-Ethoxy-5- [( 4-ethylpiperazin -l-yl)sulfonyl]phenyl]-
J. 2- [(2-amino-6-oxo-1,6-dihydro-9H-purin-9- 5-methyl-7 -propylimidazo[5, l-J] [1,2,4]triazin-4(3H)-one
yl)methoxy] ethyl L-isoleucinate, hydrochloride trihydrate.
Content: 98.0 per cent to 102.0 per cent (anhydrous substance).

CHARACTERS
Appearance: white or slightly brown or yellow powder.
So/ubility: slightly soluble in water, freely soluble in anhydrous
ethanol, practically insoluble in heptane.
IDENTIFICATION
M. 2- [(2-amino-6-oxo-l,6-dihydro-9H-purin-9-
yl)methoxy] ethyl N-formyl-L-valinate, A. Infrared absorption spectrophotometry (2.2.24).
Comparison: vardenafil hydroch/oride CRS.
0
j: N NH HN
]:0 N
:t-<.
NH 2 CH 3
.
B. Water (see Tests).
C. It gives reaction (a) of chlorides (2.3.1).
< A N
I
N N./'-.. N
AN I
N
l r O
O
CH 3
TESTS
H H H LO
Related subsíances. Liquid chromatography (2.2.29). Protect
the so/utions from light.
N. 2- [[ 6-oxo-2- [[ [( 6-oxo-6,9-dihydro-lH-purin-2-
yl)amino ] methyl]amino ]-1,6-dihydro-9H-purin-9- So/vent mixture: acetonitrile Rl, mobile phase A (20:80 V/V).
yl]methoxy]ethyl L-valinate, Test solution (a). Dissolve 50.0 mg ofthe substance to be
examined in 20 mL of acetonitrile Rl and dilute to 100.0 mL
with mobile phase A.
Test so/ution (b). Dilute 15.0 mL oftest solution (a) to 50.0 mL
with the solvent mixture.
Reference so/ution (a). Dissolve 50.0 mg of vardenafil
hydrochloride CRS in 20 mL of acetonitrile Rl and dilute to
100.0 mL with mobile phase A. Dilute 15.0 mL of the solution
to 50.0 mL with the solvent mixture.
Reference solution (b). Dilute 1.0 mL 01' test solution (a) to
P 2,2' - [methylenebis [imino( 6-oxo-l ,6-dihydro-9 H -purine- 100.0 mL with the solvent mixture. Dilute 1.0 mL of this
2,9-diyl)methyJeneoxy]]diethyl di(L-valinate), solution to 10.0 rnL with the solvent mixture.

General Notices (1) apply to all monographs and other texts 4111
Vardenafil hydrochloride trihydrate EUROPEAN PHARMACOPOEIA 8.2

Reference solution (e). Dissolve 5 mg oí vardenafil for Sulfated ash (2.4.14): maximum 0,1 per cent, determined on
system suitability CRS (eontaining impurity A) in 2 mL oí l.0 g.
aeetonitrile Rl and dilute lo 10 mL with mobile phase A.
ASSAY
Column:
- size: 1 = 0.25 m, <2) = 3.0 mm; Liquid chromatography (2.2.29) as described in the test for
related substances with the following modification.
- stationary phase: end-eapped polar-embedded octadecylsilyl
amorphous organosilica polymer R (5 ¡..tm); Injection: 10 ¡..tL oí test solution (b) and reference solution (a).
- temperature: 45 0e. Calculate the percentage content of C23H33CIN60 4S taking into
account the assigned content of vardenafil hydrochloride CRS,
Mobile phase:
- mobile phase A: solution containing 0.7 giL oí disodium IMPURITIES
hydrogen phosphate dihydrate R and 1.3 giL of potassium
Specified impurities: A.
dihydrogen phosphate R;
Other detectable impurities (the following substances would,
- mobile phase B: acetonitrile Rl ;
if present at a suÍficient leve!, be detected by one or other of
Time Mobile phase A Mobile phase B the tests in the monograph. They are limited by the general
(min) (per cent V/V) (per cent V/V) aceeptance criterion for other/unspecified impurities and/or
0-2 80 20 by the general monograph Substances for pharmaceutical use
(2034). It is thereÍore not necessary to identiÍy these impurities
2 - 22 80 -7 25 20 -7 75
for demonstration oí eompliance. See also 5.10, Controlof
22 - 27 25 75 impurities in substances for pharmaceutical use): B, C.

Flow rate: 0.5 mUmin. o CH 3

Detection: spectrophotometer at 242 nm. o o HN~

Injection: 10 ¡.tL oftest solution (a) and reÍerenee solutions (b) [N/\Y/d"'N/N--{N
and (e).
H C N I
~
~ I
O~CH3
CH 3
Identification of impurities: use the ehromatogram 3 '-/

supplied with vardenafil for system suitability CRS and the

ehromatogram obtained with reÍerenee solution (c) to identify A. 2- [2-ethoxy-5-[ (4-ethylpiperazin-l-yl)sulfonyl]phenyl]-
the peak due to impurity A. 5,7 -dimethylimidazo [5,1-j] [1,2,4]triazin-4(3H)-one,
Relative retention with reference to vardenafil (retention
time = about 16 min): impurity A = about 0.8.
System suitability: referenee solution (e) :
1 J
HN' 1"
H
3

- resolut¡on: minimum 5,0 between the peaks due to

impurity A and vardenafil.
H03Sd~NJ~
Calculation of percentage contents: o CH 3 CH 3

- [or eaeh impurity, use the concentration of vardenafil in

B. 4-ethoxy-3- (5-methyl-4-oxo-7 -propyl- 3,4-dihydro-
reference solution (b).
imidazo[5,11l [1,2,4]triazin-2-yl)benzenesulfonic acid,
Limits:
- impurity A: maximum 0.15 per eent;
- unspecified impurities: for each impurity, maximum
0.10 per cent;
- total: maximum 0.3 per cent;
- reporting threshold: 0.05 per cent.
Sulfates (2.4.13): maximum 400 ppm.
Suspend 0.5 g in 20 mL of a 5.15 giL solution of hydrochloric
acid R and stir for 15 min, Filter if complete dissolution is
not obtained. e. 2,2'- [piperazine-1 ,4-diylbis [( sulfonyl)( 4-ethoxybenzene-
Water (2.5.12): 8.8 per cent to 10.5 per cent, determined on 1,3-diyl) ]]bis[5-methyl-7 -propylimidazo[5, l-j] [1,2,4]-
60.0 mg, triazin-4(3H)-one].

4112 See the informatíon section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

z
Zidovudine .............................................................................. 4115

General Natices (1) apply ta all managraphs and ather texts 4113
 EUROPEAN PHARMACOPOEIA 8.2

4114 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
07/2014:1059
ZIDOVUDINE
Zidovudinum
ClQHlJN S0 4 M r 267.2
[30516-87-1]
DEFINITION
1- (3-Azido-2,3 -dideoxy-~- D-erythro-pentofuranosyl) -5-
methylpyrimidine-2,4( 1H,3H)-dione.
Content: 97.0 per eent to 102.0 per eent (dried substanee).
CHARACTERS
Appearance: white or slightly brownish powder.
Solubility: sparingly soluble in water, soluble in anhydrous
ethanol, praetieally insoluble in heptane.
It shows polymorphism (5.9).
IDENTIFICATION
A. Specifie optical rotation (see Tests).
B. Infrared absorption spectrophotometry (2.2.24).
Comparison: zidovudine CRS.
If the spectra obtained in the solid state show differences,
dissolve the substance to be examined and the referenee
substance separately in the minimum volume oí water R,
evaporate to dryness in a desiceator, under high vaeuum over
diphosphorous pentoxide R and record new speetra using the
residues.
TESTS
Appearance of solutioJ1. The solution is not more opaleseent
than reÍerence suspension 1 (2.2.1) and not more intensely
coloured than reference solution BYs (2.2.2, Method II).
Dissolve 0.5 g in 50 mL of water R, heating if neeessary.
Specific optical rotatioJ1 (2.2.7): + 60.5 to + 63.0 (dried
substanee), measured at 25 oc.
Dissolve 0.50 g in anhydrous ethanol R and dilute to 50.0 mL
with the same solvent.
Related substances
A. Liquid chromatography (2.2.29).
Solvent mixture. Mix 4 volumes of acetonitrile R,
20 volumes of methanol R and 76 volumes of a 2 giL
solution of ammonium acetate R previously adjusted to
pH 6.8 with dilute aeetic acid R.
Test solution (a). Dissolve 20.0 mg of the substanee to be
examined in the solvent mixture and dilute to 20.0 mL with
the solvent mixture.
Test solution (b). Dilute 10.0 mL of test solution (a) to
50.0 mL with the solvent mixture.
Reference so/ution (a). Dissolve 2 mg of thymine R
(impurity C) and 2 mg of zidovudine impurity B CRS in
the solvent mixture and dilute to 50.0 mL with the solvent
mixture. Dilute 1.0 mL of the solution to 20.0 mL with the
solvent mixture.
General Notices (1) apply to all monographs and other texts
Zidovudine
Reference solution (b). Dissolve 5 mg of zidovudine for
system suitabi/ity CRS (containing impurities A, G and H)
in reference solution (a) and dilute to 5.0 mL with reference
solution (a).
Referenee solution (e). Dilute 1.0 mL of test solution (a) to
100.0 mL with the solvent mixture. DiIute 1.0 mL of this
solution to 10.0 mL with the solvent mixture.
Referenee so/ution (d). Dissolve 20.0 mg of zidovudine CRS
in the solvent mixture and dilute to 20.0 mL with the
solvent mixture. Dilute 10.0 mL oí the solution to 50.0 mL
with the solvent mixture.
Reference solution (e). Dissolve 1 mg of zidovudine
impurity D CRS in a mixture of 4 volumes of acetonitrile R,
40 volumes of methanol R and 56 volumes of a 2 giL
solution of ammonium acetate R previously adjusted to
pH 6.8 with dilute acetic acid R and dilute to 50.0 mL with
the same mixture of soIvents. DiIute 5.0 mL oí the solution
to 10.0 mL with the same mixture of solvents.
Column:
- size: 1 = 0.25 m, 0 = 4.6 mm;
- stationary phase: base-deactivated end-capped
octadecylsilyl si/iea gel for chromatography R (5 ¡.tm).
Mobile phase:
- mobile phase A: 2 giL solution of ammonium acetate R
previously adjusted to pH 6.8 with dilute acetic acid R;
- mobi/e phase B: acetonitrile R;
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
O- 3 95 5
3 - 18 95 -7 85 5 -7 15
18 - 28 85 -7 30 15 -7 70
28 - 43 30 70
Flow rate: 1.5 mL/min.
Detection: speetrophotometer at 265 nm.
Injection: 20 ¡.tL of test solution and re fe rene e
solutions (b), (e) and (e).
Identification of impurities: use the ehromatogram
supplied with zidovudine for system suitability CRS and
the ehromatogram obtained with reÍerenee solution (b) to
identify the peaks due to impurities A, B, C, G and H; use
the chromatogram obtained with reÍerence solution (e) to
identify the peak due to impurity D.
Relative retention with referenee to zidovudine (retention
time = about 16 min): impurity C = about 0.2;
impurity A = about 0.5; impurity H = about 0.95;
impurity B = about 1.05; impurity G = about 1.5;
impurity D = about 2.0.
System suitability: reference solution (b):
- resolution: mínimum 2.0 between the peaks due to
impurity H and zidovudine; minimum 2.0 between the
peaks due to zidovudine and impurity B.
Ca/cu/ation of percentage contents:
- correction factor: multiply the peak are a of impurity C
by 0.6;
- for eaeh impurity, use the eoneentration oí zidovudine
in referenee solution (e).
Limits:
- impurity G: maximum 0.5 per cent;
- impurities A and C: for eaeh impurity, maximum
0.15 per eent;
- unspecified impurities: for eaeh impurity, maximum
0.10 per cent;
- reporting threshold: 0.05 per cent; disregard any peak
due to impurity D and any peak eluted after this
impurity.
4115
Zidovudine EUROPEAN PHARMACOPOEIA 8.2

B. Liquid chromatography (2.2.29). Test B for relaíed substances: D, J, K

Test solution. Dissolve 0.5 g of the substanee to be examined Specified impurities: A, C, G.
in 10 mL of acetonitrile Rl and dilute to 100.0 mL with the Other detectable impurities (the following substances would,
mobile phase. if present at a suffieient level, be detected by one or other of
Reference so/ution (a). Dissolve 5.0 mg of zidovudine the tests in the monograph. They are limited by the general
impurity D CRS in acetonitrile R.l and dilute to 10.0 mL acceptance criterion for other/unspecified impurities and/or
with the same solvent. by the general monograph Substances for pharmaceutical
Reference solution (b). Dilute 1.0 mL of reference use (2034). It is therefore not necessary to identify these
solution (a) to 100.0 mL with the mobile phase. impurities for demonstration of compliance. See also 5.10.
Control of impurities in substances for pharmaceutical use):
Reference so/ution (e). Dilute l.0 mL of reference B, D, E, F, H, J, K.
solution (a) to 50.0 mL with the test solution.
Column:
- size: 1= 0.15 m, 0 = 4.6 mm;
- stationary phase: base-deaetivated end-eapped
oetadeeylsilylsilica gel for chromatography R (5 f.lm).
Mobile phase: water for chromatography R, acetonitrile Rl
(30:70 VIV).
Flow rate: 1.0 mUmin. A. 1- [(2R,5S) -5-(hydroxymethyl)-2,5-dihydrofuran -2-yl]-5-
methylpyrimidine-2,4( 1H,3H)-dione,
Deteetion: speetrophotometer at 210 nm.
Injection: 20 f.lL of the test solution and referenee
solutions (b) and (c).
Run time: 10 times the retention time of zidovudine.
Identification of impurities: use the ehromatogram obtained
with referenee solution (b) to identify the peak due to
impurity D.
Relative retention with reference to zidovudine (retention
time = about 1.5 min) : impurity D = about 2.5.
B. 1- (3-ehloro-2,3-dideoxy -0- D-erythro-pentofuranosyl)-5-
System suitability: reference solution (e):
methylpyrimidine-2,4( 1H,3H)-dione,
- resolution: minimum 5.0 between the peaks due to
zidovudine and impurity D.
Calcu/ation of percentage cantents:
- fo1' eaeh impurity, use the concentration of impurity D
in reference solution (b l.
Limits:
C. 5-methylpyrimidine-2,4( 1H,3H) -dione (thymine),
- unspecified impurities: for each impurity, maximum
0.10 per cent;
- reporting threshold: 0.05 per cent; disregard any peak
eluted before impurity D. q' -
/
OH

~
Limit:
- total for tests A and B: maximum 1.0 per eent. V V
Heavy metals (2.4.8): maximum 10 ppm.
D. triphenylmethanol,
Solvent mixture: water R, anhydrous methanol R (20:80 VIV).
1.00 g complies with test H. Prepare the referenee solution
using 1 mL of lead standard solution (10 ppm Pb) R.
Loss on drying (2.2.32): maximum l.0 per cent, determined
on 1.000 g by drying in an oven at 105 oc.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.

ASSAY
E. 1-(2-deoxy-~-D-erythro-pentofuranosyl)-5-
Liquid ehromatography (2.2.29) as described in test A for
related substanees with the following modification. methylpyrimidine-2,4( lH,3H) -dione (thymidine),

Injeetion: test solution (b) and reference solution (d).

Calculate the pereentage content of C lOH 13 N s0 4 taking into
account the assigned content of zidovudine CRS.

STORAGE
Protected from Iight.

IMPURITIES F. 1-(2-deoxy-0-D-threo-pentofuranosyl)-5-
Test A for related substances: A, B, C, E, F, G, H. methylpyrimidine-2,4( 1H,3H) -dione,

4116 See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2 Zidovudine

J. 1- [3-azido-2,3-dideoxy-S-O-( triphenylmethyl)-~- D-
erythro-pentofuranosy!]-5-methylpyrimidine-2,4(lH,3H)-
dione (trityl zidovudine),

G. 1- [( 2R,4S,5S) -4-azido- 5-(hydroxymethyl)tetrahydrofuran-

2-yl]-3- [(2S,3S,5R) - 2-(hydroxymethyl) -5-( 5-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1 (2H)-yl)tetrahydrofuran-3-
yl]-5-methylpyrimidine-2,4( lH,3H)-dione,

K. 1, 1',1" -(methoxymethanetriyl)tribenzene (methyl trityl

H. unknown structure, ether).

General No/ices (1) apply to all monographs and other texts 4117
 EUROPEAN PHARMACOPOEIA 8.2

4118 See the information section on general monographs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2

1 DE
To aid users the index inc/udes a reference to the supplement in which the latest version of a text can be found.
For example: Abacavir sulfate ............................................... 8.1-3719
means the monograph Abacavir sulfate can be found on page 3719 of Supplement 8.1.
Note that where no reference to a supplement is made, the text can be found in the principal volume.

English index ..................................................................... 4121 Latin index .............................................................................. 4155

General Notices (1) apply to all monographs and other texts 4119
 EUROPEAN PHARMACOPOEIA 8.2

4120 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2
Numerks
l. General notices ................................ 8.2-3897
0 0 . 0 0 • • • • • • • • • • • • 00 • • • • • • • • •
2.1.1. Droppers ................. 15
00 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
2. L2. Comparative table of porosity of sintered-glass filters .. 15
2.L3. Ultraviolet ray lamps for analytical purposes .... 15
2.1A Sieves ............................... 16
00 • • • • • • • • • • • 00 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
2.1.5. Tubes for comparative tests ............................................ 17
2.1.6. Gas detector tubes .. oo ........................................................ 17
2.1. Apparatus .................... 15
00 • • • • • 00 • • 00 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 00 • • • • • • • • • • •
22. lO. Viscosity - Rotating viscometer method 28
22.1 L Distillation range ........................................................... 30
22.12. Boiling point .................. oo .................. 31
oo • • • • • • • • • • • • • • • • •
22. B. Determination of water by distillation 31
22.14. Melting point - capillary method ... oo ............................ 32
2.2.15. Melting point - open capillary method .... 32
22.16. Melting point - instantaneous method ..... 32
22.17. Drop point ............... 32
00 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 00
22.18. Freezing poinLoo ............................................................ 34
2.2.19. Amperometric titrationoo ............... oo .............................. 34
22.L Clarity and degree of opalescence ofliquids ..... 21
2220. Potentiometric titration ................................................ 34
2221. Fluorimetryoo .. oo ............................................................... 35
22.22. Atomic emission spectrometry 35
. 0 0 • • • • • • • • • 00 • • • • • • • • • • • • • • • • • • • • • •
2223. Atomic absorption spectrometry 36
00 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
2224. Absorption spectrophotometry, infraredoo .............. 38
2.2.25. Absorption spectrophotometry, ultraviolet and
visible ........................ ' ..... 40
'00 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
2.2.26. Paper chromatography ....................................... 42
2.2.27. Thin-layer chromatography .......................................... 42
2.2.28. Gas chromatography...................................................... 43
2.2.29. Liquid chromatography ................................................. 45
2.2.2. Degree of coloration ofliquids ............ oo ......................... 22
2.2.30. Size-exclusion chromatography ................................... 46
22.31. Electrophoresis ............................................................... 47
2.2.31. Electrophoresis (5.8.) .......................................... 8.1-3679
2.2.32. Loss on drying ..................................................... ¡'l.2-3907
2.2.33. Nuclear magneiic resonance spectrometry ................ 52
2.2.34. Thermal analysis .... ,. ...................................................... 55
2.2.35. Osmolality ....................................................................... 57
2.2.36. Potentiometric determination of ionic
concentration using ion-selective electro des ........................ 58
2.2.37. X-ray fluorescence spectrometry ................................. 59
2.2.38. Conductivity ................................................................... 59
2.2.39. Molecular mass distribution in dextrans .................... 60
2.2.3. Potentiometric determination of pH ............................. 24
2.2.40. Near-infrared spectroscopy .......................................... 62
2.2.41. Circular dichroism ......................................................... 67
2.2.42. Density of solids ............. 68
o •••••••••••••••••••••••••••••••••••••••••••••••
2.2.43. Mass spectrometry ......................................................... 69
2.2.44. Total organic carbon in water for pharmaceutical
use ............................................................................................... 71
2.2.45. Supercritical fluid chromatography ............................. 72
2.2.46. Chromatographic separation techniques .................... 72
2.2.47. Capillary electrophoresis ............................................... 79
2.2.47. Capillary electrophoresis (5.8.) ............ 8.1-3679
2.2.48. Raman spectrometry ..................................................... 84
2.2.49. Falling ball viscometer method .................................... 85
2.2.4. Relationship between reaction of solution,
approximate pH and colour of certain indicators ................ 25
2.2.54. Isoelectric focusing ........................................................ 85
2.2.54. Isoelectric focusing (5.8.) ................................... 8.1-3679
2.2.55. Peptide mapping ............................................................ 87
2.2.55. Peptide mapping (5.8.) ....................................... 8.1-3679
2.2.56. Amino acid analysis ....................................................... 90
2.2.56. Amino acid analysis (5.8.) .................................. 8.1-3679
2.2.57. Inductively coupled plasma-atomic emission
spectrometry ............................................................................. 97
2.2.58. Inductively coupled plasma-mass spectrometry ........ 98
2.2.59. Glycan analysis of glycoproteins ................................ 100
2.2.5. Relative density ................................................................. 25
2.2.60. Melting point - instrumental method ....................... 105
General Notices (1) apply to all monographs and other texts
Index
2.2.61. Characterisation of crystalline solids by
microcalorimetry and solution calorimetry ........................ 106
2.2.64. Peptide identification by nuclear magnetic resonance
spectrometry ........................................................................... 109
oo • • • • • • • • •
2.2.65. Voltametric titration .................................................... 109
2.2.66. Detection and measurement of radioactivity ........... 110
2.2.6. Refractive index ................................................................ 26
2.2.7. Optical rotation ................................................................ 26
2.2.8. Viscosity ............................................................................ 27
00 • • 00 • • • • • • • • • • • • • • •
2.2.9. Capillary viscometer method ......................................... 27
2.2. Physical and physicochemical methods ........................... 21
00 • • • • • • • •
2.3.1. Identification reactions of ion s and functional
00 • • • • • • • • • • • • • 00 • • • • • • •
groups ...................................................................................... 119
2.3.2. Identification of fatty oils by thin-layer
00 • • • • • • • • • • • • • • • • •
chromatography ...................................................................... 122
oo • • • • • • • • • • • • • • • • •
2.3.3. Identification of phenothiazines by thin-Iayer
chromatography ...................................................................... 123
2.3.4. Odaur .............................................................................. 123
2.3. Identification ...................................................................... 119
00 • • 00 • • • • •
2.4.10. Lead in sugars ............................................................... 131
2.4.11. Phosphates .................................................................... 131
2.4.12. Potassium ...................................................................... 132
2.4.13. Sulfates ........................................................................... 132
2.4.14. Sulfated ash ................................................................... 132
oo ••
2.4.14. Sulfated ash (5.8.) ................................................ 8.1-3680
2.4.15. Nickel in polyols ........................................................... 132
2.4.16. Total ash ........................................................................ 132
00 • • • • 0 0 . 0 0
2.4.17. Aluminium ................................................................... 132
2.4.18. Free formaldehyde ....................................................... 132
2.4.19. Alkaline impurities in fatty oils .................................. 133
2.4.1. Ammonium .................................................................... 127
2.4.20. Determination of metal catalyst or metal reagent
residues .................................................................................... 133
2.4.21. Foreign oils in fatty oils by thin-layer
chromatography ...................................................................... 136
2.4.22. Composition of fatty acids by gas chromatography .. 136
2.4.23. Sterols in fatty oils ........................................................ 139
2.4.24. 1dentification and control af residual solvents ......... 141
2.4.25. Ethylene oxide and dioxal1 .......................................... 145
2.4.26. N,N- Dimethylaniline ................................................... 146
2.4.27. Heavy metal s in herbal drugs and herbal drug
preparations ................................................................... 8.2-3911
2.4.28. 2-Ethylhexanoic acid ................................................... 148
2.4.29. Composition of fatty acids in oils rich in omega-3
acids .......................................................................................... 148
2.4.2. Arsenic ............................................................................. 127
2.4.30. Ethylene glycol and diethylene glycol in ethoxylated
substances ................................................................................ 150
2.4.31. Nickel in hydrogenated vegetable oils ....................... 150
2.4.32. Total cholesterol in oils rich in omega-3 acids ......... 151
2.4.3. Calcium ........................................................................... 127
2.4.4. Chlorides ......................................................................... 127
2.4.5. Fluorides .......................................................................... 128
2.4.6. Magnesium ..................................................................... 128
0 ••••••••••••
2.4.7. Magnesium and alkaline-earth metals ........................ 128
2.4.8. Heavy metals ................................................................... 128
2.4.9. 1ron .................................................................................. 131
2,4-Dichlorobenzyl alcohol ............................................ 8.1-3745
2.4. Limit tests ........................................................................... 127
2.5.10. Oxygen-flask method .................................................. 158
2.5.11. Complexometric titrations .......................................... 158
2.5.12. Water: semi-micro determination .................... 8.2-3917
2.5.13. Aluminium in adsorbed vaccines .............................. 159
2.5.14. Calcium in adsorbed vaccines .................................... 159
2.5.15. Phenol in immunosera and vaccines ......................... 159
2.5.16. Protein in polysaccharide vaccines ............................ 159
2.5.17. Nucleic acids in polysaccharide vaccines .................. 160
2.5.18. Phosphorus in polysaccharide vaccines .................... 160
2.5.19. O-Acetyl in polysaccharide vaccines ......................... 160
2.5.1. Acid value ........................................................................ 155
2.5.20. Hexosamines in polysaccharide vaccines .................. 160
2.5.21. Methylpentoses in polysaccharide vaccines .............. 161
2.5.22. Uronic acids in polysaccharide vaccines ................... 161
4121
Index
2.5.23. Sialic acid in polysaccharide vaccines ....................... 161
2.5.24. Carbon dioxide in gases .............................................. 161
2.5.25. Carbon monoxide in gases ......................................... 162
2.5.26. Nitrogen monoxide and nitrogen dioxide in gases .. 163
2.5.27. Oxygen in gases ............................................................ 163
2.5.28. Water in gases ............................................................... 163
2.5.29. Sulfur dioxide ............................................................... 164
2.5.2. Ester value ....................................................................... 155
2.5.30. Oxidising substances ................................................... 164
2.5.31. Ribose in polysaccharide vaccines ............................. 164
2.5.32. Water: micro determination ....................................... 164
2.5.33. Total protein ................................................................. 165
2.5.34. Acetic acid in synthetic peptides ................................ 168
2.5.35. Nitrous oxide in gases ................................................. 168
2.5.36. Anisidine value ............................................................. 169
2.5.37. Methyl, ethyl and isopropyl methanesulfonate in
methanesulfonic acid ............................................................. 169
2.5.38. Methyl, ethyl and isopropyl methanesulfonate in active
substances ................................................................................ 170
2.5.39. Methanesulfonyl chloride in methanesulfonic
acid ........................................................................................... 171
2.5.3. Hydroxyl value ............................................................... 155
2.5.4. Iodine value .................................................................... 155
2.5.5. Peroxide value ................................................................. 156
2.5.6. Saponification value ....................................................... 157
2.5.7. Unsaponifiable matter ................................................... 157
2.5.8. Determination of primary aromatic amino-
nitrogen .................................................................................... 157
2.5.9. Determination of nitro gen by sulfuric acid
dígestion .................................................................................. 157
2.5. Assays ................................................................................. 155
2.6.10. Histamine ...................................................................... 184
2.6.11. Depressor substances ................................................... 185
2.6.12. Microbiological examination of non-sterile products:
microbial enumeration tests .................................................. 185
2.6.12. Microbiological examination of non -sterile products:
microbial enumeration tests (5.8.) .............................. 8.1-3680
2.6.13. Microbiological examination of non-sterile products:
test for specified micro-organisms ....................................... 189
2.6.13. Microbiologica1 examination of non -sterile products:
test for specified micro-organisms (5.8.) .................... 8.1-3680
2.6.14. Bacterial endotoxins .................................................... 194
2.6.15. Prekallikrein activator ................................................. 198
2.6.16. Tests for extraneous agents in viral vaccines for human
use ............................................... 198
<0 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
2.6.17. Test for anticomplementary activity of
immunog10bulin ..................................................................... 200
2.6.18. Test for neurovirulence oflive virus vaccines .......... 202
2.6.19. Test for neurovirulence of poliomyelitis vaccine
(oral) ......................................................................................... 202
2.6.1. Sterility ............................................................................ 175
2.6.1. Sterility (5.8.) ......................................................... 8.1-3680
2.6.20. Anti-A and anti-B haemagglutinins .......................... 203
2.6.21. Nucleic acid amplification techniques .............. 8.2-3921
2.6.22. Activated coagulation factors ..................................... 209
2.6.24. Avían viral vaccines: tests for extraneous agents in
seed 10ts .......................................................................... 8.1-3659
2.6.25. Avian live virus vaccines: tests for extraneous agents in
batches of finished product ................................................... 212
2.6.26. Test for anti-D antibodies in human immunoglobu-
lin .............................................................................................. 215
2.6.27. Microbiological control of cellular products ............ 216
2.6.2. Mycobacteria .................................................................. 178
2.6.30. Monocyte-activation test... .......................................... 217
2.6.31. Microbiological examination of herbal medicinal
products for oral use and extracts used in their
preparation .............................................................................. 222
2.6.33. Residual pertussis toxin and irreversibility of pertussis
toxoid ....................................................................................... 224
2.6.7. Mycop1asmas .................................................................. 178
2.6.8. Pyrogens .......................................................................... 183
2.6.9. Abnormal toxicity .......................................................... 184
2.6. Biological tests ................................................................... 175
4122
EUROPEAN PHARMACOPOEIA 8.2
2.7.10. Assay ofhuman coagulation factor VII .................... 247
2.7.11. Assay ofhuman coagulation factor IX ...................... 248
2.7.12. Assay ofheparin in coagulation factors .................... 249
2.7.13. Assay ofhuman anti-D immunoglobulin ................. 249
2.7.14. Assay of hepatitis A vaccine ....................................... 251
2.7.15. Assay ofhepatitis B vaccine (rDNA) ......................... 252
2.7.16. Assay of pertussis vaccine (acellular) ........................ 252
2.7.17. Assay of human antithrombin III .............................. 254
2.7.18. Assay ofhuman coagulation factor II ....................... 254
2.7.19. Assay ofhuman coagu1atiol1 factor X ........................ 255
2.7.1. lmmunochemical methods ........................................... 229
2.7.20. In vivo assay of poliomyelitis vaccine (inactivated) .. 255
2.7.21. Assay ofhuman von Willebrand factoL .................... 257
2.7.22. Assay ofhuman coagulation factor XL ........... 8.2-3930
2.7.23. Numeration of CD34/CD45+ cells in
haematopoietic products ....................................................... 258
2.7.24. Flow cytometry ............................................................ 259
2.7.25. Assay of human plasmin inhibitor.. ........................... 261
2.7.27. Flocculation value (Lf) of diphtheria and tetanus toxins
and toxoids (Ramon assay) ................................................... 261
2.7.28. Colony-forming ceH assay for human
haematopoietic progenitor cells ............................................ 262
2.7.29. Nucleated ceH count and viability .............................. 263
2.7.2. Microbiological assay of antibiotics ............................. 230
2.7.30. Assay ofhuman protein C .......................................... 265
2.7.31. Assay ofhuman protein S ........................................... 266
2.7.32. Assay ofhuman a-1-proteinase inhibitor ................. 266
2.7.4. Assay ofhuman coagulation factor VIII ............ 8.2-3929
2.7.5. Assay ofheparin ............................................................. 237
2.7.6. Assay of diphtheria vaccine (adsorbed) ...................... 237
2.7.7. Assay of pertussis vaccine (whole cell) ........................ 242
2.7.8. Assay of tetanus vaccine (adsorbed) ............................ 242
2.7.9. Test for Fe function of immunoglobulin ..................... 246
2.7. Biological assays ................................................................ 229
2.8.10. Solubility in alcohol of essential oils .......................... 272
2.8.11. Assay of 1,8-cineole in essential oils .......................... 272
2.8.12. Essential oils in herbal drugs ...................................... 273
2.8.13. Pesticide residues ................................................ 8.2-3933
2.8.14. Tannins in herbal drugs .............................................. 275
2.8.15. Bitterness value .................. < ••••••••••••••••••••••••••••••••••••••••••276
2.8.16. Dry residue of extracts ................................................ 276
2.8.17. Loss on drying of extracts ........................................... 276
2.8.18. Determination of aflatoxin B¡ in herbal drugs ......... 276
2.8.1. Ash insoluble in hydrochloric acid .............................. 271
2.8.20. Herbal drugs: sampling and sample preparation .... 278
2.8.21. Test for aristolochie acids in herbal drugs ................ 279
2.8.22. Determination of ochratoxin A in herbal drugs ...... 281
2.8.23. Microscopic examination of herbal drugs ................ 282
2.8.2. Foreign matter ....................................................... 8.1-3665
2.8.3. Stomata and stomatal index .................................. ,....... 271
2.8.4. Swelling index ................................................................. 271
2.8.5. Water in essential oils .................................................... 271
2.8.6. Foreign esters in essential oils ............................ ,......... 271
2.8.7. Fatty oils and resinified essential oils in essential
oils ............................................................................................ 271
2.8.8. Odour and taste of essential oils .................................. 272
2.8.9. Residue on evaporation of essential oils ..................... 272
2.8. Methods in pharmacognosy ............................................ 271
2.9.10. Ethanol content ............................................................ 301
2.9.11. Test for methanol and 2-propanol.. ........................... 304
2.9.12. Sieve test ........................................................................ 305
2.9.14. Specific surface are a by air permeability ................... 305
2.9.16. Flowability..................................................................... 307
2.9.17. Test for extractable volume of parenteral
preparations ............................................................................ 308
2.9.17. Test for extractable volume of parenteral preparations
(5.8.) ................................................................................ 8.1-3681
2.9.18. Preparations for inhalation: aerodynamic assessment
of fine particles ........................................................................ 309
2.9.19. Particulate contamination: sub-visible particles ...... 321
2.9.19. Particu1ate contamination: sub-visible particles
(5.8.) ................................................................................ 8.1-3681
2.9.1. Disintegration of tablets and capsules ......................... 285
See the informa/ion section on general monographs (caver pages)
EUROPEAN PHARMACOPOEIA 8.2
2.9.1. Disintegration oftablets and capsules (5.8.) ...... 8.1-3680
2.9.20. Particulate contamination: visible particles ............. 323
2.9.22. Softening time determination of lipophilic
suppositories ........................................................................... 323
2.9.23. Gas pycnometric density of solids ............................. 324
2.9.25. Dissolution test for medicated chewing gums ......... 325
2.9.26. Specif1c surface are a by gas adsorption ..................... 329
2.9.26. Specif1c surface are a by gas adsorption (5.8.) .. 8.1-3681
2.9.27. Uniformity of mass of delivered doses from multidose
containers ................................................................................ 331
2.9.29. Intrinsic dissolution ..................................................... 331
2.9.2. Disintegration of suppositories and pessaries ............ 287
2.9.31. Particle size analysis by laser light diffraction .......... 333
2.9.32. Porosity and pore-size distribution of solids by
mercury porosimetry ............................................................. 336
2.9.33. Characterisation of crystalline and partially crystalline
solids by X-ray powder diffraction (XRPD) ....................... 339
2.9.34. Bulk density and tapped density of powders ............ 343
2.9.35. Powder fineness ............................................................ 346
2.9.36. Powder flow .................................................................. 346
2.9.36. Powder flow (5.8.) ............................................... 8.1-3681
2.9.37. Optical microscopy ...................................................... 349
2.9.37. Optical microscopy (5.8.) ................................... 8.1-3681
2.9.38. Particle-size distribution estimation by analytical
sieving ...................................................................................... 351
2.9.38. Particle-size distribution estimation by analytical
sieving (5.8.) ................................................................... 8.1-3681
2.9.39. Water-solid interactions: determination of
sorption-desorption isotherms and of water activity ......... 353
2.9.3. Dissolution test for solid dosage forms ....................... 288
2.9.40. Uniformity of dosage units ......................................... 357
2.9.41. Friability of granules and spheroids .......................... 359
2.9.42. Dissolution test for Iipophilic solid dosage forms ... 361
2.9.43. Apparent dissolution ................................................... 361
2.9.44. Preparations for nebulisation: characterisation ....... 363
2.9.45. Wettability of porous solids including powders ....... 365
2.9.47. Demonstration 01' uniformity of dosage units using
large sample sizes ........................................................... 8.1-3669
2.9.4. Dissolutiol1 test for transdermal patches .................... 295
2.9.5. Uniformity of mass 01' single-dose preparations ........ 297
2.9.6. Uniformity 01' content of single-dose preparations .... 298
2.9.7. Friability of uncoated tablets ........................................ 298
2.9.7. Friability of uncoated tablets (5.8.) ..................... 8.1-3681
2.9.8. Resistance to crushing of tablets ................ 299
00 • • • • • • • • • • • • • • • •
2.9.9. Measurement of consistency by penetrometry .......... 299
2.9. Pharmaceutical technical procedures ............................. 285
3.1.10. Materials based on non-plasticised poly(vinyl chloride)
for containers for non-injectable, aqueous solutions ......... 395
3.1.11. Materials based on non -plasticised poly( vinyl
chloride) for containers for dry dosage forms for oral
administration ......................................................................... 397
3.1.1.1. Materials based on plasticised poly(vinyl chloride) for
containers for human blood and blood componel1ts ......... 375
3.1.1.2. Materials based 011 plasticised poly(vinyl chloride) for
tubing used in sets for the transfusion of blood and blood
components ............................................................................. 378
3.1.13. PI as tic additives ............................................................ 398
3.1.14. Materials based on plasticised poly(vinyl chloride)
for containers for aqueous solutions for intravenous
infusion .................................................................................... 401
3.1.15. Polyethylene terephthalate for containers for
preparations not for parenteral use ...................................... 403
3.1.1. Materials for containers for human blood and blood
components ............................................................................. 375
3.1.3. Polyolefins ....................................................................... 380
3.1.4. Polyethylene without additives for containers for
parenteral preparations and for ophthalmic preparations .. 383
3.1.5. Polyethylene with additives for containers for parenteral
preparations and for ophthalmic preparations ................... 384
3.1.6. Polypropylene for containers and closures for parenteral
preparations and ophthalmic preparations ......................... 388
3.1.7. Poly(ethylene - vinyl acetate) for containers and tubing
for total parenteral nutrition prep2'ations .......................... 391
General Notices (1) apply to all monographs and other texts
Index
3.1.8. Silicone oil used as a lubricant ..................................... 393
3.1.9. Silicone elastomer for closures and tubing ................. 394
3.1. Materials used for the manufacture of containers ........ 375
3.2.1. Glass containers for pharmaceutical use ..................... 409
3.2.2.1. Plastic containers for aqueous solutions for
infusiol1 .................................................................................... 414
3.2.2. PI as tic containers and closures for pharmaceutical
use ............................................................................................. 414
3.2.3. Sterile pI as tic containers for human blood and
blood components .................................................................. 415
3.2.4. Empty sterile containers of plasticised poly(vinyl
chloride) for human blood and blood components ........... 417
3.2.5. Sterile containers of plasticised poly(vinyl chloride) for
human blood containing anticoagulant solution ............... 418
3.2.6. Sets for the transfusion 01' blood and blood
components ............................................................................. 418
3.2.8. Sterile single-use plastic syringes ................................. 419
3.2.9. Rubber closures for containers for aqueous
parenteral preparatiol1s, for powders and for
freeze-dried powders .............................................................. 421
3.2. Containers .......................................................................... 409
3-0-Desacyl-4'-monophosphoryllipid A ............................ 2000
4.1.1. Reagents .......................................................................... 425
4.1.1. Reagents ................................................................. 8.1-3675
4.1.1. Reagents ................................................................. 8.2-3937
4.1.2. Standard solutions for limit tests ................................. 536
4.1.2. Standard solutions for limit tests ........................ 8.1-3675
4.1.3. Buffer solutions .............................................................. 540
4.1.3. Buffer solutions ..................................................... 8.1-3675
4.1.3. Buffer solutions ..................................................... 8.2-3937
4.1. Reagents, standard solutions, buffer solutions .............. 425
4.2.1. Primary standards for volumetric solutions ............... 545
4.2.2. Volumetric solutions ...................................................... 546
4.2. Volumetric analysis ........................................................... 545
4-Aminobenzoic acid ............................................................. 1539
4. Reagents ................................................................................. 425
5.10. Control 01' impurities in substances for pharmaceutical
use ............................................................................................. 689
5.1.10. Guidelines for using the test for bacterial
endotoxins ............................................................................... 572
5.11. Characters section in monographs ............................... 695
5.1.1. Methods 01' preparation of sterile products ................ 555
5.1.2. Biological indicators of sterilisation ............................ 556
5.12. Reference standards .... 699
00 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.3. Efficacy of antimicrobial preservation ........................ 557
5.14. Gene transfer medicinal products for human use ...... 705
5.1.4. Microbiological quality of non-sterile pharmaceutical
preparations and substances for pharmaceutical use ......... 559
5.1.4. Microbiological quality 01' non-sterile pharmaceutical
preparations and substances for pharmaceutical use
(5.8.) ................................................................................ 8.1-3681
5.1.5. Application of the Fo concept to steam sterilisation of
aqueous preparations ............................................................. 560
5.15. Functionality-related characteristics of excipients ...... 719
5.1.6. Alternative methods for control of microbiological
quality ...................................................................................... 560
5.16. Crystallinity ..................................................................... 723
5.17.1. Recommendations on dissolution testing ................. 727
5.17. Recommendations on methods for dosage forms
testing ....................................................................................... 727
5.1.7. Viral safety ...................................................................... 57l
5.1.8. Microbiological quality ofherbal medicinal products for
oral use and extracts used in their preparation .................. 571
5.1.9. Guidelines for using the test for sterility ..................... 572
5.1. General texts 011 microbiology ........................................ 555
5.20. Metal catalyst or metal reagent residues ...................... 733
5.2.1. Terminology used in monographs on biological
products ................................................................................... 579
5.2.2. Chicken flocks free from specified pathogens for the
production and quality control of vaccines ......................... 579
5.22. Names of herbal drugs used in traditional Chinese
medicine ......................................................................... 8.2-3941
4123
Index EUROPEAN PHARMACOPOEIA 8.:

5.2.3. Cell substrates for the production of vaccines for human Aerodynamic assessment of fine particles in preparations for
use ............................................................................................. 582 inhalation (2.9.18.) ................................................................. 30~
5.2.4. Cell cultures for the production of veterinary Aflatoxin Bl in herbal drugs, determination of (2.8.18.) ..... 27E
vaccines .................................................................................... 585 Agar .......................................................................................... 113E
5.2.5. Substances of animal origin for the production of Agnus castus fruit ................................................................... 1131
immunological veterinary medicinal products .................. 587 Agrimony ................................................................................. 113t
5.2.6. Evaluation of safety of veterinary vaccines and Air, medicinal ......................................................................... 149~
immunosera ........................................................................... 588 Air, synthetic medicinal ......................................................... 149 L
5.2.7. Evaluation of efficacy of veterinary vaccines and Alanine .............................................................................. 8.2-399:
immunosera ............................................................................ 591 Albendazole ............................................................................. 1491'
5.2.8. Minimising the risk of transmitting animal spongiform Albumin solution, human ..................................................... 240 L
encephalopathy agents via human and veterinary medicinal Alchemilla ................................................................................ 1135
products ................................................................................... 592 Alcoholimetric tables (5.5.) ..................................................... 645
5.2.9. Evaluation of safety of each batch of immunosera for Alcuronium chloride .............................................................. 1491
veterinary use .......................................................................... 604 Alendronate, sodium .............................................................. 322:
5.2. General texts on biological products .............................. 579 Alexandrian senna pods ........................................................ 138~
5.3. Statistical analysis of results of biological assays and Alfacalcidol .............................................................................. 149t
tests ........................................................................................... 607 Alfadex ..................................................................................... 1495
5.4. Residual solvents ............................................................... 639 Alfentanil hydrochloride ....................................................... 1501
5.5. Alcoholimetric tables ........................................................ 649 Alfuzosin hydrochloride ........................................................ 1501
5.6. Assay of interferons .......................................................... 663 Alginate, sodium ..................................................................... 322<'
5.7. Table of physical characteristics of radionuclides Alginic acid .............................................................................. 150~
mentioned in the European Pharmacopoeia ...................... 667 Alimemazine hemitartrate ..................................................... 150~
5.8. Pharmacopoeial harmonisation ............................. 8.1-3679 Alkaline-earth metals and magnesium (2.4.7.) ..................... 12t
5.9. Polymorphism ................................................................... 685 Alkaline impurities in fatty oils (2.4.19.) ............................... 13~
Allantoin .................................................................................. 150:
A Allergen products ............................................................ 8.2-3945
Abacavir sulfate ................................................................ 8.1-3719 Allium sativum for homoeopathic preparations ......... 8.2-3981
Abbreviations and symbols (1.) ..................................... 8.2-3897 Allopurinol .............................................................................. 1505
Abnormal toxicity (2.6.9.) ........................................................ 184 all-rac-a-Tocopherol.. ............................................................. 3431'
Absorption spectrophotometry, infrared (2.2.24.) ................. 38 all-rac-a-Tocopheryl acetate .................................................. 343E
Absorption spectrophotometry, ultraviolet and visible Almagate .................................................................................. 1507
(2.2.25.) ...................................................................................... 40 Almond oil, refined ................................................................ 1508
Acacia ....................................................................................... 1135 Almond oil, virgin .................................................................. 150S
Acacia, spray-dried ................................................................. 1460 Aloes, Barbados ...................................................................... 114C
Acamprosate calcium ............................................................. 1461 Aloes, Cape .............................................................................. 1141
Acanthopanax bark ................................................................ 1136 Aloes dry extract, standardised ............................................. 1142
Acarbose ........................................................................... 8.1-3720 Alovudine (lsF) injection ....................................................... 1045
Acebutolol hydrochloride ...................................................... 1464 Alphacyclodextrin .................................................................. 1499
Aceclofenac .............................................................................. 1466 Alprazolam .............................................................................. 1509
Acemetacin .............................................................................. 1467 Alprenolol hydrochloride ...................................................... 1511
Acesulfame potassium ............................................................ 1469 Alprostadil ............................................................................... 1512
Acetate trihydrate, sodium .................................................... 3224 Alteplase for injection ............................................................ 1515
Acetazolamide ......................................................................... 1470 Alternative methods for control of microbiological quality
Acetic acid, glacial .................................................................. 1471 (5.1.6.) ...................................................................................... 560
Acetic acid in synthetic peptides (2.5.34.) ............................. 168 Altizide ..................................................................................... 1518
Acetone .................................................................................... 1472 Alum ......................................................................................... 1519
Acetylcholine chloride ........................................................... 1473 Aluminium (2.4.17.) ................................................................. 132
Acetylcysteine .......................................................................... 1473 Aluminium chloride hexahydrate ......................................... 1519
~-Acetyldigoxin ....................................................................... 1475 Aluminium hydroxide, hydrated, for adsorption ............... 1520
Acetylsalicylic acid ................................................................. 1477 Aluminium in adsorbed vaccines (2.5.13.) ............................ 159
Acetyltryptophan, N- ............................................................. 1479 Aluminium magnesium silicate ............................................ 1521
Acetyltyrosine, N- ................................................................... 1481 Aluminium oxide, hydrated .................................................. 1522
Aciclovir ................................................................................... 1482 Aluminium phosphate gel ..................................................... 1522
Acid value (2.5.1.) ..................................................................... 155 Aluminium phosphate, hydrated .......................................... 1523
Acitretin ................................................................................... 1484 Aluminium sodium silicate ................................................... 1524
Actinobacillosis vaccine (inactivated), porcine .................. 1000 Aluminium stearate ................................................................ 1525
Activated charcoal .................................................................. 1839 Aluminium sulfate .................................................................. 1527
Activated coagulation factors (2.6.22.) ................................... 209 Alverine citrate ........................................................................ 1527
Adapalene ................................................................................ 1485 Amantadine hydrochloride ................................................... 1528
Additives, plastic (3.1.13.) ....................................................... 398 Ambroxol hydrochloride ....................................................... 1529
Adenine .................................................................................... 1487 Amfetamine sulfate ................................................................ 1531
Adeno-associated-virus vectors for human use .................... 714 Amidotrizoate, sodium .......................................................... 3227
Adenosine ................................................................................ 1487 Amidotrizoic acid dihydrate ................................................. 1531
Adenovirus vaccine (inactivated), canine .............................. 945 Amikacin .......................................................................... 8.2-3996
Adenovirus vaccine (live), canine ........................................... 946 Amikacin sulfate .............................................................. 8.2-3998
Adipic acid ............................................................................... 1489 Amiloride hydrochloride ....................................................... 1538
Adrenaline ............................................................................... 1490 Amino acid analysis (2.2.56.) .................................................... 90
Adrenaline tartrate ................................................................. 1491 Amino acid analysis (2.2.56.) (5.8.) ............................... 8.1-3679
Adsorption, gas, specific surface are a by (2.9.26.) ................ 329 Aminobenzoic acid, 4- ........................................................... 1539
Adsorption, gas, specific surface area by (2.9.26.) Aminocaproic acid ................................................................. 1540
(5.8.) ................................................................................ 8.1-3681 Aminoglutethimide ................................................................ 1541
Aminophylline, anhydrous .................................................... 3398

4124 See the information sectian an general managraphs (caver pages)

EUROPEAN PHARMACOPOEIA 8.2
Aminophylline hydrate .......................................................... 3399
Aminosalicylate dihydrate, sodium ... ., ................................. 3228
Amiodarone hydrochloride ................................................... 1542
Amisulpride ............................................................................. 1544
Amitriptyline hydrochloride ................................................. 1546
Amlodipine besilate ................................................................ 1547
Ammonia C3N) injection ....................................................... 1047
Ammonia solution, concentrated ......................................... 1548
Ammonio methacrylate copolymer (type A) ...................... 1549
Ammonio methacrylate copolymer (type B) ...................... 1550
Ammonium (2.4.1.) .................................................................. 127
Ammonium bromide ............................................................. 1551
Ammonium chloride .............................................................. 1552
Ammonium glycyrrhizate ..................................................... 1552
Ammonium hydrogen carbonate ......................................... 1553
Amobarbital ............................................................................ 1554
Amobarbital sodium .............................................................. 1554
Amomum fruit ................................................................. 8.1-3701
Amomum fruit, round .................................................... 8.1-3710
Amoxicillin sodium ................................................................ 1555
Amoxicillin trihydrate ............................................................ 1557
Amperometric titration (2.2.19.) .............................................. 34
Amphotericin B ...................................................................... 1560
Ampicillin, anhydrous .......................................................... 1561
Ampicillin sodium .................................................................. 1564
Ampicillin trihydrate .............................................................. 1566
Amylmetacresol ...................................................................... 1568
Anacardium for homoeopathic preparations ............... 8.2-3981
Anaemia vaccine (live), chicken, infectious .......................... 984
Anaesthetic ether .................................................................... 2185
Analysis, thermal (2.2.34.) ......................................................... 55
Analytical sieving, particle-size distribution estimation by
(2.9.38.) .................................................................................... 351
Analytical sieving, particle-size distribution estimation by
(2.9.38.) (5.8.) ................................................................. 8.1-3681
Anamirta cocculus for homoeopathic preparations ... 8.2-3986
Anastrozole .............................................................................. 1570
Angelica archangelica root .................................................... 1142
Angelica dahurica root... ........................................................ 1143
Angelica pubescens root ...................................................... ., 1145
Angelica sinensis root ............................................................ 1147
Animal anti-T lymphocyte immunoglobulin for human
use ........................................................................................... 1575
Animal immunosera for human use ...................................... 748
Animal spongiform encephalopathies, products with risk of
transmitting agents of ............................................................ 759
Animal spongiform encephalopathy agents, minimising the
risk of transmitting via human and veterinary medicinal
products (5.2.8.) ...................................................................... 592
Aniseed .................................................................................... 1150
Anise oil ................................................................................... 1148
Anisidine value (2.5.36.) .......................................................... 169
Antazoline hydrochloride ...................................................... 1571
Anthrax spore vaccine (live) for veterinary use .................... 921
Anthrax vaccine for human use (adsorbed, prepared from
culture filtrates) ....................................................................... 817
Anti-A and anti-B haemagglutinins (2.6.20.) ........................ 203
Antibiotics, microbiological assay of (2.7.2.) ........................ 230
Antibodies (anti-D) in human immunoglobulin, test for
(2.6.26.) .................................................................................... 215
Antibodies for human use, monoclonal ................................ 753
Anticoagulant and preservative solutions for human blood
................................................................................................ 1572
Anticomplementary activity of immunoglobulin (2.6.17.) .. 200
Anti-D antibodies in human immunoglobulin, test for
(2.6.26.) .................................................................................... 215
Anti-D immunoglobulin for intravenous administration,
human .................................................................................... 2407
Anti -D immunoglobulin, human ......................................... 2406
Anti-D immunoglobulin, human, assay of (2.7.13.) ............ 249
Antimicrobial preservation, efficacy of (5.1.3.) .................... 557
Antiserum, European viper venom ...................................... 1033
Antithrombin III concentrate, human ................................. 2407
General Natices (1) apply to all monagraphs and other texts
Index
Antithrombin III, human, assay of (2.7.17.) ......................... 254
Anti-T lymphocyte immunoglobulin for human use,
animal .................................................................................... 1575
Apis for homoeopathic preparations ............................. 8.2-3983
Apomorphine hydrochloride hemihydrate ......................... 1578
Apparatus (2.1.) .......................................................................... 15
Apparent dissolution (2.9.43.) ................................................. 361
Application of the Fo concept to steam sterilisation of aqueous
preparations (5.1.5.) ............................................................... 560
Aprotinin ................................................................................. 1579
Aprotinin concentrated solution .......................................... 1581
Arachis oil, hydrogenated ...................................................... 1584
Arachis oil, refined ................................................................. 1584
Arginine ............................................................................ 8.2-4001
Arginine aspartate .................................................................. 1586
Arginine hydrochloride .................................................. 8.2-4002
Argon ....................................................................................... 1587
Aripiprazole ...................................................................... 8.1-3722
Aristolochic acids in herbal drugs, test for (2.8.21) ............. 279
Arnica flower ........................................................................... 1151
Arnica tincture ........................................................................ 1153
Arsenic (2.4.2.) .......................................................................... 127
Arsenicum album for homoeopathic preparations ..... 8.2-3983
Arsenious trioxide for homoeopathic preparations .... 8.2-3983
Articaine hydrochloride ......................................................... 1588
Artichoke leaf .......................................................................... 1154
Artichoke leaf dry extract ...................................................... 1156
Ascorbate, calcium ................................................................. 1731
Ascorbate, sodium .................................................................. 3229
Ascorbic acid ........................................................................... 1590
Ascorbyl palmitate .................................................................. 1591
Ash insoluble in hydrochloric acid (2.8.1.) ........................... 271
Ash leaf .................................................................................... 1157
Ash, sulfated (2.4.14.) ............................................................... 132
Ash, sulfated (2.4.14.) (5.8.) ........................................... 8.1-3680
Ash, total (2.4.16.) .................................................................... 132
Asparagine monohydrate ....................................................... 1592
Aspartame ................................................................................ 1593
Aspartic acid ............................................................................ 1594
Assay of 1,8-cineole in essential oils (2.8.11.) ....................... 272
Assay of diphtheria vaccine (adsorbed) (2.7.6.) .................... 237
Assay ofheparin (2.7.5.) .......................................................... 237
Assay ofheparin in coagulation factors (2.7.12.) ................. 249
Assay ofhepatitis A vaccine (2.7.14.) ..................................... 251
Assay ofhepatitis B vaccine (rDNA) (2.7.15.) ...................... 252
Assay ofhuman a-1-proteinase inhibitor (2.7.32.) .............. 266
Assay ofhuman anti-D immunoglobulin (2.7.13.) .............. 249
Assay ofhuman antithrombin III (2.7.17.) ............................ 254
Assay ofhuman coagulation factor II (2.7.18.) ..................... 254
Assay of human coagulation factor IX (2.7.11.) ................... 248
Assay ofhuman coagulation factor VII (2.7.10.) .................. 247
Assay ofhuman coagulation factor VIII (2.7.4.) ......... 8.2-3929
Assay ofhuman coagulation factor X (2.7.19.) ..................... 255
Assay ofhuman coagulation factor XI (2.7.22.) .......... 8.2-3930
Assay of human plasmin inhibitor (2.7.25.) .......................... 261
Assay ofhuman protein e (2.7.30.) ........................................ 265
Assay of human protein S (2.7.31.) ........................................ 266
Assay of human von Willebrand factor (2.7.21.) .................. 257
Assay of interferons (5.6.) ........................................................ 663
Assay of pertussis vaccine (acellular) (2.7.16.) ...................... 252
Assay of pertussis vaccine (whole cel!) (2.7.7.) ..................... 242
Assay of poliomyelitis vaccine (inactivated), in vivo
(2.7.20.) .................................................................................... 255
Assay oftetanus vaccine (adsorbed) (2.7.8.) ......................... 242
Assays (2.5.) ............................................................................... 155
Astragalus mongholicus root ................................................ 1158
Atenolol. ................................................................................... 1595
Atomic absorption spectrometry (2.2.23.) .............................. 36
Atomic emission spectrometry (2.2.22.) .................................. 35
Atomic emission spectrometry, inductively coupled plasma-
(2.2.57.) ...................................................................................... 97
Atomoxetine hydrochloride .................................................. 1596
Atorvastatin calcium trihydrate ............................................ 1598
4125
Index
Atovaquone .............................................................................. 1600
Atractylodes lancea rhizome ................................................. 1159
Atractylodes rhizome, largehead .......................................... 1160
Atracurium besilate ................................................................ 1601
Atropine ................................................................................... 1604
Atropine sulfate ....................................................................... 1605
Aujeszky's disease vaccine (inactivated) for pigs .................. 921
Aujeszky's disease vaccine (live) for pigs for parenteral
administration ......................................................................... 923
Aurothiomalate, sodium ........................................................ 3230
Aurum chloratum natronatum for homoeopathic
preparations ................................................................... 8.2-3984
Avian infectious bronchitis vaccine (inactivated) ................. 925
Avian infectious bronchitis vaccine (live) .............................. 926
Avian infectious bursal disease vaccine (inactivated) .......... 928
Avian infectious bursal disease vaccine (live) ....................... 929
Avian infectious encephalomyelitis vaccine (live) ................ 931
Avian infectious laryngotracheitis vaccine (live) .................. 932
Avianlive virus vaccines: tests for extraneous agents in batches
of finished product (2.6.25.) .................................................. 212
Avian paramyxovirus 1 (Newcastle disease) vaccine
(inactivated) ............................................................................ 995
Avian paramyxovirus 1 (Newcastle disease) vaccine (live) .. 997
Avian paramyxovirus 3 vaccine (inactivated) for
turkeys ............................................................................. 8.1-3693
Avian tuberculin purified protein derivative ....................... 3493
Avian viral tenosynovitis vaccine (live) ................................. 935
Avian viral vaccines: tests for extraneous agents in seed lots
(2.6.24.) ........................................................................... 8.1-3659
Azaperone for veterinary use ................................................ 1607
Azathioprine ............................................................................ 1608
Azelastine hydrochloride ....................................................... 1609
Azithromycin .......................................................................... 1610
B Bilberry fruit dry extract, fresh, refined and standardised .. 1250
B19 virus (B19V), validation of nucleic acid amplification
tec~niqu~s for the quantification of B19V DNA in plasma
pOOlS: gmdelmes ............................................................ 8.2-3921
Bacampicillin hydrochloride ................................................. 1615
Bacitracin ................................................................................. 1617
Bacitracin zinc ......................................................................... 1619
Baclofen ................................................................................... 1621
Bacterial endotoxins (2.6.14.) .................................................. 194
Bacterial endotoxins, guidelines for using the test for
(5.1.10.) .................................................................................... 572
Baical skullcap root ................................................................ 1161
Bambuterol hydrochloride .................................................... 1622
Barbados aloes ........................................................................ 1140
Barbital ..................................................................................... 1623
Barium chloratum for homoeopathic preparations .... 8.2-3984
Barium chloride dihydrate for homoeopathic
preparations ................................................................... 8.2-3984
Barium sulfate ......................................................................... 1624
Basic butylated methacrylate copolymer ............................. 1624
BCG for immunotherapy ......................................................... 818
BCG vaccine, freeze-dried ....................................................... 819
Bearberry leaf.. ........................................................................ 1162
Beclometasone dipropionate, anhydrous ............................. 1626
Beclometasone dipropionate monohydrate ......................... 1628
Beeswax, white ........................................................................ 1630
Beeswax, yellow....................................................................... 1630
Belamcanda chinensis rhizome ............................................. 1163
Belladonna leaf.. ...................................................................... 1165
Belladonna leaf dry extract, standardised ........................... 1166
Belladonna leaf tincture, standardised ................................. 1167
Belladonna, prepared ............................................................. 1168
Benazepril hydrochloride ...................................................... 1631
Bendroflumethiazide .............................................................. 1633
Benperidol ............................................................................... 1633
Benserazide hydrochloride .................................................... 1635
Bentonite .................................................................................. 1636
Benzalkonium chloride .......................................................... 1637
4126
EUROPEAN PHARMACOPOEIA 8.2
Benzalkonium chloride solution ........................................... 1638
Benzathine benzylpenicillin .................................................. 1647
Benzbromarone ....................................................................... 1640
Benzethonium chloride ......................................................... 1641
Benzocaine ............................................................................... 1642
Benzoic acid ............................................................................ 1643
Benzoin, Siam ......................................................................... 1169
Benzoin, Siam ......................................................................... 1169
Benzoin, Sumatra .................................................................... 1170
Benzoin tincture, Siam ........................................................... 1171
Benzoin tincture, Sumatra ..................................................... 1172
Benzoyl peroxide, hydrous .................................................... 1643
Benzyl alcohol ......................................................................... 1645
Benzyl benzoate ...................................................................... 1646
Benzylpenicillin, benzathine ................................................. 1647
Benzylpenicillin potassium ................................................... 1648
Benzylpenicillin, procaine ..................................................... 1650
Benzylpenicillin sodium ........................................................ 1651
Betacarotene ............................................................................ 1653
Betacyclodextrin ..................................................................... 1653
Betacyclodextrin, poly(hydroxypropyl) ether .............. 8.2-4050
Betadex ..................................................................................... 1653
Betahistine dihydrochloride .................................................. 1655
Betahistine mesilate ................................................................ 1656
Betamethasone ........................................................................ 1657
Betamethasone acetate ........................................................... 1659
Betamethasone dipropionate ................................................. 1661
Betamethasone sodium phosphate ....................................... 1663
Betamethasone valerate ......................................................... 1664
Betaxolol hydrochloride ......................................................... 1666
Bezafibrate ............................................................................... 1667
Bicalutamide ............................................................................ 1668
Bifonazole ................................................................................ 1670
Bilberry fruit, dried ................................................................ 1172
Bilberry fruit, fresh ................................................................. 1173
Biological assays (2.7.) ............................................................. 229
Biological assays and tests, statistical analysis of results of
(5.3.) ......................................................................................... 607
Biological indicators of sterilisation (5.1.2.) .......................... 556
Biological products, general texts on (5.2.) ........................... 579
Biological products, terminology used in monographs on
(5.2.1.) ...................................................................................... 579
Biologica! tests (2.6.) ................................................................ 175
Biotin ........................................................................................ 1671
Biperiden hydrochloride ........................................................ 1672
Biphasic insulin injection ...................................................... 2493
Biphasic isophane insulin injection ...................................... 2493
Birch leaf. ................................................................................. 1173
Bisacodyl .................................................................................. 1673
Bismuth subcarbonate ............................................................ 1675
Bismuth subgallate .................................................................. 1676
Bismuth subnitrate, heavy ..................................................... 1676
Bismuth subsalicylate ............................................................. 1677
Bisoprolol fumarate ................................................................ 1678
Bistort rhizome ....................................................................... 1175
Bitter fenne! ............................................................................. 1241
Bitter-fennel fruit oil .............................................................. 1176
Bitter-fenne! herb oil .............................................................. 1177
Bitterness value (2.8.15.) .......................................................... 276
Bitter-orange epicarp and mesocarp .................................... 1179
Bitter-orange-epicarp and mesocarp tincture ..................... llSO
Bitter-orange flower ................................................................ 1181
Bitter-orange-flower oil .......................................................... 1329
Black cohosh ..................................................................... 8.1-3702
Blackcurrant leaf.. ................................................................... 1186
Black horehound ..................................................................... 1185
Bleomycin sulfate .................................................................... 1680
Blood and blood components, empty sterile containers of
plasticised poly(vinyl chloride) for (3.2.4.) ......................... 417
Blood and blood components, human, materials for container s
for (3.1.1.) ................................................................................ 375
See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2
Blood and blood components, sets for the transfusion of
(3.2.6.) ...................................................................................... 418
Blood and blood components, sterile plastic containers for
(3.2.3.) ...................................................................................... 415
Blood, anticoagulant and preservative solutions for .......... 1572
Blood, sterile containers of plasticised poly(vinyl chloride)
containing antieoagulant solution (3.2.5.) ........................... 418
Bogbean leaf ............................................................................ 1187
Boiling point (2.2.12.) ................................................................ 31
Boldo leaf.. ............................................................................... 1188
Boldo leaf dry extraet.. ........................................................... 1189
Borage (starflower) oil, refined ............................................. 1681
Borax ........................................................................................ 1682
Bordetella bronehiseptiea vaecine (live) for dogs ................. 936
Borie acid ................................................................................. 1682
Botulinum antitoxin ............................................................... l029
Botulinum toxin type A for injeetion .................................. 1683
Botulinum toxin type B for injeetion ................................... 1684
Bovine insulin ......................................................................... 2486
Bovine leptospirosis vaecine (inaetivated) ............................ 937
Bovine parainfluenza virus vaecine (live) .............................. 938
Bovine respiratory syncytial virus vaecine (live) .................. 940
Bovine rhinotraeheitis vaecine (live), infeetious .................. 983
Bovine serum .......................................................................... 1686
Bovine tubereulin purified protein derivative ..................... 3494
Bovine viral diarrhoea vaccine (inactivated) ........................ 941
Brimonidine tartrate ....................................................... 8.2-4007
Bromazepam ........................................................................... 1687
Bromhexine hydrochloride .................................................... 1688
Bromocriptine mesilate .......................................................... 1689
Bromperidol ............................................................................ 1692
Bromperidol decanoate .......................................................... 1693
Brompheniramine maleate .................................................... 1695
Bronchitis vaccine (inactivated), infectious, avian ............... 925
Bronchitis vaccine (live), infectious, avian .... " ...................... 926
Brotizolam ............................................................................... 1696
Brucellosis vaccine (live) (Brucella melitensis Rev. 1 strain) for
veterinary use .......................................................................... 942
Buccal tablets and sublingual tablets ...................................... 795
Buckwheat herb ...................................................................... 1190
Budesonide .............................................................................. 1697
Bufexamae ............................................................................... 1699
Buffer solutions (4.1.3.) ............................................................ 540
Buffer solutions (4.1.3.) ................................................... 8.1-3675
Buffer solutions (4.1.3.) ................................................... 8.2-3937
Buflomedil hydrochloride ...................................................... 1700
Bulk density and tapped density of powders (2.9.34.) ......... 343
Bumetanide ............................................................................. 1702
Bupivacaine hydrochloride .................................................... 1703
Buprenorphine ........................................................................ 1705
Buprenorphine hydroehloride .............................................. 1706
Bursal disease vaccine (inactivated), infectious, avian ......... 928
Bursal disease vaccine (live), infectious, avian ...................... 929
Buserelin .................................................................................. 1708
Buspirone hydrochloride ....................................................... 1709
Busulfan ................................................................................... 1711
Butcher's broom ...................................................................... 1192
Butylated methacrylate copolymer, basie ............................ 1624
Butylhydroxyanisole ............................................................... 1713
Butylhydroxytoluene .............................................................. 1714
Butyl parahydroxybenzoate ................................................... 1712
C Capsicum oleoresin, refined and standardised ................... 1196
Cabergoline ............................................................................. 1717
Cachets ....................................................................................... 781
Cadmium sulfate hydrate for homoeopathic prepara-
tions ................................................................................. 8.2-3985
Cadmium sulfuricum for homoeopathic prepara-
tions ................................................................................. 8.2-3985
Caffeine .................................................................................... 1718
Caffeine monohydrate ............................................................ 1719
Calcifediol ................................................................................ 1720
General Natices (1) apply ta all monagraphs and other texts
Index
Calcipotriol, anhydrous ......................................................... 1722
Calcipotriol monohydrate ..................................................... 1724
Calcitonin (salmon) ................................................................ 1726
Calcitriol .................................................................................. 1728
Calcium (2.4.3.) ......................................................................... 127
Calcium acetate, anhydrous .................................................. 1729
Calcium aseorbate .................................................................. 1731
Calcium carbonate .................................................................. 1731
Calciurn carboxymethylcellulose .......................................... 1774
Calcium chloride dihydrate ................................................... 1732
Calcium chloride hexahydrate .............................................. 1733
Calcium dobesilate rnonohydrate ......................................... 1733
Calcium edetate, sodium ...... " ............................................... 3233
Calcium folinate ...................................................................... 1734
Calcium glucoheptonate ........................................................ 1736
Calcium gluconate .................................................................. 1737
Calcium gluconate, anhydrous .............................................. 1738
Calcium gluconate for injection ........................................... 1739
Calcium glycerophosphate .................................................... 1740
Calcium hydrogen phosphate, anhydrous ........................... 1740
Calcium hydrogen phosphate dihydrate .............................. 1742
Calcium hydroxide ...................................... " ......................... 1743
Calcium in adsorbed vaccines (2.5.14.) ................................. 159
Calcium iodatum for homoeopathic preparations ...... 8.2-3985
Calcium iodide tetrahydrate for homoeopathic
preparations ............................................. " .................... 8.2-3985
Calcium lactate, anhydrous ................................................... 1743
Calcium lactate monohydrate ............................................... 1744
Calcium lactate pentahydrate ................................................ 1744
Calcium laetate trihydrate ..................................................... 1745
Calcium levofolinate pentahydrate ....................................... 1745
Calcium levulinate dihydrate ................................................ 1748
Calcium pantothenate ............................................................ 1749
Calciurn pentetate (sodium) for radiopharmaceutical
preparations .......................................................................... 1075
Calcium phosphate ................................................................. 1749
Calcium stearate ..................................................................... 1750
Calcium sulfate dihydrate ...................................................... 1751
Calendula tlower ..................................................................... 1193
Calf coronavirus diarrhoea vaccine (inactivated) ................. 943
Calf rotavirus diarrhoea vaccine (inactivated) ...................... 944
Calicivirosis vaccine (inactivated), feline .............................. 970
Calicivirosis vaccine (live), feline ........................................... 971
Camphor, D- ............................................................................ 1752
Camphor, racemic .................................................................. 1753
Candesartan cilexetil .............................................................. 1754
Canine adenovirus vaccine (inactivated) ............................... 945
Canine adenovirus vaccine (live) ............................................ 946
Canine distemper vaccine (live) .............................. ,.............. 947
Canine leptospirosis vaccine (inactivated) ............................ 948
Canine parainfluenza virus vaccine (live) ............................. 949
Canine parvovirosis vaccine (inactivated) ............................. 950
Canine parvovirosis vaccine (live) .......................................... 951
Cape aloes ................................................................................ 1141
Capecitabine ..................................................................... 8.1-372 7
Capillary electrophoresis (2.2.47.) ............................................ 79
Capillary electrophoresis (2.2.47.) (5.8.) ...................... 8.1-3679
Capillary viscometer method (2.2.9.) ....................................... 27
Caprylate, sodium ................................................................... 3234
Caprylic acid ........................................................................... 1756
Caprylocaproyl maerogolglycerides ..................................... 1757
Capsicum ................................................................................. 1194
Capsicum soft extract, standardised .................................... 1197
Capsicum tincture, standardised .......................................... 1198
Capsules ..................................................................................... 779
Capsules and tablets, disintegration of (2.9.1.) ..................... 285
Capsules and tablets, disintegration of (2.9.1.) (5.8.) .. 8.1-3680
Capsules, gastro-resistant ........................................................ 780
Capsules, hard ........................................................................... 780
Capsules, intrauterine .............................................................. 787
Capsules, modified-release ...................................................... 780
Capsules, oromucosal ............................................................... 795
4127
Index
Capsules, rectal ......................................................................... 806
Capsules, soft. ............................................................................ 780
Capsules, vaginaL ..................................................................... 813
Captopril .................................................................................. 1758
Caraway fruit ........................................................................... 1199
Caraway oil .............................................................................. 1200
Carbachol. ................................................................................ 1760
Carbamazepine ....................................................................... 1761
Carbasalate calcium ................................................................ 1762
Carbidopa ................................................................................ 1764
Carbimazole ..................................................................... 8.1-3728
Carbocisteine ........................................................................... 1766
Carbomers ............................................................................... 1766
Carbon dioxide ....................................................................... 1768
Carbon dioxide in gases (2.5.24.) ........................................... 161
Carbon monoxide ................................................................... 1769
Carbon monoxide eSO) ......................................................... 1048
Carbon monoxide in gases (2.5.25.) ....................................... 162
Carboplatin .............................................................................. 1770
Carboprost trometamol ......................................................... 1771
Carboxymethylcellulose ......................................................... 1773
Carboxymethylcellulose calcium .......................................... 1774
Carboxymethylcellulose sodium ........................................... 1774
Carboxymethylcellulose sodium, cross-linked ................... 1969
Carboxymethylcellulose sodium, low-substituted .............. 1775
Carisoprodol. ........................................................................... 1772
Carmellose ............................................................................... 1773
Carmellose calcium ................................................................ 1774
Carmellose sodium ................................................................. 1774
Carmellose sodium and microcrystalline cellulose ............ 2776
Carmellose sodium, low-substituted .................................... 1775
Carmustine .............................................................................. 1776
Carnauba wax.......................................................................... 1777
Carprofen for veterinary use ................................................. 1778
Carrageenan ............................................................................ 1779
Carteolol hydrochloride ......................................................... 1780
Carvedilol ................................................................................ 1781
Cascara ..................................................................................... 1201
Cascara dry extract, standardised ......................................... 1202
Cassia oil .................................................................................. 1203
Castor oil, hydrogenated ........................................................ 1782
Castor oil, polyoxyL ............................................................... 2665
Castor oil, polyoxyl hydrogenated ........................................ 2664
Castor oil, refined ................................................................... 1783
Castor oil, virgin ..................................................................... 1784
Catgut, sterile .......................................................................... 1117
Catgut, sterile, in distributor for veterinary use ................. 1127
CD34/CD45+ cells in haematopoietic products, numeration
of (2.7.23.) ................................................................................ 258
Cefaclor .................................................................................... 1785
Cefadroxil monohydrate ........................................................ 1786
Cefalexin monohydrate .......................................................... 1788
Cefalotin sodium .................................................................... 1789
Cefamandole nafate ................................................................ 1791
Cefapirin sodium .................................................................... 1792
Cefatrizine propylene glycol... ............................................... 1793
Cefazolin sodium ............................................................. 8.1-3729
Cefepime dihydrochloride monohydrate ............................ 1796
Cefixime ................................................................................... 1799
Cefoperazone sodium ............................................................ 1800
Cefotaxime sodium ................................................................ 1801
Cefoxitin sodium .................................................................... 1803
Cefpodoxime proxetil ............................................................ 1805
Cefprozil monohydrate .......................................................... 1807
Cefradine ................................................................................. 1809
Ceftazidime pentahydrate ...................................................... 1811
Ceftazidime pentahydrate with sodium carbonate for
injection ................................................................................. 1813
Ceftriaxone sodium ................................................................ 1815
Cefuroxime axetil ................................................................... 1817
Cefuroxime sodium ................................................................ 1818
Celandine, greater ................................................................... 1268
Celecoxib ................................................................................. 1819
4128
EUROPEAN PHARMACOPOEIA 8.2
Celiprolol hydrochloride ....................................................... 1820
Cell count and viability, nucleated (2.7.29.) .......................... 263
Cell cultures for the production of veterinary vaccines
(5.2.4.) ...................................................................................... 585
Cell substrates for the production of vaccines for human use
(5.2.3.) ...................................................................................... 582
Cellular products, microbiological control of (2.6.27.) ........ 216
Cellulose acetate (5.8.) .................................................... 8.1-3679
Cellulose acetate .............................................................. 8.1-3731
Cellulose acetate butyrate ...................................................... 1823
Cellulose acetate phthalate (5.8.) ................................... 8.1-3679
Cellulose acetate phthalate ............................................. 8.1-3733
Cellulose, microcrystalline .................................................... 1824
Cellulose (microcrystalline) and carmellose sodium ......... 2776
Cellulose, powdered ............................................................... 1828
Centaury .................................................................................. 1204
Centella .................................................................................... 1205
Cetirizine dihydrochloride .................................................... 1831
Cetostearyl alcohol ................................................................. 1833
Cetostearyl alcohol (type A), emulsifying .................... 8.1-3734
Cetostearyl alcohol (type B), emulsifying .................... 8.1-3735
Cetostearyl isononanoate ...................................................... 1836
Cetostearyl sulfate, sodium ............................................ 8.1-3814
Cetrimide ................................................................................. 1836
Cetyl alcohoL .......................................................................... 1837
Cetyl palmitate ........................................................................ 1838
Cetylpyridinium chloride ...................................................... 1838
Ceylon cinnamon bark oil ..................................................... 1210
Ceylon cinnamon leaf oil ....................................................... 1211
CFC assay for human haematopoietic progenitor cells
(2.7.28.) .................................................................................... 262
Chamomile flower, Roman ................................................... 1206
Characterisation of crystalline and partially crystalline solids
by X-ray powder diffraction (XRPD) (2.9.33.) ................... 339
Characterisation of crystalline solids by microcalorimetry and
solution calorimetry (2.2.61.) ................................................ 106
Characterisation of preparations for nebulisation (2.9.44.) .. 363
Characters section in monographs (5.11.) ............................ 695
Charcoal, activated ................................................................. 1839
Chenodeoxycholic acid ......................................................... 1840
Chewable tablets ....................................................................... 811
Chewing gums, medicated ...................................................... 781
Chewing gums, medicated, dissolution test for (2.9.25.) ..... 325
Chicken anaemia vaccine (live), infectious ........................... 984
Chicken flocks free from specified pathogens for the
production and quality control ofvaccines (5.2.2.) ........... 579
Chitosan hydrochloride ......................................................... 1841
Chlamydiosis vaccine (inactivated), feline ........................... 972
Chloral hydrate ....................................................................... 1842
Chlorambucil .......................................................................... 1843
Chloramine .............................................................................. 3450
Chloramphenicol .................................................................... 1844
Chloramphenicol palmitate ................................................... 1845
Chloramphenicol sodium succinate ..................................... 1846
Chlorcyclizine hydrochloride ................................................ 1847
Chlordiazepoxide .................................................................... 1848
Chlordiazepoxide hydrochloride .......................................... 1849
Chlorhexidine diacetate ......................................................... 1850
Chlorhexidine digluconate solution ..................................... 1851
Chlorhexidine dihydrochloride ............................................ 1854
Chlorides (2.4.4.) ...................................................................... 127
Chlormadinone acetate ................................................... 8.2-4011
Chlorobutanol, anhydrous ..................................................... 1855
Chlorobutanol hemihydrate .................................................. 1855
Chlorocresol ............................................................................ 1856
Chloroquine phosphate ......................................................... 1857
Chloroquine sulfate ................................................................ 1857
Chlorphenamine maleate ...................................................... 1858
Chlorpromazine hydrochloride ............................................ 1859
Chlorpropamide ..................................................................... 1861
Chlorprothixene hydrochloride ............................................ 1862
Chlortalidone .......................................................................... 1863
Chlortetracycline hydrochloride ........................................... 1865
See the information section on general monographs (caver pages)
EUROPEAN PHARMACOPOEIA 8.2
Cholecalciferol ........................................................................ 1867
Cholecalciferol concentrate (oily form) ............................... 1869
Cholecalciferol COl1centrate (powder form) ........................ 1870
Cholecalciferol concentrate (water-dispersible form) ........ 1872
Cholera vaccine ..... ,....... ,..... ,.................................................... , 821
Cholera vaccine, freeze-dried .................................................. 821
Cholera vaccine (inactivated), fowl.. .................. ,................... 980
Cholera vaccine (inactivated, oral) ......................................... 822
Cholesterol... ........... ,....... " .... ,........... '", .. ,... ,................. ,.. , 8.2-4012
Cholesterol for parenteral use ............ " ..... " ......... " ............... 1874
Cholesterol in oils rich in omega-3 acids, total (2.4.32.) ..... 151
Chondroitin sulfate sodium .................................................. 1876
Chromatographic separation techniques (2.2.46,) ................. 72
Chromatography, gas (2.2.28.) ............................. " ................... 43
Chromatography, liquid (2.2.29.) ..................... " .... " ................ 45
Chromatography, papel' (2.2.26.) ............................................. 42
Chromatography, size-exclusion (2,2.30,) ............................... 46
Chromatography, supercritical fluid (2.2.45,) ............... ,......... 72
Chromatography, thin-Iayer (2.2.27.) ...................................... 42
Chromium e1Cr) edetate injection ." ................................. ,.1049
Chymotrypsin ............................ ,........................................... , 1878
Ciclesonide .. ,' ............. ,...... ,.................................. ,.......... ,...... ,1879
Ciclopirox ...... " ................................... ,' ............ ,...... " .............. 1880
Ciclopirox olamine ,... ,.......... " ................ ,..... ,.... ,........... ,........ 1881
Ciclosporin .... ,...................... ,............. "", ..................... ,...... ,... 1883
Cilastatin sodium ................................. ,.. ,................. ,...... 8.2-4013
Cilazapril ...... " .... ,.. ,.... ,. ,." ........ ' .... ," .. """, ,., ............................ 1885
Cimetidine ,.......... "." ..................... " ............. ,..... ,..... ,.............. 1887
Cimetidine hydrochloride .......... ,.......... ,...................... ,........ 1888
Cinchocaine hydrochloride ................................................... 1890
Cinchona bark, .... ,................. ,................ ,.......... ,........... ,......... 1207
Cinchona liquid extract, standardised ,............................. ".1208
Cine ole " .... ,... ", ....... ,,,,, ............................. ,... ,..... ,, .......... ,, .... ,.. 1891
Cineole in essential oils, 1,8-, assay of (2.8.11.) .................... 272
Cineole type niaouli oil" .............. " .... " ....... " ............. " ........ " 1332
Cinnamon"" .. " ........... ,............ ,........... ,.............. ,...... ,.... ,.... ,.. , 1209
Cinnamon bark oil, Ceylon .. " ..... " ............ " .......................... 1210
Cinnamon leaf oil, Ceylon ..................................................... 1211
Cinnamon tincture ...... ,.................................. ,... ,..... ,.... ,..... ,.. 1212
Cinnarizine ........ ,,,, .. ,... ,,, ....... ,... ,.... ,, .... ,, .... ,,, .................. ,, ...... 1892
Ciprofibrate ...... ,... ,....... ,..... ", .... ,."." ......... ,..... " .. " ..... ' .... " ...... 1893
Ciprofloxacin"." ........................... ,., ... " ... ,.,,, ............... ,, ...... ,,,.1894
Ciprofloxacin hydrochloride ... ""." ......... """ ..... "" ....... " ...... 1896
Circular dichroism (2.2.41.) ....... " .... " .......... " ......... " .... " .... " .... 67
Cisplatin ........... " ... ,..................... "" ...................... ,.......... ,....... 1897
Citalopram hydrobromide."" ... ,....... " ....... ,......... ,,, .......... ,... , 1899
Citalopram hydrochloride"., ............. " ........ " ....... ,......... " ..... 1900
Citric acid, anhydrous (5.8.) .......... " ............................... 8.1-3679
Citric acid, anhydrous" ................................................... 8.1-3736
Citric acid monohydrate (5.8.) ....... "." ....................... " .. 8.1-3679
Citric acid monohydrate .... " ............. " ............ " ........ ", ... 8.1-3737
Citronella oil. ..... ,............ ", ........................... " ........... " ........... , 1212
Cladribine .. ,,, ..... ,.,, .. ,..... ,,,, .. ,........... ,, .. ,,,, ......... ,..... ,,.,, ............ 1903
Clarithromycin ......... " ............. " .. " .......... ,.... ,.... " ... " .......... ,.... 1904
Clarity and degree of opalescence ofliquids (2.2.1.) .............. 21
Clary sage oil ........ " .. ,." ......... ,................ ,..... " ........ " .... " ...... ". 1213
Classical swine-fever vaccine (live, prepared in cell
cultures) ................................. " ........... " .............................. ". 1019
Clazuril for veterinary use." ... " .. " ...... " ......... " .. " ..... "." ........ 1906
Clebopride malate .............. "" .. ," ... ,, .......... ,........................... 1908
Clemastine fumarate ..... " .. " ............. " ............................. 8.1-3738
Clematis armandii stem .................... " ................. ,..... ,..... "" .. 1214
Clenbuterol hydrochloride .................... " ................. " ... " .... " 1911
Clindamycin hydrochloride ................... " ............................. 1912
Clindamycin phosphate .............................. " ......................... 1913
Clioquinol ......... " ............................ ,.... " .......................... " ...... 1914
Clobazam ............. ,.................... ,...... ,,, ...... ,, ... ,, ............ ,,, .. ,, .. ,.. 1915
Clobetasol propionate ......... ,............ ", ... " ........ ,.... ,.' .... ,......... 1916
Clobetasone butyrate, ..... "" ..................... ,.... " ... ,........... ,........ 1918
Clodronate disodium tetrahydrate ....... " ......... " ................... 1919
Clofazimine ........... " ....... ,... ,,, ..................... ,, ............... ,... ,, .... ,.1920
Clofibrate .. ,...... ,....... ,..... ",,,.,,.,,,.,,, .... ,., ... ,, .. ,.,, ...... ,..... ,...... ,,, .. 1921
Clornifene citrate ,."., .... " ........ ,............ ", ........... " ......... ,......... 1922
General Notices (1) apply to al! monographs and other texts
Index
Clomipramine hydrochloride ......... " ............. " ............. " ... ". 1924
Clonazepam ... ,............ ,." ........ ,... ,..... ,......... "., .. ", .. ,........ ,... ,.... 1925
Clonidine hydrochloride .... " ....... " .......... " ..... " .......... "." .. " ... 1926
Clopamide .. "., ... " ........... " ..... "" ..... " ............ " ......................... 1927
Clopidogrel hydrogen sulfate " .............................. " .... " ..... ". 1928
Clorazepate, dipotassium.,,, .... ,,,, ....... ,, ....... ,, ........ ,, ..... ,, ........ 2077
Closantel sodiurn dihydrate for veterinary use." ....... "."" .. 1930
Clostridium botulinum vaccine for veterinary use ........... ". 952
Clostridium chauvoei vaccine for veterinary use ... " ............ 953
Clostridium novyi alpha antitoxin for veterinary use,,, ..... 1037
Clostridium novyi (type B) vaccine for veterinary use ........ 954
Clostridium perfringens beta antitoxin for veterinary use
., ... ,..... " ......... ,., .. " .... "." .. ,....... ,....... ,."".,., .. ,......... " ... ,., .... ,... " 1038
Clostridium perfringens epsilon antitoxin for veterinary
use ........................... " .... ,.................. ,.. " .... ", ... " ... ,................ " 1039
Clostridium perfringens vaccine for veterinary use ............. 955
Clostridium septicum vaccine for veterinary use ................. 957
Closures and containers for parenteral preparations and
ophthalmic preparations, polypropylene for (3.1.6.) ......... 388
Closures and containers for pharmaceutical use, plastic
(3.2.2.) ............. """,,, ..... ,, ......... ,, .................................. ,,, ....... ,, 414
Closures and tubing, silicone elastomer for (3,1.9.) ........... " 394
Closures for containers for aqueous parenteral preparations,
for powders and for freeze-dried powders, rubber
(3.2.9.) .............. ,.... ,." ...... ,..... " .. " ...................... ,................ ,..... 421
Clotrimazole ......... ,.................... " .............. ,.......... " .. ,.............. 1931
Clove ......... ", ....... ,................. "" ................ ",,,., .......... ,... " ..... ,... 1215
Clove oil ..... "., ............................................ " .. ,.... ,., ... " ............. 1216
Cloxacillin sodium ................. " ............... " ...... ,.. " .... ,............. 1933
Clozapine ,...... ,,, .. ,, .............. ,,,, ..... ,, ........ ,...... ,.,, ....... ,.............. , 1934
Coagulation factor JI, assay of (2.7.18.) ......... ,........ " ............. 254
Coagulation factor IX, human ... " ............ " .............. " .. " ....... 2416
Coagulation factor IX, human, assay of (2.7.11.) .. " ............. 248
Coagulation factor IX (rDNA) concentrated solution,
human .... """ ..... ,.. ,......... ,....... ,.. " ... " ....... ,.. ,,, .. ,.. ,,,,, ....... , 8.2-4043
Coagulation factors, activated (2.6.22,) .. " ........ " ... " .. " ....... ".209
Coagulation factors, assay of heparin (2.7,12,) ." .. " .............. 249
Coagulation factor VIla (rDNA) concentrated so!ution,
humal1 ... " .. ,.......... ,,, ................... ,.. ,.... ,,, .. ,, ... ,..... ,,,, ......... ,,, .. ,, 2410
Coagulation factor VII, human .... """ .................... " .... " ...... 2408
Coagulation factor VII, human, assay of (2.7.10.) ... " ........... 247
Coagulation factor VIII, human ........ " .. " ............................. 2414
Coagulation factor VIII, human, assay of (2.7.4,) ....... 8.2-3929
Coagulation factor VIII (rDNA), human .......... "" ... " ......... 2415
Coagulation factor X, assay of (2.7,19.) .......... " ......... " .......... 255
Coagulation factor XI, human ............ " ................ " ........ " .... 2417
Coagulation factor XI, human, assay of (2.7.22.) ." ..... 8.2-3930
Coated granules .... " ........ " ...... "" ..... " .. " ........ " .. ,..... ,................ 786
Coated tablets ..... ,.... ,.. ,... ", ................................ "."." ................ 810
Cocaine hydrochloride .......... ,,, .. ,,, .... ,, ... ,,, .............. ,, .... ,........ 1935
Coccidiosis vaccine (live) for chickens .... " ............ " ..... 8.1-3694
Cocculus Íor homoeopathic preparations .................... 8.2-3986
Coconut oil, refined, ............... " .... ,.. ,............................. ", ...... 1936
Cocoyl caprylocaprate .... "" .............. ,.. ,.... " ...... " ....... ,............ 1937
Codeine ......... ,.... " ....... " .... " ...... " .. " ...... ".", ................. " .......... 1938
Codeine hydrochloride dihydrate ................... " .................... 1939
Codeine phosphate hemihydrate .................... " ..... " ... " ........ 1941
Codeine phosphate sesquihydrate ." .... "." ..................... " ..... 1942
Codergocrine mesilate ............. " .... " .. ,........................ ,...... " .. 1944
Cod-liver oil, farmed,,, ................................. ,........ ,,., ....... ,, .. ,, 1946
Cod-liver oil (type A) .. ""." ..... " ......... "."."." .............. " ......... 1950
Cod-liver oil (type B) ... " ..... " ...... " .... " ............... " .. "" ............ 1954
Coix seed., .... " ... " .... " .... ,.... ,.......... " .... " ................................... 1217
Cola ... ".", ...... ".,,, .... ,..... ,,,., ..... ,.............. ,, ......... ,, ..... ,............ ",1218
Colchicine " .................. " ................... " ..... ,... "., ... ,..... ,.............. 1957
Cold-water vibriosis vaccine (inactivated) for salmonids" 1023
Colestyramine ...... ,....... ,.............. ,........... ,......... ,,, .... ,..... ,... ,,,,, 1959
Colibacillosis vaccine (inactivated), neonatal piglet .... " ...... 992
Colibacillosis vaccine (inactivated), neonatal ruminant... ... 994
Colistimethate sodium." .. ".,,, .. ,, ............... ,... ,, ........ ,, ............. 1960
Colistin sulfate ...... " ............. "' ..... " ..... " ......... " ........... ,.......... , 1961
Colloidal anhydrous silica ................. "" ........ " ........... ,,, ........ 3218
Colloidal hydrated silica .......... " .. " .. " .. " ... " .............. " ........... 3219
4129
Index
Colloidal silica, hydrophobic ................................................ 3220
Colloidal silver, for external use ........................................... 3221
Colony-forming cell assay for human haematopoietic
progenitor cells (2.7.28.) ........................................................ 262
Colophony ............................................................................... 1219
Coloration ofliquids (2.2.2.) ..................................................... 22
Common selfheal fruit-spike ................................................ 1219
Common stinging nettle for homoeopathic prepara-
tions ................................................................................. 8.2-3991
Comparative table of porosity of sintered-glass filters
(2.1.2.) ........................................................................................ 15
Complexometric titrations (2.5.11.) ....................................... 158
Composition of fatty acids by gas chromatography
(2.4.22.) .................................................................................... 136
Composition of fatty acids in oils rich in omega-3 acids
(2.4.29.) .................................................................................... 148
Compressed lozenges ............................................................... 795
Concentrated solutions for haemodialysis .......................... 2376
Concentrates for injections or infusions ................................ 797
Concentrates for intrauterine solutions ................................. 787
Conductivity (2.2.38.) ................................................................ 59
Coneflower herb, purple ........................................................ 1357
Coneflower root, narrow-Ieaved ........................................... 1327
Coneflower root, pale ............................................................. 1345
Coneflower root, purple ......................................................... 1359
Conjugated estrogens ............................................................. 2174
Consistency by penetrometry, measurement of (2.9.9.) ...... 299
Containers (3.2.) ....................................................................... 409
Containers and closures for parenteral preparations and
ophthalmic preparations, polypropylene for (3.1.6.) ......... 388
Containers and closures for pharmaceutical use, plastic
(3.2.2.) ...................................................................................... 414
Containers and tubing for total parenteral nutrition
preparations, poly(ethylene - vinyl acetate) for (3.1.7.) ..... 391
Containers for aqueous solutions for infusion, plastic
(3.2.2.1.) ................................................................................... 414
Containers for aqueous solutions for intravenous infusion,
materials based on plasticised poly(vinyl chloride) for
(3.1.14.) .................................................................................... 401
Containers for dry dosage forms for oral administration,
materials based on non-plasticised poly(vinyl chloride) for
(3.1.11.) .................................................................................... 397
Containers for human blood and blood components, materials
based on plasticised poly(vinyl chloride) for (3.1.1.1.) ...... 375
Containers for human blood and blood components, materials
for (3.1.1.) ................................................................................ 375
Containers for human blood and blood components, plastic,
sterile (3.2.3.) ........................................................................... 415
Containers for non-injectable aqueous solutions, materials
based on non-plasticised poly(vinyl chloride) for
(3.1.10.) .................................................................................... 395
Containers for parenteral preparations and for ophthalmic
preparations, polyethylene with additives for (3.1.5.) ........ 384
Containers for parenteral preparations and for ophthalmic
preparations, polyethylene without additives for (3.1.4.) .. 383
Containers for pharmaceutical use, glass (3.2.1.) ................. 409
Containers for preparations not for parenteral use,
polyethylene terephthalate for (3.1.15) ................................ 403
Containers, materials used for the manufacture of (3.1.) .... 375
Containers of plasticised poly(vinyl chloride) for human blood
and blood components, empty sterile (3.2.4.) ..................... 417
Containers of plasticised poly(vinyl chloride) for human blood
containing anticoagulant solution, sterile (3.2.5.) .............. 418
Contamination, microbial: microbial enumeration tests
(2.6.12.) .................................................................................... 185
Contamination, microbial: microbial enumeration tests
(2.6.12.) (5.8.) ................................................................. 8.1-3680
Contamination, microbial: test for specified micro-organisms
(2.6.13.) .................................................................................... 189
Contamination, microbial: test for specified micro-organisms
(2.6.13.) (5.8.) ................................................................. 8.1-3680
Content uniformity of single-dose preparations (2.9.6.) ..... 298
4130
EUROPEAN PHARMACOPOEIA 8.2
Control of impurities in substances for pharmaceutical use
(5.10.) ....................................................................................... 689
Control of microbiological quality, alternative methods for
(5.1.6.) ...................................................................................... 560
Copolymer, basic butylated methacrylate ........................... 1624
Copolymer, grafted, macrogol poly(vinyl alcohol) ............ 2660
Copolymer, methacrylic acid - ethyl acrylate (1:1) ............ 2727
Copolymer, methacrylic acid - ethyl acrylate (1:1) dispersion
30 per cent ............................................................................. 2728
Copolymer, methacrylic acid - methyl methacrylate
(1:1) ........................................................................................ 2729
Copolymer, methacrylic acid - methyl methacrylate
(1:2) ........................................................................................ 2730
Copolymer (type A), ammonio methacrylate ..................... 1549
Copolymer (type B), ammonio methacrylate ..................... 1550
Copovidone ............................................................................. 1962
Copper acetate monohydrate for homoeopathic
preparations ................................................................... 8.2-3988
Copper for homoeopathic preparations ....................... 8.2-3989
Copper sulfate, anhydrous ..................................................... 1964
Copper sulfate pentahydrate ................................................. 1965
Coriander .......................................................................... 8.2-3963
Coriander oil .................................................................... 8.2-3963
Coronavirus diarrhoea vaccine (inactivated), calf ............... 943
Cortisone acetate .................................................................... 1965
Cotton, absorbent ................................................................... 1967
Cottonseed oil, hydrogenated .............................................. 1968
Couch grass rhizome .............................................................. 1222
Creams ....................................................................................... 808
Cresol, crude ........................................................................... 1968
Crocus for homoeopathic preparations ........................ 8.2-3987
Cromoglicate, sodium ............................................................ 3240
Croscarmellose sodium ......................................................... 1969
Crospovidone .......................................................................... 1970
Crotamiton .............................................................................. 1971
Crystalline and partially crystalline solids, characterisation
by X-ray powder diffraction (XRPD) of (2.9.33.) ............... 339
Crystalline solids, characterisation by microcalorimetry and
solution calorimetry (2.2.61.) ................................................ 106
Crystallinity (5.16.) ................................................................... 723
Cuprum aceticum for homoeopathic preparations ..... 8.2-3988
Cuprum metallicum for homoeopathic preparations .. 8.2-3989
Cutaneous application, liquid preparations for .................... 789
Cutaneous application, powders for.. ..................................... 799
Cutaneous application, semi-solid preparations for ............ 807
Cutaneous application, veterinary liquid preparations for.. 814
Cutaneous foams ...................................................................... 790
Cutaneous patches .................................................................... 807
Cyanocobalamin (57CO) capsules .......................................... 1049
Cyanocobalamin (57CO) solution .......................................... 1050
Cyanocobalamin (S8CO) capsules .......................................... 1051
Cyanocobalamin (S8CO) solution .......................................... 1051
Cyanocobalamin .............................................................. 8.2-4016
Cyclamate, sodium ................................................................. 3241
Cyclizine hydrochloride ......................................................... 1974
Cyclopentolate hydrochloride ............................................... 1975
Cyclophosphamide ................................................................. 1976
Cyproheptadine hydrochloride ............................................. 1977
Cyproterone acetate ................................................................ 1978
Cysteine hydrochloride monohydrate .................................. 1980
Cystine ..................................................................................... 1981
Cytarabine ............................................................................... 1982
D
Dacarbazine ............................................................................. 1987
Dalteparin sodium .................................................................. 1988
Danaparoid sodium ................................................................ 1990
Dandelion herb with root ...................................................... 1223
Dandelion root ........................................................................ 1224
Dapsone ................................................................................... 1992
Daunorubicin hydrochloride ................................................ 1993
D-Camphor .............................................................................. 1752
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Decyl oleate ............................................................................. 1994
Deferoxamine mesilate ........................................................... 1994
Degree of coloration ofliquids (2.2.2.) .................................... 22
Dembrexine hydrochloride monohydrate for veterinary
use ........................................................................................... 1995
Demeclocycline hydrochloride ............................................. 1996
Demonstration of uniformity of dosage units using large
sample sizes (2.9.47.) ..................................................... 8.1-3669
Density of powders, bulk density and tapped (2.9.34.) ........ 343
Density of solids (2.2.42.) .......................................................... 68
Density of solids, gas pyenometric (2.9.23.) .......................... 324
Density, relative (2.2.5.) ............................................................. 25
Dental type silica .................................................................... 3219
Depressor substances (2.6.11.) ................................................ 185
Deptropine citrate ................................................................... 1998
Dequalinium chloride ............................................................ 1999
Desacyl-4' -monophosphoryllipid A, 3-0- ......................... 2000
Desflurane ................................................................................ 2002
Desipramine hydrochloride ................................................... 2003
Deslanoside ............................................................................. 2004
Desloratadine .......................................................................... 2005
Desmopressin .......................................................................... 2006
Desogestrel .............................................................................. 2007
Desoxycortone acetate ........................................................... 2008
Detection and measurement ofradioactivity (2.2.66.) ........ 110
Detector tubes, gas (2.1.6.) ........................................................ 17
Determination of aflatoxin El in herbal drugs (2.8.18.) ...... 276
Determination of metal catalyst or metal reagent residues
(2.4.20.) .................................................................................... 133
Determination of nitro gen by sulfuric acid digestion
(2.5.9.) ...................................................................................... 157
Determination of primary aromatic amino-nitrogen
(2.5.8.) ...................................................................................... 157
Determination of water by distillation (2.2.13.) ..................... 31
Detomidine hydrochloride for veterinary use .................... 2009
Devil's claw dry extract .......................................................... 1225
Devil's claw root ...................................................................... 1226
Dexamethasone ....................................................................... 2010
Dexamethasone acetate .......................................................... 2012
Dexamethasone isonicotinate ............................................... 2014
Dexamethasone sodium phosphate ............................... 8.1-3743
Dexchlorpheniramine milleate .............................................. 2018
Dexpanthenol .......................................................................... 2019
Dextran 1 for injection ........................................................... 2020
Dextran 40 for injection ........................................................ 2021
Dextran 60 for injection ........................................................ 2022
Dextran 70 for injection ........................................................ 2023
Dextranomer ........................................................................... 2023
Dextrans, molecular mass distribution in (2.2.39.) ................ 60
Dextrin ..................................................................................... 2024
Dextromethorphan hydrobromide ....................................... 2025
Dextromoramide tartrate ...................................................... 2026
Dextropropoxyphene hydrochloride .................................... 2027
Diacerein .................................................................................. 2028
Diazepam ................................................................................. 2030
Diazoxide ................................................................................. 2031
Dibrompropamidine diisetionate ......................................... 2032
Dibutyl phthalate .................................................................... 2033
Dichlorobenzyl alcohol, 2,4- .......................................... 8.1-3745
Dichloromethane .................................................................... 2743
Diclazuril for veterinary use .................................................. 2034
Diclofenac potassium ...................................................... 8.2-4019
Diclofenac sodium ........................................................... 8.2-4020
Dicloxacillin sodium .............................................................. 2038
Dicycloverine hydrochloride ................................................. 2039
Didanosine .............................................................................. 2040
Diethylcarbamazine citrate .................................................... 2042
Diethylene glycol and ethylene glycol in ethoxylated
substances (2.4.30.) ................................................................. 150
Diethylene glycol monoethyl ether ...................................... 2043
Diethylene glycol palmitostearate ......................................... 2044
Diethyl phthalate .................................................................... 2041
Diethylstilbestrol. .................................................................... 2045
General Natices (1) apply ta all managraphs and ather texts
Index
Diffraction, laser light, particle size anaiysis by (2.9.31.) ... 333
Difloxacin hydrochloride trihydrate for veterinary use ..... 2046
Digitalis leaÍ.. ................................................................. ,......... 1227
Digitoxin .................................................................................. 2048
Digoxin .................................................................................... 2049
Dihydralazine sulfate, hydrated ............................................ 2051
Dihydrocodeine hydrogen tartrate ....................................... 2052
Dihydroergocristine mesilate ................................................ 2053
Dihydroergotamine mesilate ................................................. 2056
Dihydroergotamine tartrate .................................................. 2058
Dihydrostreptomycin sulfate for veterinary use ................. 2059
Dihydrotachysterol ................................................................. 2061
Diltiazem hydrochloride ........................................................ 2062
Dimenhydrinate ...................................................................... 2063
Dimercaprol ............................................................................ 2065
Dimethylacetamide ................................................................ 2066
Dimethylaniline, N,N- (2.4.26.) .............................................. 146
Dimethyl sulfoxide ................................................................. 2066
Dimeticone .............................................................................. 2067
Dimetindene maleate ............................................................. 2068
Dinoprostone .......................................................................... 2070
Dinoprost trometamol ........................................................... 2069
Dioscorea oppositifolia rhizome .................................... 8.1-3705
Diosmin ................................................................................... 2072
Dioxan and ethylene oxide (2.4.25.) ....................................... 145
Dip concentra tes ....................................................................... 814
Diphenhydramine hydrochloride ......................................... 2073
Diphenoxylate hydrochloride ................................................ 2074
Diphtheria and tetanus toxins and toxoids, flocculation value
(LO of, (Ramon assay) (2.7.27.) ............................................ 261
Diphtheria and tetanus vaccine (adsorbed) .......................... 823
Diphtheria and tetanus vaccine (adsorbed, reduced antigen(s)
content) .................................................................................... 824
Diphtheria antitoxin ............................................................... 1029
Diphtheria, tetanus and hepatitis B (rDNA) vaccine
(adsorbed) ............................................................................... 825
Diphtheria, tetanus and pertussis (acellular, component)
vaccine (adsorbed) ................................................................. 826
Diphtheria, tetanus and pertussis (acellular, component)
vaccine (adsorbed, reduced antigen(s) content) ........ 8.2-3951
Diphtheria, tetanus and pertussis (whole ceH) vaccine
(adsorbed) ............................................................................... 827
Diphtheria, tetanus and poliomyelitis (inactivated) vaccine
(adsorbed, reduced antigen(s) content) ............................... 829
Diphtheria, tetanus, pertussis (acellular, component) and
haemophilus type b conjugate vaccine (adsorbed) ............ 830
Diphtheria, tetanus, pertussis (acellular, component) and
hepatitis E (rDNA) vaccine (adsorbed) ............................... 832
Diphtheria, tetanus, pertussis (acellular, component) and
poliomyelitis (inactivated) vaccine (adsorbed) ................... 834
Diphtheria, tetanus, pertussis (acellular, component) and
poliomyelitis (inactivated) vaccine (adsorbed, reduced
antigen(s) content) ................................................................. 835
Diphtheria, tetanus, pertussis (acellular, component),
hepatitis B (rDNA), poliomyelitis (inactivated) and
haemophilus type b conjugate vaccine (adsorbed) ............ 837
Diphtheria, tetanus, pertussis (acellular, component),
poliomyelitis (inactivated) and haemophilus type b conjugate
vaccine (adsorbed) ................................................................. 840
Diphtheria, tetanus, pertussis (whole cell) and poliomyelitis
(inactivated) vaccine (adsorbed) .......................................... 842
Diphtheria, tetanus, pertussis (whole ceH), poliomyelitis
(inactivated) and haemophilus type b conjugate vaccine
(adsorbed) ............................................................................... 844
Diphtheria vaccine (adsorbed) ................................................ 846
Diphtheria vaccine (adsorbed), assay of (2.7.6.) ................... 237
Diphtheria vaccine (adsorbed, reduced antigen content) ... 847
Dipivefrine hydrochloride ..................................................... 2075
Dipotassium clorazepate ........................................................ 2077
Dipotassium phosphate ......................................................... 2078
Diprophylline .......................................................................... 2078
Dipyridamole .......................................................................... 2079
Dirithromycin ......................................................................... 2081
4131
Index
Disintegration of suppositories and pessaries (2.9.2.) ......... 287
Disintegration of tablets and capsules (2.9.1.) ...................... 285
Disintegration of tablets and capsules (2.9.1.) (5.8.) ... 8.1-3680
Disodium clodronate tetrahydrate ....................................... 1919
Disodium edetate .................................................................... 2082
Disodium etidronate .............................................................. 2195
Disodium pamidronate pentahydrate .................................. 2956
Disodium phosphate, anhydrous .......................................... 2083
Disodium phosphate dihydrate ............................................. 2084
Disodium phosphate dodecahydrate .................................... 2084
Disopyramide .......................................................................... 2085
Disopyramide phosphate ....................................................... 2086
Dispersible tablets ..................................................................... 811
Dissolution, apparent (2.9.43.) ................................................ 361
Dissolution, intrinsic (2.9.29.) ................................................ 331
Dissolution test for lipophilic solid dosage forms (2.9.42.) .. 361
Dissolution test for solid dosage forms (2.9.3.) .................... 288
Dissolution test for transdermal patches (2.9.4.) .................. 295
Dissolution testing, recommendations on (5.17.1.) ............. 727
Distemper vaccine (live), canine ............................................. 947
Distemper vaccine (live) for mustelids .................................. 962
Distillation range (2.2.11.) ......................................................... 30
Distribution estimation by analytical sieving, particle-size
(2.9.38.) .................................................................................... 351
Distribution estimation by analytical sieving, particle-size
(2.9.38.) (5.8.) ................................................................. 8.1-3681
Disulfiram ................................................................................ 2087
Dithranol ................................................................................. 2088
DL-Methionine ........................................................................ 2734
DL-Q-Tocopheryl hydrogen succinate ................................... 3442
Dobesilate monohydrate, calcium ........................................ 1733
Dobutamine hydrochloride ................................................... 2089
Docetaxel, anhydrous ............................................................. 2090
Docetaxel trihydrate ............................................................... 2092
Docusate sodium .................................................................... 2094
Dodecyl gallate ........................................................................ 2094
Dog rose ................................................................................... 1228
Domperidone .......................................................................... 2095
Domperidone maleate ............................................................ 2097
Dopamine hydrochloride ...................................................... 2098
Dopexamine dihydrochloride ............................................... 2099
Dorzolamide hydrochloride .................................................. 210 1
Dosage forms (glossary) .......................................................... 779
Dosage units, demonstration of uniformity using large sample
sizes (2.9.47.) .................................................................. 8.1-3669
Dosage units, uniformity of (2.9.40.) ..................................... 357
Dosulepin hydrochloride ....................................................... 2103
DOTATOC (gallium (68 Ga» injection ................................. 1062
Doxapram hydrochloride ...................................................... 2104
Doxazosin mesilate ................................................................. 2105
Doxepin hydrochloride .......................................................... 2106
Doxorubicin hydrochloride ................................................... 2108
Doxycycline hyclate ................................................................ 2109
Doxycycline monohydrate ..................................................... 2111
Doxylamine hydrogen succinate ........................................... 2112
Droperidol ............................................................................... 2113
Droppers (2.1.1.) ......................................................................... 15
Drop point (2.2.17.) .................................................................... 32
Drops (nasal) and sprays (liquid nasal) ................................. 792
Drops, oral ................................................................................. 791
Drospirenone .......................................................................... 2115
Dry extracts ............................................................................... 746
Drynaria rhizome ................................................................... 1229
Dry residue of extracts (2.8.16.) .............................................. 276
Duck plague vaccine (live) ....................................................... 963
Duck viral hepatitis type 1 vaccine (live) ............................... 964
Duloxetine hydrochloride ...................................................... 2116
Dutasteride ....................................................................... 8.2-4022
Dwarf pine oil ......................................................................... 1230
Dydrogesterone ....................................................................... 2120
4132
EUROPEAN PHARMACOPOEIA 8.2
E
Ear drops and ear sprays .......................................................... 782
Ear powders ............................................................................... 782
Ear preparations ........................................................................ 781
Ear preparations, semi-solid ................................................... 782
Ear sprays and ear drops .......................................................... 782
Ear tampons .............................................................................. 782
Ear washes ................................................................................. 782
Ebastine .................................................................................... 2125
Eclipta herb ............................................................................. 1231
Econazole ................................................................................. 2126
Econazole nitrate .................................................................... 2127
Edetate (chromium (51Cr» injection .................................... 1049
Edetate, disodium ................................................................... 2082
Edetate, sodium calcium ........................................................ 3233
Edetic acid ............................................................................... 2128
Edotreotide (gallium (68 Ga» injection ................................. 1062
Edrophonium chloride ........................................................... 2129
Effervescent granules ............................................................... 786
Effervescent powders ............................................................... 800
Effervescent tablets ................................................................... 811
Efficacy of antimicrobial preservation (5.1.3.) ...................... 557
Efficacy of veterinary vaccines and immunosera, evaluation of
(5.2.7.) ...................................................................................... 591
Egg drop syndrome '76 vaccine (inactivated) ....................... 965
Elder flower ............................................................................. 1232
Electrophoresis (2.2.31.) ............................................................ 47
Electrophoresis (2.2.31.) (5.8.) ....................................... 8.1-3679
Electrophoresis, capillary (2.2.47.) ........................................... 79
Electrophoresis, capillary (2.2.47.) (5.8.) ...................... 8.1-3679
Eleutherococcus ...................................................................... 1234
Emedastine difumarate .......................................................... 2129
Emetine hydrochloride pentahydrate .................................. 2130
Empty sterile containers of plasticised poly(vinyl chloride) for
human blood and blood components (3.2.4.) ..................... 417
Emulsifying cetostearyl alcohol (type A) ...................... 8.1-3734
Emulsifying cetostearyl alcohol (type B) ...................... 8.1-3735
Emulsions, solutions and suspensions, oral .......................... 790
Enalaprilat dihydrate .............................................................. 2133
Enalapril maleate .................................................................... 2131
Encephalitis vaccine (inactivated), tick-borne ...................... 908
Encephalomyelitis vaccine (live), infectious, avian .............. 931
Endotoxins, bacterial (2.6.14.) ................................................ 194
Endotoxins, bacterial, guidelines for using the test for
(5.1.10.) .................................................................................... 572
Enilconazole for veterinary use ............................................ 2134
Enoxaparin sodium ......................................................... 8.1-3749
Enoxolone ................................................................................ 2136
Enrofloxacin for veterinary use ............................................. 2137
Entacapone .............................................................................. 2139
Enzootic pneumonia vaccine (inactivated), porcine .......... 1001
Ephedra herb ........................................................................... 1236
Ephedrine, anhydrous ............................................................ 2140
Ephedrine hemihydrate ......................................................... 2141
Ephedrine hydrochloride ....................................................... 2142
Ephedrine hydrochloride, racemic ....................................... 2143
Epinastine hydrochloride ....................................................... 2144
Epinephrine ............................................................................. 1490
Epinephrine tartrate ............................................................... 1491
Epirubicin hydrochloride ...................................................... 2145
Eptacog alfa (activated) concentrated solution ................... 2410
Equine herpesvirus vaccine (inactivated) .............................. 967
Equine influenza vaccine (inactivated) .................................. 968
Equisetum stem ...................................................................... 1237
Ergocalciferol .......................................................................... 2146
Ergoloid mesilates ................................................................... 1944
Ergometrine maleate ...................................................... :....... 2148
Ergotamine tartrate ................................................................ 2149
Erysipelas vaccine (inactivated), swine ................................ 1018
Erythritol ................................................................................. 2150
Erythromycin .......................................................................... 2151
Erythromycin estolate ............................................................ 2154
See the informatíon section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Erythromycin ethylsuccinate ................................................. 2156
Erythromycin lactobionate .................................................... 2158
Erythromycin stearate ............................................................ 2160
Erythropoietin concentrated solution .................................. 2162
Eserine salicylate ..................................................................... 3027
Esketamine hydrochloride ..................................................... 2166
Esomeprazole magnesium dihydrate ............................ 8.2-4027
Esomeprazole magnesium trihydrate ............................ 8.2-4028
Essential oils .............................................................................. 743
Essential oils, assay of 1,8-cineole in (2.8.1 l.) ....................... 272
Essential oils, fatty oils and resinified essential oils in
(2.8.7.) ...................................................................................... 271
Essential oils, foreign esters in (2.8.6.) ................................... 271
Essential oils in herbal drugs (2.8.12.) ................................... 273
Essential oils, odour and taste (2.8.8.) ................................... 272
Essential oils, residue on evaporation (2.8.9.) ....................... 272
Essential oils, solubility in alcohol (2.8.10.) .......................... 272
Essential oils, water in (2.8.5.) ................................................. 271
Ester value (2.5.2.) .................................................................... 155
Estradiol benzoate .................................................................. 2169
Estradiol hemihydrate ............................................................ 2171
Estradiol valerate .................................................................... 2172
Estriol ....................................................................................... 2173
Estrogens, conjugated ............................................................. 2174
Etacrynic acid .......................................................................... 2177
Etamsylate ................................................................................ 2178
Ethacridine lactate monohydrate .......................................... 2179
Ethambutol hydrochloride .................................................... 2180
Ethanol (96 per cent) (5.8.) ............................................ 8.1-3679
Ethanol (96 per cent) ....................................................... 8.1-3751
Ethanol, anhydrous (5.8.) ............................................... 8.1-3679
Ethanol, anhydrous .......................................................... 8.1-3753
Ethanol content (2.9.10.) ......................................................... 301
Ether ......................................................................................... 2185
Ether, anaesthetic ... " ............................................................... 2185
Ethinylestradiol ....................................................................... 2186
Ethionamide ............................................................................ 2188
Ethosuximide .......................................................................... 2188
Ethoxylated substances, ethylene glycol and diethylene glycol
in (2.4.30.) ............................................................................... 150
Ethyl acetate ............................................................................ 2190
Ethyl acrylate - methacrylic acid copolymer (1:1) .............. 2727
Ethyl acrylate - methacrylic acid copolymer (1:1) dispersion
30 per cent ............................................................................. 2728
Ethylcellulose ........................................................................... 2192
Ethylcellulose (5.8.) ......................................................... 8.1-3679
Ethylenediamine ..................................................................... 2193
Ethylene glycol and diethylene glycol in ethoxylated substances
(2.4.30.) .................................................................................... 150
Ethylene glycol monopalmitostearate .................................. 2193
Ethylene glycol monostearate ................................................ 2193
Ethylene oxide and dioxan (2.4.25.) ....................................... 145
Ethylhexanoic acid, 2- (2.4.28.) ............................................... 148
Ethylmorphine hydrochloride ............................................... 2194
Ethyl oleate .............................................................................. 2190
Ethyl parahydroxybenzoate ................................................... 2191
Ethyl parahydroxybenzoate sodium ..................................... 3243
Etidronate disodium ............................................................... 2195
Etilefrine hydrochloride ......................................................... 2196
Etodolac ................................................................................... 2197
Etofenamate ............................................................................. 2199
Etomidate ................................................................................. 2201
Etoposide ................................................................................. 2202
Eucalyptus leaf ................................................................. 8.2-3965
Eucalyptus oil .......................................................................... 1239
Eucommia bark. ...................................................................... 1240
Eugenol .................................................................................... 2205
European goldenrod ............................................................... 1265
European viper venom antiserum ........................................ 1033
Evaluation of efficacy of veterinary vaccines and immunosera
(5.2.7.) ...................................................................................... 591
Evaluation of safety of each batch of immunosera for
veterinary use (5.2.9.) ............................................................. 604
General Notices (1) apply to all monographs and other texts
Index
Evaluation of safety of veterinary vaccines and immunosera
(5.2.6.) ...................................................................................... 588
Evening primrose oil, refined ................................................ 2206
Excipients, functionality- related characteristics of (5.15.) .. 719
Extractable volume of parenteral preparations, test for
(2.9.17.) .................................................................................... 308
Extractable volume of parenteral preparations, test for (2.9.17.)
(5.8.) ................................................................................ 8.1-3681
Extracts ...................................................................................... 744
Extracts, dry .............................................................................. 746
Extracts, dry residue of (2.8.16.) ............................................. 276
Extracts, liquid .......................................................................... 745
Extracts, loss on drying of(2.8.17.) ........................................ 276
Extracts, soft .............................................................................. 746
Extracts used in the preparation of herbal medicinal products
for oral use, microbiological examination (2.6.31.) ........... 222
Extracts used in the preparation of herbal medicinal products
for oral use, microbiological quality (5.l.8.) ....................... 571
Extracts, water for preparation of.. ....................................... 3558
Extraneous agents in viral vaccines for human use, tests for
(2.6.16.) .................................................................................... 198
Extraneous agents: tests in batches of finished product of
avian live virus vaccines (2.6.25.) ......................................... 212
Extraneous agents: tests in seed 10ts of avian viral vaccines
(2.6.24.) ........................................................................... 8.1-3659
Eye drops ................................................................................... 783
Eye lotions ................................................................................. 783
Eye preparations ....................................................................... 782
Eye preparatiol1s, semi-solid ................................................... 784
F
Fo concept to steam sterilisation of aqueous preparations,
applicatiol1 of 1.5.) ............................................................. 560
Factor II, human coagulation, assay of (2.7.18.) ................... 254
Factor IX, human coagulation .............................................. 2416
Factor IX, human coagulation, assay of ................. 248
Factor IX (rDNA) concentrated solution, human
coagulation ..................................................................... 8.2-4043
Factor VIIa (rDNA) concentrated solution, human coagulation
................................................................................................ 2410
Factor VII, human coagulation ............................................. 2408
Factor VII, human coagulation, assay of (2.7.10.) ................ 247
Factor VIII, human coagulation ........................................... 2414
Factor VIII, human coagulation, assay of (2.7.4.) ....... 8.2-3929
Factor VIII (rDNA), human coagulation ............................ 2415
Factor X, human coagulation, assay of (2.7.19.) ................... 255
Factor XI, human coagulation .............................................. 2417
Factor XI, human coagulation, assay of (2.7.22.) ........ 8.2-3930
Falling ball viscometer method (2.2.49.) ................................. 85
Famotidine ............................................................................... 2211
Fat, hard ................................................................................... 2386
Fatty acids, composition by gas chromatography (2.4.22.) .. 136
Fatty acids in oils rich in omega-3 acids, composition of
(2.4.29.) .................................................................................... 148
Fatty oils, alkaline impurities in (2.4.19.) .............................. 133
Fatty oils and resinified essential oils in essential oils
(2.8.7.) ...................................................................................... 271
Fatty oils, foreign oils in, by thin-layer chromatography
(2.4.21.) .................................................................................... 136
Fatty oils, identification by thin-Iayer chromatography
(2.3.2.) ...................................................................................... 122
Fatty oils, sterols in (2.4.23.) .................................................... 139
Fatty oils, vegetable ................................................................... 775
Fc function of immunoglobulin, test for (2.7.9.) .................. 246
Febantel for veterinary use .................................................... 2212
Feeding stuffs for veterinary use, medicated, premixes for .. 800
Felbinac .................................................................................... 2213
Feline calicivirosis vaccine (inactivated) ................................ 970
Feline calicivirosis vaccine (Uve) ............................................. 971
Feline chlamydiosis vaccine (inactivated) ............................. 972
Feline infectious enteritis (feline panleucopenia) vaccine
(inactivated) ............................................................................ 973
4133
Index
Feline infectious enteritis (feline panleucopenia) vaccine
(live) ......................................................................................... 974
Feline leukaemia vaccine (inactivated) ......................... 8.1-3697
Feline panleucopenia vaccine (inactivated) ........................... 973
Feline panleucopenia vaccine (live) ....................................... 974
Feline viral rhinotracheitis vaccine (inactivated) ................. 976
Feline viral rhinotracheitis vaccine (live) .............................. 977
Felodipine ................................................................................ 2214
Felypressin ............................................................................... 2215
Fenbendazole for veterinary use ........................................... 2217
Fenbufen .................................................................................. 2218
Fennel, bitter ........................................................................... 1241
Fennel, sweet ........................................................................... 1242
Fenofibrate ............................................................................... 2219
Fenoterol hydrobromide ........................................................ 2220
Fentanyl. ................................................................................... 2221
Fentanyl citrate ........................................................................ 2223
Fenticonazole nitrate ....................................................... 8.2-4033
Fenugreek ................................................................................ 1244
Fermentation, products oL ..................................................... 758
Ferric chloride hexahydrate ................................................... 2225
Ferrous fumarate ..................................................................... 2226
Ferrous gluconate ................................................................... 2227
Ferrous sulfate, dried .............................................................. 2228
Ferrous sulfate heptahydrate ................................................. 2229
Ferrum metallicum for homoeopathic preparations .. 8.2-3989
Feverfew ................................................................................... 1244
Fexofenadine hydrochloride .................................................. 2230
Fibrinogen, human ................................................................. 2418
Fibrin sealant kit .............................................................. 8.2-4034
Filgrastim concentrated solution .......................................... 2233
Films, orodispersible ................................................................ 796
Finasteride ............................................................................... 2235
Fineness, powder (2.9.35.) ....................................................... 346
Fish oil, rich in omega-3 acids .............................................. 2236
Flavoxate hydrochloride ......................................................... 2238
Flecainide acetate ............................................................. 8.1-3757
Fleeceflower root.. ................................................................... 1245
Flocculation value (Lf) of diphtheria and tetanus toxins and
toxoids (Ramon assay) (2.7.27.) ............................................ 261
Flowability (2.9.16.) .................................................................. 307
Flow cytometry (2.7.24.) .......................................................... 259
FLT (1sF) injection .................................................................. 1045
Flubendazole ........................................................................... 2241
Flucloxacillin magnesium octahydrate ................................ 2242
Flucloxacillin sodium ............................................................. 2243
Fluconazole .............................................................................. 2245
Flucytosine ............................................................................... 2246
Fludarabine phosphate ........................................................... 2248
Fludeoxyglucose (1sF) injection ..................................... 8.2-3957
Fludrocortisone acetate .......................................................... 2250
Flumazenil ............................................................................... 2251
Flumazenil (N-[llClmethyl) injection .................................. 1054
Flumequine .............................................................................. 2253
Flumetasone pivalate .............................................................. 2254
Flunarizine dihydrochloride .................................................. 2255
Flunitrazepam ......................................................................... 2256
Flunixin meglumine for veterinary use ............................... 2257
Fluocinolone acetonide .......................................................... 2258
Fluocortolone pivalate ............................................................ 2259
Fluorescein .............................................................................. 2260
Fluorescein sodium ................................................................ 2262
Fluoride (1sF) solution for radiolabelling............................. 1055
Fluorides (2.4.5.) ....................................................................... 128
Fluorimetry (2.2.21.) .................................................................. 35
Fluorodeoxythymidine (1sF) injection ................................. 1045
Fluorodopa (1sF) (prepared by electrophilic substitution)
injection ................................................................................. 1056
Fluoromisonidazole (1sF) injection ....................................... 1058
Fluorouracil ............................................................................. 2263
Fluoxetine hydrochloride ....................................................... 2264
Flupentixol dihydrochloride .................................................. 2266
Fluphenazine decanoate ......................................................... 2268
4134
EUROPEAN PHARMACOPOEIA 8.2
Fluphenazine dihydrochloride .............................................. 2269
Fluphenazine enantate ........................................................... 2271
Flurazepam monohydrochloride .......................................... 2272
Flurbiprofen ............................................................................. 2273
Fluspirilene .............................................................................. 2274
Flutamide ................................................................................. 2275
Fluticasone propionate .................................................... 8.1-3758
Flutrimazole ............................................................................ 2278
Fluvastatin sodium ................................................................. 2279
Fluvoxamine maleate .............................................................. 2281
FMISO (1sF) injection ............................................................ 1058
Foams, cutaneous ..................................................................... 790
Foams, intrauterine .................................................................. 787
Foams, medicated ..................................................................... 784
Foams, rectal ............................................................................. 807
Foams, vaginal.. ......................................................................... 813
Folic acid .................................................................................. 2283
Folinate, calcium ..................................................................... 1734
Follitropin ......................................................................... 8.1-3760
Follitropin concentrated solution .................................. 8.1-3766
Foot-and-mouth disease (ruminants) vaccine
(inactivated) ............................................................................ 978
Foreign esters in essential oils (2.8.6.) .................................... 271
Foreign matter (2.8.2.) .................................................... 8.1-3665
Foreign oils in fatty oils by thin-layer chromatography
(2.4.21.) .................................................................................... 136
Formaldehyde, free (2.4.18.) .................................................... 132
Formaldehyde solution (35 per cent) ................................... 2295
Formoterol fumarate dihydrate ............................................. 2296
Foscarnet sodium hexahydrate ............................................. 2297
Fosfomycin calcium ................................................................ 2299
Fosfomycin sodium ................................................................ 2300
Fosfomycin trometamol ......................................................... 2301
Fosinopril sodium .................................................................. 2302
Fourstamen stephania root .................................................... 1246
Fowl cholera vaccine (inactivated) ......................................... 980
Fowl-pox vaccine (live) ............................................................ 981
Framycetin sulfate .................................................................. 2305
Frangula bark .......................................................................... 1247
Frangula bark dry extract, standardised .............................. 1249
Frankincense, Indian .............................................................. 1276
Fraxinus rhynchophylla bark ................................................ 1249
Free formaldehyde (2.4.18.) ..................................................... 132
Freezing point (2.2.18.) .............................................................. 34
Fresh bilberry fruit dry extract, refined and standardised .. 1250
Friability of granules and spheroids (2.9.41.) ........................ 359
Friability of uncoated tablets (2.9.7.) ..................................... 298
Friabilityofuncoated tablets (2.9.7.) (5.8.) .................. 8.1-3681
Fructose .................................................................................... 2306
Fucus ........................................................................................ 1286
Fulvestrant ........................................................................ 8.2-4035
Fumitory .................................................................................. 1252
Functional groups and ions, identification reactions of
(2.3.1.) ...................................................................................... 119
Functionality-related characteristics of excipients (5.15.) ... 719
Furosemide .............................................................................. 2309
Furunculosis vaccine (inactivated, oil-adjuvanted, injectable)
for salmonids ........................................................................... 982
Fusidate, sodium ..................................................................... 3245
Fusidic acid .............................................................................. 2310
G
Gabapentin .............................................................................. 2317
Galactose .................................................................................. 2318
Galantamine hydrobromide .................................................. 2319
Gallium (67 Ga) citrate injection ............................................ 1060
Gallium (6S Ga) chloride solution for radiolabelling ........... 1060
Gallium (6S Ga) DOTATOC injection ................................... 1062
Gallium (68 Ga) edotreotide injection ................................... 1062
Ganciclovir .............................................................................. 2321
Gargles ....................................................................................... 794
Garlic for homoeopathic preparations .......................... 8.2-3981
See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2
Garlic powder ............................................ ,..... ,.. " .. " .. ,,,.,,,, .. ,,,1254
Gas adsorption, specific surface area by (2,9.26.) "." ... "" ..... 329
Gas adsorption, specific surface are a by (2,9.26.)
(5.8,) .",,,,,,,, .. ,,,,,,,,.,, .. ,,,,,, ... ,, .. ,, .. ,.,,,, .. ,.,,., .. ,,,, .. ,,,, .... ,,,,,., 8.1-3681
Gas chromatography (2,2.28,) ... """" ......... " .. """." ... " .... ".".".43
Gas detector tubes (2.l.6.) ..... ""."." .......... "."" ... """ .. "."""."" 17
Gases, carbon dioxide in (2.5.24.) """" .. " ... ".,.""" ...... ,., ... "" 161
Gases, carbon monoxide in (2.5,25,) ." ....... " .. " ... "" ... " .......... 162
Gases, nitro gen monoxide and nitro gen dioxide in
(2.5.26.) '" .. "., " ... ". " .. """""'" .... " "" .. " .. " " ....... ," .. " ...... " " .. "., 163
Gases, nitrous oxide in (2.5,35.) ....... " ... " ...... " .. "" ... """" ...... 168
Gases, oxygen in (2.5.27,) " ....... " ........... " ... " .. " .. """ ... "."""." 163
Gases, water in (2.5,28.) ................ " ... " .. " .. ""." .. ".""""" ..... ". 163
Gas-gangrene antitoxin, mixed .............. " .. " ... " .... " .. " .. " ... ".1030
Gas-gangrene antitoxin (novyi) .... " ....... "" ...... """ .. ".""" .. " 1030
Gas-gangrene antitoxin (perfringens)."" ... "" .. """" ........ " .. 1031
Gas-gangrene antitoxin (septicum) ... ,... " ... " ... " .. ".""" .. " .... 1032
Gas pycnometric density of solids (2.9.23.)" .. " ..... " ....... ""." 324
Gastro-resistant capsules .... """ ... " ................... ,....... " ... "" .. " .. 780
Gastro-resistant granules .......... "."""."".,,, .. ,,,,.,,,,, ........... ",,.' 786
Gastro-resistant tablets """"." ... " .. " ... """."" .. "" ... "" .......... ". 811
Gelatin""." .. "., ..... ",,, .. ,,,,,,, .. ,, .......... ,,,, ............ ,,., ....... ,,".,8.1-3775
Gels .. ", ........ " .... " .. "'." ...... " .. " ...... " ........ ", .... ,........ ',,'.,, ..... " ... ,.. 808
Geis for injections" .... " .. """ ... ,... """.""." .. "" .. ,,, ..... ,..... ,, ... ,, ... 798
Gemcitabine hydrochloride ... " ... ".".".",,, ... ,, .. ,, ...... ,, ... ,...... ,, 2324
Gemfibrozil .... ,.................................... ".,, .......................... ,..... 2325
General notices (1.) ... "" .. " .. " ..... " .. "" ....... " ... " ............... 8.2-3897
General texts on biological products (5.2.) .... """."" ............ 579
General texts on microbiology (5.1.) .................. " ................. 555
Gene transfer medicinal products for human use (5.14.) .... 705
Gentamicin sulfate .......................................... ,... ,................... 2326
Gentian root ".".' ........... ,......................................... " ..... ,........ 1254
Gentian tincture, ......... " ...... ,....... ,.............. ,......... ,.................. 1255
Gestodene .. " .... " ... ,............ """ .. "" .... " ........ " .. ,...... " ... ,,, ... ,... ,, 2328
Ginger ....... '" ............ " .. ", .. ,...... ,..... "", ................. ,..... ,' .... ,....... 1256
Gingival solutions ....... ",,,,,,,,, .. ,.... ,...... ,, ........ ,... ,, ...... ,.... ,......... 794
Ginkgo dry extract, refined and quantified ...................... ". 1257
Ginkgo leaf ..... ,........ " ... " .. ,,,,,, ... ,..... ,, .. ,, ..... ,.... ,........ ,,., ..... ,' .. ,, 1259
Ginseng ,,, ........... ,,,., ......... ,,, ... ,,, .. ,.. ,, ......... ,... ,... ,,, .. ,...... ,,, .... ,.,, 1261
Ginseng dry extract ................ " ......... " .................... "" ... "." ... 1262
Glass containers for pharmaceutical use (3.2.1.) ............. " ... 409
Glibenclamide .. " ... ,,, ................ ,,, ....... ,, .. ,, ........ ,.. ,, .... ,,,, ..... ,... , 2330
Gliclazide ..... ,,, .... ,, .......... ,, ................. ,, .. ' ............... ,.,, ............ ,, 2332
Glimepiride .... ,.... ,....... "" ......................... ,,, ... ,, .. ,, ..... ,.... ,........ 2333
Glipizide .... " ..... " .......... " .......... ,,... ,.... ,..... " ........ " ...... ,......... ,.,. 2335
Glossary (dosage forms) ............. " ........................ " ................. 779
Glucagon, human ................ ,..................... ,.... ,... ,...... ,.. " ........ 2337
Glucoheptonate, calcium ....................................... "." ........... 1736
Glucosamine hydrochloride .. " ...................... ,.......... " ........... 2338
Glucosamine sulfate sodium chloride" ....... " ....................... 2339
Glucose, anhydrous ....................... ,,, ......... " .... " ......... ,........... 2340
Glucose, liquid ....... ,..... " ................................. ,............ ,........ ,. 2341
Glucose, liquid, spray-dried " ... " ........ "" ............................... 2342
Glucose monohydrate ... " ..... ,............ "",,, ............... ,.... ,......... 2343
Glutamic acid .... ,.. ,... " .... ,' .......... '" .... ', ... " .............. " ..... ,.... ,.... 2344
Glutathione., ,... " ., .. " ... ,.... " ,.. " ......... " " .. ,., ..... ,...... ", .. ", .. ,...... ,. 2345
Glycan analysis of glycoproteins (2.2.59,) ............................. 100
Glycerol., .. "." .......................... ,.......... ,,, .. ,.... ,........... ,, ............ ,,2346
Glycerol (85 per cent) ......................... " ............ "." .... " .......... 2348
Glycerol dibehenate ... ,........... " ..................... " ... ,................ ,... 2349
Glycerol diste arate ....... " .......... ,................. ,.... ,....................... 2350
Glycerol formal ... ,....... ,........... ,................ ,.... ,.... " .... ,............ " 2351
Glycerol monocaprylate." .. ,........................... ,." ...... ,............. 2351
Glycerol monocaprylocaprate ........... " .................................. 2352
Glycerol monolinoleate ................. " .......... ,.... ,............... " ...... 2353
Glycerol mono-oleate .. "",.", .... ,..... ,,, ............. ,.......... ,............ 2354
Glycerol monostearate 40-55 ................................................ 2355
Glycerol triacetate ... ,.... "", .... ,................................................. 3459
Glyceryl trinitrate solution ................. " ................................. 2356
Glycine ' ..... " ..... ', ... ,........... ", .......... " .......... " ....................... ,... , 2357
Glycoproteins, glycan analysis of (2,2.59.) ............................ 100
Glycopyrronium bromide"." ............ " .. ,,, ... ,.. ,, .... ,....... ,.... ,.. ,, 2358
Glycyrrhizate ammonium ...... ,... " ......... " ......... ,...... " ............ , 1552
General Notices (1) apply to all monographs and other texts
Index
Goldenrod ...... ,......... ,.... " ............. ,,,, .......... ,.... ,, ............... , 8,1-3706
Goldenrod, European."" ..... ,.... ",,,,,, ..... ,.. ,... ,..... ,................... 1265
Goldenseal rhizome ... " .. " ........... ,......... " ....... " .. ,,, .............. ,, .. 1266
Gonadorelin acetate., ... "", ........ ,..... "" ........... " ..................... ,. 2360
Gonadotrophin, chorionic .. ,., ..... """ ............. ,.. ,........ ,.... " ... " 2361
Gonadotrophin, equine serum, for veterinary use ....... " .... 2362
Goserelin""., .... ,... ,..... " ..... ", .. ,., .. " ....... ,....... ,., ..... ,.. " .... ,..... ,.... 2363
Grafted copolymer, macro gol poly(vinyl alcohol) .......... ", 2660
Gramicidin ......... ,........ ,,,,,,, ....... ,,, ........... ,.. ,..... ,, ... ,.. ,... ,...... ,,,, 2365
Granisetron hydrochloride ................. ,.......... " ...... ,............... 2366
Granules ... ,... ".,." .... " ....... ,.... ,...... ,... " .... ,.......... ",., ... "., ... ,., ....... 785
Granules and powders for oral solutions and suspensions .. 791
Granules and powders for syrups ..... "" ........ "" ............ " ... " .. , 791
Granules and spheroids, friability of (2.9.41.) ................. " .... 359
Granules, coated '., .. " .................. ,." ............. " ... ,.............. " ...... , 786
Granules, effervescent ", ............. ,... " ..... ,...... ,.... ,............... " ..... 786
Granules, gastro-resistant ........... ,.. " ........ ,......... " .................... 786
Granules, modified-release, .......... ",,, ................................ ,, .... 786
Greater celandine ............ " .............. ", ......................... ,........... 1268
Griseofulvin ... ,.... ,..... " .. ",,, ............... ,,, .................. ,................. 2367
Guaiacol ......... ,.... ,..... ".""" ................ " .............................. "" .. 2368
Guaifenesin .... ,............... ,,, ......... ,................ ,......... ,, .. ,.. ,........... 2370
Guanethidine monosulfate ...... " .... "" ....... " ...................... " ... 2371
Guar."., ............ ,... ,......... " ................... " ....... ,.......................... " 1269
Guar galactomannan ...... "" ........................ ,...... ,................... , 2371
Guidelines for using the test for bacterial endotoxins
(5,1.10.) ....................... ,.. ,......... ,....... ,..... ,................................. 572
Guidelines fol' using the test for sterility (5.1.9,) .................. 572
H
Haemagglutinins, anti-A and anti-B (2.6.20.) ...... " .... " ....... " 203
Haematopoietic products, numeration of CD34/CD45+ ceUs
in (2.7.23,) .... ,,, .... ,... ,,, ..... ,... ,.................. ,.............. ,, ....... ,, .... ,.. 258
Haematopoietic progenitor cells, human, colony-forming ceH
assay for (2.7,28,) .... " .................................. "." .... " ...... ""." .... 262
Haematopoíetic stem ceUs, human ....................... " .............. 2419
Haemodiafiltration and haemofiltration, solutions fOL ..... 2378
Haemodialysis, cOl1centrated solutions fol' ......... " .. " .......... 2376
Haemodialysis solutions, concentrated, water fol'
diluting.", .... ,. " ... " .... ,.. ", ..... ,.... ,., .. ,", ............ ,""" 2375
,'o , •••••• , , •••• ,.
Haemodialysis, solutions for ... " ..... "" ............................... "" 2376
Haemofiltration and haemodiafiltration, solutions fOL ..... 2378
Haemophilus type b (conjugate), diphtheria, tetanus and
pertussis (acellular, component) vaccine (adsorbed)" ....... 830
Haemophilus type b (conjugate), diphtheria, tetanus, pel'tussis
(acellular, component) and poliomyelitis (inactivated)
vaccine (adsorbed) .... """ ....... ,............. ,................... ,............. 840
Haemophilus type b (conjugate), diphtheria, tetanus, pertussis
(acellular, component), hepatitis B and poliomyelitis
(inactivated) vaccine (adsorbed) ....... " ................................. 837
Haemophilus type b (conjugate), diphtheria, tetanus,
pertussis (whole ceH) and poliomyelitis (inactivated) vaccine
(adsorbed) ........... ,............ ,............................... " ...... ' ............. ' 844
Haemophilus type b conjugate vaccine ...... "."." .................... 848
Haemorrhagic disease vaccine (inactivated), rabbiL ......... 1007
Halofantrine hydrochloride ....... ,................ ,.... " ........... ,........ 2381
Haloperidol." ...... ,. ,., ..... " ...... ,. ,. ,.. ,.,., .. ,.. ,,'o ••• " ,."" 2382
,., ••• , ••••• " . , •••
Haloperidol decanoate ", ..... ,........... " .................. ,.... ,." ... "." .. 2383
Halothane ..... " .. " .......................... ",,, ..... ,....... ,..... ,...... ,,, .. ,...... 2385
Hamamelis leaf... ...... ,.. ,... ,......... ,.. ".""."., .. " ......... " .............. " 1270
Hard capsules .. " .. ", .... " .. "" ........ ,......... ,........... " ..... ,.............. ".780
Hard fat .' ......... ' ......... ' .. ' .. ', ......... ,..... ", ..... ,.............. " .... " ......... 2386
Hard paraffin ............. ,................ ,............. ,.. " ............... ,...... "" 2964
Harmonisation, pharmacopoeial (5.8.) .................. " ..... 8.1-3679
Hawthorn berries" ........... " ... ,.... ,........ " ...... ,................ ,.......... 1271
Hawthorn leaf and flower ...................................................... 1272
Hawthorn leaf and flower dry extract.. ............. " ...... " ......... 1273
Hawthorn leaf and flower liquid extract, quantified ." ....... 1274
Heavy bismuth subnitrate ............. " ......... "." ... " ... " .......... "", 1676
Heavy kaolin ..... ,.. ,.. ,.. ,,, ..... ,......... ,, ........ ,...... ,, ... ,,, .................. , 2565
Heavy magnesium carbonate ....... " .............. " ... " .. " ..... " ....... 2670
Heavy magnesium oxide ........................ " ........... " ........ "" ..... 2677
4135
Index
Heavy metals (2.4.8.) ................................................................ 128
Heavy metals in herbal drugs and herbal drug preparations
(2.4.27.) ........................................................................... 8.2-3911
Hedera helix for homoeopathic preparations ..................... 1448
Helium ..................................................................................... 2387
Heparin, assay of (2.7.5.) ......................................................... 237
Heparin calcium ..................................................................... 2388
Heparin in coagulation factors, assay of (2.7.12.) ................. 249
Heparins, low-molecular-mass ............................................. 2392
Heparin sodium ...................................................................... 2390
Hepatitis A immunoglobulin, human .................................. 2420
Hepatitis A (inactivated, adsorbed) and typhoid polysaccharide
vaccine ..................................................................................... 851
Hepatitis A (inactivated) and hepatitis B (rDNA) vaccine
(adsorbed) ............................................................................... 852
Hepatitis A vaccine, assay of (2.7.14.) .................................... 251
Hepatitis A vaccine (inactivated, adsorbed) .......................... 853
Hepatitis A vaccine (inactivated, virosome) ......................... 854
Hepatitis B immunoglobulin for intravenous administration,
human .................................................................................... 2421
Hepatitis B immunoglobulin, human .................................. 2420
Hepatitis B (rDNA), diphtheria and tetanus vaccine
(adsorbed) ............................................................................... 825
Hepatitis B (rDNA), diphtheria, tetanus and pertussis
(acellular, component) vaccine (adsorbed) ......................... 832
Hepatitis B (rDNA), diphtheria, tetanus, pertussis (acellular,
component), poliomyelitis (inactivated) and haemophilus
type b conjugate vaccine (adsorbed) .................................... 837
Hepatitis B vaccine (rDNA) .................................................... 857
Hepatitis B vaccine (rDNA), assay of (2.7.15.) ...................... 252
Hepatitis C virus (HCV), validation of nucleic acid
amplification techniques for the detection of HCV RNA in
plasma pools: guidelines .............................................. 8.2-3921
Hepatitis type I vaccine (live), viral, duck ............................. 964
Heptaminol hydrochloride ........................................ ., .......... 2394
Herbal drug preparations .................................................... ., .. 746
Herbal drugs .............................................................................. 746
Herbal drugs and herhal drug preparations, heavy metals in
(2.4.27.) ........................................................................... 8.2-3911
Herbal drugs, determination of aflatoxin Bl in (2.8.18.) ..... 276
Herbal drugs, essential oils in (2.8.12.) .................................. 273
Herbal drugs for homoeopathic preparations ..................... 1429
Herbal drugs, microscopic examination of (2.8.23) ............. 282
Herbal drugs: sampling and sample preparation (2.8.20.) .. 278
Herbal drugs, tannins in (2.8.14.) ........................................... 275
Herbal drugs, test for aristolochic acids in (2.8.21) ............. 279
Herbal medicinal products for oral use and extracts used in
their preparation, microbiological examination (2.6.31.) .. 222
Herbal medicinal products for oral use and extracts used in
their preparation, microbiological quality (5.1.8.) ............. 571
Herbal preparations .................................................................. 746
Herbal substances ..................................................................... 746
Herbal teas ................................................................................. 747
Herbal teas, instant ................................................................... 748
Herpesvirus vaccine (inactivated), equine ............................. 967
Herpes zoster (shingles) vaccine (live) ................................... 902
Hexamidine diisetionate ........................................................ 2395
Hexetidine ............................................................................... 2396
Hexosamines in polysaccharide vaccines (2.5.20.) ............... 160
Hexylresorcinol ....................................................................... 2397
Highly purified water ............................................................. 3559
Histamine (2.6.10.) ................................................................... 184
Histamine dihydrochloride ................................................... 2398
Histidine ........................................................................... 8.2-4041
Histidine hydrochloride monohydrate ......................... 8.2-4042
Homatropine hydrobromide ................................................. 2401
Homatropine methylbromide ............................................... 2402
Homoeopathic pillules, impregnated ................................... 1441
Homoeopathic preparations .................................................. 1430
Homoeopathic preparations, Allium sativum fOl ....... 8.2-3981
Homoeopathic preparations, Anacardium for.. ........... 8.2-3981
Homoeopathic preparations, Apis for.. ......................... 8.2-3983
Homoeopathic preparations, arsenicum album for .... 8.2-3983
4136
EUROPEAN PHARMACOPOEIA 8.2
Homoeopathic preparations, aurum chloratum natronatum
for .................................................................................... 8.2-3984
Homoeopathic preparations, barium chloratum for... 8.2-3984
Homoeopathic preparations, cadmium sulfuricum
for .................................................................................... 8.2-3985
Homoeopathic preparations, calcium iodatum for ..... 8.2-3985
Homoeopathic preparations, Cocculus for .................. 8.2-3986
Homoeopathic preparations, Crocus for ...................... 8.2-3987
Homoeopathic preparations, cuprum aceticum for.. .. 8.2-3988
Homoeopathic preparations, cuprum metallicum
for .................................................................................... 8.2-3989
Homoeopathic preparations, ferrum metallicum for .. 8.2-3989
Homoeopathic preparations, hedera helix for .................... 1448
Homoeopathic preparations, herbal drugs for.. .................. 1429
Homoeopathic preparations, hydrastis canadensis for ...... 1449
Homoeopathic preparations, hyoscyamus for .................... 1450
Homoeopathic preparations, hypericum fOL. ..................... 1451
Homoeopathic preparations, kalium bichromicum
for .................................................................................... 8.2-3990
Homoeopathic preparations, magnesium phosphoricum
for .................................................................................... 8.2-3991
Homoeopathic preparations, mother tinctures for ..... 8.1-3715
Homoeopathic preparations, pillules for ............................. 1441
Homoeopathic preparations, sulfur for ............................... 1456
Homoeopathic preparations, Urtica dioica for ............ 8.2-3991
Homoeopathic stocks (methods of preparation 00 and
potentisation ........................................................................ , 1431
Honey ....................................................................................... 2403
Honey bee for homoeopathic preparations .................. 8.2-3983
Hop strobile ............................................................................. 1274
Human a -1- proteinase inhibitor .......................................... 2428
Human a-1-proteinase inhibitor, assay of (2.7.32.) .............. 266
Human albumin injection, iodinated (l25I) ......................... 1064
Human albumin solution ...................................................... 2404
Human anti-D immunoglobulin ................ ' ... 2406
0 0 , . • • 00 • • • • • • • • • • • • , .
Human anti-D immunoglobulin, assay of (2.7.13.) ............. 249
Human anti-D immunoglobulin for intravenous
administration ....................................................................... 2407
Human antithrombin III, assay of (2.7.17.) .......... 254
0 ••••••••••••••••
Human antithrombin III concentrate .................................. 2407
Human coagulation factor Il, assay of (2.7.18.) .................... 254
Human coagulation factor IX ............................................... 2416
Human coagulation factor IX, assay of (2.7.11.) .................. 248
Human coagulation factor IX (rDNA) concentrated
solution ........................................................................... 8.2-4043
Human coagulation factor VII .............................................. 2408
Human coagulation factor VIIa (rDNA) concentrated
solution .................................................................................. 2410
Human coagulation factor VII, assay of (2.7.10.) ...... 247
0 •••••• , •••
Human coagulation factor VIII ............................................ 2414
Human coagulation factor VIII, assay of (2.7.4.) ........ 8.2-3929
Human coagulation factor VIII (rDNA) ............................. 2415
Human coagulation factor X, assay of (2.7.19.) .................... 255
Human coagulation factor Xl ............................................... 2417
Human coagulation factor XI, assay of (2.7.22.) ......... 8.2-3930
Human fibrinogen .................................................................. 2418
Human glucagon ..................................................................... 2337
Human haematopoietic progenitor cells, colony-forming cel!
assay for (2.7.28.) .................................................................... 262
Human haematopoietic stem cens .................. ,..................... 2419
Human hepatitis A immunoglobulin ................................... 2420
Human hepatitis B immunoglobulin ................................... 2420
Human hepatitis B immunoglobulin fOI intravenous
administration ....................................................................... 2421
Human insulin ........................................................................ 2491
Human measles immunoglobulin ........................................ 2421
Human normal immunoglobulin ......................................... 2421
Human normal immunoglobulin for intravenous
administration .................................................. 0 ••••••••••••••••• , 2423 ••
Human papillomavirus vaccine (rDNA) ............................... 859
Human plasma for fractionation .......................................... 2425
Human plasma (pooled and treated for virus
inactivation) ................................................................... 8.2-4048
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Human plasmin inhibitor, assay of (2.7.25.) ......................... 261
Human protein C, assay of (2.7.30.) ....................................... 265
Human protein S, assay of (2.7.31.) ........................................ 266
Human prothrombin complex .............................................. 2429
Human rabies immunoglobulin ........................................... 2431
Human rubella immunoglobulin ......................................... 2432
Human tetanus immunoglobulin ......................................... 2432
Human varicella immunoglobulin ....................................... 2434
Human varicella immunoglobulin for intravenous
administration ....................................................................... 2434
Human von Willebrand factor .............................................. 2435
Human von Willebrand factor, assay of (2.7.21.) ................. 257
Hyaluronate, sodium .............................................................. 3248
Hyaluronidase ........................................................................ 2436
Hydralazine hydrochloride .................................................... 2437
Hydrastis canadensis for homoeopathic preparations ....... 1449
Hydrochloric acid, concentrated .......................................... 2438
Hydrochloric acid, dilute ....................................................... 2438
Hydrochlorothiazide .............................................................. 2439
Hydrocodone hydrogen tartrate 2.5-hydrate ...................... 2440
Hydrocortisone ....................................................................... 2442
Hydrocortisone acetate .......................................................... 2444
Hydrocortisone hydrogen succinate ..................................... 2446
Hydrogenated ara chis oil ....................................................... 1584
Hydrogenated castor oil ......................................................... 1782
Hydrogenated cottonseed oil ................................................. 1968
Hydrogenated soya-bean oil .................................................. 3289
Hydrogenated vegetable oils, nickel in (2.4.31.) ................... 150
Hydrogenated wool fat ........................................................... 3569
Hydrogen peroxide solution (30 per cent) .......................... 2448
Hydrogen peroxide solution (3 per cent) ............................ 2448
Hydromorphone hydrochloride ............................................ 2449
Hydrophobic colloidal silica .................................................. 3220
Hydrous wool fat .................................................................... 3570
Hydroxocobalamin acetate .................................................... 2450
Hydroxocobalamin chloride .................................................. 2451
Hydroxocobalamin sulfate ..................................................... 2452
Hydroxycarbamide ................................................................. 2453
Hydroxyethylcellulose ............................................................ 2455
Hydroxyethylmethylcellulose ................................................ 2745
Hydroxyethyl salicylate .......................................................... 2454
Hydroxyethyl starches ............................................................ 3307
Hydroxyl value (2.5.3.) ............................................................. 155
Hydroxypropylbetadex .................................................... 8.2-4050
Hydroxypropylcellulose ......................................................... 2458
Hydroxypropylmethylcellulose ............................................. 2466
Hydroxypropylmethylcellulose (5.8.) ............................ 8.1-3679
Hydroxypropylmethylcellulose phthalate ............................ 2468
Hydroxypropyl starch ............................................................. 3303
Hydroxypropyl starch, pregelatinised .................................. 3305
Hydroxyzine hydrochloride ................................................... 2459
Hymecromone ......................................................................... 2460
Hyoscine .................................................................................. 2461
Hyoscine butylbromide .......................................................... 2462
Hyoscine hydrobromide ........................................................ 2464
Hyoscyamine sulfate ............................................................... 2465
Hyoscyamus for homoeopathic preparations ..................... 1450
Hypericum ............................................................................... 1391
Hypericum for homoeopathic preparations ........................ 1451
Hypromellose .......................................................................... 2466
Hypromellose (5.8.) ......................................................... 8.1-3679
Hypromellose phthalate ......................................................... 2468
Ibuprofen ................................................................................. 2473
Iceland moss ............................................................................ 1275
ICH (5.8.) .......................................................................... 8.1-3679
Ichthammol ............................................................................. 2475
Identification (2.3.) ................................................................... 119
Identification and control of residual solvents (2.4.24.) ...... 141
Identification of fatty oils by thin-layer chromatography
(2.3.2.) ...................................................................................... 122
General Natices (1) apply ta all managraphs and ather texts
Index
Identification of phenothiazines by thin-layer chromatography
(2.3.3.) ...................................................................................... 123
Identification reactions of ions and functional groups
(2.3.1.) ...................................................................................... 119
Idoxuridine .............................................................................. 2476
Ifosfamide ................................................................................ 2476
Imipenem monohydrate ........................................................ 2478
Imipramine hydrochloride .......................................... 2479
0 .........
Immunochemical methods (2.7.l.) ..... 229
0 .......................... 0 .......
Immunoglobulin for human use, anti-T lymphocyte,
animal .......................................... o ••••••••••••••••••••••••••••••••••••••••• 1575
Immunoglobulin for intravenous administration, human
anti-D ...................................................... 2407
0 ..............................
Immunoglobulin for intravenous administration, human
hepatitis B .............................................................................. 2421
Immunoglobulin for intravenous administration, human
normal... ................................................................................. 2423
Immunoglobulin fol' intravenous administration, human
varicella .................................................................................. 2434
Immunoglobulin, human anti-D .......................................... 2406
Immunoglobulin, human anti-D, assay of (2.7.13.) ............. 249
Immunoglobulin, human hepatitis A .................................. 2420
Immunoglobulin, human hepatitis B ................................... 2420
Immunoglobulin, human measles ........................................ 2421
Immunoglobulin, human normaL ...................................... 2421
Immunoglobulin, human rabies ........................................... 2431
Immunoglobulin, human rubella ......................................... 2432
Immunoglobulin, human tetanus ......................................... 2432
Immunoglobulin, human varicella ....................................... 2434
Immunoglobulin, test for anticomplementary activity of
(2.6.17.) .................................................................................... 200
Immunoglobulin, test for Fc function of (2.7.9.) .................. 246
Immunological veterinary medicinal products, substances of
animal origin for the production of (5.2.5.) ........................ 587
Immunosera and vaccines, phenol in (2.5.15.) ... 159
0.0 . . . . . . . . . . . . . . .
Immunosera and vaccines, veterinary, evaluation of efficacy
of (5.2.7.) ............................................................. ., ................... 591
Immunosera and vaccines, veterinary, evaluation of saÍety
(5.2.6.) .................................... 588
0 ............ 0 ....................................
Immunosera for human use, animaL .................................... 748
Immunosera for veterinary use .......................... 750
o ....................
Immunosera for veterinary use, evaluation of the safety of
each batch (5.2.9.) ......................... 604
0 ....... ., ................................
Implants .................................. 0 ..................................................798
Impurities in substances for pharmaceutical use, control of
(5.10.) ....................................................................................... 689
Indapamide .............................................................................. 2480
ludian frankincense .................................. 1276
o .............................
Indicators, relationship between approximate pH and colour
(2.2.4.) ........................................................................................ 25
Indinavir sulfate ...................................................................... 2482
e
Indium 11 In) chloride solution ........................................... 1065
Indium (lllIn) oxine solution ..................................... 1066
0 ..........
Indium (l 11 In) pentetate injection .......... 1066
0 .............................
Indometacin ..................................................................... 8.2-4055
Inductively coupled plasma-atomic emission spectrometry
(2.2.57.) ...................................................................................... 97
Inductively coupled plasma-mass spectrometry (2.2.58.) ..... 98
Infectious bovine rhinotracheitis vaccine (live) .................... 983
Infectious bronchitis vaccine (inactivated), avian ................ 925
Infectious bronchitis vaccine (live), avian ............................. 926
Infectious bursal disease vaccine (inactivated), avian .......... 928
Infectious bursal disease vaccine (live), avian ....................... 929
Infectious chicken anaemia vaccine (live) ............................. 984
Infectious encephalomyelitis vaccine (live) , avian ................ 931
Infectious enteritis vaccine (inactivated), feline 973
00 . . . . . . . . . . . . . . . . .
Infectious enteritis vaccine (live), feline ................................ 974
Infectious laryngotracheitis vaccine (live), avian ................. 932
Infectious rhinotracheitis vaccine (live), turkey ................. 1022
Influenza vaccine (inactivated), equine ................................. 968
Influenza vaccine (inactivated), porcine .............................. 1003
Influenza vaccine (split virion, inactivated) .......................... 861
Influenza vaccine (surface antigen, inactivated) ................... 863
4137
Index
Influenza vaccine (surface antigen, ínactivated, prepared in
cel! cultures) ............................................................................ 865
Influenza vaccine (surface antigen, inactivated, virosome) .. 867
Influenza vaccine (whole virion, inactivated) ....................... 868
Influenza vaccine (whole virion, inactivated, prepared in cel!
cultures) ................................................................................... 870
Infrared absorption spectrophotometry (2.2.24.) ................... 38
Infusiol1s .................................................................................... 797
Inhalation gas, krypton (81mKr) ................... ;......................... 1071
Inhalatíon powders ................................................................... 803
Inhalation, preparations for .................................................... 800
Inhalation, preparations for: aerodynamic assessment of fine
particles (2.9.18.) ................. " ................................................. 309
Injectable insulin preparations .............................................. 2499
Injections ................................................................................... 797
Injections, gel s for ..................................................................... 798
Injections or infusions, concentrates for ............................... 797
Injections or infusions, powders for. ...................................... 797
Inositol, myo- .......................................................................... 2810
Inserts, ophthalmic ................................................................... 784
Instant herbal teas .................................................................... 748
Insulin aspart. .......................................................................... 2485
Insulin, bovine .................................................................... " .. 2486
Insulin glargine ....................................................................... 2489
Insulin, human ........................................................................ 2491
Insulin injection, biphasic ..................................................... 2493
Insulin injection, biphasic isophane ..................................... 2493
Insulin injection, isophane .................................................... 2494
Insulin injection, soluble ....................................................... 2494
Insulin Iispro ........................................................................... 2494
Insulin, porcine ....................................................................... 2497
Insulin preparations, injectable ............................................. 2499
Insulin zinc injectable suspension ........................................ 2501
Insulin zinc injectable suspension (amorphous) ................ 2502
Insulin zinc injectable suspensiol1 (crystalline) .................. 2502
Interferon alfa-2 concentrated solution ............................... 2502
Interferon beta-la concentrated solution ............................ 2505
Interferon gamma-lb concentrated solution ............... 8.2-4056
Interferons, assay of (5.6.) ........................................................ 663
International System (SI) units (1.) ............................... 8.2-3897
Intramammary preparations for veterinary use ................... 786
Intraruminal devices ................................................................ 787
Intrauterine capsules ................................................................ 787
Intrauterine foams .................................................................... 787
Intrauterine preparations for veterinary use ......................... 787
Intrauterine solutions, suspensions ........................................ 787
Intrauterine sticks ..................................................................... 787
Intrauterine tablets ................................................................... 787
Intrinsic dissolution (2.9.29.) .............................. " .................. 331
In vivo assay of poliomyelitis vaccine (inactivated)
(2.7.20.) .................................................................................... 255
Iobenguane (123I) injectiol1 .................................................... 1067
Iobenguane (131I) injection for diagnostic use ..................... 1068
Iobenguane (1 3J 1) injection for therapeutic use ................... 1069
Iobenguane sulfate for radiopharmaceutical prepara-
tions ........................................................................................ 1070
Iodinated (125I) human albumin injection ........................... 1064
Iodinated povidone ................................................................ 3081
Iodine ....................................................................................... 2511
Iodine value (2.5.4.) .................................................................. 155
Iodixanol .................................................................................. 2511
Iodohippurate (sodium) dihydrate for radiopharmaceutical
preparations .......................................................................... 1085
Iodomethylnorcholesterol (131I) injection ............................ 1070
Iohexol... ................................................................................... 2514
IOl1ic concentration, potentiometric determination of using
ion-selective electro des (2.2.36.) ............................................. 58
10ns and functional groups, identification reactions of
(2.3.1.) ...................................................................................... 119
Ion-selective electro des, potentiometric determination of
ionic concentration (2.2.36.) ................................................... 58
Iopamidol... .............................................................................. 2518
Iopanoic acid ........................................................................... 2519
4138
EUROPEAN PHARMACOPOEIA 8.2
Iopromide ................................................................................ 2520
Iotrolan .................................................................................... 2523
Ioxaglic acid ...................................................................... 8.1-3779
Ipecacuanha liquid extract, standardised ............................ 1277
Ipecacuanha, prepared ........................................................... 1278
Ipecacuanha root .................................................................... 1278
Ipecacuanha tincture, standardised ...................................... 1279
Ipratropium bromide ............................................................. 2527
Irbesartan ................................................................................. 2528
Iron (2.4.9.) ................................................................................ 131
Iron for h01110eopathic preparations ............................. 8.2-3989
Irrigation, preparations for. ..................................................... 805
Isatis root ................................................................................. 1280
Isoconazole .............................................................................. 2530
Isoconazole nitrate .................................................................. 2531
Isoelectric focusing (2.2.54.) ..................................................... 85
Isoelectric focusing (2.2.54.) (5.8.) ................................ 8.1-3679
Isoflurane ................................................................................. 2532
Isoleucine ................................................................................. 2533
Isomalt ..................................................................................... 2534
Isoniazid ................................................................................... 2536
Isophane insulin injection ..................................................... 2494
Isoprenaline hydrochloride ................................................... 2536
Isoprenaline sulfate ................................................................. 2537
Isopropyl alcohol .................................................................... 2538
Isopropyl myristate ................................................................. 2539
Isopropyl palmitate ................................................................. 2540
Isosorbide dinitrate, diluted ................................................. 2540
Isosorbide mononitrate, diluted .......................................... 2542
Isotretinoin .............................................................................. 2543
Isoxsuprine hydrochloride ..................................................... 2545
Ispaghula husk ........................................................................ 1281
Ispaghula seed ......................................................................... 1282
Isradipine ................................................................................. 2547
Itraconazole .............. ,........ ,..................................................... 2548
Ivermectin ................................................................................ 2549
leaf ............................................................................... 8.1-3707
J
Javanese turmeric .................................................................... 1409
Java tea ..................................................................................... 1284
Josamycin ................................................................................. 2555
Josamycin propionate ............................................................. 2557
Juniper ...................................................................................... 1285
Juniper oil ................................................................................ 1285
K
Kalium bichromicum for homoeopathic prepara-
tions ................................................................................. 8.2-3990
Kanamycin acid sulfate .......................................................... 2563
Kanamycin mono sulfate ........................................................ 2564
Kaolin, heavy ........................................................................... 2565
Kelp ........................................................................................... 1286
Ketamine hydrochloride ........................................................ 2565
Ketobemidone hydrochloride ............................................... 2566
Ketoconazole ........................................................................... 2567
Ketoprofen ............................................................................... 2569
Ketorolac trometamol ............................................................ 2571
Ketotifen hydrogen fumarate ......................................... 8.1-3783
Knotgrass ................................................................................. 1287
Krypton (81mKr) inhalation gas ............................................. 1071
Kudzuvine root ....................................................................... 1288
Kudzuvine root, Thomson ..................................................... 1402
L
Labetalol hydrochloride ......................................................... 2577
Lactic acid ................................................................................ 2578
Lactic acid, (5)- ....................................................................... 2579
Lactitol monohydrate ............................................................. 2580
Lactobionic acid ...................................................................... 2581
Lactose, anhydrous ................................................................. 2582
Lactose monohydrate ............................................................. 2584
5ee the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Lactulose .................................................................................. 2585
Lactulose, liquid ...................................................................... 2587
Lamivudine .............................................................................. 2589
Lamotrigine ...................................................................... 8.1-3787
Lansoprazole ........................................................................... 2592
Largehead atraetylodes rhizome ........................................... 1160
Laryngotraeheitis vaecine (live), infeetious, avian ............... 932
Laser light diffraetion, particle size analysis by (2.9.31.) .... 333
Laurilsuifate, sodium .............................................................. 3254
Lauromacrogol400 ................................................................. 2594
Lauroyl macrogolglycerides ................................................... 2596
Lavender flower ...................................................................... 1289
Lavender oil ............................................................................. 1291
Lavender oil, spike .................................................................. 1390
Lead in sugars (2.4.10.) ............................................................ 131
Leflunomide ............................................................................ 2597
Lemon oil ................................................................................. 1292
Lemon verbena leaf ................................................................ 1293
Leptospirosis vaccine (inactivated), bovine ........................... 937
Leptospirosis vaecine (inactivated), canine ........................... 948
Letrozole .................................................................................. 2598
Leucine ..................................................................................... 2599
Leukaemia vaccine (inactivated), feline ........................ 8.1-3697
Leuprorelin .............................................................................. 2601
Levamisole for veterinary use ............................................... 2602
Levamisole hydrochloride ..................................................... 2603
Levetiracetam .......................................................................... 2604
Levocabastine hydrochloride ......................................... 8.2-4063
Levocarnitine ........................................................................... 2607
Levodopa ................................................................................. 2608
Levodropropizine .................................................................... 2610
Levofolinate pentahydrate, ealcium ...................................... 1745
LevomenthoL ........................................................................... 2611
Levomepromazine hydrochloride ......................................... 2612
Levomepromazine maleate .................................................... 2613
Levomethadone hydrochloride ............................................. 2614
Levonorgestrel ......................................................................... 2615
Levothyroxine sodium ........................................................... 2618
Levulinate dihydrate, calcium ............................. ,................. 1748
Lidoeaine ................................................................................. 2620
Lidocaine hydroehloride ........................................................ 2621
Light liquid paraffin ............................................................... 2965
Light magnesium carbonate .................................................. 2671
Light magnesium oxide .......................................................... 2677
Lime flower .............................................................................. 1295
Limit tests (2.4.) ........................................................................ 127
Limit tests, standard solutions for (4.1.2.) ............................. 536
Limit tests, standard solutions for (4.1.2.) .................... 8.1-3675
Lineomycin hydrochloride .................................................... 2622
Linen thread, sterile, in distributor for veterinary use ..... 1128
Linoleoyl macrogolglycerides ................................................ 2624
Linseed ..................................................................................... 1295
Linseed oi!, virgin ............................................................ 8.2-4065
Liothyronine sodium .............................................................. 2625
Lipophilic solid dosage forms, dissolution test for
(2.9.42.) .................................................................................... 361
Liquid chromatography (2.2.29.) .............................................. 45
Liquid extracts .......................................................................... 745
Liquid glucose ......................................................................... 2341
Liquid glucose, spray-dried ................................................... 2342
Liquid lactulose ....................................................................... 2587
Liquid maltitol ........................................................................ 2688
Liquid paraffin ........................................................................ 2966
Liquid preparations for cutaneous application ..................... 789
Liquid preparations for cutaneous application, veterinary .. 814
Liquid preparations for oral use ............................................. 790
Liquids, clarity and degree of opalescence of (2.2.1.) ............ 21
Liquid sorbitol (crystallising) ................................................ 3286
Liquid sorbitol (non -crystallising) ....................................... 3286
Liquid sorbitol, partially dehydrated .................................... 3287
Liquorice dry extraet for flavouring purposes .................... 1296
Liquorice ethanolic liquid extract, standardised ................ 1297
Liquorice root ......................................................................... 1298
General Natices (1) apply ta all managraphs and ather texts
Index
Lisinopril dihydrate ................................................................ 2627
Lithium carbonate .................................................................. 2628
Lithium citrate ........................................................................ 2628
L- Methionine ([llC]methyl) injection .................................. 1073
Lobeline hydrochloride .......................................................... 2629
Lomustine ................................................................................ 2630
Long pepper ..................................................................... 8.2-3966
Loosestrife ............................................................................... 1300
Loperamide hydrochloride .................................................... 2631
Loperamide oxide monohydrate ........................................... 2633
Lopinavir .................................................................................. 2634
Loratadine ................................................................................ 2638
Lorazepam ............................................................................... 2639
Losartan potassium ................................................................ 2641
Loss on drying (2.2.32.) .................................................. 8.2-3907
Loss on drying of extracts (2.8.17.) ........................................ 276
Lovage root .............................................................................. 1301
Lovastatin ................................................................................ 2643
Low-molecular-mass heparins .............................................. 2392
Lozenges and pastilles .............................................................. 795
Lozenges, compressed .............................................................. 795
Lubricant, silicone oil (3.1.8.) .................................................. 393
Lufenuron (anhydrous) for veterinary use .......................... 2644
Lymecycline ............................................................................. 2646
Lynestrenol .............................................................................. 2648
Lyophilisates, oral ..................................................................... 812
Lysine acetate .......................................................................... 2649
Lysine hydrochloride .............................................................. 2650
M
Macrogol15 hydroxystearate ................................................ 2655
Macrogol 20 glycerol monostearate ...................................... 2656
Macrogol 30 dipolyhydroxystearate ..................................... 2657
Macrogo140 sorbitol heptaoleate .......................................... 2657
Macrogol 6 glycerol caprylocaprate ...................................... 2655
Macrogol cetostearyl ether .................................................... 2658
Macrogolglycerol coeoates ..................................................... 2663
Macrogolglyeerol hydroxystearate ........................................ 2664
Macrogolglyeerol ricinoleate ................................................. 2665
Maerogollauryl ether ............................................................. 2658
Macrogol oleate ....................................................................... 2659
Macrogol oleyl ether ............................................................... 2660
Macrogol poly(vinyl alcohol) grafted copolymer ............... 2660
Macrogols ................................................................................ 2665
Macrogol stearate ............................................................. 8.2-4069
Macrogol stearyl ether ........................................................... 2662
Magaldrate ........................................................................ 8.2-4069
Magnesium (2.4.6.) ................................................................... 128
Magnesium acetate tetrahydrate ........................................... 2668
Magnesium aluminium silicate ............................................. 1521
Magnesium and alkaline-earth metals (2.4.7.) ...................... 128
Magnesium aspartate dihydrate ............................................ 2669
Magnesium carbonate, heavy ................................................ 2670
Magnesium carbonate, light.. ................................................ 2671
Magnesium chloride 4.5-hydrate .......................................... 2671
Magnesium chloride hexahydrate ........................................ 2672
Magnesium citrate, anhydrous .............................................. 2673
Magnesium citrate dodecahydrate ........................................ 2673
Magnesium citrate nonahydrate ........................................... 2674
Magnesium gluconate ..................................................... 8.2-4070
Magnesium glycerophosphate ............................................... 2675
Magnesium hydroxide ................................................. ,.......... 2676
Magnesium lactate dihydrate ................................................ 2676
Magnesium oxide, heavy ....................................................... 2677
Magnesium oxide, light... ....................................................... 2677
Magnesium peroxide .............................................................. 2678
Magnesium phosphoricum for homoeopathic
preparations ................................................................... 8.2-3991
Magnesium pidolate ............................................................... 2679
Magnesium stearate ................................................................ 2680
Magnesium sulfate heptahydrate .......................................... 2682
Magnesium trisilicate ............................................................. 2683
4139
Index
Magnolia officinalis bark ................................................ 8.1-3709
Magnolia officinalis flower .................................................... 1304
Maize oil, refined .................................................................... 2683
Maize starch ............................................................................ 2684
Maize starch (5.8.) ........................................................... 8.1-3679
Malathion .......................................... ,...................................... 2685
Maleic acid ............................................................................... 2685
Malic acid ................................................................................ 2686
Mallow flower .......................................................................... 1305
Mallow leaf .............................................................................. 1306
Maltitol ..................................................................................... 2687
Maltitol, liquid ........................................................................ 2688
Maltodextrin ............................................................................ 2689
Mandarin epicarp and mesocarp .......................................... 1307
Mandarin oiL ........................................................................... 1308
Manganese gluconate ...................................................... 8.2-4071
Manganese glycerophosphate, hydrated .............................. 2691
Manganese sulfate monohydrate .......................................... 2691
Mannheimia vaccine (inactivated) for cattIe ......................... 986
Mannheimia vaccine (inactivated) for sheep ........................ 987
Mannitol (5.8.) ................................................................. 8.1-3679
Mannitol ........................................................................... 8.2-4072
Maprotiline hydrochloride .................................................... 2694
Marbofloxacin for veterinary use ......................................... 2695
Marek's disease vaccine (live) .................................................. 989
Marshmallow leaf ................................................................... 1309
Marshmallow root .................................................................. 1310
Mass spectrometry (2.2.43.) ...................................................... 69
Mass spectrometry, inductively coupled plasma- (2.2.58.) ... 98
Mass uniformity of delivered dos es from multidose containers
(2.9.27.) .................................................................................... 331
Mass uniformity of single-dose preparations (2.9.5.) .......... 297
Mastic ....................................................................................... 1311
Materials based on non-plasticised poly(vinyl chloride) f01
containers for dry dosage forms for oral administration
(3.1.11.) .................................................................................... 397
Materials based on non-plasticised poly(vinyl chloride)
for containers for non-injeetable, aqueous solutions
(3.1.10.) .................................................................................... 395
NIaterials based on plasticised poly( vinyl chloride) for
eontainers for aqueous solutions for intravenous infusion
(3.1.14.) .................................................................................. ,. 401
Materials based on plasticised poly(vinyl ehloride) for
container s for human blood and blood components
(3.1.1.1.) .................................... " .................................... " ....... 375
Materials based on plasticised poly(vinyl chloride) for
tubing used in sets for the transfusion of blood and blood
components (3.1.1.2.) .................. " ..................... " ... ,.............. 378
Materials for eontainers for human blood and blood
components (3.1.1.) ........................................................ " ...... 375
Materials used for the manufacture of containers (3.1.) ...... 375
Matricaria flower .................................................................... 1311
Matricaria liquid extract ................... " " ................................. 1313
Matricaria oil ....................... " ........... " ................. " .................. 1314
Meadowsweet ............. " ... " ................................................. " ... 1316
Measles immunoglobulin, human ........................................ 2421
Measles, mumps and rubella vaccine (live) ............... " ........ " 872
Measles, mumps, rubella and varicella vaccine (live) ....... ".873
Measles vaccine (live) ..................................... " ........................ 874
Measurement and detection of radioactivity (2.2.66.) ......... 11 O
Measurement of consistency by penetrometry (2.9.9.) ' ....... 299
Mebendazole ........................................................................... 2696
Meclozine dihydrochloride .................................................... 2698
Medieated chewing gums .... " ................................................ " 781
Medicated chewing gums, dissolution test for (2.9.25,) ....... 325
Medicated feeding stuffs for veterinary use, premixes for .. 800
Medicated foams ....................................................................... 784
Medicated pI aster s .................................................................... 809
Medicated tampons ......................... ,........................................ 812
Medicated vaginal tampons ...... " ............................................. 814
Medicinal air ........................................................................... 1492
Medicinal air, synthetic. ......................................................... 1494
Medium-chain triglycerides ................ " ................................ 3471
4140
EUROPEAN PHARMACOPOEIA 8.2
Medronic acid for radiopharmaeeutical preparations ....... 1072
Medroxyprogesterone aceta te ................................................ 2699
Mefenamic acid ..... ,............. " ............. ,.................................... 2701
Mefloquine hydrochloride ..................................................... 2702
Megestrol acetate ...................................... ,......................... ,... 2704
Meglumine ............... ,., ........................ ,................................. ,.. 2706
Melilot ...................................................................................... 1317
Melissa leaf .................................................. "." ....................... 1318
Melissa leaf dry extraet ...................................... " .................. 1319
Meloxicam .............................................................. " ............... 2707
Melphalan ........................................................... " ................... 2708
Melting point - capillary method (2.2.14.) ........... " ................. 32
Melting point - instantaneous method (2.2.16.) " ....... " ..... " ... 32
Melting point - instrumental method (2.2.60.) ..... " .... " ....... 105
Melting point - open capillary method (2.2.15.) .................... 32
Menadione ................................... " ......................... " ............... 2710
Meningoeoccal group e conjugate vaccine ........................... 875
Meningococcal polysaccharide vaccine .............................. ". 877
Menthol, racemic .................................................................... 2711
Mepivacaine hydroehloride .... " ............................ " ............... 2712
Meprobamate ............................................... ,.......................... 2713
Mepyramine maleate ....................... " ..................................... 2714
Mercaptopurine ...................................................................... 2715
Mercuric chloride ............................. ,..................................... 2715
Mercury porosimetry, porosity and pore-size distribution of
solids by (2.9.32.) ................................................................. ".336
Meropenem trihydrate ........................................................... 2716
Mesalazine ........................ "" .................................... ", ............ 2717
Mesna ....................................................................................... 2720
Mesterolone ,............................................................................ 2721
Mestranol ...................................... ,......... " ............................... 2722
Metabisulfite, potassium ......................... " ............................. 3073
Metabisulfite, sodium .................................................. ,.......... 3254
Metacresol. ................. ,............................................................. 2723
Metal catalyst or metal reagent residues (5.20.) .................... 733
Metal eatalyst or metal reagent residues, determinatíon of
(2.4.20.) ........ ,., .................... " ....................... " .......................... 133
Metamizole sodium mOllohydrate ........................... " .... 8.1-3791
Metered-dose preparations for inhalation, 110n-
pressurised ............... ,........................... ,................................. ,.803
Metered-dose preparations for inhalation, pressurised ....... 801
Metformin hydrochloride ...................................................... 2725
Methacrylate eopolymer, basic butylated ............................ 1624
Methacrylic acid - ethyl acrylate copolymer (1:1) .............. 2727
Methacrylic acid - ethyl acrylate copolymer (1:1) dispersion
30 per cent .......... " ....... " ................... " ................................... 2728
Methacrylic acid - methyl methacrylate copolymer (1:1) .. 2729
Methacrylic acid - methyl methacrylate copolymer (1:2) .. 2730
Methadone hydrochloride ..................................................... 2731
Methanesulfonate (methyl, ethyl and isopropyl) in active
substances (2.5.38.) ................................................................. 170
Methanesulfonic acid, methanesulfonyl chloride in
(2.5.39.) ......................... ,..... " ....... ,........................................... 171
Methanesulfonic acid, methyl, ethyl and isopropyl
methanesulfonate in (2.5.37.) ................................................ 169
Methanesulfonyl chloride in methanesulfonic acid
(2.5.39.) ................... ,........ " ................................ ,................... " 171
Methanol ....................... ,............... ,.......................................... 2732
Methanol and 2-propanol, test for (2,9.11.) ............ "" ..... " ... 304
Methenamine ............................ " ........ " ............................... ,,, 2733
Methionine ..... " .............................. ,........................................ 2733
Methionine ([llC]methyl) injeetion, L- ...... " .... " .... ,............. 1073
Methionine, DL- ......... " ............ ,.. ,.......... " ................. ,............. 2734
Methods in pharmaeognosy (2.8.) .......................................... 271
Methods of preparation of homoeopathic stocks and
potentisation ............... ,................................... ,..................... 1431
Methods of preparation of sterile products (5.1.1.) ............. 555
Methotrexate .................................... " ..................................... 2735
Methylcellulose .................. ,...................... ,............................. 2739
Methylcellulose (5.8.) ..... " ............................................... 8.1-3679
Methyldopa .............................................. ,,, ............................. 2741
Methylene blue ....... ,........ ,." .... ,.......................... ,.................... 2757
Methylene chloride ................................................................. 2743
See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2
Methylergometrine maleate .................................................. 2744
Methyl, ethyl and isopropyl methanesulfonate in active
substances (2.5.38.) ................................................................. 170
Methyl, ethyl and isopropyl methanesulfonate in
methanesulfonic acid (2.5.37.) .............................................. 169
Methylhydroxyethylcellulose ................................................. 2745
Methyl methacrylate - methacrylic acid copolymer (1:1) .. 2729
Methyl methacrylate - methacrylic acid copolymer (1:2) .. 2730
Methyl nicotinate .................................................. " ................ 2737
Methyl parahydroxybenzoate ................................................ 2738
Methyl parahydroxybenzoate, sodium ................................. 3255
Methylpentoses in polysaccharide vaccines (2.5.21.) ........... 161
Methylphenidate hydrochloride .......................... " ............... 2746
Methylphenobarbital .............................................................. 2747
Methylprednisolone ................................................................ 2748
Methylprednisolone acetate ................................................... 2751
Methylprednisolone hydrogen succinate ............................. 2753
Methylpyrrolidone, N- ........................................................... 2754
Methylrosaniiinium chloride ................................................ 2755
Methyl salicylate ..................................................................... 2739
Methyltestosterone ................................................................. 2756
Methylthioninium chloride ................................................... 2757
Metixene hydrochloride ......................................................... 2759
Metoclopramide ...................................................................... 2760
Metoclopramide hydrochloride ............................................ 2761
Metolazone .............................................................................. 2762
Metoprolol succinate .............................................................. 2763
Metoprolol tartrate ................................................................. 2765
Metrifonate .............................................................................. 2766
Metronidazole ......................................................................... 2768
Metronidazole benzoate ......................................................... 2769
Mexiletine hydrochloride ...................................................... 2770
Mianserin hydrochloride ....................................................... 2771
Miconazole .............................................................................. 2773
Miconazole nitrate .................................................................. 2774
Microbial enumeration tests (microbiological examination of
non-sterile products) (2.6.12.) .............................................. 185
Microbial enumeration tests (microbiological examination of
non-sterile products) (2.6.12.) (5.8.) ........................... 8.1-3680
Microbiological assay of antibiotics (2.7.2.) .......................... 230
Microbiological control of cellular products (2.6.27.) ......... 216
Microbiological examination of herbal medicinal products for
oral use and extracts used in their preparation (2.631.) ... 222
Microbiological examination of non-sterile products:
microbial enumeration tests (2.6.12.) .................................. 185
Microbiological examination of non-sterile products:
microbial enumeration tests (2.6.12.) (5.8.) ............... 8.1-3680
Microbiological examination of non -sterile products: test for
specified micro-organisms (2.6.13.) ..................................... 189
Microbiological examination of non -sterile products: test for
specified micro-organisms (2.6.13.) (5.8.) .................. 8.1-3680
Microbiological quality, alternative methods for control of
(5.1.6.) ...................................................................................... 560
Microbiological quality of herbal medicinal products for oral
use and extracts used in their preparation (5.1.8.) ............. 571
Microbiological quality of non-sterile pharmaceutical
preparations and substances for pharmaceutical use
(5.1.4.) ...................................................................................... 559
Microbiological quality of non-sterile pharmaceutical
preparations and substances for pharmaceutical use (5.1.4.)
(5.8.) ................................................................................ 8.1-3681
Microbiology, general texts on (5.1.) ..................................... 555
Microcalorimetry and solution calorimetry, characterisation
of crystalline solids by (22.61.) ............................................ 106
Microcrystalline cellulose ...................................................... 1824
Microcrystalline cellulose and carmellose sodium ............ 2776
Micro determination of water (2.5.32.) .................................. 164
Microscopic examination of herbal drugs (2.8.23) .............. 282
Microscopy, optical (2.9.37.) ................................................... 349
Microscopy, optical (2.9.37.) (5.8.) ............................... 8.1-3681
Midazolam ............................................................................... 2777
Milk thistle dry extract, refined and standardised ............. 1320
Milk thistle fruiL .................................................................... 1321
General Notices (1) apply to all monographs and other texts
Index
Minimising the risk of transmitting animal spongiform
encephalopathy agents via human and veterinary medicinal
products (5.2.8.) ...................................................................... 592
Minocycline hydrochloride dihydrate .................................. 2779
Minoxidil ................................................................................. 2780
Mint oil, partIy dementholised ............................................. 1323
Mirtazapine ............................................................................. 2781
MisoprostoL .............. ,........................................... ,........ ,......... 2783
.............. ,........... ,.. ,., ................ ,.............................. 2784
Mitoxantrone hydrochloride ............................. " .................. 2786
Modaflnil ................. ,............................................................... 2787
Modified-release capsules .... ,................................................... 780
Modified-release granules ........................................................ 786
Modified-release tablets ........................................................... 811
Mofetil mycophenolate .......................................................... 2808
Molecular mass distribution in dextrans (2.2.39.) .................. 60
Molgramostim concentrated solution .................................. 2788
Molsidomine ........................................................................... 2791
Molybdate dihydrate, sodium ............................................... 3256
Mometasone furoate ............................................................... 2792
Monoclonal antibodies for human use .................................. 753
Monocyte-activation test (2.6.30.) .......................................... 217
Monophosphoryllipid A, 3-0-desacyl-4 1 - .......................... 2000
Montelukast sodium ............................................................... 2794
Morantel hydrogen tartrate for veterinary use ................... 2796
Morphine hydrochloride ....................................................... 2797
Morphine sulfate ..................................................................... 2799
Moss, Iceland ........................................................................... 1275
Mother tinctures for homoeopathic preparations ....... 8.1-3715
Motherwort ............................................................................. 1324
Mouthwashes ............................................................................. 794
Moxidectin for veterinary use ............................................... 2800
Moxifloxacin hydrochloride .................................................. 2803
Moxonidine ............................................................................. 2804
Mucoadhesive 796
Mulleil1 flower ......................................................................... 1325
Multidose containers, uniformity of mass of delivered doses
(2.9.27.) .................................................................................... 331
Mumps, measles and rubella vaccine (live) ........................... 872
Mumps, measles, rubella and varicella vaccine (live) .......... 873
Mumps vaccine (live) ............................................................... 879
Mupirocin ................................................................................ 2805
Mupirocin calcium ................................................................. 2807
Mycobacteria (2.6.2.) ................................................................ 178
Mycophenolate mofetil .......................................................... 2808
Mycoplasma gallisepticum vaccine (inactivated) ................. 990
Mycoplasmas (2.6.7.) ................................................................ 178
myo-Inositol .... ,....................................................................... 2810
Myrrh ....................................................................................... 1326
Myrrh tincture ........................................................................ 1327
Myxomatosis vaccine (live) for rabbits .................................. 991
N
Nabumetone ............................................................................ 2813
N-Acetyltryptophan ............................................................... 1479
N-Acetyltyrosine ..................................................................... 1481
Nadolol.. ................................................................................... 2814
Nadroparin calcium ............................................................... 2815
Naftidrofuryl hydrogen oxalate ............................................ 2817
Nalidixic acid .......................................................................... 2819
Naloxone hydrochloride dihydrate ....................................... 2820
Naltrexone hydroch!oride ...................................................... 2822
N ames of herbal drugs used in traditional Chinese medicine
(5.22.) .............................................................................. 8.2-3941
Nandrolone decanoate ........................................................... 2824
Naphazoline hydrochloride ................................................... 2825
Naphazoline nitrate ................ ,............................................... 2826
Naproxen ........................................ ,., ............................... ,...... 2827
Naproxen sodium ................................................................... 2829
Narrow-Ieaved coneflower root ............................................ 1327
Nasal drops and liquid nasal sprays ....................................... 792
Nasal powders ........................................................................... 793
4141
Index
Nasal preparations .................................................................... 792
Nasal preparations, semi-solid ................................................ 793
Nasal sprays (liquid) and nasal drops .................................... 792
Nasal sticks ................................................................................ 793
Nasal washes .............................................................................. 793
Nateglinide .............................................................................. 2831
Near-infrared spectroscopy (2.2.40.) ........................................ 62
Nebulisation, characterisation of preparations for
(2.9.44.) .................................................................................... 363
Nebulisation, liquid preparations for ..................................... 801
Neohesperidin-dihydrochalcone .......................................... 2833
Neomycin sulfate .................................................................... 2834
Neonatal piglet eolibacillosis vaccine (inaetivated) .............. 992
Neonatal ruminant colibacillosis vaecine (inactivated) ....... 994
Neostigmine bromide ...................................................... 8.2-4077
Neostigmine metilsulfate ................................................ 8.2-4078
Neroli oil .................................................................................. 1329
Netilmicin sulfate .................................................................... 2837
Nettle leaf... .............................................................................. 1331
Neurovirulence test for poliomyelitis vaccine (oral)
(2.6.19.) .................................................................................... 202
Neurovirulence test of live viral vaecines (2.6.18.) ............... 202
Nevirapine, anhydrous ........................................................... 2839
Nevirapine hemihydrate ........................................................ 2840
Neweastle disease vaccine (inaetivated) ................................. 995
Newcastle disease vaccine (live) .............................................. 997
Niaouli oil, cine ole type ......................................................... 1332
Nicergoline .............................................................................. 2841
Nickel in hydrogenated vegetable oils (2.4.31.) .................... 150
Nickel in polyols (2.4.15.) ........................................................ 132
Niclosamide, anhydrous ........................................................ 2843
Niclosamide monohydrate .................................................... 2844
Nicotinamide ........................................................................... 2845
Nicotine .................................................. ,................................. 2845
Nicotine ditartrate 2846
Nicotine resinate ..................................................................... 2847
Nieotinic acid ................................................. ,........................ 2849
Nifedipine ................................................................................ 2850
Niflumic acid ........................................................................... 2851
Nifuroxazide ............................................................................ 2853
Nikethamide ............................................................................ 2854
Nilutamide ............................................................................... 2855
Nimesulide ............................................................................... 2856
Nimodipine ............................................................................. 2857
Nitrazepam .............................................................................. 2858
Nitrendipine ...................................................... ,..................... 2859
Nitric acid ................................................................................ 2860
Nitric oxide .............................................................................. 2861
Nitrofural ................................................................................. 2862
Nitrofurantoin ......................................................................... 2863
Nitrogen ................................................................................... 2863
Nitrogen determination by sulfuric acid digestion (2.5.9.) .. 157
Nitrogen determination, primary aromatic amino (2.5.8.) .. 157
Nitrogen, low-oxygen ............................................................. 2864
Nitrogen mOl1oxide and nitrogen dioxide in gases
(2.5.26.) .................................................................................... 163
Nitroprusside, sodium .............................................. ,............ 3257
Nitrous oxide ........................................................................... 2865
Nitrous oxide in gases (2.5.35.) ............................................... 168
Nizatidine ................................................................................ 2866
N-Methylpyrrolidone ............................................................. 2754
NMR spectrometry (2.2.33.) ..................................................... 52
NMR speetrometry, peptide identification by (2.2.64.) ....... 109
N,N-Dimethylaniline (2.4.26.) ................................................ 146
Nomegestrol acetate ............................................................... 2868
Nonoxinol 9 ............................................................................. 2869
Non-sterile pharmaceutical preparations and substances for
pharmaeeutieal use, microbiological quality of (5.1.4.) ..... 559
Non -sterile pharmaceutical preparations and substances
for pharmaeeutical use, microbiological quality of (5.l.4.)
(5.8.) ................................................................................ 8.1-3681
Non -sterile products, microbiologieal examination of
(microbial enumeration tests) (2.6.12,) ............................... 185
4142
EUROPEAN PHARMACOPOEIA 8.2
Non-sterile products, microbiological examination of
(microbial enumeration tests) (2.6,12.) (5.8.) ............ 8.1-3680
Non-sterile products, microbiological examination of (test for
specified micro-organisms) (2.6.13.) .................................... 189
Non-sterile products, microbiological examination of (test for
specified micro-organisms) (2.6.13.) (5.8.) ................ 8.1-3680
Noradrenaline hydrochloride ................................................ 2869
Noradrenaline tartrate ........................................................... 2871
Norepinephrine hydrochloride ............................................. 2869
Norepinephrine tartrate ................................... ,..................... 2871
Norethisterone ........................................................................ 2872
Norethisterone acetate ........................................................... 2874
Norfloxacin .............................................................................. 2875
Norflurane ......................................................... ,..................... 2877
Norgestimate ........................................................... " ............ ,.2883
Norgestrel ................................................................................ 2884
Normal immunoglobulin for intravenous aclministration,
human .................................................................................... 2423
Normal immunoglobulin, human ........................................ 2421
Nortriptyline hydrochloride .................................................. 2884
Noscapine ................................................................................ 2886
Noscapine hydrochloride ....................................................... 2887
Notoginseng root ........ ,........................................................... 1333
Nuclear magnetic resonanee spectrometry (2.2.33.) .............. 52
Nuclear magnetic resonance spectrometry, peptide
identifieation by (2.2.64.) ................................................... ,... 109
Nucleated ceH count and viability (2.7.29.) ........................... 263
Nucleic aeid amplifieation techniques (2.6.2l.) ........... 8.2-3921
Nucleic acids in polysaceharide vaccines (2.5.17.) ............... 160
Numeration of CD34/CD45+ cells in haematopoietic products
(2.7.23.) ...................... ,...................................... ,...................... 258
Nutmeg oil ............................................................................... 1334
Nystatin ............................................................................... ,.... 2888
O
O-Acetyl in polysaccharide vaecines (2.5. 160
Oak bark ............................. " ......... ,................. ,....................... 1335
Octoxinol10 .............................................. ,............................. 2893
Octyldodecanol ....................................... ,.. ,............................ 2894
Octyl gallate ........................................................... ,................. 2893
Odour (2.3.4.) ............................................................................ 123
Odour and taste of essential oils (2.8.8.), ............................... 272
Ofloxacin ................ ,... ,............................................................. 2895
Oils, essential. ............................................................................ 743
Oils, fatty, identification by thin-layer chromatography
(2.3.2.) ...................................................................................... 122
Oils, fatty, vegetable .................................................................. 775
Oils rich in omega-3 acids, composition of fatty acids in
(2.4.29.) ......... ,.................................................... ,..................... 148
Oils rieh in omega-3 acids, total cholesterol in (2.4.32.) ..... 151
Ointments .................................................................................. 808
Olanzapine .................................. ,............................................ 2896
Oleie acid ........................................ ,........................... ,............ 2898
Oleoresins ................................ " ........................ " ..... " ............... 746
Oleoyl macrogolglycerides .................................................... 2898
Oleyl alcohol... .......................... ,........................ ,..................... 2899
Olive leaf ......................................................................... ,........ 1335
Olive leaf dry extract.. .................... " .......................... "" ... " ... 1337
Olive oil, refined .............................................................. ,...... 2899
Olive oil, virgin ...................................... " " ................... " ........ 2900
Olmesartan medoxomil ...................... ,.................. " .............. 2901
Olsalazine sodium .................................................................. 2903
Omega-3-acid ethyl esters 60." ....................... " .................... 2905
Omega-3-acid ethyl esters 90 ................................................ 2907
Omega-3 acids, composition of fatty acicls in oils rich in
(2.4.29.) .................. " ................................................................ 148
Omega-3 acids, fish oil fich in .............................. " .............. 2236
Omega-3 acids, total cholesterol in oils rich in (2.4.32.) .... , 151
Omega-3-aeid triglyeerides ................................................... 2Q09
Omeprazole ................. ,.. ,................................. ' ...................... 2911
Omeprazole magnesium ...................... " .............. ,................. 2912
Omeprazole sodium ......................................... " .................... 2913
See the information section on general monographs (ca ver pages)
EUROPEAN PHARMACOPOEIA 8.2
Ondansetron hydroehloride dihydrate ................................ 2915
Opaleseenee ofliquids, clarity and degree of (2.2.1.) ............. 21
Ophthalmic inserts ................................................................... 784
Opium dry extraet, standardised .......................................... 1337
Opium, prepared .................................................................... 1339
Opium, raw .............................................................................. 1340
Opium tincture, standardised ............................................... 1341
Optical microseopy (2.9.37.) ................................................... 349
Optical microseopy (2.9.37.) (5.8.) ................................ 8.1-3681
Optical rotation (2.2.7.) ............................................................. 26
Oral drops .................................................................................. 791
Orallyophilisates ...................................................................... 812
Oral powders ............................................................................. 799
Oral solutions, emulsions and suspensions ........................... 790
Oral use, liquid preparations for ............................................ 790
Oral use, veterinary semi -solid preparations for.. ....... 8.1-3689
Orbifloxacin for veterinary use ............................................. 2916
Orciprenaline sulfate .............................................................. 2918
Oregano ................................................................................... 1342
Organ preservation, solutions for.. ....................................... 3273
Oriental eashew for homoeopathic preparations ........ 8.2-3981
Orientvine stem ...................................................................... 1344
Orodispersible film s ................................................................. 796
Orodispersible tablets .............................................................. 811
Oromueosal eapsules ................................................................ 795
Oromueosal drops, oromueosal sprays and sublingual
sprays ........................................................................................ 794
Oromueosal preparations ........................................................ 793
Oromucosal preparations, semi -solid .................................... 794
Oromueosal solutions and oromucosal suspensions ............ 794
Oromueosal sprays, oromucosal drops and sublingual
sprays ........................................................................................ 793
Oromueosal suspensions and oromucosal solutions ............ 793
Orphenadrine citrate .............................................................. 2919
Orphenadrine hydroehloride ................................................ 2921
Oseltamivir phosphate ........................................................... 2922
Osmolality (2.2.35.) .................................................................... 57
Ouabain ................................................................................... 2924
Oxaeillin sodium monohydrate ............................................ 2925
Oxaliplatin ............................................................................... 2927
Oxazepam ................................................................................ 2929
Oxcarbazepine ......................................................................... 2931
Oxeladin hydrogen citrate ..................................................... 2932
Oxfendazole for veterinary use ............................................. 2933
Oxidising substanees (2.5.30.) ................................................. 164
Oxitropium bromide .............................................................. 2934
Oxolinic acid ........................................................................... 2936
Oxprenolol hydroehloride ..................................................... 2937
Oxybuprocaine hydrochloride .............................................. 2938
Oxybutynin hydrochloride .................................................... 2939
Oxycodone hydrochloride ..................................................... 2940
Oxygen ..................................................................................... 2941
Oxygen eSO) ........................................................................... 1074
Oxygen (93 per cent) .............................................................. 2942
Oxygen-flask method (2.5.10.) ................................................ 158
Oxygen in gases (2.5.27.) ......................................................... 163
Oxymetazoline hydrochloride ............................................... 2943
Oxytetracyclíne dihydrate ...................................................... 2945
Oxytetracycline hydrochloríde ....................................... 8.1-3795
Oxytocin .................................................................................. 2948
Oxytocin concentrated solution ............................................ 2949
p Patches, transdermal, dissolution test for (2.9.4.) ................. 295
Paclitaxel .................................................................................. 2953
Pale coneflower root ............................................................... 1345
Palmítie acid ............................................................................ 2956
Pamidronate disodium pentahydrate ................................... 2956
Pancreas powder .............................................................. 8.2-4083
Pancuronium bromíde ........................................................... 2959
Panleucopenia vaecine (inactivated), feline .......................... 973
Panleucopenia vaccine (live), feline ....................................... 974
Pansy, wild (flowering aerial parts) ...................................... 1420
General Notices (1) apply to all monographs and other texts
Index
Pantoprazole sodium sesquihydrate ..................................... 2960
Pantothenate, ealcium ............................................................ 1749
Papaverine hydrochloride ...................................................... 2962
Papel' chromatography (2.2.26.) ............................................... 42
Papillomavirus vaccine (rDNA), human .............................. 859
Paraben, butyl ......................................................................... 1712
Paraben, ethyl .......................................................................... 2191
Paraben, methyl ...................................................................... 2738
Paraben, propyl ....................................................................... 3122
Paraben, sodium ethyl. ........................................................... 3243
Pal'aben, sodium methyl ........................................................ 3255
Paraben, sodium propyl ......................................................... 3263
Paracetamol ............................................................................. 2963
Pal'affin, hard ........................................................................... 2964
Paraffin, light liquid ............................................................... 2965
Paraffin, liquid ........................................................................ 2966
Paraffin, white soft .................................................................. 2966
Paraffin, yellow soft ................................................................ 2967
Parahydroxybenzoate, butyl .................................................. 1712
Parahydroxybenzoate, ethyl .................................................. 2191
Parahydroxybenzoate, methyl ............................................... 2738
Parahydroxybenzoate, propyl ................................................ 3122
Parahydroxybenzoate, sodium ethyl .................................... 3243
Parahydroxybenzoate, sodium methyl... .............................. 3255
Parahydroxybenzoate, sodium propyl... ............................... 3263
Parainfluenza virus vaccine (live), bovine ............................. 938
Paraínfluenza virus vaccine (live), canine ............................. 949
Paraldehyde ............................................................................. 2968
Paramyxovirus 1 (Newcastle disease) vaccine (inactivated),
avían ......................................................................................... 995
Paramyxovirus 1 (Newcastle disease) vaccine (live), avian .. 997
Paramyxovirus 3 vaccine (inaetivated) for turkeys,
avían ................................................................................ 8.1-3693
Paren ter al preparations ............................................................ 796
Parenteral preparations, test for extractable volume of
(2.9.17.) .................................................................................... 308
Parenteral preparations, test for extractable volume of (2.9.17.)
(5.8.) ................................................................................ 8.1-3681
Parnaparin sodium ................................................................. 2968
Paroxetine hydroehloride, anhydrous .................................. 2969
Paroxetine hydrochloride hemihydrate ............................... 2971
Particles, fine, aerodynamic assessment of in preparations for
inhalation (2.9.18.) ................................................................. 309
Particle size analysis by laser light diffraetion (2.9.31.) ....... 333
Particle-size distribution estimation by analytical sieving
(2.9.38.) .................................................................................... 351
Particle-size distribution estimation by analytical sieving
(2.9.38.) (5.8.) ................................................................. 8.1-3681
Particulate contaminatiol1: sub-visible particles (2.9.19.) '" 321
Particulate eontamination: sub-visible particles (2.9.19.)
(5.8.) ................................................................................ 8.1-3681
Particulate contamination: visible particles (2.9.20.) ........... 323
Parvovirosis vaccine (inactivated), canine ............................. 950
Parvovirosis vaccine (inactivated), porcine ......................... 1004
Parvovírosis vaccine (live), canine .......................................... 951
Passion flower ......................................................................... 1347
Passion flower dry extract ..................................................... 1347
Pastes .......................................................................................... 809
Pasteurella vaccine (inactivated) for sheep ............................ 999
Pastilles and lozenges ............................................................... 795
Patches, cutaneous .................................................................... 807
Patches, transdermal ................................................................ 798
Pea starch .......................................................................... 8.1-3799
Pefloxacin mesilate dihydrate ................................................ 2973
Pelargonium root .................................................................... 1348
Pemetrexed disodium heptahydrate ..................................... 2975
Penbutolol sulfate ................................................................... 2977
Penetrometry, measurement of consisteney by (2.9.9.) ....... 299
Penicillamine ........................................................................... 2978
Penicillin G, benzathine ......................................................... 1647
Penicillin G potassium ........................................................... 1648
Penicillin G, procaine ............................................................. 1650
4143
Index
Penicillin G sodium ................................................................ 1651
Penicillin V .............................................................................. 3006
Penicillin V potassium ........................................................... 3007
Pentaerythrityl tetranitrate, diluted ...................................... 2980
Pentamidine diisetionate ....................................................... 2982
Pentazocine .............................................................................. 2982
Pentazocine hydrochloride .................................................... 2983
Pentazocine lactate ................................................................. 2984
Pentetate sodium calcium for radiopharmaceutical
preparations .......................................................................... 1075
Pentobarbital ........................................................................... 2984
Pentobarbital sodium ............................................................. 2985
PentoxifyIline .......................................................................... 2986
Pentoxyverine hydrogen citrate ............................................ 2988
Pepper ...................................................................................... 1349
Pepper, long ...................................................................... 8.2-3966
Peppermint leaf. ...................................................................... 1350
Peppermint leaf dry extract.. ................................................. 1352
Peppermint oil ........................................................................ 1353
Pepsin powder ......................................................................... 2989
Peptide identification by nuclear magnetic resonance
spectrometry (2.2.64.) ............................................................ 109
Peptide mapping (2.2.55.) .......................................................... 87
Peptide mapping (2.2.55.) (5.8.) .................................... 8.1-3679
Peptides, synthetic, acetic acid in (2.5.34.) ............................ 168
Perborate, hydrated sodium .................................................. 3258
Pergolide mesilate ................................................................... 2990
Perindopril tert-butylamine .................................................. 2991
Peritoneal dialysis, solutions for ........................................... 2994
Peroxide value (2.5.5.) .............................................................. 156
Perphenazine ........................................................................... 2996
Pertussis (acellular, component), diphtheria and tetanus
vaccine (adsorbed) ................................................................. 826
Pertussis (acellular, component), diphtheria and tetanus
vaccine (adsorbed, reduced antigen(s) content) ........ 8.2-3951
Pertussis (acellular, component), diphtheria, tetanus and
haemophilus type b conjugate vaccine (adsorbed) ............ 830
Pertussis (acellular, component), diphtheria, tetanus and
hepatitis B (rDNA) vaccine (adsorbed) ............................... 832
Pertussis (acellular, component), diphtheria, tetanus and
poliomyelitis (inactivated) vaccine (adsorbed) ................... 834
Pertussis (acellular, component), diphtheria, tetanus and
poliomyelitis (inactivated) vaccine (adsorbed, reduced
antigen(s) content) ................................................................. 835
Pertussis (acellular, component), diphtheria, tetanus,
hepatitis B (rDNA), poliomyelitis (inactivated) and
haemophilus type b conjugate vaccine (adsorbed) ............ 837
Pertussis (acellular, component), diphtheria, tetanus,
poliomyelitis (inactivated) and haemophilus type b conjugate
vaccine (adsorbed) ................................................................. 840
Pertussis toxin (residual) and pertussis toxoid (irreversibility
of) (2.6.33.) .............................................................................. 224
Pertussis vaccine (acellular), assay of (2.7.16.) ...................... 252
Pertussis vaccine (acellular, component, adsorbed) ............. 880
Pertussis vaccine (acellular, co-purified, adsorbed) ............. 882
Pertussis vaccine (whole cell, adsorbed) ................................ 883
Pertussis vaccine (whole cell), assay of (2.7.7.) ..................... 242
Pertussis (whole cell), diphtheria and tetanus vaccine
(adsorbed) ............................................................................... 827
Pertussis (whole cell), diphtheria, tetanus and poliomyelitis
(inactivated) vaccine (adsorbed) .......................................... 842
Pertussis (whole cell), diphtheria, tetanus, poliomyelitis
(inactivated) and haemophilus type b conjugate vaccine
(adsorbed) ............................................................................... 844
Peru balsam ............................................................................. 1354
Pessaries ..................................................................................... 813
Pessaries and suppositories, disintegration of (2.9.2.) ......... 287
Pesticide residues (2.8.13.) .............................................. 8.2-3933
Pethidine hydrochloride ........................................................ 2997
Pharmaceutical preparations ................................................... 756
Pharmaceutical technical procedures (2.9.) .......................... 285
Pharmacognosy, methods in (2.8.) ......................................... 271
Pharmacopoeial harmonisation (5.8.) .......................... 8.1-3679
4144
EUROPEAN PHARMACOPOEIA 8.2
Phenazone ................................................................................ 2999
Pheniramine maleate .............................................................. 3000
Phenobarbital .......................................................................... 3001
Phenobarbital sodium ............................................................ 3002
Phenol ...................................................................................... 3003
Phenol in immunosera and vaccines (2.5.15.) ...................... 159
Phenolphthalein ...................................................................... 3003
Phenolsulfonphthalein ........................................................... 3004
Phenothiazines, identification by thin-Iayer chromatography
(2.3.3.) ...................................................................................... 123
Phenoxyethanol ...................................................................... 3005
Phenoxymethylpenicillin ....................................................... 3006
Phenoxymethylpenicillin potassium .................................... 3007
Phentolamine mesilate ........................................................... 3009
Phenylalanine ................................................................... 8.2-4085
Phenylbutazone ....................................................................... 3011
Phenylbutyrate, sodium ......................................................... 3258
Phenylephrine ......................................................................... 3013
Phenylephrine hydrochloride ................................................ 3014
Phenylmercuric acetate .......................................................... 3015
Phenylmercuric borate ........................................................... 3016
Phenylmercuric nitrate .......................................................... 3016
Phenylpropanolamine hydrochloride .................................. 3017
Phenytoin ................................................................................. 3017
Phenytoin sodium ................................................................... 3019
Phloroglucinol, anhydrous .................................................... 3020
Phloroglucinol dihydrate ....................................................... 3022
Pholcodine ............................................................................... 3024
Phosphates (2.4.11.) .................................................................. 131
Phosphoric acid, concentrated .............................................. 3025
Phosphoric acid, dilute .......................................................... 3025
Phosphorus in polysaccharide vaccines (2.5.18.) ................. 160
pH, potentiometric determination of (2.2.3.) ......................... 24
Phthalylsulfathiazole .............................................................. 3026
Physical and physicochemical methods (2.2.) ........................ 21
Physostigmine salicylate ........................................................ 3027
Phytomenadione ..................................................................... 3027
Phytosterol ............................................................................... 3029
Pico sulfate, sodium ................................................................ 3260
Picotamide monohydrate ....................................................... 3030
Piglet colibacillosis vaccine (inactivated), neonatal ............. 992
Pillules for homoeopathic preparations ............................... 1441
Pillules, homoeopathic, impregnated ................................... 1441
Pilocarpine hydrochloride ..................................................... 3031
Pilocarpine nitrate .................................................................. 3032
Pimobendan ............................................................................ 3033
Pimozide .................................................................................. 3034
Pindolol .................................................................................... 3036
Pine (dwarf) oil ....................................................................... 1230
Pine sylvestris oil .................................................................... 1355
Pioglitazone hydrochloride ................................................... 3037
Pipemidic acid trihydrate ...................................................... 3038
Piperacillin ............................................................................... 3039
Piperacillin sodium ................................................................ 3041
Piperazine adipate .................................................................. 3042
Piperazine citrate .................................................................... 3043
Piperazine hydrate .................................................................. 3044
Piracetam ................................................................................. 3045
Pirenzepine dihydrochloride monohydrate ........................ 3046
Piretanide ................................................................................. 3047
Piroxicam ................................................................................. 3048
Pivampicillin ........................................................................... 3050
Pivmecillinam hydrochloride ................................................ 3051
Plasma for fractionation, human .......................................... 2425
Plasma (pooled and treated for virus inactivation),
human ............................................................................. 8.2-4048
Plasmid vectors for human use, bacterial cells used for the
manufacture of. ....................................................................... 707
Plasmin inhibitor, assay ofhuman (2.7.25.) .......................... 261
Plasters, medicated ................................................................... 807
Plastic additives (3.1.13.) ......................................................... 398
Plastic containers and closures for pharmaceutical use
(3.2.2.) ...................................................................................... 414
See the information section on general monographs (caver pages)
EUROPEAN PHARMACOPOEIA 8.2
Plastic containers for aqueous solutions for infusion
(3.2.2.1.) ................................................................................... 414
Plastic container s for human blood and blood components,
sterile (3.2.3.) ........................................................................... 415
Plastic syringes, single-use, sterile (3.2.8.) ............................. 419
Pneumococcal polysaccharide conjugate vaccine
(adsorbed) ............................................................................... 885
Pneumococcal polysaccharide vaccine .................................. 887
Pneumonia vaccine (inactivated), porcine enzootic .......... 1001
Poliomyelitis (inactivated), diphtheria and tetanus vaccine
(adsorbed, reduced antigen(s) content) ............................... 829
Poliomyelitis (inactivated), diphtheria, tetanus and pertussis
(acellular, component) vaccine (adsorbed) ......................... 834
Poliomyelitis (inactivated), diphtheria, tetanus and pertussis
(acellular, component) vaccine (adsorbed, reduced antigen(s)
content) .................................................................................... 835
Poliomyelitis (inactivated), diphtheria, tetanus and pertussis
(whole ceH) vaccine (adsorbed) ............................................ 842
Poliomyelitis (inactivated), diphtheria, tetanus, pertussis
(acellular, component) and haemophilus type b conjugate
vaccine (adsorbed) ................................................................. 840
Poliomyelitis (inactivated), diphtheria, tetanus, pertussis
(acellular, component), hepatitis B (rDNA) and haemophilus
type b conjugate vaccine (adsorbed) .................................... 837
Poliomyelitis (inactivated), diphtheria, tetanus, pertussis
(whole celI) and haemophilus type b conjugate vaccine
(adsorbed) ............................................................................... 844
Poliomyelitis vaccine (inactivated) ......................................... 889
Poliomyelitis vaccine (inactivated), in vivo assay of
(2.7.20.) .................................................................................... 255
Poliomyelitis vaccine (oral) ..................................................... 891
Poliomyelitis vaccine (oral), test for neurovirulence
(2.6.19.) .................................................................................... 202
Poloxamers .............................................................................. 3052
Polyacrylate dispersion 30 per cent... ................................... 3054
Polyamide 6/6 suture, sterile, in distributor for veterinary use
................................................................................................ 1128
Polyamide 6 suture, sterile, in distributor for veterinary use
................................................................................................ 1128
Polyethyleneglycols ................................................................. 2665
Polyethylene terephthalate for container s for preparations not
for parenteral use (3.1.15.) .................................................... 403
Poly(ethylene terephthalate) suture, sterile, in distributor for
veterinary use ....................................................................... 1129
Poly(ethylene - vinyl acetate) for container s and tubing far
total parenteral nutrition preparations (3.1. 7.) ................... 391
Polyethylene with additives for containers for parenteral
preparations and for ophthalmic preparations (3.1.5.) ...... 384
Polyethylene without additives for containers for parenteral
preparations and for ophthalmic preparations (3.1.4.) ...... 383
Polymorphism (5.9.) ................................................................. 685
Polymyxin B sulfate ................................................................ 3055
Polyoleflns (3.1.3.) .................................................................... 380
Polyoxyl castor oH ................................................................... 2665
Polyoxyl hydrogenated castor oil .......................................... 2664
Polypropylene for containers and closures for parenteral
preparations and ophthalmic preparations (3.1.6.) ............ 388
Polysaccharide vaccines, hexosamines in (2.5.20.) ............... 160
Polysaccharide vaccines, methylpentoses in (2.5.21.) .......... 161
Polysaccharide vaccines, nucleic acids in (2.5.17.) ............... 160
Polysaccharide vaccines, O-acetyl in (2.5.19.) ....................... 160
Polysaccharide vaccines, phosphorus in (2.5.18.) ................. 160
Polysaccharide vaccines, protein in (2.5.16.) ......................... 159
Polysaccharide vaccines, ribose in (2.5.31.) .......................... 164
Polysaccharide vaccines, sialic acid in (2.5.23.) .................... 161
Polysaccharide vaccines, uronic acids in (2.5.22.) ................ 161
Polysorbate 20 ......................................................................... 3056
Polysorbate 40 ......................................................................... 3057
Polysorbate 60 ......................................................................... 3058
Polysorbate 80 ......................................................................... 3058
Polystyrene sulfonate, sodium .............................................. 3261
Poly(vinyl acetate) .................................................................. 3060
Poly(vinyl acetate) dispersion 30 per cent.. ......................... 3061
General Notices (1) apply to all monographs and other texts
Index
Poly( vinyl alcohol) .................................................................. 3062
Poly(vinyl alcohol) macrogol grafted copolymer ............... 2660
Poly(vinyl chloride) (non-plasticised) for containers for dry
dosage forms for oral administratiol1, materials based 011
(3.1.11.) .................................................................................... 397
Poly(vinyl chloride), non-plasticised, materials based on for
containers for non -injectable aqueous solutions (3.1.10.) .. 395
Poly(vinyl chIoride), plasticised, empty sterile containers of
for human blood and blood components (3.2.4.) .............. 417
Poly(vinyl chloride), plasticised, materials based on for
containers far aqueous solutions for intravenous infusion
(3.1.14.) .................................................................................... 401
Poly(vinyl chloride), plasticised, materials based on for
containers for human blood and blood components
(3.1.1.1.) ................................................................................... 375
Poly(vinyl chloride), plasticised, materials based on for
tubing used in sets for the transfusion of blood and blood
components (3.1.1.2.) ............................................................. 378
Poly(vinyl chloride), plasticised, sterile containers of for
human blood containing anticoagulant solution (3.2.5.) .. 418
Poppy petals, red ..................................................................... 1363
Porcine actinobacillosis vaccine (inactivated) .................... 1000
Porcine enzootic pneumonia vaccine (inactivated) ........... 1001
Porcine influenza vaccine (inactivated) ............................... 1003
Porcine insulin ........................................................................ 2497
Porcine parvovirosis vaccine (inactivated) .......................... 1004
Porcine progressive atrophic rhinitis vaccine
(inactivated) .......................................................................... 1005
Pore-size distribution of solids by mercury porosimetry,
porosity and (2.9.32.) ............................................................. 336
Poria ......................................................................................... 1356
Porosimetry, mercury, porosity and pore-size distribution of
solids by (2.9.32.) .................................................................... 336
Porosity and pore-size distribution of solids by mercury
porosimetry (2.9.32.) ............. " .. ,............................................ 336
Porosity of sintered-glass filters (2.1.2.) ................................... 15
Porous solids including powders, wettability of (2.9.45.) .... 365
Potassium (2.4.12.) ................................................................... 132
Potassium acetate .................................................................... 3063
Potassium bromide ................................................................. 3063
Potassium carbonate ............................................................... 3064
Potassium chloride ................................................................. 3065
Potassium citrate ..................................................................... 3065
Potassium clavulanate ............................................................ 3066
Potassium clavulanate, diluted .............................................. 3068
Potassium dichromate for homoeopathic prepara-
tions ................................................................................. 8.2-3990
Potassium dihydrogen phosphate ......................................... 3070
Potassium disulfite .................................................................. 3073
Potassium hydrogen aspartate hemihydrate ....................... 3070
Potassium hydrogen carbonate ............................................. 3071
Potassium hydrogen tartrate ................................................. 3072
Potassium hydroxide .............................................................. 3072
Potassium iodide ..................................................................... 3073
Potassium metabisulfite ......................................................... 3073
Potassium nitrate .................................................................... 3074
Potassium perchlorate ............................................................ 3075
Potassium permanganate ....................................................... 3075
Potassium sodium tartrate tetrahydrate .............................. 3076
Potassium sorbate ................................................................... 3076
Potassium sulfate ................... '" .............................................. 3077
Potato starch ............................................................................ 3078
Potato starch (5.8.) ........................................................... 8.1-3679
Potentiometric determination of ionic concentration using
ion -selective electrodes (2.2.36.) ............................................. 58
Potentiometric determination of pH (2.2.3.) .......................... 24
Potentiometric titration (2.2.20.) .............................................. 34
Potentisation, methods of preparation of homoeopathic stocks
and .......................................................................................... 1431
Poultices ..................................................................................... 809
Pour-on preparations ............................................................... 814
Povidone .................................................................................. 3078
Povidone, iodinated ................................................................ 3081
4145
Index
Powdered cellulose ................................................................. 1828
Powder fineness (2.9.35.) ......................................................... 346
Powder flow (2.9.36.) ................................................................ 346
Powder flow (2.9.36.) (5.8.) ............................................ 8.1-3681
Powders and granules for oral solutions and suspensions .. 791
Powders and granules for syrups ............................................ 791
Powders and tablets for rectal solutions and suspensions ... 807
Powders, bulk density and tapped density of (2.9.34.) ......... 343
Powders, ear .............................................................................. 782
Powders, effervescent ............................................................... 800
Powders for cutaneous application ......................................... 799
Powders for eye drops and powders for eye lotions ............. 784
Powders for injections or infusions ........................................ 797
Powders for oral drops ............................................................. 791
Powders, inhalation .................................................................. 803
Powders, nasal ........................................................................... 793
Powders, oral ............................................................................. 799
Powders, wettability of porous solids including (2.9.45.) .... 365
Pramipexole dihydrochloride monohydrate ....................... 3082
Pravastatin sodium ................................................................. 3083
Prazepam ................................................................................. 3085
Praziquantel.. ........................................................................... 3086
Prazosin hydrochloride .......................................................... 3087
Prednicarbate ................................................................... 8.1-3799
Prednisolone ............................................................................ 3090
Prednisolone acetate ............................................................... 3091
Prednisolone pivalate ............................................................. 3093
Prednisolone sodium phosphate ........................................... 3094
Prednisone ............................................................................... 3095
Pregelatinised hydroxypropyl starch .................................... 3305
Pregelatinised starch ............................................................... 3306
Prekallikrein activator (2.6.15.) ............................................... 198
Premixes for medicated feeding stuffs for veterinary use ... 800
Preparations for inhalation ..................................................... 800
Preparations for inhalation: aerodynamic assessment of fine
particles (2.9.18.) .................................................................... 309
Preparations for irrigation ....................................................... 805
Preparations for nebulisation: characterisation (2.9.44.) .... 363
Pressurised pharmaceutical preparations .............................. 805
Prilocaine ................................................................................. 3097
Prilocaine hydrochloride ....................................................... 3098
Primaquine diphosphate ........................................................ 3099
Primary aromatic amino-nitrogen, determination of
(2.5.8.) ...................................................................................... 157
Primary standards for volumetric solutions (4.2.1.) ............ 545
Primidone ................................................................................ 310 1
Primula root ............................................................................ 1356
Probenecid ............................................................................... 3102
Procainamide hydrochloride ................................................. 3102
Procaine benzylpenicillin ...................................................... 1650
Procaine hydrochloride .......................................................... 3103
Prochlorperazine maleate ...................................................... 3104
Products of fermentation ......................................................... 758
Products of recombinant DNA technology ........................... 763
Products with risk of transmitting agents of animal spongiform
encephalopathies .................................................................... 759
Progenitor cells, human haematopoietic, colony-forming cell
assay for (2.7.28.) .................................................................... 262
Progesterone ............................................................................ 3105
Progressive atrophic rhinitis vaccine (inactivated),
porcine ................................................................................... 1005
Proguanil hydrochloride ........................................................ 3106
Proline ...................................................................................... 3107
Promazine hydrochloride ...................................................... 3108
Promethazine hydrochloride ................................................. 3109
Propacetamol hydrochloride ................................................. 3110
Propafenone hydrochloride ................................................... 3112
Propanol. ........................................................................... 8.1-3801
Propanol and methanol, 2-, test for (2.9.11.) ........................ 304
Propantheline bromide .......................................................... 3114
Propofol ................................................................................... 3115
Propranolol hydrochloride .................................................... 3117
Propylene glycol.. .................................................................... 3118
4146
EUROPEAN PHARMACOPOEIA 8.2
Propylene glycol dicaprylocaprate ........................................ 3118
Propylene glycol dilaurate ..................................................... 3119
Propylene glycol monolaurate ............................................... 3120
Propylene glycol monopalmitostearate ................................ 3121
Propylene glycol monostearate ............................................. 3121
Propyl gallate ........................................................................... 3121
Propyl parahydroxybenzoate ................................................. 3122
Propyl parahydroxybenzoate, sodium ................................. 3263
Propylthiouracil ...................................................................... 3124
Propyphenazone .............................................................. 8.1-3802
Protamine sulfate .................................................................... 3125
Protein C, human, assay of (2.7.30.) ....................................... 265
Protein in polysaccharide vaccines (2.5.16.) ......................... 159
Protein S, human, assay of (2.7.31.) ....................................... 266
Protein, total (2.5.33.) .............................................................. 165
Prothrombin complex, human .............................................. 2429
Protirelin .................................................................................. 3127
Proxyphylline .......................................................................... 3128
Pseudoephedrine hydrochloride ........................................... 3129
Psyllium seed ........................................................................... 1357
Purified water .......................................................................... 3561
Purified water, highly ............................................................. 3559
Purple coneflower herb .......................................................... 1357
Purple coneflower root .......................................................... 1359
Pycnometric density of solids, gas (2.9.23.) .......................... 324
Pygeum africanum bark ........................................................ 1361
Pyrantel embonate .................................................................. 3130
Pyrazinamide .......................................................................... 3131
Pyridostigmine bromide ........................................................ 3132
Pyridoxine hydrochloride ...................................................... 3133
Pyrimethamine ....................................................................... 3134
Pyrogens (2.6.8.) ....................................................................... 183
Pyrrolidone .............................................................................. 3135
Q
Quality of non-sterile pharmaceutical preparations and
substances for pharmaceutical use, microbiological
(5.1.4.) ...................................................................................... 559
Quality of non-sterile pharmaceutical preparations and
substances for pharmaceutical use, microbiological (5.1.4.)
(5.8.) ................................................................................ 8.1-3681
Quantified hawthorn leaf and flower liquid extract. .......... 1274
Quetiapine fumarate ....................................................... 8.2-4091
Quillaia bark ............................................................................ 1362
Quinapril hydrochloride ................................................. 8.1-3807
Quinidine sulfate .................................................................... 3141
Quinine hydrochloride .......................................................... 3142
Quinine sulfate ........................................................................ 3144
R
Rabbit haemorrhagic disease vaccine (inactivated) ........... 1007
Rabies immunoglobulin, human .......................................... 2431
Rabies vaccine for human use prepared in cell
cultures ............................................................................ 8.2-3952
Rabies vaccine (inactivated) for veterinary use .................. 1008
Rabies vaccine (live, oral) for foxes and raccoon dogs ...... 1011
Racecadotril ............................................................................. 3149
Racementhol.. .......................................................................... 2711
Racemic camphor ................................................................... 1753
Racemic ephedrine hydrochloride ....................................... 2143
Racemic menthol .................................................................... 2711
Racephedrine hydrochloride ................................................. 2143
Raclopride ([llC]methoxy) injection .................................... 1076
Radioactivity, detection and measurement of (2.2.66.) ....... 110
Radionuclides, table of physical characteristics (5.7.) .......... 667
Radiopharmaceutical preparations ........................................ 759
Radiopharmaceutical preparations, iobenguane sulfate
for ........................................................................................... 1070
Radiopharmaceutical preparations, medronic acid for ..... 1072
Radiopharmaceutical preparations, pentetate sodium calcium
for ........................................................................................... 1075
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Radiopharmaceutical preparations, sodium iodohippurate
dihydrate fOI"., .... ,................. " ... ,............................................ 1085
Radiopharmaceutical preparations, tetra -O-acetyl-mannose
triflate for .............................................................................. 1110
Raloxifene hydrochloride ...................................................... 3150
Raman spectrometry (2.2.48,) ................................................... 84
Ramipril, .................................. ,.. ,...... ,.... " ......... ,..................... 3152
Raman assay, flocculation value (Lf) of diphtheria and tetanus
toxins and toxoíds (2,7,27,) ................................................... 261
Ranitidine hydrochloride ......................................... ,............. 3154
Rapeseed oil, refined .............................................................. 3155
Reagents (4.) ................................. ,......................... ,.................. 425
Reagents (4,1.1,) ........................................................................ 425
Reagents (4,1.1.) ............................................................... 8.1-3675
Reagents (4,1.1.) ............................................................... 8.2-3937
Reagents, standard solutions, buffer solutions (4.1.) ........... 425
Recombinant DNA technology, products of.. ... ,................. ,. 763
Recommendations on dissolution testing (5,17.1.) .............. 727
Recommendations on methods for dosage forms testing
(5.17.) ....................................................................................... 727
Rectal capsules ................................... " ......... ,........................... 806
Rectal foams .............................................................................. 807
Rectal preparations., ................................................................. 806
Rectal preparations, semi-solid ...................... ,........................ 807
Rectal solutions and suspensions, powders and tablets for .. 806
Rectal solutions, emulsions and suspensions ........................ 807
Rectal tampons .... "" ... ,........... ,.......... ,.... ,.... ,.... " ................. ,., ... 807
Red poppy petals .......................................... ,.......... ,., ........ ,.... 1363
Reference standards (5.12,) ................ ,.................................... 699
Refractive index (2.2.6.) ............................................................. 26
Relationship between reaction of solution, approximate pH
and colour of certain indicators (2.2.4.) ................................ 25
Relative density (2.2.5.) ." .... " ....... ,.. ,............ ,... ,............ ,......... ,.. 25
Repaglinide ............................................ ,., ............................... 3156
Reserpine ........ ,....... ,.................................... ,.,.,., ..................... 3157
Residual pertussis toxin and irreversibility of pertussis toxoid
(2.6.33.) .... ,...... ,."., ...... ,................ ,........................................... 224
Residual solvents (5A.) ............................................................ 639
Residual solvents, identification and control (2.4.24,) .... "." 141
Residue 011 evaporation of essential oils (2.8.9.) ................... 272
Resistance to crushing of tablets (2.9.8.) ............................... 299
Resorcinol ...................................... ,......................... " ..... ", ...... 3158
Respiratory syncytial virus vaccine (live), bovine ................ 940
Restharrow root ................................... " .. " ....... " ............. 8.2-3967
Retroviridae-derived vectors for human use ......................... 712
Rhatany rooL" .... ,.................................... ,.............................. 1365
Rhatany tincture .................. " ........ ,............ ,.. ,.................. ,..... 1365
Rhinotracheitis vaccine (inactivated), viral, feline ............... 976
Rhinotracheitis vaccine (live), bovine, infectious ................. 983
Rhinotracheitis vaccine (live), infectious, turkey ............... 1022
Rhinotracheitis vaccine (live), viral, feline ............................ 977
Rhubarb .... " ....... " .. ,....... ,.............. ,., ..................... ,."., ...... ,...... 1366
Ribavirin ............................ "., ................ " ....... ", ...................... 3159
Riboflavin ....... ,.................... " .......... ,........................................ 3160
Riboflavin sodium phosphate .. " .......................... " ............... 3162
Ribose in polysaccharide vaccines (2.5.31.) .......................... 164
Ribwort plantain ........ ,...................... ,............... " ................ ,... 1367
Rice starch ,...................... ,........................ " ............................. 3163
Rifabutin .............. " .................................................................. 3164
Rifampicin ......... ,..................................................................... 3165
Rifamycin sodium ........................ " .................................. 8.2-4097
Rifaximin .......................................................... ,...................... 3167
Rilmenidine dihydrogen phosphate ..................................... 3169
Risedronate sodium 2.5-hydrate ............................ " ............. 3170
Risperidone .' ........................................................................... 3171
Ritonavir ................................. ,................. ,.... ,...................... ,.. 3173
Rivastigmine ......... ,.................... " ..................................... ,...... 3176
Rivastigmine hydrogen tartrate ............................................ 3178
Rizatriptan benzoate ...... " ...................... " .............................. 3179
Rocuronium bromide ............................................................. 3181
Roman chamomile flower" ............. ,............... ,...................... 1206
Ropivacaine hydrochloride monohydrate ....................... " .. 3183
Roselle ....... " .............................................................. " ....... ' ..... 1368
General Natices (1) apply ta all managraphs and other texts
Index
Rosemary leaf.. ........ " ..... ,,,,,,, ................ ,....... ,, ... ,, ................... 1369
Rosemary oi! ............................. ,.............................. " ............. 1370
Rotating viscometer method - viscosity (2,2.10.) ................... 28
Rotation, optical (2.2.7.) .............................. " ............................ 26
Rotavirus diarrhoea vaccine (inactivated), calf ... " ............... 944
Rotavirus vaccine (live, oral) ............. " .............. " ... " ............... 898
Round amomum fruit ..................................................... 8.1-3710
Roxithromycin .................. " .......... ,........ "", ................. ,..... ,.. " 3185
RRR-Ct- Tocopherol ... ,,, ............... ,, ... ,........ ,..... ,, ................... ,, .. 3437
RRR-a- Tocopheryl acetate" ................................ " ................. 3439
RRR-a- Tocopheryl hydrogen succinate ..... " ........................ 3443
Rubber closures for containers for aqueous parenteral
preparations, for powders and for freeze-dried powders
(3.2.9,) .................................................................... ,." .............. 421
Rubella immunoglobulin, human ........................................ 2432
Rubella, measles and mumps vaccine (live) ........................ " 872
Rubella, measles, mumps and varicella vaccine (live) .......... 873
Rubella vaccine (live) ............................................................... 900
Ruminant colibacillosis vaccine (inactivated), neonataL. ... 994
Rutoside trihydrate ............ " ................................................... 3187
S
Saccharin ......... ,........................... " ....... ,.......... ,.... "., ................ 3191
Saccharin sodium .. " .............................................................. , 3192
Safety, viral (5.1.7,) ........................................ " ........ " ............. " 571
Safflower flower ...... " .. ,,,,, ......... ,,.,, ........ ,, ...... ,................ , 8.2-3968
Safflower oil, refined ............. " .. " ............................................ 3193
Saffron for homoeopathic preparations ................. "." .. 8.2-3987
Sage leaf (salvia officinalis) ............. " ......... """ ...................... 1373
Sage leaf, three-lobed ... " ...................... "." ............ ""." .. , 8.2-3970
Sage oi!, Spanish ..................................... " ............................... 1389
Sage tincture, ....... " .... " ....... " ................ ,.......... " ...................... l374
Salbutamol ..... ,.... ,.... ,..... """ ....... " ..... ,..... " ......... ,.......... ", ....... 3193
Salbutamol sulfate ............ ,............. " ................................. " .... 3195
Salicylic acid." ................... " .. "" ..................... "" ................ " ... 3198
Salmeterol xinafoate ................... """" .................. "." ...... 8.1-3813
Salmonella Enteritidis vaccine (inactivated) for chickens" 1012
Salmonella Enteritidis vaccine oral) for chickens ..... 1013
Salmonella Typhimurium vaccine (inactivated) for
chickens ..... ,........... " ........ ,."., ......... ,............ " ..... " ..... ,..... ",.,.1015
Salmonella Typhimurium vaccine (live, oral) for
chickens .............. ' .................. ,........................... ,............ ,...... 1016
Salmon oil, farmed ............ " .................. " .............. " ........... " .. 3201
Salvia miltiorrhiza root and rhizome ................................. " 1374
Sanguisorba root ......................... ,........................................... 1376
Saponification value (2.5.6,) ........ " ..................................... " ... 157
Saquinavir mesilate .. ,... ,.",., .... ,............. " ...... ,.......... ,..... ,..... ", 3202
Saw palmetto extract .............................................................. 1377
Saw palmetto fruit ........... " ................................... " ............... , 1379
Schisandra fruit... ...................................................... ,........ ", .. 1381
Scopolamine .............. ,............................. ' ............... " .............. 2461
Scopolamine butylbromide ............................ " ..................... 2462
Scopolamine hydrobromide .................................................. 2464
Selamectin for veterinary use ....... " .................... " ................. 3204
Selegiline hydrochloride ................................................. 8.2-4101
Selenium disulfide .... ,............................. ,....... ,....................... 3207
Selfheal fruit-spike, common ............... " ......... " .... " ............ " 1219
Semi-micro determination of water (2.5.12.) ............... 8.2-3917
Semi-solid ear preparations ... " .. " ............................................ 782
Semicsolid eye preparations .................................................... 784
Semi-solid intrauterine preparations ................. " .................. 787
Semi-solid nasal preparations ........................ " .... " ................. 793
Semi-solid oromucosal preparations ...................................... 794
Semi-solid preparations for cutaneous application" .... " ...... 807
Semi-solid preparations for oral use, veterinary ......... 8.1-3689
Semi-solid rectal preparations .... " .......................................... 807
Semi-solid vaginal preparations ............................................. 813
Senega root ................................................... ,......................... , 1382
Senna leaf.." .......... "."."." ..... ,....... ,., ......................... ,........... ,.. 1383
Senna leaf dry extract, standardised .................................... 1384
Senna pods, Alexandrian ....................................................... 1384
Senna pods, Tinnevelly .............. " .......................................... 1385
4147
Index
Separation techniques, chromatographic (2.2.46.) ................. 72
Serine ........................................................................................ 3208
Sertaconazole nitrate .............................................................. 3209
Sertraline hydrochloride ........................................................ 3210
Sesame oil, refined .................................................................. 3212
Sets for the transfusion of blood and blood components
(3.2.6.) ...................................................................................... 418
Sevoflurane .............................................................................. 3214
Shampoos .................................................................................. 790
Shellac ..................................................................................... 3216
Shingles (herpes zoster) vaccine (live) ................................... 902
Sialic acid in polysaccharide vaccines (2.5.23.) ..................... 161
Siam benzoin tincture ............................................................ 1171
Sieves (2.1.4.) ............................................................................... 16
Sieve test (2.9.12.) ..................................................................... 305
Sieving, analytical, particle-size distribution estimation by
(2.9.38.) .................................................................................... 351
Sieving, analytical, particle-size distribution estimation by
(2.9.38.) (5.8.) ................................................................. 8.1-3681
SI (International System) units (1.) ............................... 8.2-3897
Sildenafil citrate ...................................................................... 3217
Silica, colloidal anhydrous ..................................................... 3218
Silica, colloidal hydrated ........................................................ 3219
Silica, dental type .................................................................... 3219
Silica, hydrophobic colloidal ................................................. 3220
Silicate, aluminium magnesium ............................................ 1521
Silicate, aluminium sodium ................................................... 1524
Silicone elastomer for closures and tubing (3.1.9.) ............... 394
Silicone oil used as a lubricant (3.1.8.) ................................... 393
Silk suture, sterile, braided, in distributor for veterinary use
................................................................................................ 1129
Silver, colloidal, for external use ........................................... 3221
Silver nitrate ............................................................................ 3221
Simeticone ............................................................................... 3222
Simvastatin .............................................................................. 3223
Single-dose preparations, uniformity of content (2.9.6.) ..... 298
Single-dose preparations, uniformity of mass (2.9.5.) ......... 297
Sintered-glass filters (2.1.2.) ...................................................... 15
Size-exclusion chromatography (2.2.30.) ................................. 46
(S)-Lactic acid ......................................................................... 2579
Smallpox vaccine (live) ............................................................ 903
Sodium acetate ([l_lle]) injection ........................................ 1078
Sodium acetate trihydrate ...................................................... 3224
Sodium alendronate ............................................................... 3225
Sodium alginate ...................................................................... 3226
Sodium aluminium silicate .................................................... 1524
Sodium amidotrizoate ............................................................ 3227
Sodium aminosalicylate dihydrate ....................................... 3228
Sodium ascorbate ................................................................... 3229
Sodium aurothiomalate ......................................................... 3230
Sodium benzoate .................................................................... 3232
Sodium bromide ..................................................................... 3232
Sodium calcium edetate ......................................................... 3233
Sodium calcium pentetate for radiopharmaceutical
preparations .......................................................................... 1075
Sodium caprylate .................................................................... 3234
Sodium carbonate, anhydrous .............................................. 3235
Sodium carbonate decahydrate ............................................. 3236
Sodium carbonate monohydrate .......................................... 3236
Sodium carboxymethylcellulose ........................................... 1774
Sodium carboxymethylcellulose, cross-linked .................... 1969
Sodium carboxymethylcellulose, low-substituted .............. 1775
Sodium cetostearyl sulfate .............................................. 8.1-3814
Sodium chloride ...................................................................... 3238
Sodium chromate (51 er) sterile solution .............................. 1079
Sodium citrate ......................................................................... 3239
Sodium cromoglicate ............................................................. 3240
Sodium cyclamate ................................................................... 3241
Sodium dihydrogen phosphate dihydrate ........................... 3242
Sodium disulfite ...................................................................... 3254
Sodium ethyl parahydroxybenzoate ..................................... 3243
Sodium fluoride ...................................................................... 3244
Sodium fluoride (1sP) injection ............................................. 1079
4148
EUROPEAN PHARMAeOPOEIA 8.2
Sodium fusidate ...................................................................... 3245
Sodium glycerophosphate, hydrated .................................... 3247
Sodium hyaluronate ............................................................... 3248
Sodium hydrogen carbonate ................................................. 3250
Sodium hydroxide .................................................................. 3251
Sodium iodide ......................................................................... 3251
Sodium iodide (mI) injection ............................................... 1080
Sodium iodide (1231) solution for radiolabelling ................. 1081
Sodium iodide (131 1) capsules for diagnostic use ................ 1082
Sodium iodide (131I) capsules for therapeutic use .............. 1083
Sodium iodide ( 1311) solution ................................................ 1084
Sodium iodide (1 31 1) solution for radiolabelling ................. 1084
Sodium iodohippurate (123I) injection ................................. 1086
Sodium iodohippurate (131I) injection ................................. 1087
Sodium iodohippurate dihydrate for radiopharmaceutical
preparations .......................................................................... 1085
Sodium lactate solution ......................................................... 3252
Sodium laurilsulfate ............................................................... 3254
Sodium metabisulfite ............................................................. 3254
Sodium methyl parahydroxybenzoate ................................. 3255
Sodium molybdate (99Mo) solution (fission) ...................... 1088
Sodium molybdate dihydrate ................................................ 3256
Sodium nitrite ......................................................................... 3257
Sodium nitroprusside ............................................................. 3257
Sodium perborate, hydrated .................................................. 3258
Sodium pertechnetate (99mTc) injection (fission) ............... 1090
Sodium pertechnetate (99mTc) injection (non-fission) ....... 1091
Sodium phenylbutyrate .......................................................... 3258
Sodium phosphate (32P) injection ......................................... 1092
Sodium picosulfate ................................................................. 3260
Sodium polystyrene sulfonate ............................................... 3261
Sodium propionate ................................................................. 3262
Sodium propyl parahydroxybenzoate .................................. 3263
Sodium risedronate 2.5-hydrate ........................................... 3170
Sodium salicylate .................................................................... 3264
Sodium selenite pentahydrate ............................................... 3264
Sodium (S)-lactate solution ................................................... 3253
Sodium starch glycolate (type A) .......................................... 3265
Sodium starch glycolate (type B) .......................................... 3266
Sodium starch glycolate (type e) .......................................... 3267
Sodium stearate ....................................................................... 3267
Sodium stearyl fumarate ........................................................ 3268
Sodium sulfate, anhydrous .................................................... 3269
Sodium sulfate decahydrate ................................................... 3270
Sodium sulfite, anhydrous ..................................................... 3270
Sodium sulfite heptahydrate .................................................. 3271
Sodium tetrachloroaurate dihydrate for homoeopathic
preparations ................................................................... 8.2-3984
Sodium thiosulfate .................................................................. 3271
Sodium valproate .................................................................... 3272
Soft capsules .............................................................................. 780
Softening time determination of lipophilic suppositories
(2.9.22.) .................................................................................... 323
Soft extracts ............................................................................... 746
Solid dosage forms, dissolution test for (2.9.3.) .................... 288
Solid dosage forms, recommendations on dissolution testing
of (5.17.1.) ................................................................................ 727
Solids by mercury porosimetry, porosity and pore-size
distribution of (2.9.32.) .......................................................... 336
Solids, density of (2.2.42.) .......................................................... 68
Solids, gas pycnometric density of (2.9.23.) .......................... 324
Solids (porous) including powders, wettability of (2.9.45.) .. 365
Solubility in alcohol of essential oils (2.8.10.) ....................... 272
Soluble tablets ........................................................................... 811
Solution calorimetry and microcalorimetry, characterisation
of crystalline solids by (2.2.61.) ............................................ 106
Solutions, emulsions and suspensions, oral .......................... 790
Solutions for haemodialysis ................................................... 2376
Solutions for haemodialysis, concentrated, water for
diluting ................................................................................... 2375
Solutions for haemofiltration and haemodiafiltration ....... 2378
Solutions for organ preservation .......................................... 3273
Solutions for peritoneal dialysis ............................................ 2994
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Solutions, suspensions, intrauterine ....................................... 787
Solvents, residual (5.4.) ............................................................ 639
Solvents, residual, identification and control (2.4.24.) ......... 141
Somatostatin ..................................................................... 8.1-3816
Somatropin .............................................................................. 3275
Somatropin concentrated solution ....................................... 3277
Somatropin for injection ....................................................... 3279
Sophora flower ........................................................................ 1386
Sophora flower-bud ................................................................ 1388
Sorbic acid ............................................................................... 3281
Sorbitan laurate ....................................................................... 3282
Sorbitan oleate ......................................................................... 3282
Sorbitan palmitate .................................................................. 3282
Sorbitan sesquioleate .............................................................. 3283
Sorbitan stearate ..................................................................... 3283
Sorbitan trioleate .................................................................... 3284
Sorbitol ..................................................................................... 3284
Sorbitol, liquid (crystallising) ............................................... 3286
Sorbitol, liquid (non-crystallising) ....................................... 3286
Sorbitol, liquid, partially dehydrated ................................... 3287
Sotalol hydrochloride ............................................................. 3288
Soya-bean oil, hydrogenated ................................................. 3289
Soya-bean oil, refined ............................................................. 3290
Spanish sage oil ....................................................................... 1389
Specific surface area by air permeability (2.9.14.) ................ 305
Specific surface area by gas adsorption (2.9.26.) .................. 329
Specific surface area by gas adsorption (2.9.26.)
(5.8.) ........ 8.1-3681
00 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
Spectinomycin dihydrochloride pentahydrate .................... 3290
Spectinomycin sulfate tetrahydrate for veterinary use ...... 3292
Spectrometry, atomic absorption (2.2.23.) .............................. 36
Spectrometry, atomic emission (2.2.22.) ................................. 35
Spectrometry, mass (2.2.43.) ..................................................... 69
Spectrometry, nuclear magnetic resonance (2.2.33.) ............. 52
Spectrometry, Raman (2.2.48.) ................................................. 84
Spectrometry, X-ray fluorescence (2.2.37.) ............................. 59
Spectrophotometry, infrared absorption (2.2.24.) ................. 38
Spectrophotometry, ultraviolet and visible absorption
(2.2.25.) ...................................................................................... 40
Spectroscopy, near-infrared (2.2.40.) ....................................... 62
SPF chicken flocks for the production and quality control of
vaccines (5.2.2.) ....................................................................... 579
Spheroids and granules, friability of (2.9.41.) ........... 359
Spike lavender oil. ................................................................... 1390
Spiramycin ............................................................................... 3294
Spirapril hydrochloride monohydrate ................................. 3296
Spironolactone ........................................................................ 3298
Spot-on preparations ................................................................ 814
Sprays (liquid nasal) and drops (nasal) .................................. 792
Sprays, veterinary ..................................................................... 814
Squalane ................................................................................... 3300
Standard solutions for limit tests (4.1.2.) ............................... 536
Standard solutions for limit tests (4.1.2.) ...................... 8.1-3675
Standards, reference (5.12.) ..................................................... 699
Stannous chloride dihydrate .................................................. 3302
Stanozolol ................................................................................ 3302
Star anise .................................................................................. 1394
Star anise oil ............................................................................ 1395
Starches, hydroxyethyl ........................................................... 3307
Starch glycolate (type A), sodium ......................................... 3265
Starch glycolate (type B), sodium ......................................... 3266
Starch glycolate (type C), sodium ......................................... 3267
Starch, hydroxypropyl ............................................................ 3303
Starch, hydroxypropyl, pregelatinised .................................. 3305
Starch, maize ........................................................................... 2684
Starch, maize (5.8.) .......................................................... 8.1-3679
Starch, pea ........................................................................ 8.1-3799
Starch, potato .......................................................................... 3078
Starch, potato (5.8.) ......................................................... 8.1-3679
Starch, pregelatinised ............................................................. 3306
Starch, rice ............................................................................... 3163
Starch, wheat ........................................................................... 3563
Starch, wheat (5.8.) .......................................................... 8.1-3679
General Notices (1) apply to all monographs and other texts
Index
Starflower (borage) oil, refined ............................................. 1681
Statistical analysis of results of biological assays and tests
(5.3.) ......................................................................................... 607
Stavudine ................................................................................. 3311
Steam sterilisatiol1 of aqueous preparations, application of the
Po concept (5.1.5.) ................................................................... 560
Stearic acid ............................................................................... 3313
Stearoyl macrogolglycerides .................................................. 3314
Stearyl alcohol ............... ,. ........................................................ 3314
Stem cells, human haematopoietic ....................................... 2419
Stephania root, fourstamen ................................................... 1246
Sterile braided silk suture in distributor for veterinary
use ........................................................................................... 1129
Sterile catgut ............................................................................ 1117
Sterile catgut in distributor for veterinary use .................... 1127
Sterile containers of plasticised poly(vinyl chloride) for human
blood containing anticoagulant solution (3.2.5.) ............... 418
Sterile linen thread in distributor for veterinary use ......... 1128
Sterile non ·absorbable strands in distributor for veterinary
use ........................................................................................... 1129
Sterile non-absorbable sutures .............................................. 1118
Sterile plastic containers for human blood and blood
components (3.2.3.) ................................................................ 415
Sterile polyamide 6/6 suture in distributor for veterinary
use ........................................................................................... 1128
Sterile polyamide 6 suture in distributor for veterinary
use ........................................................................................... 1128
Sterile poly(ethylene terephthalate) suture in distributor for
veterinary use ........................................................................ 1129
Sterile products, methods of preparation (5.1.1.) ................. 555
Sterile single-use plastic syringes (3.2.8.) .............................. 419
Sterile synthetic absorbable braided sutures ....................... 1122
Sterile synthetic absorbable monofilament sutures ............ 1123
Sterilisation procedures, biological indicators (5.1.2.) ......... 556
Sterility (2.6.1.) .......................................................................... 175
Sterility (2.6.1.) (5.8.) ...................................................... 8.1-3680
Sterility, guidelines for using the test for (5.1.9.) .................. 572
Sterols in fatty oils (2.4.23.) ..................................................... 139
Sticks .......................................................................................... 809
Sticks, intrauterine .................................................................... 787
Sticks, nasal ............................................................................... 793
Sto John's wort. ......................................................................... 1391
00 • • • • • • • • • • St. John's wort dry extract, quantified .................................. 1393
Stomata and stomatal index (2.8.3.) ....................................... 271
Stramonium leaf ..................................................................... 1397
Stramonium, prepared ........................................................... 1399
Strands, sterile 110n -absorbable, in distributor for veterinary
use .......................................................................................... 1129
Streptokinase concentrated solution .................................... 3315
Streptomycin sulfate ............................................................... 3317
Strontium (89 Sr) chloride injection ....................................... 1092
Subdivision of tablets ............................................................... 809
Sublingual sprays, oromucosal drops and oromucosal
sprays ........................................................................................ 793
Sublingual tablets and buce al tablets ...................................... 795
Substances for pharmaceutical use ......................................... 765
Substances for pharmaceutical use, control of impurities in
(5.10.) ................................................................................
H ••••• 689
Substances of animal origin for the production of
immunological veterinary medicinal products (5.2.5.) ..... 587
Sub-visible particles, particulate contamination (2.9.19.) ... 321
Sub· visible particles, particulate contamination (2.9.19.)
(5.8.) ................................................................................ 8.1-3681
Sucralfate ................................................................................. 3318
Sucralose .................................................................................. 3319
Sucrose ..................................................................................... 3321
Sucrose monopalmitate .......................................................... 3322
Sucrose stearate ....................................................................... 3323
Sufentanil ................................................................................. 3325
Sufentanil citrate ..................................................................... 3326
Sugars, lead in (2.4.10.) ............................................................ 131
Sugar spheres ........................................................................... 3327
Sulbactam sodium .................................................................. 3328
4149
Index
Sulfacetamide sodium ............................................................ 3330
Sulfadiazine ............................................................................. 3331
Sulfadimidine ................................................................... 8.1-3817
Sulfadoxine .............................................................................. 3334
Sulfafurazole ............................................................................ 3334
Sulfaguanidine ........................................................................ 3335
Sulfamerazine .......................................................................... 3336
Sulfamethizole ......................................................................... 3337
Sulfamethoxazole ........................... ,........................................ 3338
Sulfamethoxypyridazine for veterinary use ......................... 3339
Sulfanilamide .................................. ,........................................ 3340
Sulfasalazine ........................ ,............... ,............................ ,...... 3340
Sulfated ash (2.4.14.) ................................................................ 132
Sulfated ash (2.4.14.) (5.8.) ............................................. 8.1-3680
Sulfates (2.4.13.) ........................................................................ 132
Sulfathiazole ............................................................................ 3342
Sulfinpyrazone ..... "" .................. ,..... ,......... " ................ ,..... ,..... 3343
Sulfur dioxide (2.5.29.), ........................................ ,................... 164
Sulfur for external use ............................................................ 3344
Sulfur for homoeopathic preparations ......................... ,....... 1456
Sulfuric acid ...................... ,.. ,................................................... 3345
Sulindac. ......... " ..... ,........ ,....... ,............. ,.. ,................... ,............ 3345
Sulpiride .................. ,......................................................... 8.1-3818
Sultamicillin ............................................................................ 3348
Sultamicillin tosilate dihydrate ............................................. 3350
Sumatra benzoin ..................................................................... 1170
Sumatra benzoin tincture ...................................................... 1172
Sumatriptan succinate ............................................................ 3352
Sunflower oil, reflned ............................................................. 3354
Supercritical fluid chromatography (2.2.45.) .......................... 72
Suppositories ............................................................................. 806
Suppositories and pessaries, disintegration of (2.9.2.) ......... 287
Suppositories, lipophilic, softening time determination
(2.9.22.) .................................................................................... 323
'''''''Vll~, solutions and emulsions, oral .......................... 790
Suspensions, solutions, intrauterine ....................................... 787
Sutures, sterile non -absorbable ............................................. 1118
Sutures, sterile synthetic absorbable braided ..................... 1122
Sutures, sterile synthetic absorbable monofllament .......... 1123
Suxamethonium chloride ...................................................... 3354
Suxibuzone .............................................................................. 3355
Sweet fennel ............................................................................. 1242
Sweet orange oil ...................................................................... 1400
Swelling index (2.8.4.) .............................................................. 271
Swine erysipelas vaccine (inactivated) ................................. 1018
Swine-fever vaccine (live, prepared in cel! cultures),
classical .................................................................................. 1019
Symbols and abbreviations (1.) ...................................... 8.2-3897
Synthetic absorbable braided sutures, sterile ...................... 1122
Synthetic absorbable monofilament sutures, sterile ........... 1123
Syringes, plastic, sterile single-use (3.2.8.) ............................ 419
Syrups ......................................................................................... 791
T (2.6.17.) .................................................................................... 200
Table of physical characteristics of radionuclides mentioned in
the European Pharmacopoeia (5.7.) ..................................... 667
Tablets ........................................................................................ 809
Tablets and capsules, disintegration of (2.9.1.) ..................... 285
Tablets and capsules, disintegration of (2.9.1.) (5.8.) .. 8.1-3680
Tablets and powders for rectal solutions and suspensions .. 807
Tablets, buccal ........................................................................... 795
Tablets, chewable ...................................................................... 811
Tablets, coated ........................................................................... 810
Tablets, dispersible .................................................................... 811
Tablets, effervescent... ............................................................... 811
Tablets for intrauterine solutions and suspensions .............. 787
Tablets for use in the mouth .................................................... 812
Tablets for vaginal solutions and suspensions ...................... 813
Tablets, gastro-resistant. ........................................................... 811
Tablets, intrauterine .................................................................. 787
Tablets, modified-release ......................................................... 811
Tablets, orodispersible .............................................................. 811
4150
EUROPEAN PHARMACOPOEIA 8.2
Tablets, resistan ce to crushing (2.9.8.) ................................... 299
Tablets, soluble .......................................................................... 811
Tablets, subdivision of. ............................................................. 809
Tablets, sublingual .................................................................... 795
Tablets, uncoated ...................................................................... 810
Tablets, uncoated, friability of (2.9.7.) ................................... 298
Tablets, uncoated, friability of (2.9.7.) (5.8.) ................ 8.1-3681
Tablets, vaginal.. ........................................................................ 813
Tadalafil .................................................................................... 3359
Tale ........................................................................................... 3361
Tamoxifen citrate .................................................................... 3363
Tampons, ear ............................................................................. 782
Tampons, medicated ............................................................... 812
Tampons, rectal ......................................................................... 807
Tampons, vaginal, medicated .................................................. 814
Tamsulosin hydrochloride ..................................................... 3364
Tannic acid .............................................................................. 3366
Tannins in herbal drugs (2.8.14.) ............................................ 275
Tapped density and bulk density of powders (2.9.34.) ......... 343
Tartaric acid ............................................................................. 3367
Teat dips ..................................................................................... 814
Tea tree oil ............................................................................... 1401
Teat sprays ................................................................................. 814
Technetium C9lU Tc) bicis ate injection .................................. 1093
Technetium C9lU Tc) colloidal rhenium sulfide injection ... 1094
Technetium C9ffi Tc) colloidal sulfur injection ..................... 1095
e
Technetium 9ffi Tc) colloidal tin injection .......................... 1095
Technetium (99lUTc) etifenin injection .................................. 1096
Technetium C9lU Tc) exametazime injection ........................ 1097
Technetium C9I\1Tc) gluconate injection .............................. 1098
Technetium C9m Tc) human albumin injection ................... 1099
Technetium C91ll Tc) macrosalb injection ............................. 1100
Technetium C9I\1Tc) mebrofenin injection ........................... 1101
Technetium (99mTc) medronate injection ............................ 1102
Technetium C91ll Tc) mertiatide injection ............................. 1104
Technetium C9il1 Tc) microspheres injection ........................ 1105
Technetium (99mTc) pentetate injection ............................... 1106
Technetium C9il1 Tc) sestamibi injection ............................... 1107
Technetium (9911lTc) succimer injection ................................ 1108
Technetium C9m Tc) tin pyrophosphate injection ............... 1109
Teicoplanin .............................................................................. 3367
Telmfsartan .............................................................................. 3369
Temazepam .............................................................................. 3371
Tenosynovitis vaccine (live), viral, avian ............................... 935
Tenoxicam ............................................................................... 3372
Terazosin hydrochloride dihydrate ...................................... 3373
Terbinaflne hydrochloride ..................................................... 3375
Terbutaline sulfate .................................................................. 3377
Terconazole .......... ,................... ",.,., ......................................... 3378
Terfenadine .............................................................................. 3379
Terminology used in monographs on biological products
(5.2.1.) ...................................................................................... 579
Test for anticomplementary activity of immunoglobulin
Test for anti-D antibodies in human immunoglobulin
(2.6.26.) .................................................................................... 215
Test for aristolochic acids in herbal drugs (2.8.21) .............. 279
Test for extractable volume of parenteral preparations
(2.9.17.) .................................................................................... 308
Test for extractable volume of parenteral preparations (2.9.17.)
(5.8.) ................................................................................ 8.1-3681
Test for Fc function of immunoglobulin (2.7.9.) .................. 246
Test for methanol and 2-propanol (2.9.11.) .......................... 304
Test for neurovirulence oflive virus vaccines (2.6.18.) ........ 202
Test for neurovirulence of poliomyelitis vaccine (oral)
(2.6.19.) .................................................................................... 202
Test for specifled micro-organisms (microbiological
examination of non-sterile products) (2.6.13.) ................... 189
Test for specified micro-organisms (microbiological
examination of non-sterile products) (2.6.13.)
(5.8.) ................................................................................ 8.1-3680
Testosterone ............................................................................. 3380
Testosterone decanoate .......................................................... 3382
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Testosterone enantate .......................... " ................... " ............ 3383
Testosterone isocaproate ........................................................ 3385
Testosterone propionate ......................................................... 3386
Tests for extraneous agents in viral vaccines for human use
(2.6.16.) .................................................................................. " 198
Tetanus and diphtheria toxins and toxoids, flocculation value
(Lf) of, (Ramon assay) (2.7.27.) ............................................ 261
Tetanus and diphtheria vaccine (adsorbed) .......................... 823
Tetanus and diphtheria vaccine (adsorbed, reduced antigen(s)
content) .................................................................................... 824
Tetanus antitoxin for human use .......................................... 1033
Tetanus antitoxin for veterinary use ..................................... 1040
Tetanus, diphtheria and hepatitis B (rDNA) vaccine
(adsorbed) ............................................................................... 825
Tetanus, diphtheria and pertussis (acellular, component)
vaccine (adsorbed) ............................................... " ................ 826
Tetanus, diphtheria and pertussis (acellular, component)
vaccine (adsorbed, reduced antigen(s) content) ........ 8.2-3951
Tetanus, diphtheria and pertussis (whole cell) vaccine
(adsorbed) ............................................................................... 827
Tetanus, diphtheria and poliomyelitis (inactivated) vaccine
(adsorbed, reduced antigen(s) content) ............................... 829
Tetanus, diphtheria, pertussis (acellular, component) and
haemophilus type b conjugate vaccine (adsorbed) ............ 830
Tetanus, diphtheria, pertussis (acellular, component) and
hepatitis B (rDNA) vaccine (adsorbed) ............................... 832
Tetanus, diphtheria, pertussis (acellular, component) and
poliomyelitis (inactivated) vaccine (adsorbed) ................... 834
Tetanus, diphtheria, pertussis (acellular, component) and
poliomyelitis (inactivated) vaccine (adsorbed, reduced
antigen(s) content) ................................................................. 835
Tetanus, diphtheria, pertussis (acellular, component),
hepatitis B (rDNA), poliomyelitis (inactivated) and
haemophilus type b conjugate vaccine (adsorbed) ............ 837
Tetanus, diphtheria, pertussis (acellular, component),
poliomyelitis (inactivated) and haemophilus type b conjugate
vaccine (adsorbed) ................................................................. 840
Tetanus, diphtheria, pertussis (whole cell) and poliomyelitis
(inactivated) vaccine (adsorbed) .......................................... 842
Tetanus, diphtheria, pertussis (whole cel!), poliomyelitis
(inactivated) and haemophilus type b conjugate vaccine
(adsorbed) ............................................................................... 844
Tetanus immunoglobulin, human ........................................ 2432
Tetanus vaccine (adsorbed) ..................................................... 907
Tetanus vaccine (adsorbed), assay of (2.7.8.) ........................ 242
Tetanus vaccine for veterinary use ....................................... 1021
Tetracaine ~~drochloride ....................................................... 3387
Tetracosactlde .......................................................................... 3388
Tetracyeline ............................................................................. 3390
Tetracycline hydrochloride .................................................... 3391
Tetra-O-acetyl-mannose triflate for radiopharmaceutical
preparations .......................................................................... 1110
Tetrazepam .............................................................................. 3393
Tetryzoline hydrochloride ..................................................... 3394
Thallous (2 D1 TI) chloride injection ........................................ 1111
Theobromine ........................................................................... 3395
Theophylline ........................................................................... 3395
Theophylline-ethylenediamine, anhydrous ......................... 3398
Theophylline-ethylenediamine hydrate ............................... 3399
Theophylline monohydrate ................................................... 3396
Thermal analysis (2.2.34.) .......................................................... 55
Thermogravimetry (2.2.34.) ...................................................... 55
Thiamazole .............................................................................. 3401
Thiamine hydrochloride ........................................................ 3402
Thiamine nitrate ..................................................................... 3403
Thiamphenicol ........................................................................ 3405
Thin-layer chromatography (2.2.27.) ....................................... 42
Thioctic acid ............................................................................ 3405
Thiomersal. .............................................................................. 3406
Thiopental sodium and sodium carbonate ......................... 3407
Thioridazine ............................................................................ 3409
Thioridazine hydrochloride .................................................. 3410
Thomson kudzuvine root ...................................................... 1402
General Notices (1) apply to all monographs and other texts
Index
Three-Iobed sage leaf ...................................................... 8.2-3970
Threonine ................................................................................ 3411
Thyme ............................................................................... 8.2-3971
Thyme oi!, thymol type .......................................................... 1405
Thyme, wild ...................................................................... 8.2-3974
Thymol ..................................................................................... 3412
Thymol type thyme oil ........................................................... 1405
Tiabendazole ........................................................................... 3413
Tiamulin tor veterinary use ................................................... 3414
Tiamulin hydrogen fumarate for veterinary use ................. 3416
Tianeptine sodium .................................................................. 3418
Tiapride hydrochloride ................................................... 8.1-3823
Tiaprofenic acid ...................................................................... 3420
Tibolone ................................................................................... 3421
Ticarcillin sodium .................................................................. 3423
Tick-borne encephalitis vaccine (inactivated) ...................... 908
Ticlopidine hydrochloride ..................................................... 3424
Tilidine hydrochloride hemihydrate .................................... 3426
Timolol maleate ...................................................................... 3427
Tinctures .................................................................................... 745
Tinidazole ................................................................................ 3429
Tinnevelly senna pods ............................................................ 1385
Tinzaparin sodium ................................................................. 3430
Tioconazole ............................................................................. 3430
Tiotropium bromide monohydrate ...................................... 3431
Titanium dioxide .................................................................... 3433
Titration, amperometric (2.2.19.) ............................................. 34
Titration, potentiometric (2.2.20.) ............................................ 34
Titrations, complexometric (2.5.11.) ...................................... 158
Titration, voltametric (2.2.65.) ................................................ 109
Tobramycin .............................................................................. 3434
Tocopherol, all-rac-a- ............................................................. 3436
Tocopherol, RRR-a- ................................................................ 3437
Tocopheryl acetate, all-rac-a- ............................................... 3438
((-Tocopheryl acetate concentrate (powder form) .............. 3441
Tocopheryl acetate, RRR-a- ............................ " ..................... 3439
Tocopheryl hydrogen succinate, DL-((- ................................ 3442
Tocopheryl hydrogen succinate, RRR-a- ............................. 3443
Tolbutamide ............................................................................. 3445
Tolfenamic acid ....................................................................... 3446
Tolnaftate ................................................................................. 3447
Tolu balsam ............................................................................. 1406
Torasemide, anhydrous .......................................................... 3449
Tormentil ................................................................................. 1407
Tormentil tincture .................................................................. 1407
Tosylchloramide sodium ....................................................... 3450
Total ash (2.4.16.) ...................................................................... 132
Total cholesterol in oils rich in omega-3 acids (2.4.32.) ...... 151
Total organic carbon in water for pharmaceutical use
(2.2.44.) ...................................................................................... 71
Total protein (2.5.33.) ............................................................... 165
Toxicity, abnormal (2.6.9.) ....................................................... 184
Traditional Chinese medicine, names of herbal drugs used in
(5.22.) .............................................................................. 8.2-3941
Tragacanth ............................................................................... 1408
Tramadol hydrochloride ........................................................ 3450
Tramazoline hydrochloride monohydrate ........................... 3452
Trandolapril ............................................................................. 3453
Tranexamic acid ...................................................................... 3454
Transdermal patches ................................................................ 798
Transdermal patches, dissolution test for (2.9.4.) ................. 295
Trapidil ..................................................................................... 3455
Trehalose dihydrate ................................................................ 3456
Tretinoin .................................................................................. 3458
Triacetin ................................................................................... 3459
Triamcinolone ......................................................................... 3459
Triamcinolone acetonide ....................................................... 3460
Triamcinolone hexacetonide ................................................. 3462
Triamterene ............................................................................. 3463
Tribenoside ....................................................................... 8.1-3824
Tributyl acetylcitrate ............................................................... 3466
Trichloroacetic acid ................................................................ 3468
Triethanolamine ...................................................................... 3481
4151
Index
Triethyl citrate ........................................... ;............................. 3468
Trifluoperazine hydrochloride .............................................. 3469
Triflusal .................................................................................... 3470
Triglycerides, medium-chain ................................................ 3471
Triglycerides, omega-3-acid .................................................. 2909
Triglycerol diisostearate ......................................................... 3472
Trihexyphenidyl hydrochloride ............................................ 3473
Trimebutine maleate .............................................................. 3474
Trimeprazine hemitartrate .................................................... 1504
Trimetazidine dihydrochloride ............................................. 3475
Trimethadione ......................................................................... 3476
Trimethoprim .......................................................................... 3477
Trimipramine maleate ............................................................ 3479
Tri-n-butyl phosphate ............................................................ 3467
Tritiated eH) water injection ................................................ 1111
Trolamine ................................................................................. 3481
Trometamol ............................................................................. 3483
Tropicamide ............................................................................. 3483
Tropisetron hydrochloride ..................................................... 3485
Trospium chloride .................................................................. 3486
Troxerutin ................................................................................ 3488
Trypsin ..................................................................................... 3489
Tryptophan .............................................................................. 3490
TSE, animal, minimising the risk of transmitting via human
and veterinary medicinal products (5.2.8.) ......................... 592
TSE, animal, products with risk of transmitting agents of.. 759
Tuberculin for human use, oId .............................................. 3492
Tuberculin purified protein derivative, avian ..................... 3493
Tuberculin purified protein derivative, bovine ................... 3494
Tuberculin purified protein derivative for human use ....... 3495
Tuberculosis (BCG) vaccine, freeze-dried ............................. 819
Tubes for comparative tests (2.1.5.) .......................................... 17
Tubing and closures, silicone elastomer for (3.1.9.) ............. 394
Tubing and containers for total parenteral nutrition
preparations, poly(ethylene - vinyl acetate) for (3.1.7.) ..... 391
Tubing used in sets for the transfusion ofblood and blood
components, materials based on plasticised poly( vinyl
chloride) for (3.1.1.2.) ............................................................ 378
Turkey infectious rhinotracheitis vaccine (live) ................. 1022
Turmeric, Javanese .................................................................. 1409
Turmeric rhizome ................................................................... 1410
Turpentine oiL ................................................................ 8.2-3973
Tylosin for veterinary use ...................................................... 3497
Tylosin phosphate bulk solution for veterinary use ........... 3498
Tylosin tartrate for veterinary use ........................................ 3500
Typhoid polysaccharide and hepatitis A (inactivated,
adsorbed) vaccine ................................................................... 851
Typhoid polysaccharide vaccine ............................................. 910
Typhoid vaccine ........................................................................ 911
Typhoid vaccine, freeze-dried ................................................. 911
Typhoid vaccine (live, oral, strain Ty 21a) ............................ 912
Tyrosine ............................................................................ 8.2-4105
Tyrothricin ............................................................................... 3502
U Validation of nucleic acid amplification techniques for the
Ubidecarenone ........................................................................ 3507
Udder-washes ............................................................................ 814
Ultraviolet and visible absorption spectrophotometry
(2.2.25.) ...................................................................................... 40
Ultraviolet ray lamps for analytical purposes (2.1.3.) ............ 15
Uncoated tablets ....................................................................... 810
Undecylenic acid ..................................................................... 3508
Uniformity of content of single-dose preparations (2.9.6.) .. 298
Uniformity of dosage units (2.9.40.) ...................................... 357
Uniformity of dosage units, demonstration using large sample
sizes (2.9.47.) .................................................................. 8.1-3669
Uniformity of mass of delivered doses from multidose
containers (2.9.27.) ................................................................. 331
Uniformity of mass of single-dose preparations (2.9.5.) ..... 297
Units of the International System (SI) used in the
Pharmacopoeia and equivalence with other units
(1.) ................................................................................... 8.2-3897
4152
EUROPEAN PHARMACOPOEIA 8.2
Unsaponifiable matter (2.5.7.) ................................................. 157
Urea .......................................................................................... 3508
Urofollitropin .......................................................................... 3509
Urokinase ................................................................................. 3510
Uronic acids in polysaccharide vaccines (2.5.22.) ................ 161
Ursodeoxycholic acid ............................................................ 3512
Urtica dioica for homoeopathic preparations .............. 8.2-3991
V
Vaccines, adsorbed, aluminium in (2.5.13.) .......................... 159
Vaccines, adsorbed, calcium in (2.5.14.) ................................ 159
Vaccines and immunosera, phenol in (2.5.15.) ..................... 159
Vaccines and immunosera, veterinary, evaluation of efficacy
of (5.2.7.) .................................................................................. 591
Vaccines and immunosera, veterinary, evaluation of safety
(5.2.6.) ...................................................................................... 588
Vaccines for human use ........................................................... 767
Vaccines for human use, cell substrates for the production of
(5.2.3.) ...................................................................................... 582
Vaccines for human use, viral, tests for extraneous agents in
(2.6.16.) .................................................................................... 198
Vaccines for veterinary use ...................................................... 770
Vaccines, polysaccharide, hexosamines in (2.5.20.) ............. 160
Vaccines, polysaccharide, methylpentoses in (2.5.21.) ......... 161
Vaccines, polysaccharide, nucleic acids in (2.5.17.) ............. 160
Vaccines, polysaccharide, O-acetyl in (2.5.19.) ..................... 160
Vaccines, polysaccharide, phosphorus in (2.5.18.) ............... 160
Vaccines, polysaccharide, protein in (2.5.16.) ....................... 159
Vaccines, polysaccharide, ribose in (2.5.31.) ......................... 164
Vaccines, polysaccharide, sialic acid in (2.5.23.) .................. 161
Vaccines, polysaccharide, uronic acids in (2.5.22.) .............. 161
Vaccines, SPF chicken flocks for the production and quality
control of (5.2.2.) ................................................................... 579
Vaccines, veterinary, cell cultures for the production of
(5.2.4.) ...................................................................................... 585
Vaccines, virallive, test for neurovirulence (2.6.18.) ........... 202
Vaginal capsules ........................................................................ 813
Vaginal foams ............................................................................ 813
Vaginal preparations ................................................................ 812
"agI'nal
v' preparatI'ons , semI' -SOII'd .......................................... .. 813
Vaginal solutions and suspensions, tablets for. ..................... 813
Vaginal solutions, emulsions and suspensions ...................... 813
Vaginal tablets ........................................................................... 813
Vaginal tampons, medicated ................................................... 814
Valaciclovir hydrochloride, anhydrous ................................ 3517
Valaciclovir hydrochloride, hydrated ............................ 8.2-4109
Valerian dry aqueous extract ............................................... 1412
Valerian dry hydroalcoholic extract .............................. 8.2-3974
Valerian root ............................................................................ 1413
Valerian root, cut .................................................................... 1415
Valerian tincture ..................................................................... 1416
Validation of nucleic acid amplification techniques for the
detection of B19 virus (BI9V) DNA in plasma pools:
guidelines ........................................................................ 8.2-3921
detection ofhepatitis C virus (HCV) RNA in plasma pools:
guidelines ........................................................................ 8.2-3921
Valine ....................................................................................... 3520
Valnemulin hydrochloride for veterinary use .................... 3521
Valproate, sodium ................................................................... 3272
Valproic acid ............................................................................ 3523
Valsartan .................................................................................. 3524
Vancomycin hydrochloride ................................................... 3525
Vanillin ..................................................................................... 3527
Vapour, preparations to be converted into ............................ 801
Vardenafil hydrochloride trihydrate .............................. 8.2-4111
Varicella immunoglobulin for intravenous administration,
human .................................................................................... 2434
Varicella immunoglobulin, human ...................................... 2434
Varicella, measles, mumps and rubella vaccine (live) .......... 873
Varicella vaccine (live) ............................................................. 913
Vectors for human use, adenovirus ........................................ 708
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Vectors for human use, plasmid ............................................. 706
Vectors fol' human use, plasmid, bacterial cells used for the
manufacture of. ....................................................................... 707
Vectors for human use, poxvirus ............................................ 710
Vecuronium bromide ............................................................. 3528
Vedaprofen for veterinary use ............................................... 3529
Vegetable fatty oils .................................................................... 775
Venlafaxine hydrochloride .................................................... 3530
Verapamil hydrochloride ....................................................... 3532
Verbena herb ........................................................................... 1417
Veterinary liquid preparations for cutaneous application ... 814
Veterinary medicinal products, immunological, substances of
animal origin for the production of (5.2.5.) ........................ 587
Veterinary semi-solid preparations for oral use .......... 8.1-3689
Veterinary vaccines and immunosera, evaluation of efficacy of
(5.2.7.) ...................................................................................... 591
Viability, nucleated cel! count and (2.7.29.) .......................... 263
Vibriosis (cold-water) vaccine (inactivated) for
salmonids ............................................................................... 1023
Vibriosis vaccine (inactivated) for salmonids ..................... 1024
VICH (5.8.) ....................................................................... 8.1-3679
Vigabatrin ................................................................................ 3534
Vinblastine sulfate .................................................................. 3535
Vincristine sulfate ................................................................... 3536
Vindesine sulfate ..................................................................... 3537
Vinorelbine tartrate ................................................................ 3539
Vinpocetine ............................................................................. 3541
Viper venom antiserum, European ...................................... 1033
Viral diarrhoea vaccine (inactivated), bovine ....................... 941
Viral hepatitis type I vaccine (live), duck .............................. 964
Viral rhinotracheitis vaccine (inactivated), feline ................ 976
Viral rhinotracheitis vaccine (live), feline ............................. 977
Viral safety (5.1.7.) .................................................................... 571
Viral tenosynovitis vaccine (live), avian ................................ 935
Viral vaccines for human use, tests for extraneous agents in
(2.6.16.) .................................................................................... 198
Viscometer method, capillary (2.2.9.) ...................................... 27
Viscometer method, falling ball (2.2.49.) ................................ 85
Viscose wadding, absorbent .................................................. 3542
Viscosity (2.2.8.) .......................................................................... 27
Viscosity - rotating viscometer method (2.2.10.) ................... 28
Visible and ultraviolet absorption spectrophotometry
(2.2.25.) ...................................................................................... 40
Visible particles, particulate contamination (2.9.20.) .......... 323
Vitamin A ................................................................................ 3544
Vitamin A concentrate (oily form), synthetic ..................... 3545
Vitamin A concentrate (powder form), synthetic .............. 3546
Vitamin A concentrate (solubilisate/emulsion), synthetic .. 3547
Voltametric titration (2.2.65.) ................................................. 109
Volumetric analysis (4.2.) ........................................................ 545
Volumetric solutions (4.2.2.) ................................................... 546
Volumetric solutions, primary standards for (4.2.1.) ........... 545
von Willebrand factor, human .............................................. 2435
von WiIlebrand factor, human, assay of (2.7.21.) ................. 257
Voriconazole ............................................................................ 3548
W Zinc sulfate hexahydrate ........................................................ 3595
Warfarin sodium .............................................................. 8.1-3829
Warfarin sodium clathrate .............................................. 8.1-3830
Washes, nasal ............................................................................. 793
Water (150) injection .............................................................. 1112
Water, determination by distillation (2.2.13.) ......................... 31
Water fo1' diluting concentrated haemodialysis solutiol1S .. 2375
Water for injections ................................................................ 3555
Water fo1' pharmaceutical use, total organic carbon in
(2.2.44.) ...................................................................................... 71
General Notices (1) apply to all rnonographs and other texts
Index
Water for preparation of extracts .......................................... 3558
Water, highly purified ............................................................ 3559
Water in essential oils (2.8.5.) ................................................. 271
Water in gases (2.5.28.) ............................................................ 163
Water: micro determination (2.5.32.) .................................... 164
Water, purified ........................................................................ 3561
Water: semi-micro determination (2.5.12.) ................. 8.2-3917
Water-solid interactions: determination of sorption-
desorption isotherms and of water activity (2.9.39) .......... 353
Wettability of porous solids including powders (2.9.45.) .... 365
Wheat-germ oil, refined ......................................................... 3563
Wheat-germ oil, virgin ........................................................... 3564
Wheat starch ............................................................................ 3563
Wheat starch (5.8.) .......................................................... 8.1-3679
White beeswax ........................................................................ 1630
White horehound ................................................................... 1419
White 50ft paraffin .................................................................. 2966
Wild pansy (flowering aerial parts) ...................................... 1420
Wild thyme ....................................................................... 8.2-3974
Willow bark ............................................................................. 1422
Willow bark dry extract.. ....................................................... 1423
Wool aleohols .......................................................................... 3564
Wool fat .................................................................................... 3565
Wool fat, hydrogenated .......................................................... 3569
Wool fat, hydrous .................................................................... 3570
Wormwood .............................................................................. 1424
X
Xanthan gum ........................................................................... 3575
Xenon ( 133 Xe) injection .......................................................... 1113
X-ray fluorescence spectrometry (2.2.37.) ............................... 59
X-ray powder diffraction (XRPD), characterisation of
crystalline and partially crystalline solids by (2.9.33.) ....... 339
Xylazine hydrochloride for veterinary use ................... 8.1-3835
Xylitol ....................................................................................... 3577
Xylometazoline hydrochloride .............................................. 3579
Xylose ....................................................................................... 3580
Y
Yarrow ............................................................................... 8.2-3976
Yellow beeswax ........................................................................ 1630
Yellow fever vaccine (live) ....................................................... 914
Yellow 50ft paraffin ................................................................. 2967
Yersiniosis vaccine (inactivated) for salmonids .................. 1025
Yohimbine hydrochloride ...................................................... 3585
Z
Zidovudine ....................................................................... 8.2-4115
Zinc acetate dihydrate ............................................................ 3590
Zinc acexamate ....................................................................... 3591
Zinc chloride ........................................................................... 3592
Zinc gluconate ......................................................................... 3593
Zinc oxide ................................................................................ 3594
Zinc stearate ............................................................................ 3594
Zinc sulfate heptahydrate ...................................................... 3595
Zinc sulfate monohydrate ...................................................... 3595
Zinc undecylenate .................................................................. 3596
Ziprasidone hydrochloride monohydrate ............................ 3596
Ziprasidone mesilate trihydrate ..................................... 8.1-3839
Zolpidem tartrate .................................................................... 3598
Zopiclone ................................................................................. 3600
Zoster (shingles) vaccine (live), herpes .................................. 902
Zuclopenthixol decanoate ...................................................... 3601
4153
 EUROPEAN PHARMACOPOEIA 8.2

4154 See the information section on general monographs (cover pages)

EUROPEA N PHARMACOPOEIA 8.2 Index

Numerics Aeidum sulfuricum ................................................................. 3345

a-1-Proteínasi inhibitor humanum ...................................... 2428
A Acidum
Abacavíri sulfas ........................................... ,.................... 8.1-3719
Absinthii herba ........................................................................ 1424
Acaciae gummi ........................................................................ 1135
Acaciae gummi dispersione desiccatum ., .............................. 1460
Acamprosatum calcicum ........................................................ 1461
Acanthopanacis gracilistyli cortex ......................................... 1136
Acidum tartarícum ................................................................. 3367
Acidum thiocticum .................................................................. 3405
tiaprofenicum ............................................................ 3420
Acidum tolfenamicum ............................................................ 3446
Acidum tranexamicum ........................................................... 3454
Acidum trichloraeeticum ........................................................ 3468
Acidum undecylenicum .......................................................... 3508
Acidum ursodeoxycholicum ................................................... 3512
Acídum valproicum ................................................................ 3523

~~~f~ff::• ·• • •·• · •·• ·• • • ·• • •·• • • .• • •. •. • • .• .• • • • • • ¡~l!

Acarbosum ........................................................................ 8.1-3720
Acebutololi hydrochloridum ................................................... 1464
Aceclofenacum ......................................................................... 1466
Acemetacinum ......................................................................... 1467
Adeps A 3-0-desacyl-4'-monophosphorylatus ..................... 2000
Acesulfamum kalicum ............................................................ 1469
Adeps lanae .............................................................................. 3565
Acetazolamídum ..................................................................... 1470
Adeps lanae cum aqua ............................................................ 3570
Acetonum ................................................................................. 1472
Adeps lanae hydrogenatus ...................................................... 3569
Acetylcholiní chlorídum .......................................................... 1473
Adeps solidus ........................................................................... 2386
Acetylcysteinum ....................................................................... 1473
Adrenalini tartras ................................................................... 1491
f3-Acetyldigoxinum .................................................................. 1475
Adrenalinum ........................................................................... 1490
Aciclovirum .............................................................................. 1482
Aer medicinalis .............. .......................................................... 1492
Acidi methacryliei et ethylís acrylatis polymerisati 1:1 dispersio
Aer medicínalis artificiosus .. .................................................. 1494
30 per centum ........................................................................ 2728
Aether ....................................................................................... 2185
Acidi methacrylici et ethylis acrylatis polymerisatum 1:1 ... 2727
Aether anaestheticus ............................................................... 2185
Acidi methacrylící et methylis methacrylatis polymerísatum
Aetherolea .................................................................................. 743
1:1 ........................................................................................... 2729
Agar .......................................................................................... 1136
Aeidi methacrylici et methylis methacrylatis polymerisatum

~ígt~~;~:~":~·4~~~
1:2 ........................................................................................... 2730
Acidum 4-amínobenzoicum ................................................... 1539
Acídum aceticum glaciale ....................................................... 1471
Acidum acetylsalicylicum ....................................................... 1477
Albumini humani so/utio ....................................................... 2404
~~;~~: :*r~~c~:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ~~~~ Alchemillae herba .................................................................... 1139
AlcohoI2,4-dichlorobenzylicus ....................................... 8.1-3745
Acidum amidotrizoicum dihydricum ................................... 1531
Alcohol benzylicus ................................................................... 1645
Acidum aminocaproieum ....................................................... 1540
Alcohol cetylicus ...................................................................... 1837
Acidum aseorbicum ................................................................ 1590
Alcohol cetylieus et stearylicus ............................................... 1833
Acidum aspartieum ................................................................. 1594
Alcohol cetylicus et stearylicus emulsificans A .............. 8.1-3734
~~;~~: ~~~:c~~:.::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: i~:; Alcohol cetylicus et stearylicus emulsificans B .............. 8.1-3735
Alcoholes adipis lanae ............................................................. 3564
Acidum caprylieum ................................................................. 1756
Alcohol isopropylieus .............................................................. 2538
Acidum chenodeoxycholicum ................................................. 1840
Alcohol oleicus ......................................................................... 2899
Aeidum citricum anhydricum ......................................... 8.1-3736
Alcoholstearylieus ................................................................... 3314
Acidum citricum monohydricum ................................... 8.1-3737
Alcuronii chloridum ................................................................ 1497
Acidum edeticum .................................................................... 2128
Acidum etacrynicum ............................................................... 2177
~~~~~~~::.~.:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: i!~~
~~;~~: j~~i~~~·::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ~~~~ Alfentanili hydrochloridum ................................................... 1501
Alfuzosini hydrochloridum .................................................... 1502
Acidum glutamieum ............................................................... 2344
Alimemazini hemitartras ....................................................... 1504
Acidum hydroehlorídum concentratum ................................ 2438
Allantoinum ............................................................................. 1505
Aeidum hydrochloridum dilutum ......................................... 2438
Allii sativi bulbi pulvis ............................................................ 1254
Aeidum íopanoicum ................................................................ 2519
Allium sativum ad praeparationes homoeopathicas ..... 8.2-3981
Acidum ioxaglicum .......................................................... 8.1-3779

~j~f¡jg::;~< m~
Aeidum laeticum ..................................................................... 2578
Acidum laetobionicum ........................................................... 2581

~~:~~: ::¡~~~~.::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ~~~~ Aloes extractum siccum normatum ....................................... 1142

Acidum medronícum ad radiopharmaceutica ..................... 1072
Alovudíni (1sp) solutio iniectabilis ......................................... 1045
Acidum mefenamicum ........................................................... 2701
Alprazolamum ......................................................................... 1509
Acidum nalidixieum ............................................................... 2819
Alprenololi hydroehlorídum ................................................... 1511
Acidum nicotinicum ............................................................... 2849
Alprostadílum .......................................................................... 1512
Acidum niflumicum ................................................................ 2851
Alteplasum ad iniectabile ....................................................... 1515

1~¡~~: ~~S2:~:~::::::::::::::: . : : : : : : : : : : : : .: : : :::::::::::::::.j~~~

Althaeae folium ....................................................................... 1309

Aeidum palmiticum ................................................................ 2956

~¡~7~~:::~~~~.::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: i~i~
Alumen ..................................................................................... 1519
Aeidum phosphorieum eoneentratum ................................... 3025
Aluminii chloridum hexahydricum ....................................... 1519
Acidum phosphoricum dilutum ............................................. 3025
Aluminii hydroxidum hydricum ad adsorptionem ............. 1520
Acidum pipemidicum trihydrieum ........................................ 3038
Aluminii magnesii si/ieas ........................................................ 1521
Acidum salicylicum .. ............................................................... 3198
Aluminii natrii silicas ............................................................. 1524
Aeidum (S)-laeticum ............................................................... 2579
Aluminii oxidum hydricum ................................................... 1522
~~;~~: ~~;:;~~u:·::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ~;~; Aluminíi phosphas hydricus ................................................... 1523
Aluminii phosphatis liquamen ............................................... 1522

General Notices (1) apply to all monographs and other texts 4155
Index
Aluminii stearas ...................................................................... 1525
Aluminii sulfas ........................................................................ 1527
Alverini citras .......................................................................... 1527
Amantadini hydrochloridum ................................................. 1528
Ambroxoli hydrochloridum .................................................... 1529
Amfetamini sulfas ................................................................... 1531
Amikacini sulfas ............................................................... 8.2-3998
Amikacinum ..................................................................... 8.2-3996
Amiloridi hydrochloridum ..................................................... 1538
Aminoglutethimidum ............................................................. 1541
Amiodaroni hydrochloridum ................................................. 1542
Amisulpridum ......................................................................... 1544
Amitriptylini hydrochloridum ............................................... 1546
Amlodipini besilas ................................................................... 1547
Ammoniae (13N) solutio iniectabilis ...................................... 1047
Ammoniae solutio concentrata .............................................. 1548
Ammonii bromidum ............................................................... 1551
Ammonii chloridum ............................................................... 1552
Ammonii glycyrrhizas ............................................................. 1552
Ammonii hydrogenocarbonas ................................................ 1553
Ammonio methacrylatis copolymerum A ............................. 1549
Ammonio methacrylatis copolymerum B ............................. 1550
Amobarbitalum ....................................................................... 1554
Amobarbitalum natricum ...................................................... 1554
Amomi fructus .................................................................. 8.1-3701
Amomi jructus rotundus ................................................. 8.1-3710
Amoxicillinum natricum ........................................................ 1555
Amoxicillinum trihydricum ................................................... 1557
Amphotericinum B .................................................................. 1560
Ampicillinum anhydricum ..................................................... 1561
AmPicillinum natricum .......................................................... 1564
Ampicillinum trihydricum ..................................................... 1566
Amygdalae oleum raffinatum ................................................ 1508
Amygdalae oleum virginale .................................................... 1509
Amyla hydroxyethyla .............................................................. 3307
Amylmetacresolum .................................................................. 1568
Amylum hydroxypropylum .................................................... 3303
Amylum hydroxypropylum pregelificatum ........................... 3305
Amylum pregelificatum .......................................................... 3306
Anamirta cocculus ad praeparationes
homoeopathicas .............................................................. 8.2-3986
Anastrozolum .......................................................................... 1570
Angelicae archangelicae radix ................................................ 1142
Angelicae dahuricae radix ...................................................... 1143
Angelicae pubescentis radix .................................................... 1145
Angelicae sinensis radix .......................................................... 1147
Anisi aetheroleum ................................................................... 1148
Anisi jructus ............................................................................. 1150
Anisi stellati aetheroleum ....................................................... 1395
Anisi stellati fructus ................................................................ 1394
Antazolini hydrochloridum .................................................... 1571
Anticorpora monoclonalia ad usum humanum .................... 753
Antithrombinum III humanum densatum ........................... 2407
Apis mellifera ad praeparationes homoeopathicas ........ 8.2-3983
Apomorphíni hydrochloridum hemihydricum ..................... 1578
Aprotinini solutio concentrata ............................................... 1581
Aprotininum ............................................................................ 1579
Aqua ad dílutionem solutionum concentratarum ad
haemodialysim ...................................................................... 2375
Aqua ad extracta praeparanda .............................................. 3558
Aqua ad iniectabile ................................................................. 3555
Aquae eSO) solutio iniectabilis .............................................. 1112
Aquae tritiatae eH) solutio iniectabilis ................................ 1111
Aqua purificata ....................................................................... 3561
Aqua valde purificata ............................................................. 3559
Arachidis oleum hydrogenatum ............................................. 1584
Arachidis oleum raffinatum ................................................... 1584
Argenti nitras ........................................................................... 3221
Argentum colloidale ad usum externum ............................... 3221
Arginini aspartas ..................................................................... 1586
Arginini hydrochloridum ................................................ 8.2-4002
Argininum ......................................................................... 8.2-4001
Argon ........................................................................................ 1587
4156
EUROPEAN PHARMACOPOEIA 8.2
Aripiprazolum .................................................................. 8.1-3722
Arnicae flos .............................................................................. 1151
Arnicae tinctura ...................................................................... 1153
Arsenii trioxidum ad praeparationes homoeopathicas .. 8.2-3983
Articaini hydrochloridum ...................................................... 1588
Ascorbylis palmitas ................................................................. 1591
Asparagínum monohydricum ................................................ 1592
Aspartamum ............................................................................ 1593
Astragali mongholici radix ..................................................... 1158
Atenololum .............................................................................. 1595
Atomoxetíní hydrochloridum ................................................ 1596
Atorvastatinum calcicum trihydricum .................................. 1598
Atovaquonum .......................................................................... 1600
Atractylodis lanceae rhízoma ................................................. 1159
Atractylodis macrocephalae rhizoma .................................... 1160
Atracuríí besilas ....................................................................... 1601
Atropini sulfas ......................................................................... 1605
Atropinum ............................................................................... 1604
Aurantii amarí epícarpií et mesocarpii tinctura .................. 1180
Aurantii amarí epicarpíum et mesocarpium ....................... 1179
Aurantii amari flos ................................................................. 1181
Aurantii dulcis aetheroleum .................................................. 1400
Aurícularía ................................................................................ 781
Azaperonum ad usum veterinaríum ..................................... 1607
Azathioprinum ........................................................................ 1608
Azelastini hydrochloridum ..................................................... 1609
Azithromycinum ..................................................................... 1610
B
Bacampicillini hydrochloridum ............................................. 1615
Bacitracinum ........................................................................... 1617
Bacitracinum zincum .............................................................. 1619
Baclofenum .............................................................................. 1621
Ballotae nigrae herba .............................................................. 1185
Balsamum peruvianum .......................................................... 1354
Balsamum tolutanum ............................................................. 1406
Bambuteroli hydrochloridum ................................................ 1622
Barbitalum ............................................................................... 1623
Baríí chlorídum dihydrícum ad praeparatíones
homoeopathícas .............................................................. 8.2-3984
Barií sulfas ............................................................................... 1624
BCG ad immunocurationem .................................................... 818
Beclometasoni dípropíonas anhydrícus ................................. 1626
Beclometasoní dipropíonas monohydricus ........................... 1628
Belamcandae chínensis rhizoma ............................................ 1163
Belladonnae folii extractum siccum normatum ................... 1166
Belladonnae folii tinctura normata ....................................... 1167
Belladonnae folium ................................................................. 1165
Belladonnae pulvis normatus ................................................. 1168
Benazeprili hydrochlorídum .................................................. 1631
Bendroflumethiazídum ........................................................... 1633
Benperidolum .......................................................................... 1633
Benserazídi hydrochlorídum .................................................. 1635
Bentonitum .............................................................................. 1636
Benzalkoníi chloridi solutio .................................................... 1638
Benzalkoníi chlorídum ........................................................... 1637
Benzbromaronum ................................................................... 1640
Benzethonii chloridum ............................................................ 1641
Benzocaínum ........................................................................... 1642
Benzoe sumatranus ................................................................. 1170
Benzoe tonkinensis .................................................................. 1169
Benzois sumatraní tinctura .................................................... 1172
Benzoís tonkinensis tínctura .................................................. 1171
Benzoylis peroxídum cum aqua ............................................. 1643
Benzylis benzoas ...................................................................... 1646
Benzylpenicillinum benzathinum .......................................... 1647
Benzylpenícillinum kalícum ................................................... 1648
Benzylpenicillínum natricum ................................................. 1651
Benzylpenícillinum procaínum .............................................. 1650
Betacarotenum ........................................................................ 1653
Betadexum ............................................................................... 1653
Betahistini dihydrochloridum ................................................ 1655
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Betahistini mesilas ................................................................... 1656
Betamethasoni acetas .............................................................. 1659
Betamethasoni dipropionas .................................................... 1661
Betamethasoni natrii phosphas .............................................. 1663
Betamethasoni valeras ............................................................ 1664
Betamethasonum ........................................ ............................. 1657
Betaxololi hydrochloridum ..................................................... 1666
Betulae folium ......................................................................... 1173
Bezafibratum ........................................................................... 1667
Bicalutamidum ........................................................................ 1668
Bifonazolum ............................................................................. 1670
Biotinum .................................................................................. 1671
Biperideni hydrochloridum .................................................... 1672
Bisacodylum ............................................................................. 1673
Bismuthi subcarbonas ............................................................. 1675
Bismuthi subgallas .................................................................. 1676
Bismuthi subnitras ponderosus .............................................. 1676
Bismuthi subsalicylas .............................................................. 1677
Bisoprololi fumaras ................................................................. 1678
Bistortae rhizoma .................................................................... 1175
Bleomycini sulfas ..................................................................... 1680
Boldi folii extractum siccum ................................................... 1189
Boldi folium ............................................................................. 1188
Boraginis officinalis oleum raffinatum ................................. 1681
Borax ........................................................................................ 1682
Brimonidini tartras .......................................................... 8.2-4007
Bromazepamum ...................................................................... 1687
Bromhexini hydrochloridum .................................................. 1688
Bromocriptini mesilas ............................................................. 1689
Bromperidoli decanoas ........................................................... 1693
Bromperidolum ....................................................................... 1692
Brompheniramini maleas ...................................................... 1695
Brotizolamum .......................................... ................................ 1696
Budesonidum ........................................................................... 1697
Bufexamacum .......................................................................... 1699
Buflomedili hydrochloridum .................................................. 1700
Bumetanidum .......................................................................... 1702
Bupivacaíni hydrochloridum ................................................. 1703
Buprenorphiní hydrochloridum ............................................. 1706
Buprenorphinum ..................................................................... 1705
Buserelinum ............................................................................. 1708
Buspíroni hydrochloridum ..................................................... 1709
Busulfanum .............................................................................. 1711
Butylhydroxyanisolum ............................................................ 1713
Butylhydroxytoluenum ........................................................... 1714
Butylis parahydroxybenzoas .................................................. 1712
e Carthami oleum raffinatum ................................................... 3193
Cabergolínum .......................................................................... 1717
Cadmii sulfas hydricus ad praeparationes
homoeopathicas .............................................................. 8.2-3985
Calcifediolum ........................................................................... 1720
Calcií acetas anhydricus ......................................................... 1729
Calcii ascorbas ......................................................................... 1731
Calcii carbonas ........................................................................ 1731
Calcii chloridum dihydricum ................................................. 1732
Calcii chloridum hexahydricum ............................................ 1733
Calcii dobesilas monohydricus ............................................... 1733
Calcii folinas ............................................................................ 1734
Calcii glucoheptonas ............................................................... 1736
Calcii gluconas ......................................................................... 1737
Calcii gluconas ad iniectabile ............................................ ..... 1739
Calcii gluconas anhydricus ..................................................... 1738
Calcii glycerophosphas ............................................................ 1740
Calcii hydrogenophosphas anhydricus .................................. 1740
Calcii hydrogenophosphas dihydricus ................................... 1742
Calcii hydroxidum .................................................................. 1743
Calcii iodidum tetrahydricum ad praeparationes
homoeopathicas .............................................................. 8.2-3985
Calcii lactas anhydricus .......................................................... 1743
Calcii lactas monohydricus .................................................... 1744
Ca/di lactas pentahydricus .................................................... 1744
General Notices (1) apply to all monographs and other texts
Index
Ca/cii lactas trihydricus .......................................................... 1745
Calcii laevulinas dihydricus ................................................... 1748
Calcii levofolinas pentahydricus ............................................ 1745
Calcii pantothenas .................................................................. 1749
Caldi stearas ............................................................................ 1750
Caldi sulfas dihydricus ........................................................... 1751
Calcipotriolum anhydricum ............................................. ...... 1722
Ca/cipotriolum monohydricum ............................................. 1724
Calcitoninum salmonis ........................................................... 1726
Calcitriolum ............................................................................. 1728
Calendulae flos ........................................................................ 1193
Camphora racemica ................................................................ 1753
Candesartanum cilexetili ....................................................... 1754
Capecitabinum ................................................................. 8.1-3727
Capsici extractum spissum normatum .................................. 1197
Capsici fructus ......................................................................... 1194
Capsici oleoresina raffinata et normata ................................ 1196
Capsici tinctura normata ....................................................... 1198
Capsulae ..................................................................................... 779
Captoprilum ............................................................................ 1758
Carbacholum ........................................................................... 1760
Carbamazepinum .................................................................... 1761
Carbasalatum calcicum .. ........................................................ 1762
Carbidopum ............................................................................. 1764
Carbimazolum .......................................... ........................ 8.1-3728
Carbo activatus ....................................................................... 1839
Carbocisteinum ....................................................................... 1766
Carbomera ............................................................................... 1766
Carbonei dioxidum ................................................................. 1768
Carbonei monoxidum ............................................................. 1769
Carbonei monoxidum eSO) ................................................... 1048
Carboplatinum ........................................................................ 1770
Carboprostum trometamolum ............................................... 1771
Carboxymethylamylum natricum A ..................................... 3265
Carboxymethylamylum natricum B ...................................... 3266
Carboxymethylamylum natricum C ..................................... 3267
Carisoprodolum ......................................... .............................. 1772
Carmellosum ............................................................................ 1773
Carmellosum calcicum ........................................................... 1774
Carmellosum natricum ........................................................... 1774
Carmellosum natricum conexum .......................................... 1969
Carmellosum natricum substitutum humile ........................ 1775
Carmustinum .......................................................................... 1776
Carprofenum ad usum veterinarium .................................... 1778
Carrageenanum ....................................................................... 1779
Carte%lí hydrochloridum ..................................................... 1780
Carthami flos .................................................................... 8.2-3968
Carvedilolum ........................................................................... 1781
Carvi aetheroleum .................................................................. 1200
Carvi fructus ............................................................................ 1199
Caryophylli floris aetheroleum ............................................... 1216
Caryophylli flos ........................................................................ 1215
Cefaclorum ............................................................................... 1785
Cefadroxilum monohydricum ................................................ 1786
Cefalexinum monohydricum ................................................. 1788
Cefalotinum natricum ............................................................ 1789
Cefamandoli nafas .................................................................. 1791
Cefapirinum natricum ............................................................ 1792
Cefatrizinum propylen glycolum ........................................... 1793
Cefazolinum natricum ..................................................... 8.1-3729
Cefepimi dihydrochloridum monohydricum ........................ 1796
Cefiximum ............................................................................... 1799
Cefoperazonum natricum .............................................. ......... 1800
Cefotaximum natricum .......................................................... 1801
Cefoxitinum natricum ............................................................ 1803
Cefpodoximum proxetili ......................................................... 1805
Cefprozilum monohydricum .................................................. 1807
Cefradinum .............................................................................. 1809
Ceftazidimum pentahydricum ............................................... 1811
Ceftazidimum pentahydricum et natrii carbonas ad
iniectabile ............................................................................... 1813
Ceftríaxonum natricum .............................................. ............ 1815
4157
Index
Cefuroximum axetili ............................................................... 1817
Cefuroximum natricum .......................................................... 1818
Celecoxibum ............................................................................. 1819
Celiprololi hydrochloridum .................................................... 1820
Cellulae stirpes haematopoieticae humanae ........................ 2419
Cellulosi acetas ................................................................. 8.1-3731
Cellulosi acetas butyras ........................................................... 1823
Cellulosi acetas phthalas .................................................. 8.1-3733
Cellulosi pulvis ......................................................................... 1828
Cellulosum microcristallinum ................................................ 1824
Cellulosum microcristallinum et carmellosum natricum .... 2776
Centaurii herba ....................................................................... 1204
Centellae asiaticae herba ........................................................ 1205
Cera alba .................................................................................. 1630
Cera carnauba ......................................................................... 1777
Cera flava ................................................................................. 1630
Cetirizini dihydrochloridum .................................................. 1831
Cetobemidoni hydrochloridum .............................................. 2566
Cetostearylis isononanoas ...................................................... 1836
Cetrimidum ............................................................................. 1836
Cetylis palmitas ....................................................................... 1838
Cetylpyridinii chloridum ........................................................ 1838
Chamomillae romanae flos .................................................... 1206
Chelidonii herba ...................................................................... 1268
Chinidini sulfas ....................................................................... 3141
Chinini hydrochloridum ......................................................... 3142
Chinini sulfas ........................................................................... 3144
Chitosani hydrochloridum ..................................................... 1841
Chlorali hydras ........................................................................ 1842
Chlorambucilum ..................................................................... 1843
Chloramphenicoli natrii succinas .......................................... 1846
Chloramphenicoli palmitas .................................................... 1845
Chloramphenicolum ............................................................... 1844
Chlorcyclizini hydrochloridum .............................................. 1847
Chlordiazepoxidi hydrochloridum ........................................ 1849
Chlordiazepoxidum ................................................................. 1848
Chlorhexidini diacetas ............................................................ 1850
Chlorhexidini digluconatis solutio ......................................... 1851
Chlorhexidini dihydrochloridum ........................................... 1854
Chlormadinoni acetas ...................................................... 8.2-4011
Chlorobutanolum anhydricum .............................................. 1855
Chlorobutanolum hemihydricum .......................................... 1855
Chlorocresolum ........................................................................ 1856
Chloroquini phosphas ............................................................. 1857
Chloroquini sulfas ................................................................... 1857
Chlorphenamini maleas ......................................................... 1858
Chlorpromazini hydrochloridum .......................................... 1859
Chlorpropamidum .................................................................. 1861
Chlorprothixeni hydrochloridum .......................................... 1862
Chlortalidonum ....................................................................... 1863
Chlortetracyclini hydrochloridum ......................................... 1865
Cholecalciferoli pulvis ............................................................. 1870
Cholecalciferolum .................................................................... 1867
Cholecalciferolum densatum oleosum ................................... 1869
Cholecalciferolum in aqua dispergibile ................................. 1872
Cholesterolum ................................................................... 8.2-4012
Cholesterolum ad usum parenteralem .................................. 1874
Chondroitini natrii sulfas ....................................................... 1876
Chorda resorbilis sterilis ......................................................... 1117
Chorda resorbilis sterilis in fuso ad usum veterinarium ..... 1127
Chromii (SICr) edetatis solutio iniectabilis ........................... 1049
Chymotrypsinum ..................................................................... 1878
Ciclesonidum ........................................................................... 1879
Ciclopirox olaminum .............................................................. 1881
Ciclopiroxum ........................................................................... 1880
Ciclosporinum ......................................................................... 1883
Cilastatinum natricum .................................................... 8.2-4013
Cilazaprilum ............................................................................ 1885
Cimetidini hydrochloridum .................................................... 1888
Cimetidinum ............................................................................ 1887
Cimicifugae rhizoma ........................................................ 8.1-3702
Cinchocaini hydrochloridum ................................................. 1890
Cinchonae cortex ..................................................................... 1207
4158
EUROPEAN PHARMACOPOEIA 8.2
Cinchonae extractum fluidum normatum ............................ 1208
Cineolum .................................................................................. 1891
Cinnamomi cassiae aetheroleum ........................................... 1203
Cinnamomi cortex .................................................................. 1209
Cinnamomi corticis tinctura .................................................. 1212
Cinnamomi zeylanici corticis aetheroleum .......................... 1210
Cinnamomi zeylanicifolii aetheroleum ................................ 1211
Cinnarizinum .......................................................................... 1892
Ciprofibratum .......................................................................... 1893
Ciprofloxacini hydrochloridum ............................................. 1896
Ciprofloxacinum ...................................................................... 1894
Cisplatinum ............................................................................. 1897
Citaloprami hydrobromidum ................................................. 1899
Citaloprami hydrochloridum ................................................. 1900
Citri reticulatae aetheroleum ................................................. 1308
Citri reticulatae epicarpium et mesocarpium ....................... 1307
Citronellae aetheroleum ......................................................... 1212
Cladribinum ............................................................................ 1903
Clarithromycinum .................................................................. 1904
Clazurilum ad usum veterinarium ....................................... 1906
Clebopridi malas ..................................................................... 1908
Clemastini fumaras .......................................................... 8.1-3738
Clematidis armandii caulis .................................................... 1214
Clenbuteroli hydrochloridum ................................................. 1911
Clindamycini hydrochloridum ............................................... 1912
Clindamycini phosphas .......................................................... 1913
Clioquinolum ........................................................................... 1914
Clobazamum ........................................................................... 1915
Clobetasoli propionas .............................................................. 1916
Clobetasoni butyras ................................................................. 1918
Clofaziminum .......................................................................... 1920
Clofibratum .............................................................................. 1921
Clomifeni citras ....................................................................... 1922
Clomipramini hydrochloridum .............................................. 1924
Clonazepamum ....................................................................... 1925
Clonidini hydrochloridum ...................................................... l926
Clopamidum ............................................................................ 1927
CloPidogreli hydrogenosulfas ................................................. 1928
Closantelum natricum dihydricum
ad usum veterinarium .......................................................... 1930
Clotrimazolum ........................................................................ 1931
Cloxacillinum natricum ......................................................... 1933
Clozapinum ............................................................................. 1934
Cocaini hydrochloridum ......................................................... 1935
Cocois oleum raffinatum ........................................................ 1936
Cocoylis caprylocapras ............................................................ 1937
Codeini hydrochloridum dihydricum .................................... 1939
Codeini phosphas hemihydricus ............................................ 1941
Codeini phosphas sesquihydricus ........................................... 1942
Codeinum ................................................................................. 1938
Codergocrini mesilas ............................................................... 1944
Coffeinum ................................................................................ 1718
Coffeinum monohydricum ..................................................... 1719
Coicis semen ............................................................................. 1217
Colae semen ............................................................................. 1218
Colchicinum ............................................................................. 1957
Colestyraminum ...................................................................... 1959
Colistimethatum natricum ..................................................... 1960
Colistini sulfas ......................................................................... 1961
Colophonium ........................................................................... 1219
Compressi ................................................................................... 809
Copolymerum macrogolo et alcoholi poly(vinylico}
constatum ............................................................................... 2660
Copolymerum methacrylatis butylati basicum ..................... 1624
Copovidonum .......................................................................... 1962
Coriandri aetheroleum .................................................... 8.2-3963
Coriandri jructus .............................................................. 8.2-3963
Corpora ad usum pharmaceuticum ........................................ 765
Cortisoni acetas ....................................................................... 1965
Crataegi folii cum flore extractum fluidum quantificatum .. 1274
Crataegi folii cum flore extractum siccum ............................ 1273
Crataegi folium cum flore ....................................................... 1272
Crataegi fructus ....................................................................... 1271
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Cresolum crudum .................................................................... 1968
Croci sativi stigma ad praeparationes
homoeopathicas .............................................................. 8.2-3987
Crospovidonum ....................................................................... 1970
Crotamitonum ......................................................................... 1971
Cupri acetas monohydricus ad praeparationes
homoeopathicas .............................................................. 8.2-3988
Cupri sulfas anhydricus .......................................................... 1964
Cupri sulfas pentahydricus ..................................................... 1965
Cuprum ad praeparationes homoeopathicas ................. 8.2-3989
Curcumae longae rhizoma ..................................................... 1410
Curcumae xanthorrhizae rhizoma ........................................ 1409
Cyamopsidis seminis pulvis .................................................... 1269
Cyanocobalamini CS 7 Co) capsulae ......................................... 1049
Cyanocobalamini CS 7 Co) solutio ............................................ 1050
Cyanocobalamini CS 8 Co) capsulae ......................................... 1051
Cyanocobalamini CSSCo) solutio ............................................ 1051
Cyanocobalaminum ......................................................... 8.2-4016
Cyclizini hydrochloridum ....................................................... 1974
Cyclopentolati hydrochloridum ............................................. 1975
Cyclophosphamidum .............................................................. 1976
Cynarae folii extractum siccum ............................................. 1156
Cynarae folium ........................................................................ 1154
Cyproheptadini hydrochloridum ........................................... 1977
Cyproteroni acetas .................................................................. 1978
Cysteini hydrochloridum monohydricum ............................. 1980
Cystinum .................................................................................. 1981
Cytarabinum ............................................................................ 1982
D Dimeticonum ........................................................................... 2067
Dacarbazinum ......................................................................... 1987
Dalteparinum natricum ......................................................... 1988
Danaparoidum natricum ....................................................... 1990
Dapsonum ................................................................................ 1992
Daunorubicini hydrochloridum ............................................. 1993
D-Camphora ............................................................................ 1752
Decylis oleas ............................................................................. 1994
Deferoxamini mesilas ............................................................. 1994
Dembrexini hydrochloridum monohydricum ad usum
veterinarium .......................................................................... 1995
Demeclocyclini hydrochloridum ............................................ 1996
Deptropini citras ...................................................................... 1998
Dequalinii chloridum .............................................................. 1999
Desfluranum ............................................................................ 2002
Desipramini hydrochloridum ................................................. 2003
Deslanosidum .......................................................................... 2004
Desloratadinum ....................................................................... 2005
Desmopressinum ..................................................................... 2006
Desogestrelum .......................................................................... 2007
Desoxycortoni acetas ............................................................... 2008
Detomidini hydrochloridum ad usum veterinarium ........... 2009
Dexamethasoni acetas ............................................................ 2012
Dexamethasoni isonicotinas ................................................... 2014
Dexamethasoni natrii phosphas ..................................... 8.1-3743
Dexamethasonum ................................................................... 2010
Dexchlorpheniramini maleas ................................................. 2018
Dexpanthenolum ..................................................................... 2019
Dextranomerum ...................................................................... 2023
Dextranum 1 ad iniectabile ................................................... 2020
Dextranum 40 ad iniectabile .................................................. 2021
Dextranum 60 ad iniectabile .................................................. 2022
Dextranum 70 ad iniectabile .................................................. 2023
Dextrinum ................................................................................ 2024
Dextromethorphani hydrobromidum ................................... 2025
Dextromoramidi tartras ......................................................... 2026
Dextropropoxypheni hydrochloridum ................................... 2027
Diacereinum ............................................................................ 2028
Diazepamum ........................................................................... 2030
Diazoxidum ............................................................................. 2031
Dibrompropamidini diisetionas ............................................. 2032
Dibutylis phthalas ................................................................... 2033
Diclazurilum ad usum veterinarium .................................... 2034
General Notices (1) apply to all monographs and other texts
Index
Diclofenacum kalicum ..................................................... 8.2-4019
Diclofenacum natricum ................................................... 8.2-4020
Dicloxacillinum natricum ...................................................... 2038
Dicycloverini hydrochloridum ............................................... 2039
Didanosinum ........................................................................... 2040
Diethylcarbamazini citras ...................................................... 2042
Diethylenglycoli aether monoethylicus .................................. 2043
Diethylenglycoli palmitostearas ............................................. 2044
Diethylis phthalas .................................................................... 2041
Diethylstilbestrolum ................................................................ 2045
Diflox~cin~ hydrochloridum trihydricum ad usum
vetermanum .......................................................................... 2046
Digitalis purpureae folium ..................................................... 1227
Dlgltoxmum ............................................................................. 2048
Digoxinum ............................................................................... 2049
Dihydralazini sulfas hydricus ................................................ 2051
Dihydrocodeini hydrogenotartras .......................................... 2052
Dihydroergocristini mesilas .................................................... 2053
Dihydroergotamini mesilas .................................................... 2056
Dihydroergotamini tartras ..................................................... 2058
Dihydrostreptomycini sulfas ad usum veterinarium ........... 2059
Dihydrotachysterolum ............................................................ 2061
Dikalii clorazepas .................................................................... 2077
Dikalii phosphas ...................................................................... 2078
Diltiazemi hydrochloridum .................................................... 2062
Dimenhydrinatum .................................................................. 2063
Dimercaprolum ....................................................................... 2065
Dimethylacetamidum ............................................................. 2066
Dimethylis sulfoxidum ............................................................ 2066
Dimetindeni maleas ................................................................ 2068
Dinatrii clodronas tetrahydricus ........................................... 1919
Dinatrii edetas ......................................................................... 2082
Dinatrii etidronas .................................................................... 2195
Dinatrii pamidronas pentahydricus ...................................... 2956
Dinatrii phosphas anhydricus ................................................ 2083
Dinatrii phosphas dihydricus ................................................. 2084
Dinatrii phosphas dodecahydricus ........................................ 2084
Dinitrogenii oxidum ............................................................... 2865
Dinoprostonum ....................................................................... 2070
Dinoprostum trometamolum ................................................. 2069
Dioscoreae oppositifoliae rhizoma .................................. 8.1-3705
Diosminum .............................................................................. 2072
Diphenhydramini hydrochloridum ....................................... 2073
Diphenoxylati hydrochloridum .............................................. 2074
Dipivefrini hydrochloridum ................................................... 2075
Diprophyllinum ....................................................................... 2078
Dipyridamolum ....................................................................... 2079
Dirithromycinum .................................................................... 2081
Disopyramidi phosphas .......................................................... 2086
Disopyramidum ........................................... ............................ 2085
Disulfiramum .......................................................................... 2087
Dithranolum ............................................................................ 2088
DL-Methioninum ..................................................................... 2734
DL-a- Tocopherylis hydrogenosuccinas .................................. 3442
Dobutamini hydrochloridum ................................................. 2089
Docetaxelum anhydricum ...................................................... 2090
Docetaxelum trihydricum ...................................................... 2092
Dodecylis gallas ....................................................................... 2094
Domperidoni maleas ............................................................... 2097
Domperidonum ....................................................................... 2095
Dopamini hydrochloridum .................................................... 2098
Dopexamini dihydrochloridum ............................................. 2099
Dorzolamidi hydrochloridum ................................................ 2101
Dosulepini hydrochloridum ................................................... 2103
Doxaprami hydrochloridum .................................................. 2104
Doxazosini mesilas .................................................................. 2105
Doxepini hydrochloridum ...................................................... 2106
Doxorubicini hydrochloridum ............................................... 2108
Doxycyclini hyclas ................................................................... 2109
Doxycyclinum monohydricum ............................................... 2111
Doxylamini hydrogenosuccinas ............................................. 2112
Droperidolum .......................................................................... 2113
4159
Index
DrosPirenonum ....................................................................... 2115
Drynariae rhizoma .................................................................. 1229
Duloxetini hydrochloridum .................................................... 2116
Dutasteridum .................................................................... 8.2-4022
Dydrogesteronum .................................................................... 2120
E Eugenolum ............................................................................... 2205
Ebastinum ................................................................................ 2125
Echinaceae angustifoliae radix ............................................... 1327
Echinaceae pallidae radix ....................................................... 1345
Echinaceae purpureae herba .................................................. 1357
Echinaceae purpureae radix ................................................... 1359
Ecliptae herba .......................................................................... 1231
Econazoli nitras ....................................................................... 2127
Econazolum ............................................................................. 2126
Edrophonii chloridum ............................................................. 2129
Eleutherococci radix ................................................................ 1234
Emedastini difumaras ............................................................. 2129
Emetini hydrochloridum pentahydricum ............................. 2130
Emplastra transcutanea ............................................................ 798
Enalaprilatum dihydricum ..................................................... 2133
Enalaprili maleas .................................................................... 2131
Enilconazolum ad usum veterinarium ................................. 2134
Enoxaparinum natricum ................................................. 8.1-3749
Enoxolonum ............................................................................. 2136
Enrofloxacinum ad usum veterinarium ............................... 2137
Entacaponum ........................................................................... 2139
Ephedrae herba ....................................................................... 1236
Ephedrini hydrochloridum ..................................................... 2142
Ephedrini racemici hydrochloridum ..................................... 2143
Ephedrinum anhydricum ....................................................... 2140
Ephedrinum hemihydricum ................................................... 2141
Epinastini hydrochloridum .................................................... 2144
Epirubicini hydrochloridum ................................................... 2145
Equiseti herba .......................................................................... 1237
Ergocalciferolum ...................................................................... 2146
Ergometrini maleas ................................................................. 2148
Ergotamini tartras ................................................................... 2149
Erythritolum ............................................................................ 2150
Erythromycini estolas .............................................................. 2154
Erythromycini ethylsuccinas .................................................. 2156
Erythromycini lactobionas ..................................................... 2158
Erythromycini stearas ............................................................. 2160
Erythromycinum ..................................................................... 2151
Erythropoietini solutio concentrata ....................................... 2162
Eserini salicylas ....................................................................... 3027
Esketamini hydrochloridum ................................................... 2166
Esomeprazolum magnesicum dihydricum ..................... 8.2-4027
Esomeprazolum magnesicum trihydricum .................... 8.2-4028
Estradioli benzoas ................................................................... 2169
Estradioli valeras ..................................................................... 2172
Estradiolum hemihydricum ................................................... 2171
Estriolum .................................................................................. 2173
Estrogeni coniuncti .................................................................. 2174
Etamsylatum ............................................................................ 2178
Ethacridini lactas monohydricus ........................................... 2179
Ethambutoli hydrochloridum ................................................ 2180
Ethanolum (96 per centum) ............................................ 8.1-3751
Ethanolum anhydricum .................................................. 8.1-3753
Ethinylestradiolum .................................................................. 2186
Ethionamidum ......................................................................... 2188
Ethosuximidum ....................................................................... 2188
Ethylcellulosum ........................................................................ 2192
Ethylendiaminum .................................................................... 2193
Ethylenglycoli monopalmitostearas ....................................... 2193
Ethylis acetas ............................................................................ 2190
Ethylis oleas ............................................................................. 2190
Ethylis parahydroxybenzoas ................................................... 2191
Ethylis parahydroxybenzoas natricus .................................... 3243
Ethylmorphini hydrochloridum ............................................. 2194
Etilefrini hydrochloridum ....................................................... 2196
Etodolacum .............................................................................. 2197
4160
EUROPEAN PHARMACOPOEIA 8.2
Etofenamatum ......................................................................... 2199
Etomidatum ............................................................................. 2201
Etoposidum .............................................................................. 2202
Eucalypti aetheroleum ............................................................ 1239
Eucalypti folium ............................................................... 8.2-3965
Eucommiae cortex ................................................................... 1240
Extracta ...................................................................................... 744
F
Factor humanus von Willebrandi .......................................... 2435
Factoris IX coagulationis humani (ADNr) solutio
concentrata ..................................................................... 8.2-4043
Factoris VIIa coagulationis humani (ADNr) solutio
concentrata ............................................................................ 2410
Factor IX coagulationis humanus .......................................... 2416
Factor VII coagulationis humanus ........................................ 2408
Factor VIII coagulationis humanus ....................................... 2414
Factor VIII coagulationis humanus (ADNr) ........................ 2415
Factor XI coagulationis humanus .......................................... 2417
Fagopyri herba ......................................................................... 1190
Famotidinum ........................................................................... 2211
Febantelum ad usum veterinarium ....................................... 2212
Felbinacum .............................................................................. 2213
Felodipinum ............................................................................. 2214
Felypressinum .......................................................................... 2215
Fenbendazolum ad usum veterinarium ................................ 2217
Fenbufenum ............................................................................. 2218
Fenofibratum ........................................................................... 2219
Fenoteroli hydrobromidum .................................................... 2220
Fentanyli citras ........................................................................ 2223
Fentanylum .............................................................................. 2221
Fenticonazoli nitras ......................................................... 8.2-4033
Ferri chloridum hexahydricum .............................................. 2225
Ferrosifumaras ....................................................................... 2226
Ferrosi gluconas ....................................................................... 2227
Ferrosi sulfas desiccatus .......................................................... 2228
Ferrosi sulfas heptahydricus ................................................... 2229
Ferrum ad praeparationes homoeopathicas .................. 8.2-3989
Fexofenadini hydrochloridum ................................................ 2230
Fibrini glutinum ............................................................... 8.2-4034
Fibrinogenum humanum ....................................................... 2418
Fila non resorbilia sterilia ...................................................... 1118
Fila non resorbilia sterilia in fuso ad usum veterinarium .. 1129
Fila resorbilia synthetica monofilamenta sterilia ................. 1123
Fila resorbilia synthetica torta sterilia .................................. 1122
Filgrastimi solutio concentrata ............................................... 2233
Filipendulae ulmariae herba .................................................. 1316
Filum bombycis tortum sterile in fuso ad usum
veterinarium .......................................................................... 1129
Filum ethyleni polyterephthalici sterile in fuso ad usum
veterinarium .......................................................................... 1129
Filum lini sterile in fuso ad usum veterinarium .................. 1128
Filum polyamidicum-6/6 sterile in fuso ad usum
veterinarium .......................................................................... 1128
Filum polyamidicum-6 sterile in fuso ad usum
veterinarium .......................................................................... 1128
Finasteridum ............................................................................ 2235
Flavoxati hydrochloridum ...................................................... 2238
Flecainidi acetas ............................................................... 8.1-3757
Flubendazolum ........................................................................ 2241
Flucloxacillinum magnesicum octahydricum ....................... 2242
Flucloxacillinum natricum ..................................................... 2243
Fluconazolum .......................................................................... 2245
Flucytosinum ........................................................................... 2246
Fludarabini phosphas ............................................................. 2248
Fludeoxyglucosi (1sF) solutio iniectabilis ........................ 8.2-3957
Fludrocortisoni acetas ............................................................. 2250
Flumazenili (N-[llC}methyl) solutio iniectabilis .................. 1054
Flumazenilum .......................................................................... 2251
Flumequinum .......................................................................... 2253
Flumetasoni pivalas ................................................................ 2254
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2 Index

Flunarizini dihydrochloridum ............................................. 2255 Glossa ......................................................................................... 779

0<

Flunitrazepamum ................................................................. ,.. 2256 Glucagonum humanum .......................................................... 2337

Flunixini megluminum ad usum veterinarium 2257 Glucosamini hydrochloridum ................................................ 2338
0< . . . . . 0< • • • 0< . . . . .

Fluocinoloni acetonidum ........................................................ 2258 Glucosamini sulfas natrii ehloridum ..................................... 2339
Fluocortoloni pivalas .............................................................. 2259 Glucosum anhydricum ........................................................... 2340
Fluoresceinum ................................................................... 2260 Glucosum liquidum ................................................................. 2341
0< . . . .

Fluoresceinum natricum ................................ 2262 Glucosum liquidum dispersione desiccatum ......................... 2342
o< . . . . . . . . . . . . . . . . . . . . . . .

Fluoridi (l8F) solutio ad radio-signandum ................... ,....... 1055 Glucosum monohydricum ...................................................... 2343
Fluorodopae (l8F) ab electrophila substitutione solutio Glutathionum .......................................................................... 2345
iniectabilis ........................................ ,..................................... 1056 Glycerol-formalum .................................................................. 2351
Fluoromisonidazoli eSF) solutio iniectabilis ......................... 1058 Glyceroli dibehenas ................................................................. 2349
Fluorouracilum ........................................................................ 2263 Glyceroli distearas ................................................................... 2350
Fluoxetini hydrochloridum .................................................... 2264 Glyceroli monocaprylas .......................................................... 2351
Flupentixoli dihydrochloridum .............................................. 2266 Glyceroli monocaprylocapras ................................................. 2352
Fluphenazini decanoas ........................................................... 2268 Glyceroli monolinoleas .......................................................... 2353
Fluphenazini dihydrochloridum ............................................ 2269 Glyceroli mono-oleas ............................................................... 2354
Fluphenazini enantas ............................................................. 2271 Glyceroli monostearas 40-55 .................................................. 2355
Flurazepami monohydrochloridum ...................................... 2272 Glyceroli trinitratis solutio ..................................................... 2356
Flurbiprofenum ....................................................................... 2273 Glyeerolum ............................................................................... 2346
Fluspirilenum .......................................................................... 2274 G/yeerolum (85 per eentum) .................................................. 2348
Flutamidum ............................................................................. 2275 Glycinum ............................................... ................................... 2357
Fluticasoni propionas ....................................................... 8.1-3758 Glycopyrronii bromidum ........................................................ 2358
Flutrimazolum ......................................... ................................ 2278 Gonadorelini acetas ................................................................ 2360
Fluvastatinum natricum ......................................................... 2279 Gonadotropinum chorionicum .............................................. 2361
Fluvoxamini maleas ................................................................ 2281 Gonadotropinum sericum equinum ad usum
Foeniculi amari fructus .......................... 1241 veterinarium .......................................................................... 2362
0 < . 0 < . . . 0< . . . . . . . . . . . . . . . . . . . . . .

Foeniculi amari fructus aetheroleum .................................... 1176 Goserelinum ........................................... .................................. 2363
Foeniculi amari herbae aetheroleum .................................... 1177 GossYPii oleum hydrogenatum ............................................... 1968
Foeniculi dulcis fructus ..... 1242 Gramicidinum ......................................................................... 2365
0< . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Follitropini solutio concentrata ....................................... 8.1-3766 Graminis rhizoma ................................................................... 1222

Follitropinum .................................................................... 8.1-3760 Granisetroni hydrochloridum ................................................ 2366
Formaldehydi solutio (35 per centum) .................................. 2295 Granula ad praeparationes homoeopathicas ........................ 1441
Formoteroli fumaras dihydricus ............................................ 2296 Granula homoeopathica imbuta ............................................ 1441
Foscarnetum natricum hexahydricum .................................. 2297 Granulata ................... ,............................................................... 785
Fosfomycinum calcicum .......................................... ,.............. 2299 Griseofulvinum ........... ,............................................................ 2367
Fosfomycinum natricum ........................................................ 2300 Guaiacolum ............................................................................. 2368
Fosfomycinum trometamolum ..... 2301 Guaifenesinum ......................................................................... 2370
o< . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Fosinoprilum natricum ......................................................... 2302 Guanethidini monosulfas ....................................................... 2371

o<

Framyeetini sulfas ................................................................... 2305 Guar galactomannanum ........................................................ 2371

Frangulae cortex ...................................................................... 1247
Frangulae corticis extractum siccum normatum ................. 1249 H
Fraxinifolium .......................................................................... 1157 Halofantrini hydrochloridum ................................................ 2381
Fraxini rhynchophyllae cortex ............................................... 1249 Haloperidoli decanoas ............................................................ 2383
Fructosum ................................................................................ 2306 Haloperidolum ........................................................................ 2382
Fueus veZ Ascophyllum ............................................................ 1286 Halothanum ............................................................................. 2385
Fulvestrantum .................................................................. 8.2-4035 Hamamelidis folium ............................................................... 1270
Fumariae herba ....... 1252 Harpagophyti extractum siccum ............................................ 1225
0< . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Furosemidum ........................................................................... 2309 Ha rpagop hy ti radix ................................................................. 1226

Hederae folium ................................................................. 8.1-3707
G Hedera helix ad praeparationes homoeopathicas ................ 1448
Gabapentinum ......................................................................... 2317 Helianthi annui oleum raffinatum ........................................ 3354
Galactosum .............................................................................. 2318 Helium ...................................................................................... 2387
Galantamini hydrobromidum ............................................... 2319 Heparina massae molecularis minoris .................................. 2392
Gallii (67 Ga) citratis solutio iniectabilis ................................. 1060 Heparinum caleieum .............................................................. 2388
Gallii (68 Ga) chloridi solutio ad radio-signandum ............... 1060 Heparinum natricum .............................................................. 2390
Gallii (68 Ga) edotreotidi solutio iniectabilis .......................... 1062 Heptaminoli hydroehloridum ................................................ 2394
Ganciclovirum ......................................................................... 2321 Hexamidini diisetionas ........................................................... 2395
Gelatina ............................................................................. 8.1-3775 Hexetidinum ............................................................................ 2396
Gemcitabini hydrochloridum ................................................. 2324 Hexylresorcinolum .................................................................. 2397
Gemfibrozilum ......................................................................... 2325 Hibisei sabdariffae flos ............................................................ 1368
Gentamicini sulfas ................................................................... 2326 Histamini dihydrochloridum ................................................. 2398
Gentianae radix ....................................................................... 1254 Histidini hydrochloridum monohydrieum ..................... 8.2-4042
Gentianae tinctura .................................................................. 1255 Histidinum ........................................................................ 8.2-4041
Gestodenum ............................................................................. 2328 Homatropini hydrobromidum ............................................... 2401
Ginkgonis extractum siccum raffinatum et quantificatum .. 1257 Homatropini methylbromidum ............................................. 2402
Ginkgonis folium ..................................................................... 1259 Hyaluronidasum ..................................................................... 2436
Ginseng extractum siccum ...................................................... 1262 Hydralazini hydrochloridum ................................................. 2437
Ginseng radix ........................................................................... 1261 Hydrargyri diehloridum ......................................................... 2715
Glibenclamidum ...................................................................... 2330 Hydrastis canadensis ad praeparationes homoeopathicas .. 1449
Gliclazidum .............................................................................. 2332 Hydrastis rhizoma ................................................................... 1266
Glimepiridum .......................................................................... 2333 Hydrochlorothiazidum ........................................................... 2439
Glipizidum ............................................................................... 2335 Hydrocodoni hydrogenotartras 2.5-hydricus ....................... 2440

General Notices (1) apply to all monographs and other texts 4161
Index
Hydrocortisoni acetas ............................................................. 2444
Hydrocortisoni hydrogenosuccinas ........................................ 2446
Hydrocortisonum .................................................................... 2442
Hydrogenii peroxidum 30 per centum .................................. 2448
Hydrogenii peroxidum 3 per centum .................................... 2448
Hydromorphoni hydrochloridum .......................................... 2449
Hydroxocobalamini acetas ..................................................... 2450
Hydroxocobalamini chloridum .............................................. 2451
Hydroxocobalamini sulfas ...................................................... 2452
Hydroxycarbamidum .............................................................. 2453
Hydroxyethylcellulosum ......................................................... 2455
Hydroxyethylis salicylas .......................................................... 2454
Hydroxypropylbetadexum ............................................... 8.2-4050
Hydroxypropylcellulosum ....................................................... 2458
Hydroxyzini hydrochloridum ................................................ 2459
Hymecromonum ...................................................................... 2460
Hyoscini butylbromidum ........................................................ 2462
Hyoscini hydrobromidum ...................................................... 2464
Hyoscinum ............................................................................... 2461
Hyoscyamini sulfas ................................................................. 2465
Hyoscyamus niger ad praeparationes homoeopathicas ....... 1450
Hyperici herba ......................................................................... 1391
Hyperici herbae extractum siccum quantificatum ............... 1393
Hypericum perforatum ad praeparationes
homoeopathicas ..................................................................... 1451
Hypromellosi phthalas ............................................................ 2468
Hypromellosum ....................................................................... 2466
1 Iobenguani (1 31 1) so/utio iniectabilis ad usum
Ibuprofenum ............................................................................ 2473
1chthammolum ........................................................................ 2475
Idoxuridinum .......................................................................... 2476
Iecoris aselli domestici oleum ................................................. 1946
Iecoris aselli oleum A .............................................................. 1950
Iecoris ase/li o/eum B .............................................................. 1954
Ifosfamidum ............................................................................. 2476
Imipenemum monohydricum ................................................ 2478
Imipramíni hydrochloridum .................................................. 2479
Immunoglobulinum anti- T lymphocytorum ex animale ad
usum humanum .................................................................... 1575
Immunoglobulinum humanum anti-D ................................ 2406
Immunoglobulinum humanum anti-D ad usum
intravenosum ......................................................................... 2407
Immul1oglobulinum humanum hepatitidís A ...................... 2420
1mmunoglobulinum humanum hepatitidis B ...................... 2420
1mmul1oglobulinum humanum hepatitidis B ad usum
intravenosum ......................................................................... 2421
Immunoglobulinum humanum morbillicum ....................... 2421
Immunoglobulinum humanum normale .............................. 2421
Immunoglobulinum humanum normale ad usum
intravenosum ......................................................................... 2423
Immunoglobulinum humanum rabicum .............................. 2431
Immunoglobulinum humanum rubellae .............................. 2432
1mmunoglobulinum humanum tetanicum ........................... 2432
Immunoglobulinum humanum varicellae ............................ 2434
Immunoglobulinum humanum varicellae ad usum
il1travenosum ......................................................................... 2434
1mmul1osera ad usum veterinarium ....................................... 750
Immunosera ex animale ad usum humanum ......... " ............. 748
Immunoserum botulinicum ................................................... 1029
Immunoserum Clostridii novyi alpha ad usum
veterinarium .......................................................................... 1037
1mmunoserum Clostridii perfringentis beta ad usum
veterinarium .......................................................................... 1038
Immunoserum Clostridii perfringentis epsilon ad usum
veterinarium .......................................................................... 1039
1mmunoserum contra venena viperarum europaearum ..... 1033
1mmul1oserum diphthericum ................................................. 1029
Immunoserum gangraenicum (Clostridium novyi) ............. 1030
1mmunoserum gangraenicum (Clostridium perfringens) ... 1031
1mmunoserum gangraenicum (Clostridium septicum) ....... 1032
1mmul1oserum gangraenicum mixtum ................................. 1030
4162
EUROPEAN PHARMACOPOEIA 8.2
1mmunoserum tetanicum ad usum humanum .................... 1033
1mmunoserum tetanicum ad usum veterinarium ............... 1040
1ndapamidum .......................................................................... 2480
1ndii (1111n) chloridi solutio .................................................... 1065
1ndii (lJ1n) oxini solutio ........................................................ 1066
1ndii (1111n) pentetatis solutio iniectabilis ............................. 1066
1ndinaviri sulfas ...................................................................... 2482
1ndometacinum ................................................................ 8.2-4055
Inhalanda ............................................. ...................................... 800
1nsulini zinci amorphi suspensio iniectabilis ........................ 2502
Insulini zinci cristallini suspensio iniectabilis ...................... 2502
1nsulini zinci suspensio iniectabilis ........................................ 2501
Insulinum aspartum ............................................................... 2485
1nsulinum biphasicum iniectabile ......................................... 2493
1nsulinum bovinum ................................................................ 2486
1nsulinum glarginum .............................................................. 2489
Insulinum humanum .............................................................. 2491
Insulinum isophanum biphasicum iniectabile ..................... 2493
1nsulinum isophanum iniectabile .......................................... 2494
Insulinum lisprum ................................................................... 2494
Insulinum porcinum ............................................................... 2497
Insulinum solubile iniectabile ................................................ 2494
1nteljeroni alfa-2 solutio concentrata ................................... 2502
Interferoni beta-l a solutio concentrata ................................. 2505
1nterferoni gamma-l b solutio concentrata .................... 8.2-4056
int-rac-a- Tocopherolum ......................................................... 3436
int-rac-a- Tocopherylis acetas ................................................. 3438
10benguani ( 1231) solutio iniectabilis ...................................... 1067
diagnosticum ...................................................................... .... 1068
Iobenguani (1 31 1) solutio iniectabilis ad usum
therapeuticum ........................................................................ 1069
10benguani sulfas ad radiopharmaceutica ............................ 1070
Iodinati ( 1251) humani albumini solutio iniectabilis ............ 1064
Iodixanolum ............................................................................ 2511
Iodomethylnorcholesteroli (131I) solutio iniectabilis ............. 1070
Iodum ....................................................................................... 2511
Iohexolum ................................................................................ 2514
Iopamidolum ........................................................................... 2518
Iopromidum ............................................................................. 2520
Iotrolanum ............................................................................... 2523
Ipecacuanhae extractum fluidum normatum ...................... 1277
Ipecacuanhae pulvis normatus .............................................. 1278
Ipecacuanhae radix ................................................................. 1278
Ipecacuanhae tinctura normata ............................................ 1279
Ipratropii bromidum ............................................................... 2527
Irbesartanum ........................................................................... 2528
Isatidis radix ......................... " ................................................. 1280
Isoconazoli nitras .................................................................... 2531
Isoconazolum ........................................................................... 2530
Isofluranum ............................................................................. 2532
Isoleucinum .... " .............................................................. .......... 2533
Isomaltum ................................................................................ 2534
Isoniazidum ............................................................................. 2536
Isoprenalini hydrochloridum ................................................. 2536
Isoprenalini sulfas ................................................................... 2537
Isopropylis myristas ................................................................. 2539
Isopropylis palmitas ................................................................ 2540
Isosorbidi dinitras dilutus ....................................................... 2540
Isosorbidi mononitras dilutus ......... "" .......................... " ....... 2542
1sotretinoinurn ......................................................................... 2543
Isoxsuprini hydrochloridum ................................................... 2545
Isradipinum .......................... " ................................................. 2547
Itraconazolum ..................................................................... " .. 2548
Ivermectinum ........................................................................... 2549
J
Josamycini propio nas ........ " .................................................... 2557
Josamycinum ......................... " ................................................ 2555
Juniperi aetheroleum .................. " ........................................ " 1285
Juniperi galbulus ..................................................................... 1285
See the informatíon section on general mOl1ographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
K Lini oleum virginale ......................................................... 8.2-4065
Kalii acetas ............................................................................... 3063
Kalii bichromas ad praeparationes homoeopathicas .... 8.2-3990
Kalii bromidum ....................................................................... 3063
Kalii carbonas .......................................................................... 3064
Kalii chloridum ....................................................................... 3065
Kalii citras ................................................................................ 3065
Ka/ii clavulanas ....................................................................... 3066
Ka/ii clavulanas dilutus .......................................................... 3068
Kalii dihydrogenophosphas .................................................... 3070
Kalii hydrogenoaspartas hemihydricus ................................. 3070
Kalii hydrogenocarbonas ........................................................ 3071
Kalii hydrogenotartras ............................................................ 3072
Kalii hydroxidum .................................................................... 3072
Kalii iodidum ........................................................................... 3073
Kalii metabisulfis ..................................................................... 3073
Kalii natrii tartras tetrahydricus ........................................... 3076
Kalii nitras ............................................................................... 3074
Kalii perchloras ........................................................................ 3075
Kalii permanganas .................................................................. 3075
Kalii sorbas .............................................................................. 3076
Kalii sulfas ................................................................................ 3077
Kanamycini monosulfas ......................................................... 2564
Kanamycini sulfas acidus ....................................................... 2563
Kaolinum ponderosum ........................................................... 2565
Ketamini hydrochloridum ...................................................... 2565
Ketoconazolum ........................................................................ 2567
Ketoprofenum .......................................................................... 2569
Ketorolacum trometamolum .................................................. 2571
Ketotifeni hydrogenofumaras .......................................... 8.1-3783
Kryptonum (SllnKr) ad inhalationem ................................... 1071
L Macrogolglyceridorum caprylocaprates ................................. 1757
Labetaloli hydrochloridum ..................................................... 2577
Lacca ......................................................................................... 3216
Lactitolum monohydricum .................................................... 2580
Lactosum anhydricum ............................................................ 2582
Lactosum monohydricum ....................................................... 2584
Lactulosum .............................................................................. 2585
Lactulosum liquidum .............................................................. 2587
Lamivudinum .......................................................................... 2589
Lamotriginum .................................................................. 8.1-3787
Lansoprazolum ........................................................................ 2592
Lanugo cellulosi absorbens ..................................................... 3542
Lanugo gossypii absorbens ...................................................... 1967
Lauromacrogolum 400 ........................................................... 2594
Lavandulae aetheroleum ........................................................ 1291
Lavandulae flos ........................................................................ 1289
Leflunomidum ......................................................................... 2597
Leonuri cardiacae herba ......................................................... 1324
Letrozolum ............................................................................... 2598
Leucinum ................................................................................. 2599
Leuprorelinum ......................................................................... 2601
Levamisoli hydrochloridum ................................................... 2603
Levamisolum ad usum veterinarium .................................... 2602
Levetiracetamum ..................................................................... 2604
Levistici radix .......................................................................... 1301
Levocabastini hydrochloridum ........................................ 8.2-4063
Levocarnitinum ....................................................................... 2607
Levodopum .............................................................................. 2608
Levodropropizinum ..................................... ............................ 2610
Levomentholum ....................................................................... 2611
Levomepromazini hydrochloridum ....................................... 2612
Levomepromazini maleas ....................................................... 2613
Levomethadoni hydrochloridum ........................................... 2614
Levonorgestrelum .................................................................... 2615
Levothyroxinum natricum ..................................................... 2618
Lichen islandicus ..................................................................... 1275
Lidocaini hydrochloridum ...................................................... 2621
Lidocainum .............................................................................. 2620
Limonis aetheroleum .............................................................. 1292
Lincomycini hydrochloridum ................................................. 2622
General Notices (1) apply to all monographs and other texts
Index
Lini semen ................................................................................ 1295
Liothyroninum natricum ....................................................... 2625
Liquiritiae extractum fluidum ethanolicum normatum ..... 1297
Liquiritiae extractum siccum ad saporandum ..................... 1296
Liquiritiae radix ...................................................................... 1298
Lisinoprilum dihydricum ........................................................ 2627
Lithii carbonas ......................................................................... 2628
Lithii citras .... ........................................................................... 2628
L-Methionini ([llC}methyl) solutio iniectabilis .................... 1073
Lobelini hydrochloridum ........................................................ 2629
Lomustinum ............................................................................. 2630
Loperamidi hydrochloridum .................................................. 2631
Loperamídi oxidum monohydricum ..................................... 2633
Lopinavirum ............................................................................ 2634
Loratadinum ............................................. ............................... 2638
Lorazepamum .......................................................................... 2639
Losartanum kalicum ............................................................... 2641
Lovastatinum ........................................................................... 2643
Lufenuronum anhydricum ad usum veterinarium ............. 2644
Lupuliflos ................................................................................ 1274
Lymecyclinum .......................................................................... 2646
Lynestrenolum ......................................................................... 2648
Lysini acetas ............................................................................. 2649
Lysini hydrochloridum ............................................................ 2650
Lythri herba ............................................................................. 1300
M
Macrogol20 glyceroli monostearas ........................................ 2656
Macrogol 40 sorbitoli heptaoleas ........................................... 2657
Macrogol 6 glyceroli caprylocapras ........................................ 2655
Macrogola ................................................................................ 2665
Macrogolglyceridorum laurates ............................................. 2596
Macrogolglyceridorum linoleates ........................................... 2624
Macrogolglyceridorum oleates ................................................ 2898
Macrogolglyceridorum stearates ............................................ 3314
Macrogolglyceroli cocoates ..................................................... 2663
Macrogolglyceroli hydroxystearas .......................................... 2664
Macrogolglyceroli rícinoleas ................................................... 2665
Macrogoli 15 hydroxystearas ................................................. 2655
Macrogoli 30 dipolyhydroxystearas ....................................... 2657
Macrogoli aether cetostearylicus ............................................ 2658
Macrogoli aether laurilicus .................................................... 2658
Macrogoli aether oleicus ......................................................... 2660
Macrogoli aether stearylicus ................................................... 2662
Macrogolí oleas ........................................................................ 2659
Macrogoli stearas .............................................................. 8.2-4069
Magaldratum .................................................................... 8.2-4069
Magnesii acetas tetrahydricus ................................................ 2668
Magnesii aspartas dihydricus ................................................. 2669
Magnesii chloridum 4.5-hydrícum ........................................ 2671
Magnesii chloridum hexahydricum ....................................... 2672
Magnesii citras anhydricus ..................................................... 2673
Magnesii citras dodecahydricus ............................................. 2673
Magnesii citras nonahydricus ................................................ 2674
Magnesii gluconas ............................................................ 8.2-4070
Magnesii glycerophosphas ....................................................... 2675
Magnesii hydrogenophosphas trihydricus ad praeparationes
homoeopathicas .............................................................. 8.2-3991
Magnesii hydroxidum ............................................................. 2676
Magnesii lactas dihydricus ..................................................... 2676
Magnesii oxidum leve ............................................................. 2677
Magnesii oxidum ponderosum ............................................... 2677
Magnesii peroxidum ................................................................ 2678
Magnesii pidolas ...................................................................... 2679
Magnesii stearas ...................................................................... 2680
Magnesii subcarbonas levis .................................................... 2671
Magnesii subcarbonas ponderosus ......................................... 2670
Magnesii sulfas heptahydricus ............................................... 2682
Magnesii trisilieas .................................................................... 2683
Magnoliae officinalis cortex ............................................ 8.1-3709
4163
Index
Magnoliae officinalis flos ........................................................ 1304
Malathionum ........................................................................... 2685
Maltitolum ............................................................................... 2687
Maltitolum liquidum .............................................................. 2688
Maltodextrinum ...................................................................... 2689
Malvae folium .......................................................................... 1306
Malvae sylvestris flos ............................................................... 1305
Mangani gluconas ............................................................ 8.2-4071
Mangani glycerophosphas hydricus ....................................... 2691
Mangani sulfas monohydricus ............................................... 2691
Mannitolum ...................................................................... 8.2-4072
Maprotilini hydrochloridum .................................................. 2694
Marbofloxacinum ad usum veterinarium ............................ 2695
Marrubii herba ........................................................................ 1419
Masticabilia gummis medicata ................................................ 781
Mastix ....................................................................................... 1311
Matricariae aetheroleum ........................................................ 1314
Matricariae extractum fluidum ............................................. l313
Matricariae flos ....................................................................... 1311
Maydis amylum ....................................................................... 2684
Maydis oleum raffinatum ....................................................... 2683
Mebendazolum ........................................................................ 2696
Meclozini dihydrochloridum .................................................. 2698
Medroxyprogesteroni acetas ................................................... 2699
Mefloquini hydrochloridum ................................................... 2702
Megestroli acetas ..................................................................... 2704
Megluminum ........................................................................... 2706
Mel ............................................................................................ 2403
Melaleucae aetheroleum ......................................................... 1401
Meliloti herba .......................................................................... 1317
Melissae folii extractum siccum ............................................. l319
Melissae folium ........................................................................ 1318
Meloxicamum .......................................................................... 2707
Melphalanum .......................................................................... 2708
Menadionum ........................................................................... 2710
Menthae arvensis aetheroleum partim mentholum
depletum ................................................................................. 1323
Menthae piperitae aetheroleum ............................................. l353
Menthae piperitae folii extractum siccum ............................ l352
Menthae piperitae folium ....................................................... l350
Mentholum racemicum .......................................................... 2711
Menyanthidis trifoliatae folium ............................................. 1187
Mepivacaini hydrochloridum ................................................. 2712
Meprobamatum ....................................................................... 2713
Mepyramini maleas ................................................................ 2714
Mercaptopurinum ................................................................... 2715
Meropenemum trihydricum ................................................... 2716
Mesalazinum ........................................................................... 2717
Mesnum .................................................................................... 2720
Mesterolonum .......................................................................... 2721
Mestranolum ............................................................................ 2722
Metacresolum .......................................................................... 2723
Metamizolum natricum monohydricum ....................... 8.1-3791
Metformini hydrochloridum .................................................. 2725
Methadoni hydrochloridum ................................................... 2731
Methanolum ............................................................................ 2732
Methenaminum ....................................................................... 2733
Methioninum ........................................................................... 2733
Methotrexatum ........................................................................ 2735
Methylcellulosum .................................................................... 2739
Methyldopum .......................................................................... 2741
Methyleni chloridum ............................................................... 2743
Methylergometrini maleas ...................................................... 2744
Methylhydroxyethylcellulosum .............................................. 2745
Methylis nicotinas ................................................................... 2737
Methylis parahydroxybenzoas ............................................... 2738
Methylis parahydroxybenzoas natricus ................................. 3255
Methylis salicylas ..................................................................... 2739
Methylphenidati hydrochloridum .......................................... 2746
Methylphenobarbitalum ......................................................... 2747
Methylprednisoloni acetas ...................................................... 2751
Methylprednisoloni hydrogenosuccinas ................................ 2753
Methylprednisolonum ............................................................. 2748
4164
EUROPEAN PHARMACOPOEIA 8.2
Methylrosanilinii chloridum .................................................. 2755
Methyltestosteronum ............................................................... 2756
Methylthioninii chloridum ..................................................... 2757
Metixeni hydrochloridum ....................................................... 2759
Metoclopramidi hydrochloridum ........................................... 2761
Metoclopramidum ................................................................... 2760
Metolazonum ........................................................................... 2762
Metoprololi succinas ............................................................... 2763
Metoprololi tartras .................................................................. 2765
Metrifonatum .......................................................................... 2766
Metronidazoli benzoas ............................................................ 2769
Metronidazolum ...................................................................... 2768
Mexiletini hydrochloridum .................................................... 2770
Mianserini hydrochloridum ................................................... 277l
Miconazoli nitras .................................................................... 2774
Miconazolum ........................................................................... 2773
Midazolamum ......................................................................... 2777
Millefolii herba ................................................................. 8.2-3976
Minocyclini hydrochloridum dihydricum ............................. 2779
Minoxidilum ............................................................................ 2780
Mirtazapinum ......................................................................... 2781
Misoprostolum ......................................................................... 2783
Mitomycinum .......................................................................... 2784
Mitoxantroni hydrochloridum ............................................... 2786
Modafinilum ............................................................................ 2787
Molgramostimi solutio concentrata ....................................... 2788
Molsidominum ........................................................................ 2791
Mometasoni furoas ................................................................. 2792
Montelukastum natricum ...................................................... 2794
Moranteli hydrogenotartras ad usum veterinarium ............ 2796
Morphini hydrochloridum ..................................................... 2797
Morphini sulfas ....................................................................... 2799
Moxidectinum ad usum veterinarium .................................. 2800
Moxifloxacini hydrochloridum .............................................. 2803
Moxonidinum .......................................................................... 2804
MuPirocinum ........................................................................... 2805
Mupirocinum calcicum ........................................................... 2807
Musci medicati .......................................................................... 784
Mycophenolas mofetil ............................................................. 2808
myo-Inositolum ....................................................................... 2810
Myristicae fragrantis aetheroleum ......................................... l334
Myrrha ..................................................................................... 1326
Myrrhae tinctura ..................................................................... 1327
Myrtilli fructus recens ............................................................. 1173
Myrtilli fructus recentis extractum siccum raffinatum et
normatum .............................................................................. 1250
Myrtilli fructus siccus .............................................................. 1172
N
Nabumetonum ......................................................................... 2813
N-Acetyltryptophanum ........................................................... 1479
N-Acetyltyrosinum .................................................................. 1481
Nadololum ............................................................................... 2814
Nadroparinum calcicum ........................................................ 2815
Naftidrofuryli hydrogenooxalas ............................................. 2817
Naloxoni hydrochloridum dihydricum ................................. 2820
Naltrexoni hydrochloridum ................................................... 2822
Nandroloni decanoas .............................................................. 2824
Naphazolini hydrochloridum ................................................. 2825
Naphazolini nitras .................................................................. 2826
Naproxenum ............................................................................ 2827
Naproxenum natricum ........................................................... 2829
Nasalia ....................................................................................... 792
Nateglinidum ........................................................................... 2831
Natrii acetas trihydricus ......................................................... 3224
Natrii acetatis ([1_11e]) solutio iniectabilis ........................... 1078
Natrii alendronas .................................................................... 3225
Natrii alginas ........................................................................... 3226
Natrii amidotrizoas ................................................................. 3227
Natrii aminosalicylas dihydricus ........................................... 3228
Natrii ascorbas ......................................................................... 3229
Natrii aurothiomalas .............................................................. 3230
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2
Natrií benzoas .......................................................................... 3232
Natrii bromidum ..................................................................... 3232
Natrii calcii edetas ................................................................... 3233
Natrii calcii pentetas ad radiopharmaceutiea ...................... 1075
Natrii eaprylas ......................................................................... 3234
Natrii carbonas anhydrieus .................................................... 3235
Natrii carbonas decahydricus ................................................. 3236
Natrii carbonas monohydricus .............................................. 3236
Natrii cetylo- et stearylosulfas ......................................... 8.1-3814
Natrii chloridum ..................................................................... 3238
Natrii chromatis CS 1Cr) solutio sterilis ................................... 1079
Natrii citras .............................................................................. 3239
Natrii cromoglicas ................................................................... 3240
Natrii cyclamas ........................................................................ 3241
Natrii dihydrogenophosphas dihydricus ............................... 3242
Natrii docusas .......................................................................... 2094
Na/rii fluoridi (1sP) solutio iniectabilis .................................. 1079
Natrii fluoridum ...................................................................... 3244
Natrii jusidas ........................................................................... 3245
Natrii glycerophosphas hydricus ............................................ 3247
Natrii hyaluronas .................................................................... 3248
Natrii hydrogenocarbonas ...................................................... 3250
Natrii hydroxidum .................................................................. 3251
Natrii iodídi (1231) solutioad radio-signandum ..................... 1081
Natrii iodidi (1231) solutio iniectabilis .................................... 1080
Natrií iodidi (1 31 1) capsulae ad usum diagnosticum ............. 1082
Natrii iodidi (131 1) capsulae ad usum therapeuticum ........... 1083
Natrii iodidi ( 1311) so/utio ........................................................ 1084
Natrii iodidi (131 1) so/utio ad radio-signandum .................... 1084
Natrii iodidum ......................................................................... 3251
Natdi iodohippuras dihydricus ad radiopharmaceutica ..... 1085
Natrii iodohippurati (1231) solutio iniectabilis ....................... l086
Natrii iodohippurati (131I) solutio iniectabilis ....................... 1087
Natdi lactatis solutio .............................................................. 3252
Natrii laurilsulfas .................................................................... 3254
Natrii metabisulfis ................................................................... 3254
Natrii molybdas dihydricus .................................................... 3256
Natrii molybdatís (99Mo) jissione jormati solutio ................ 1088
Natríi nitris .............................................................................. 3257
Natdi nitroprussias ................................................................. 3257
Natrií perboras hydricus ......................................................... 3258
Natrii pertechnetatis (99mTc) jissione jormati solutio
iniectabilis .............................................................................. 1090
Natrii pertechnetatis (99mTc) sine jissione jormati solutio
iniectabilis .............................................................................. 1091
Natrii phenylbutyras ............................................................... 3258
e
Natrii phosphatis 2 p) solutio iniectabilis ............................ 1092
Natrii picosulfas ....................................................................... 3260
Natrii polystyrenesulfonas ...................................................... 3261
Natrii propionas ...................................................................... 3262
Natrii rísedronas 2.5-hydricus ............................................... 3170
Natrii salicylas ......................................................................... 3264
Natdi selenis pentahydricus ................................................... 3264
Natrii (S)-lactatis solutio ........................................................ 3253
Natrii stearas ........................................................................... 3267
Natrii stearylis jumaras .......................................................... 3268
Natrii sulfas anhydricus ......................................................... 3269
Natrií sulfas decahydricus ...................................................... 3270
Natrii sulfis anhydricus .......................................................... 3270
Natrií sulfis heptahydricus ..................................................... 3271
Natrii tetraehloroauras dihydricus ad praeparationes
homoeopathicas .............................................................. 8.2-3984
Natrii thiosulfas ....................................................................... 3271
Natríí valproas ......................................................................... 3272
Neohesperidin-dihydrochalconum ......................................... 2833
Neomycini sulfas ..................................................................... 2834
Neostigmini bromidum .................................................... 8.2-4077
Neostigmini metilsulfas .................................................... 8.2-4078
Neroli aetheroleum .................................................................. 1329
Netilmicini sulfas ..................................................................... 2837
Nevirapinum anhydricum ...................................................... 2839
Nevirapinum hemihydricum .................................................. 2840
Niaouli typo cineolo aetheroleum .......................................... 1332
General Notices (1) apply to all monographs and other texts
Index
Nicergolinum ........................................................................... 2841
Nicethamidum ......................................................................... 2854
Niclosamidum anhydricum .................................................... 2843
Niclosamidum monohydrieum .............................................. 2844
Nicotinamidum ....................................................................... 2845
Nieotini ditartras dihydricus .................................................. 2846
Nieotini resinas ........................................................................ 2847
Nicotinum ................................................................................ 2845
Nifedipinum ............................................................................. 2850
Nifuroxazidum ........................................................................ 2853
Nilutamidum ........................................................................... 2855
Nimesulidum ........................................................................... 2856
Nimodipinum .......................................................................... 2857
Nitrazepamum ......................................................................... 2858
Nitrendipinum ......................................................................... 2859
Nitrojuralum ............................................................................ 2862
Nitrojurantoinum .................................................................... 2863
Nitrogenii oxidum ................................................................... 2861
Nitrogenium ............................................................................. 2863
Nitrogenium oxygenio depletum ............................................ 2864
Nizatidinum ............................................................................. 2866
N-Methylpyrro/idonum .......................................................... 2754
Nomegestro/i acetas ................................................................. 2868
Nonoxinolum 9 ........................................................................ 2869
Noradrenalini hydrochloridum ............................................. 2869
Noradrenalini tartras ............................................................. 2871
Norethisteroni acetas .............................................................. 2874
Norethisteronum ..................................................................... 2872
Norfloxacinum ........................................................................ 2875
Norfluranum ............................................................................ 2877
Norgestimatum ........................................................................ 2883
Norgestrelum ........................................................................... 2884
Nortriptylini hydroch/oridum ................................................ 2884
Noscapini hydrochloridum ..................................................... 2887
Noscapinum ............................................................................. 2886
Notoginseng radix ................................................................... 1333
Nystatinum .............................................................................. 2888
O
Octoxinolum 10 ....................................................................... 2893
Octyldodecanolum .................................................................. 2894
Octylis gallas ............................................................................ 2893
Oenotherae oleum raffinatum ................................................ 2206
Ofloxacinum ............................................................................ 2895
Olanzapinum ........................................................................... 2896
Oleae jolii extractum siccum .................................................. 1337
Oleae jolium ............................................................................. 1335
Olea herbaria ............................................................................ 775
O/ibanum indicum .................................................................. 1276
Oliva e oleum raffinatum ........................................................ 2899
Olivae oleum virginale ............................................................ 2900
Olmesartanum medoxomilum ............................................... 2901
Olsalazinum natricum ............................................................ 2903
Omega-3 acidorum esteri ethylici 60 ..................................... 2905
Omega-3 acidorum esteri ethylici 90 ..................................... 2907
Omega-3 acidorum triglycerida ............................................. 2909
Omeprazolum .......................................................................... 2911
Omeprazolum magnesicum .................................................... 2912
Omeprazolum natricum ......................................................... 2913
Ondansetroni hydrochloridum dihydricum ......................... 2915
Ononidis radix .................................................................. 8.2-3967
Ophthalmica .............................................................................. 782
Opii extractum siccum normatum ........................................ 1337
Opii pulvis normatus .............................................................. 1339
Opii tinetura normata ............................................................ 1341
Opium crudum ........................................................................ 1340
Orbifloxacinum ad usum veterinarium ................................ 2916
Orciprenalini sulfas ................................................................. 2918
Origani herba .......................................................................... 1342
Orphenadrini citras ................................................................ 2919
Orphenadrini hydroehloridum .............................................. 2921
Orthosiphonis jo/ium .............................................................. 1284
4165
Index
Oryzae amylum ....................................................................... 3163
Oseltamiviri phosphas ............................................................ 2922
Ouabainum .............................................................................. 2924
Oxacillinum natricum monohydricum ................................. 2925
Oxaliplatinum ......................................................................... 2927
Oxazepamum .......................................................................... 2929
Oxcarbazepinum ..................................................................... 2931
Oxeladini hydrogenocitras ..................................................... 2932
Oxfendazolum ad usum veterinarium .................................. 2933
Oxitropii bromidum ................................................................ 2934
Oxprenololi hydrochloridum ................................................. 2937
Oxybuprocaini hydrochloridum ............................................ 2938
Oxybutynini hydrochloridum ................................................ 2939
Oxycodoni hydrochloridum ................................................... 2940
Oxygenium ............................................................................... 2941
Oxygenium (150) ..................................................................... 1074
Oxygenium 93 per centum ..................................................... 2942
Oxymetazo/ini hydrochloridum ............................................. 2943
Oxytetracyclini hydrochloridum ..................................... 8.1-3795
Oxytetracyclinum dihydricum ............................................... 2945
Oxytocini solutio concentrata ................................................ 2949
Oxytocinum ............................................................................. 2948
p Pini sylvestris aetheroleum ..................................................... 1355
Paclitaxelum ............................................................................ 2953
Pancreatis pulvis ............................................................... 8.2-4083
Pancuronii bromidum ............................................................ 2959
Pantoprazolum natricum sesquihydricum ........................... 2960
Papaverini hydrochloridum ................................................... 2962
Papaveris rhoeados flos ........................................................... 1363
Paracetamolum ....................................................................... 2963
Paraffinum /iquidum .............................................................. 2966
Paraffinum perliquidum ......................................................... 2965
Paraffinum so/idum ................................................................ 2964
Paraldehydum ......................................................................... 2968
Parenteralia ............................................................................... 796
Parnaparinum natricum ........................................................ 2968
Paroxetini hydrochloridum anhydricum .............................. 2969
Paroxetini hydrochloridum hemihydricum .......................... 297l
Passiflorae herba ...................................................................... 1347
Passiflorae herbae extractum siccum ..................................... 1347
Pefloxacini mesilas dihydricus ............................................... 2973
Pelargonii radix ....................................................................... 1348
Pemetrexedum dinatricum heptahydricum .......................... 2975
Penbutolo/i sulfas .................................................................... 2977
Penicillaminum ....................................................................... 2978
Pentaerythrity/i tetranitras dilutus ........................................ 2980
Pentamidini diisetionas .......................................................... 2982
Pentazocini hydrochloridum .................................................. 2983
Pentazocini lactas .................................................................... 2984
Pentazocinum .......................................................................... 2982
Pentobarbitalum ..................................................................... 2984
Pentobarbitalum natricum ..................................................... 2985
Pentoxifyllinum ....................................................................... 2986
Pent?yveri~i hydrogenocitras ............................................... 2988
Peps¡n¡ pulv¡s ........................................................................... 2989
Pergolidi mesilas ...................................................................... 2990
Perphenazinum ....................................................................... 2996
Pethidini hydrochloridum ...................................................... 2997
Pharmaceutica ........................................................................... 756
Phenazonum ............................................................................ 2999
Pheniramini maleas ................................................................ 3000
Phenobarbitalum ..................................................................... 3001
Phenobarbitalum natricum .................................................... 3002
Phenolphthaleinum ................................................................. 3003
Phenolsulfonphthaleinum ....................................................... 3004
Phenolum ................................................................................. 3003
Phenoxyethanolum ................................................................. 3005
Phenoxymethylpenicillinum ................................................... 3006
Phenoxymethylpenicillinum ka/icum .................................... 3007
Phentolamini mesilas .............................................................. 3009
Phenylalaninum ............................................................... 8.2-4085
4166
EUROPEAN PHARMACOPOEIA 8.2
Phenylbutazonum ................................................................... 3011
Phenylephrini hydrochloridum .............................................. 3014
Phenylephrinum ...................................................................... 3013
Phenylhydrargyri acetas ......................................................... 3015
Phenylhydrargyri boras .......................................................... 3016
Phenylhydrargyri nitras .......................................................... 3016
Phenylpropanolamini hydrochloridum ................................. 3017
Phenytoinum ........................................................................... 3017
Phenytoinum natricum ........................................................... 3019
Phloroglucinolum anhydricum .............................................. 3020
Phloroglucinolum dihydricum ............................................... 3022
Pholcodinum ............................................................................ 3024
Phthalylsulfathiazolum ........................................................... 3026
Physostigmini salicylas ........................................................... 3027
Phytomenadionum .................................................................. 3027
Phytosterolum .......................................................................... 3029
Picotamidum monohydricum ................................................ 3030
Pilocarpini hydrochloridum ................................................... 3031
Pilocarpini nitras ..................................................................... 3032
Pimobendanum ....................................................................... 3033
Pimozidum ............................................................................... 3034
Pindololum .............................................................................. 3036
Pini pumilionis aetheroleum .................................................. 1230
Pioglitazoni hydrochloridum ................................................. 3037
Piperacil/inum ........................................................................ 3039
Piperacil/inum natricum ........................................................ 3041
Piperazini adipas ..................................................................... 3042
Piperazini citras ....................................................................... 3043
Piperazinum hydricum ........................................................... 3044
Piperis fructus .......................................................................... 1349
Piperis longi fructus ......................................................... 8.2-3966
Piracetamum ........................................................................... 3045
Pirenzepini dihydrochloridum monohydricum .................... 3046
Piretanidum ............................................................................. 3047
Piroxicamum ........................................................................... 3048
Piscis oleum omega-3 acidis abundans ................................. 2236
Pisi amylum ...................................................................... 8.1-3799
Pivampicillinum ...................................................................... 3050
Pivmecillinami hydrochloridum ........................................... 3051
Plantae ad ptisanam ................................................................. 747
Plantae medicinales .................................................................. 746
Plantae medicinales ad praeparationes homoeopathicas .... 1429
Plantae medicinales praeparatae ............................................. 746
Plantaginis lanceolatae fo/ium ............................................... 1367
Plantaginis ovatae semen ....................................................... 1282
Plantaginis ovatae seminis tegumentum ............................... 1281
Plasma humanum ad separationem ..................................... 2425
Plasma humanum coagmentatum conditumque ad
exstinguendum virum .................................................... 8.2-4048
Poloxamera .............................................................................. 3052
Polyacrylatis dispersio 30 per centum ................................... 3054
Poly(alcohol viny/icus) ............................................................ 3062
Polygalae radix ........................................................................ 1382
Polygoni avicularis herba ....................................................... 1287
Polygoni multiflori radix ........................................................ 1245
Polymyxini B sulfas ................................................................. 3055
Polysorbatum 20 ...................................................................... 3056
Polysorbatum 40 ...................................................................... 3057
Polysorbatum 60 ...................................................................... 3058
Polysorbatum 80 ...................................................................... 3058
Poly(viny/is acetas) .................................................................. 3060
Poly(vinylis acetas) dispersio 30 per centum ........................ 3061
Poria ......................................................................................... 1356
Povidonum ............................................................................... 3078
Povidonum iodinatum ............................................................ 3081
Praeadmixta ad alimenta medicata ad usum veterinarium .. 800
Praeparationes ad irrigationem ............................................... 805
Praeparationes buccales ............................................................ 793
Praeparationes celeres ad ptisanam ........................................ 748
Praeparationes homoeopathicae ............................................ 1430
Praeparationes insu/ini iniectabiles ....................................... 2499
Praeparationes intramammariae ad usum veterinarium ..... 786
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2 Index

Praeparationes intraruminales ................................................ 787 Q

Praeparationes intra-uterinae ad usum veterinarium .......... 787 Quercus cortex ......................................................................... 1335
Praeparationes liquidae ad usum dermicum .......................... 789 Quetiapini fumaras .......................................................... 8.2-4091
Praeparationes liquidae perora/iae .......................................... 790 Quillajae cortex ....................................................................... 1362
Praeparationes liquidae veterinariae ad usum dermicum ... 814 Quinaprili hydrochloridum ............................................. 8.1-3807
Praeparationes molles ad usum dermicum ............................. 807
Praeparationes molles veterinariae peroraliae .............. 8.1-3689 R
Praeparationes pharmaceuticae in vasis cum pressu ............. 805
Racecadotrilum ....................................................................... 3149
Pramipexoli dihydrochloridum monohydricum .................. 3082
Raclopridi ([llC]methoxy) solutio iniectabilis ...................... 1076
Pravastatinum natricum ........................................................ 3083
Radiopharmaceutica ................................................................. 759
Prazepamum ............................................ ................................ 3085
Raloxifeni hydrochloridum .................................................... 3150
Praziquantelum ....................................................................... 3086
Ramiprilum .............................................................................. 3152
Prazosini hydrochloridum ...................................................... 3087
Ranitidini hydrochloridum .................................................... 3154
Prednicarbatum ................................................................ 8.1-3799
Rapae oleum raffinatum ......................................................... 3155
Prednisoloni acetas ................................................ .................. 3091
Ratanhiae radix ....................................................................... 1365
Prednisoloni natrii phosphas ................................................. 3094
Ratanhiae tinctura .................................................................. 1365
Prednisoloni pivalas ................................................................ 3093
Rectalia ....................................................................................... 806
Prednisolonum ........................................................................ 3090
Repaglinidum ............................................................... ............ 3156
Prednisonum ............................................................................ 3095
Reserpinum .............................................................................. 3157
Pri/ocaini hydrochloridum ..................................................... 3098
Resorcinolum ........................................................................... 3158
Pri/ocainum ............................................................................. 3097
Rhamni purshianae cortex ..................................................... 1201
Primaquini diphosphas ........................................................... 3099
Rhamni purshianae extractum siccum normatum .............. 1202
Primidonum ............................................................................ 3101
Rhei radix ................................................................................. 1366
Primulae radix ................................................. ........................ 1356
Rhenii sulfidi col/oidalis et technetii (99IJ1Tc) solutio
Probenecidum .......................................................................... 3102
iniectabilis .............................................................................. 1094
Procainamidi hydrochloridum ............................................... 3102
Ribavirinum ............................................................................. 3159
Procaini hydrochloridum ....................................................... 3103
Ribis nigri folium ..................................................................... 1186
Proch/orperazini maleas ......................................................... 3104
Riboflavini natrii phosphas .................................................... 3162
Producta ab arte ADN recombinandorum ............................. 763
Riboflavinum ........................................................................... 3160
Producta ab fermentatione ....................................................... 758
Ricini oleum hydrogenatum ................................................... 1782
Producta allergenica ........................................................ 8.2-3945
Ricini oleum raffinatum ......................................................... 1783
Producta cum possibili transmissione vectorium
Ricini oleum virginale ............................................................. 1784
enkephalopathiarum spongiformium animalium ................ 759
Rifabutinum ....................................................... ...................... 3164
Progesteronum ......................................................................... 3105
RifamPicinum .......................................................................... 3165
Proguanili hydrochloridum ................................. ., ................. 3106
Rifamycinum natricum ................................................... 8.2-4097
Prolinum .................................................................................. 3107
Rifaximinum ............................................................................ 3167
Promazini hydrochloridum .................................................... 3108
Rilmenidini dihydrogenophosphas ........................................ 3169
Promethazini hydrochloridum ............................................ ... 3109
Risperidonum .......................................................................... 3171
Propacetamoli hydrochloridum ......................... ., .................. 3110
Ritonavirum ............................................................................. 3173
Propafenoni hydrochloridum ................................................. 3112
Rivastigmini hydrogenotartras .............................................. 3178
Propanolum ...................................................................... 8.1-3801
Rivastigminum ........................................................................ 3176
Propanthelini bromidum ........................................................ 3114
Rizatriptani benzoas ............................................................... 3179
Propofolum .............................................................................. 3115
Rocuronii bromidum .............................................................. 3181
Propranololi hydrochloridum ................................................ 3117
Ropivacaini hydrochloridum monohydricum ...................... 3183
Propylenglycoli dicapry/ocapras ............................................. 3118
Rosae pseudo-fructus .............................................................. 1228
Propylenglyco/i di/auras ......................................................... 3119
Rosmarini aetheroleum .......................................................... 1370
Propylenglycoli monolauras ................................................... 3120
Rosmarini folium .................................................................... 1369
Propylenglycoli monopalmitostearas ..................................... 3121
Roxithromycinum ................................................................... 3185
Propylenglycolum .................................................................... 3118
RRR-a- Tocopherolum ............................................................. 3437
Propylis gallas .......................................................................... 3121
RRR-a- Tocopherylis acetas .................................................... 3439
Propylis parahydroxybenzoas ................................................ 3122
RRR-a- Tocopherylis hydrogenosuccinas ............................... 3443
Propylis parahydroxybenzoas natricus ................................. 3263
Rusci rhizoma .......................................................................... 1192
Propylthiouraci/um ................................................................. 3124
Rutosidum trihydricum .......................................................... 3187
Propyphenazonum ........................................................... 8.1-3802
Protamini sulfas ...................................................................... 3125
Prothrombinum multiplex humanum .................................. 2429 S
Protirelinum ............................................................................ 3127 Sabalis serrulatae extractum .................................................. 1377
Proxyphyllinum ....................................................................... 3128 Sabalis serrulatae fructus ........................................................ 1379
Prunellae spica ......................................................... ................ 1219 Sacchari monopalmitas .......................................................... 3322
Pruni africanae cortex ............................................................ 1361 Saccharinum ............................................................................ 3191
Pseudoephedrini hydrochloridum ......................................... 3129 Saccharinum natricum ........................................................... 3192
Psyllii semen ............................................................................. 1357 Sacchari sphaerae .................................................................... 3327
Puerariae lobatae radix .......................................................... 1288 Sacchari stearas ....................................................................... 3323
Puerariae thomsonii radix ..................................................... 1402 Saccharum ............................................................................... 3321
Pulveres ad usum dermicum .................................................... 799 Salbutamoli sulfas .................................................................. 3195
Pulveres perorales ...................................................................... 799 Salbutamolum ......................................................................... 3193
Pyranteli embonas ......................................................... .......... 3130 Salicis cortex ............................................................................ 1422
Pyrazinamidum ....................................................................... 3131 Salicis corticis extractum siccum ........................................... 1423
Pyridostigmini bromidum ...................................................... 3132 Salmeteroli xinafoas ......................................................... 8.1-3813
Pyridoxini hydrochloridum .................................................... 3133 Salmonis domestici oleum ...................................................... 3201
Pyrimethaminum .................................................................... 3134 Salviae lavandulifoliae aetheroleum ..................................... 1389
Pyrrolidonum .......................................................................... 3135 Salviae miltiorrhizae radix et rhizoma ................................. 1374
Salviae officinalis folium ........................................................ 1373

General Notices (1) apply to all monographs and other texts 4167
Index
Sa/viae sclareae aethero/eum ................................................. 1213
Sa/viae tinctura ....................................................................... 1374
Sa/viae tri/obae fo/ium ..................................................... 8.2-3970
Sambuci flos ............................................................................. 1232
Sanguisorbae radix .................................................................. 1376
Saquinaviri mesi/as ................................................................. 3202
Schisandrae chinensis jructus ................................................. 1381
Scopo/amini buty/bromidum ................................................. 2462
Scopo/amini hydrobromidum ................................................ 2464
Scopo/aminum ......................................................................... 2461
Scutel/ariae baica/ensis radix ................................................. 1161
Se/amectinum ad usum veterinarium ................................... 3204
Se/egi/ini hydroch/oridum ............................................... 8.2-4101
Selenii disulfidum .................................................................... 3207
Semecarpus anacardium ad praeparationes
homoeopathicas .............................................................. 8.2-3981
Sennae fo/ii extractum siccum normatum ............................ 1384
Sennae fo/ium .......................................................................... 1383
Sennae fructus acutifoliae ...................................................... 1384
Sennae fructus angustifo/iae ................................................... 1385
Serinum .................................................................................... 3208
Serpyl/i herba .................................................................... 8.2-3974
Sertaconazoli nitras ................................................................ 3209
Sertralini hydroch/oridum ...................................................... 3210
Serum bovinum ....................................................................... 1686
Sesami o/eum raffinatum ....................................................... 3212
Sevofluranum ........................................................................... 3214
Si/denafi/i citras ....................................................................... 3217
Si/ica ad usum denta/em ........................................................ 3219
Si/ica col/oidalis anhydrica ..................................................... 3218
Si/ica col/oida/is hydrica ......................................................... 3219
Si/ica hydrophobica col/oida/is ............................................... 3220
Si/ybi mariani extractum siccum raffinatum et normatum .. 1320
Si/ybi mariani fructus ............................................................. 1321
Simeticonum ............................................................................ 3222
Simvastatinum ......................................................................... 3223
Sinomenii caulis ...................................................................... 1344
Soiae o/eum hydrogenatum .................................................... 3289
Soiae o/eum raffinatum .......................................................... 3290
So/ani amy/um ........................................................................ 3078
Solidaginis herba .............................................................. 8.1-3706
Solidaginis virgaureae herba .................................................. 1265
So/utiones ad conservationem partium corporis .................. 3273
So/utiones ad haemoco/aturam haemodiaco/aturamque .... 2378
So/utiones ad haemodia/ysem ................................................ 2376
So/utiones ad peritonea/em dia/ysem .................................... 2994
So/utiones anticoagu/antes et sanguinem humanum
conservantes ........................................................................... 1572
Somatostatinum ............................................................... 8.1-3816
Somatropini so/utio concentrata ............................................ 3277
Somatropinum ......................................................................... 3275
Somatropinum iniectabi/e ...................................................... 3279
Sophorae japonicae flos .......................................................... 1386
Sophorae japonicae flos immaturus ...................................... 1388
Sorbitani /auras ....................................................................... 3282
Sorbitani oleas ......................................................................... 3282
Sorbitani palmitas ................................................................... 3282
Sorbitani sesquio/eas ............................................................... 3283
Sorbitani stearas ...................................................................... 3283
Sorbitani trio/eas ..................................................................... 3284
Sorbito/um ............................................................................... 3284
Sorbito/um liquidum cristal/isabi/e ....................................... 3286
Sorbito/um liquidum non cristallisabi/e ................................ 3286
Sorbito/um liquidum partim deshydricum ........................... 3287
Sota/oli hydroch/oridum ......................................................... 3288
Spectinomycini dihydroch/oridum pentahydricum ............. 3290
Spectinomycini sulfas tetrahydricus ad usum
veterinarium .......................................................................... 3292
Spicae aethero/eum ................................................................. 1390
Spiramycinum ......................................................................... 3294
Spirapri/i hydroch/oridum monohydricum .......................... 3296
Spirono/actonum ..................................................................... 3298
Squa/anum ............................................................................... 3300
4168
EUROPEAN PHARMACOPOEIA 8.2
Stanni col/oida/is et technetii (99m tC) so/utio iniectabi/is ...... 1095
Stanni pyrophosphatis et technetii (99mTc) so/utio
iniectabi/is .............................................................................. 1109
Stannosi ch/oridum dihydricum ............................................ 3302
Stanoz%/um ........................................................................... 3302
Stavudinum .............................................................................. 3311
Stephaniae tetrandrae radix ................................................... 1246
Stramonii fo/ium ..................................................................... 1397
Stramonii pu/vis normatus ..................................................... 1399
Streptokinasi so/utio concentrata ........................................... 3315
Streptomycini sulfas ................................................................ 3317
Strontii (89Sr) ch/oridi so/utio iniectabi/is ............................. 1092
Styli ............................................................................................. 809
Sucralfatum .............................................................................. 3318
Sucra/osum ............................................................................... 3319
Sufentani/i citras ..................................................................... 3326
Sufentani/um ........................................................................... 3325
Su/bactamum natricum .......................................................... 3328
Sulfacetamidum natricum ...................................................... 3330
Sulfadiazinum ......................................................................... 3331
Sulfadimidinum ................................................................ 8.1-3817
Sulfadoxinum .......................................................................... 3334
Sulfafurazo/um ........................................................................ 3334
Sulfaguanidinum ..................................................................... 3335
Sulfamerazinum ...................................................................... 3336
Sulfamethizo/um ..................................................................... 3337
Sulfamethoxazo/um ................................................................ 3338
Sulfamethoxypyridazinum ad usum veterinarium .............. 3339
Sulfani/amidum ....................................................................... 3340
Sulfasa/azinum ........................................................................ 3340
Sulfathiazo/um ......................................................................... 3342
Sulfinpyrazonum ..................................................................... 3343
Sulfur ad praeparationes homoeopathicas ............................ 1456
Sulfur ad usum externum ....................................................... 3344
Sulfuris col/oidalis et technetii (99mTc) so/utio iniectabi/is ... 1095
Sulindacum .............................................................................. 3345
Su/piridum ........................................................................ 8.1-3818
Sultamicillini tosi/as dihydricus ............................................. 3350
Sultamicil/inum ....................................................................... 3348
Sumatriptani succinas ............................................................ 3352
Suxamethonii ch/oridum ........................................................ 3354
Suxibuzonum ........................................................................... 3355
T
Tada/afi/um .............................................................................. 3359
Ta/cum ...................................................................................... 3361
Tamoxifeni citras ..................................................................... 3363
Tamponae medicatae ................................................................ 812
Tamsu/osini hydroch/oridum ................................................. 3364
Tanaceti parthenii herba ........................................................ 1244
Tanninum ................................................................................ 3366
Taraxaci officina/is herba cum radice ................................... 1223
Taraxaci officinalis radix ........................................................ 1224
Technetii ('9mTc) bicisati so/utio iniectabi/is ......................... 1093
Technetii (99mTc) et etifenini so/utio iniectabilis ................... 1096
Technetii (99mTc) exametazimi so/utio iniectabilis ............... 1097
Technetii (99mTc) g/uconatis so/utio iniectabi/is .................... 1098
Technetii (99mTc) humani a/bumini so/utio iniectabi/is ....... 1099
Technetii (99mTc) macrosa/bi suspensio iniectabilis .............. 1100
Technetii ('9mTc) mebrofenini so/utio iniectabi/is ................ 1101
Technetii ('9mTc) medronati so/utio iniectabi/is ................... 1102
Technetii ('9mTc) mertiatidi so/utio iniectabilis .................... 1104
Technetii ('9mTc) microsphaerarum suspensio iniectabilis .. ll05
Technetii ('9mTc) pentetatis so/utio iniectabi/is .................... 1106
Technetii (99mTc) sestamibi so/utio iniectabi/is ..................... 1107
Technetii (99mTc) succimeri so/utio iniectabi/is ..................... 1108
Teicop/aninum ......................................................................... 3367
Telmisartanum ........................................................................ 3369
Temazepamum ........................................................................ 3371
Tenoxicamum .......................................................................... 3372
Terazosini hydroch/oridum dihydricum ............................... 3373
Terbinafini hydroch/oridum .................................................. 3375
See the information section on genera/ monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.2 Index

Terbutalini sulfas .................................................................... 3377 Triamcinolonum .................................. " ................................. 3459

Terconazolum .......................................................................... 3378 Triamterenum ....................................................... ,................. 3463
Terebinthinae aetheroleum ............................................. 8.2-3973 Tribenosidum ................................................................... 8.1-3824
Terfenadinum .......................................................................... 3379 Tributylis acetylcitras .............................................................. 3466
tert-Butylamini perindoprílum .............................................. 2991 Tricalcii phosphas ................................................................... 1749
Testosteroni decanoas ............. ,................ ,........ ,....... ,............. 3382 Triethylis citras .................. ,..................................................... 3468
Testosteroni enantas ............................................................... 3383 Trifluoperazini hydrochloridum ................ ,........................... 3469
Testosteroni isocaproas ....... ,................................................... 3385 Triflusalum .............................................................................. 3470
Testosteroni propionas ........ ,........................................ ,.......... 3386 Tríglycerida saturata media ................................................... 3471
Testosteronum ...................... " ................................................. 3380 Triglyceroli diisostearas .......................................................... 3472
Tetracaini hydrochloridum ........................................ ,........... 3387 Trigonellae foenugraeci semen ............................................... 1244
Tetracosactidum ...................................................................... 3388 Trihexyphenidyli hydrochloridum ......................................... 3473
Tetracyclini hydrochloridum .................................................. 3391 Trimebutini maleas .......................................... " ..................... 3474
Tetracyclinum ...................... ,., ......................................... ,....... 3390 Trimetazidini dihydrochloridum ........................................... 3475
Tetra-O-acetylmannosi triflas ad radiopharmaceutica ....... lllO Trimethadionum .......... ,.......................................................... 3476
Tetrazepamum ... ,........................ ,........................................... 3393 Trimethoprimum ..................................... ,.............................. 3477
Tetryzolini hydrochloridum ................................................... 3394 Trimipramini maleas .............................................................. 3479
Thallosi e01TI) chloridi solutio iniectabilis ........................... 1111 Tri-n-butylis phosphas ............................................................ 3467
Theobrominum, ................ ,.......................... .................... ,....... 3395 Tritici aestivi oleum raffinatum ............................................. 3563
Theophyllinum ........ ,................... ,....... ,................................... 3395 Tritici aestivi oleum virginale ................................................ 3564
Theophyllinum et ethylenediaminum anhydricum ............. 3398 Tritici amylum ........................................................................ 3563
Theophyllinum et ethylenediaminum hydricum .................. 3399 Trolaminum .. ,........................................... ,.................... ,.. ,...... 3481
Theophyllinum monohydricum ............................................. 3396 Trometamolum ........ ,......................... ,... ,... .. ", ..... ,., ................. 3483
Thiamazolum .......................................................................... 3401 Tropicamidum, ........................................................................ 3483
Thiamini hydrochloridum ...................................................... 3402 Tropisetroni hydrochloridum ................................................. 3485
Thiamini nitras ....................................................................... 3403 Trospii chloridum ............................................. ,...................... 3486
Thiamphenicolum ................................................................... 3405 Troxerutinum ........ ,.............................. ,....... ,.......................... 3488
Thiomersalum ............... ,.... ,...................................... ,............. 3406 Trypsinum ................................................................................ 3489
Thiopentalum natricum et natrii carbonas .......................... 3407 Tryptophanum ...... ,..................... ,., ... ,., .................................... 3490
Thioridazini hydrochloridum ................................................ 3410 Tuberculini aviarii derivatum proteinosum purificatum ... 3493
Thioridazinum ...................... " ............ ,................................... 3409 Tuberculini bovini derivatum proteinosum purificatum .... 3494
Threoninum ............................................................................. 3411 Tuberculini derivatum proteinosum purificatum ad usum
Thymi herba ................................... ,.......... ,......... ,....... ,.... 8.2-3971 humanum ..... ,......................... ,........... ,.................................. 3495
Thymi typo thymolo aetheroleum ......................................... 1405 Tuberculinum pristinum ad usum humanum ..................... 3492
Thymolum ..... ,........ "."" ... " ..... ,........ ,.,." ,... ,.............. ", .. ",., ..... 3412 Tylosini phosphatis solutio ad usum veterinarium." ........ ". 3498
Tiabendazolum .................................... ,..................... " ............ 3413 Tylosini tartras ad usum veterinarium ................................. 3500
Tiamulini hydrogenofumaras ad usum veterinarium ......... 3416 Tylosinum ad usum veterinarium ......................................... 3497
Tiamulinum ad usum veterinarium ...................................... 3414 Tyrosinum ..... ,................................................................... 8.2-4105
Tianeptinum natricum ........................................................... 3418 Tyrothricinum ......................................................................... 3502
Tiapridi hydrochloridum ................................................. 8.1-3823
Tibolonum .............................. ,................................................. 3421 U
Ticarcillinum natricum ....................................... ,................... 3423 Ubidecarenonum ..................................................................... 3507
TicloPidini hydrochloridum ................................................... 3424 Ureum ... ,........... ,.... " ...... " ...... ,...................... ,....... ,................. , 3508
Tiliae flos .................. ,................................ ,..... ,.......... ', ... ,........ 1295 Urofollitropinum ..................................................................... 3509
Tilidini hydrochloridum hemihydricum ............................... 3426 Urokinasum ............................................................................. 3510
Timololi maleas ....................................................................... 3427 Urtica dioica ad praeparationes homoeopathicas ......... 8.2-3991
Tincturae maternae Urticae folium .......................................................................... 1331
ad praeparationes homoeopathicas .............................. 8.1-3 715 Uvae ursi folium ...................................................................... 1162
Tinidazolum .............................. ,............. ,.. ,...... ,....... ,., .. "" ...... 3429
Tinzaparinum natricum ...................... ,.................................. 3430 V
Tioconazolum .......................... ,............................................... 3430
Tiotropii bromidum monohydricum ..................................... 3431 Vaccina ad usum humanum .................................................... 767
Titanii dioxidum ......................................... ,........ ,.................. 3433 Vaccina ad usum veterinarium ................................................ 770
Tobramycinum ................................ ,....................................... 3434 Vaccinum actinobacillosidis inactivatum ad suem .............. lOOO
a- Tocopherylis acetatis pulvis ................................................ 3441 Vaccinum adenovirosidis caninae vivum ............... " .............. 946
Tolbutamidum ........................................................................ 3445 Vaccinum adenovirosis caninae inactivatum ......................... 945
Tolnaftatum ................................................ ,.... ,....................... 3447 Vaccinum anaemiae infectivae pulli vivum ........................... 984
Torasemidum anhydricum ..................................................... 3449 Vaccinum anthracis adsorbatum ab colato culturarum ad usum
Tormentillae rhizoma ............................................. " .............. 1407 humanum ............................................................................... , 817
Tormentillae tinctura ............ ,............................ ,.................... 1407 Vaccinum anthracis vivum ad usum veterinarium ............... 921
Tosylchloramidum natricum ................................................. 3450 Vaccinum aphtharum epizooticarum inactivatum ad
Toxinum botulinicum A ad iniectabile ................................. 1683 ruminantes ........ ,...................................................................... 978
Toxinum botulinicum B ad iniectabile ................................. 1684 Vaccinum Bordetellae bronchisepticae vivum ad canem ...... 936
Tragacantha, ................... ,................... ,.................................... 1408 Vaccinum bronchitidis infectivae aviariae inactivatum ........ 925
Tramadoli hydrochloridum .................................................... 3450 Vaccinum bronchitidis infectivae aviariae vivum .................. 926
Tramazolini hydrochloridum monohydricum ..................... 3452 Vaccinum brucellosis (Brucella melitensis stirpis Rev. 1) vivum
Trandolaprilum ....................................................................... 3453 ad usum veterinarium ............................................................ 942
Trapidilum ., ..... ,....................................... ,............................... 3455 Vaccinum bursitidis infectivae aviariae inactivatum ............ 928
Trehalosum dihydricum ......................................................... 3456 Vaccinum bursitidis infectivae aviariae vivum ...................... 929
Tretinoinum .................................... ,............................... ......... 3458 Vaccinum calicivirosis felinae inactivatum ............................ 970
Triacetinum ................................................................ ,.. " ... ,.... 3459 Vaccinum calicivirosis felinae vivum ...................................... 971
Triamcinoloni acetonidum .................................................... 3460 Vaccinum chlamydiosidis felinae inactivatum ....................... 972
Triamcinoloni hexacetonidum .............................................. 3462 Vaccinum cholerae .... ' ............................................................... 821

General Notices (1) apply to all monographs and other texts 4169
Index
Vaccinum cholerae aviaria e inactivatum ............................... 980
Vaccinum cho/erae cryodesiccatum ......................................... 821
Vaccinum cho/erae perorale inactivatum ............................... 822
Vaccinum Clostridii botulini ad usum veterinarium ............ 952
Vaccinum Clostridii chauvoei ad usum veterinarium ........... 953
Vaccinum Clostridii novyi B ad usum veterinarium ............. 954
Vaccinum Clostridii perfringentis ad usum veterinarium .... 955
Vaccinum Clostridii septici ad usum veterinarium ............... 957
Vaccinum coccidiosidiS vivum ad pullum ...................... 8.1-3694
Vaccinum colibacillosis fetus a partu recentis inactivatum ad
ruminantes ............................................................................... 994
Vaccinum colibacillosis fe tus a partu recentis inactivatum ad
suem ......................................................................................... 992
Vaccinum diarrhoeae viralis bovinae inactivatum ................ 941
Vaccinum diphtheriae adsorbatum ......................................... 846
Vaccinum diphtheriae, antigeniis minutum, adsorbatum .... 847
Vaccinum diphtheriae et tetani adsorbatum .......................... 823
Vaccinum diphtheriae et tetani, antigeni-o(-is) minutum,
adsorbatum .............................................................................. 824
Vaccinum diphtheriae, tetani et hepatitidis B (ADNr)
adsorbatum .............................................................................. 825
Vaccinum diphtheriae, tetani et pertussis ex cellulis integris
adsorbatum .............................................................................. 827
Vaccinum diphtheriae, tetani et pertussis sine cellulis ex
elementis praeparatum adsorbatum ..................................... 826
Vaccinum diphtheriae, tetani et pertussis sine cellulis
ex elementis praeparatum, antigeni-o(-is) minutum,
adsorbatum ..................................................................... 8.2-3951
Vaccinum diphtheriae, tetani et poliomyelitidis inactivatum,
antigeni-o(-is) minutum, adsorbatum .................................. 829
Vaccinum diphtheriae, tetani, pertussis ex cellulis integris et
poliomyelitidis inactivatum adsorbatum .............................. 842
Vaccinum diphtheriae, tetani, pertussis ex cellulis integris,
poliomyelitidis inactivatum et haemophili stirpis b coniugatum
adsorbatum .............................................................................. 844
Vaccinum diphtheriae, tetani, pertussis sine cellulis ex
elementis praeparatum et haemophili stirpis b coniugatum
adsorbatum .............................................................................. 830
Vaccinum diphtheriae, tetani, pertussis sine cellulis ex elementis
praeparatum et hepatitidis B (ADNr) adsorbatum ............. 832
Vaccinum diphtheriae, tetani, pertussis sine cellulis ex elementis
praeparatum et poliomyelitídis inactivatum adsorbatum .. 834
Vaccinum diphtheriae, tetani, pertussis sine cellulis ex elementis
praeparatum et poliomyelitidis inactivatum, antigeni-o(-is)
minutum, adsorbatum ............................................................ 835
Vaccinum diphtheriae, tetani, pertussis sine cellulis ex
elementis praeparatum, hepatitidis B (ADNr), poliomyelitidis
inactivatum et haemophili stirpis b coniugatum
adsorbatum .... ,.............................................. ,.......................... 837
Vaccinum diphtheriae, tetani, pertussis sine cellulis ex elementis
praeparatum, poliomyelitidis inactivatum et haemophili
stirpis b coniugatum adsorbatum .......................................... 840
Vaccinum encephalitidis ixodibus advectae inactivatum ...... 908
Vaccinum encephalomyelitidis infectivae aviariae vivum .... 931
Vaccinum erysipelatis suillae inactivatum ............................ 1018
Vaccinum febris flavae vivum .................................................. 914
Vaccinum febris typhoidis ........................................................ 911
Vaccinum febris typhoidis cryodesiccatum ............................. 911
Vaccinum febris typhoidis polysaccharidicum ........................ 910
Vaccinum febris typhoidis vivum perorale (stirpis Ty 21a) .. 912
Vaccinum furunculosidis inactivatum ad salmonidas cum
adiuvatione oleosa ad iniectionem ........................................ 982
Vaccinum haemophili stirpis b coniugatum ........................... 848
Vaccinum hepatitidis A inactivatum adsorbatum ................. 853
Vaccinum hepatitidis A inactivatum adsorbatum et febris
typhoidis polysaccharidicum .................................................. 851
Vaccinum hepatitidis A inactivatum et hepatitidis B (ADNr)
adsorbatum .............................................................................. 852
Vaccinum hepatitidis A inactivatum virosomale ................... 854
Vaccinum hepatitidis B (ADNr) .............................................. 857
Vaccinum hepatitidis viralis anatis stirpis 1 vivum ............... 964
Vaccinum herpesviris equini inactivatum .............................. 967
Vaccinum inactivatum diarrhoeae vituli coronaviro i/latae .. 943
4170
EUROPEAN PHARMACOPOEIA 8.2
Vaccinum inactivatum diarrhoeae vituli rotaviro íllatae ..... 944
Vaccinum influenza e equinae inactivatum ............................ 968
Vaccinum influenzae inactivatum ad suem ......................... 1003
VacGÍnum influenzae inactivatum ex cellulis corticisque
antigeniis praeparatum .......................................................... 865
Vaccinum influenza e inactivatum ex cellulis virisque integris
praeparatum ............................................................................ 870
Vaccinum influenzae inactivatum ex corticis antigeniis
praeparatum ............................................................................ 863
Vaccinum influenzae inactivatum ex corticis antigeniis
praeparatum virosomale ........................................................ 867
Vaccinum influenzae inactivatum ex viris integris
praeparatum ............................................................................ 868
Vaccinum injIuenzae inactivatum ex virorum fragmentis
praeparatum ............................................................................ 861
Vaccinum laryngotracheitidis infectivae aviariae vivum ...... 932
Vaccinum leptospirosis bovina e ínactivatum ......................... 937
Vaccinum leptospirosis caninae inactivatum ......................... 948
Vaccinum leucosis felinae inactivatum .......................... 8.1-3697
Vaccinum mannheimiae bovinae inactivatum ...................... 986
Vaccinum mannheimiae inactivatum ad ovem ..................... 987
Vaccinum meningococcale classis C coniugatum ................... 875
Vaccinum meningococcale polysaccharidicum ....................... 877
Vaccinum morbi Aujeszkyi ad suem inactivatum ................. 921
Vaccinum morbi Aujeszkyi vivum ad suem ad usum
parenteralem ............................................................................ 923
Vaccinum morbi Carrei vivum ad canem ............................... 947
Vaccinum morbi Carrei vivum ad mustelidas ....................... 962
Vaccinum morbi haemorrhagici cuniculi inactivatum ........ 1007
Vaccinum morbillorum, parotitidis et rubellae vivum .......... 872
Vaccinum morbillorum, parotitidis, rubellae et varicellae
vivum ........................................................................................ 873
Vaccinum morbillorum vivum ................................................. 874
Vaccinum morbi Marek vivum ................................................ 989
Vaccinum morbi partus diminutionis MCMLXXVI inactivatum
ad pullum ... .............................................................................. 965
Vaccinum Mycoplasmatis galliseptici inactivatum ................ 990
Vaccinum myxomatosidis vivum ad cuniculum .................... 991
Vaccinum panleucopeniae felinae infectivae inactivatum .... 973
Vaccinum panleucopeniae felinae infectivae vivum .............. 974
Vaccinum papillomaviri humani (ADNr) .............................. 859
Vaccinum parainfluenzae viri canini vivum .......................... 949
Vaccinum paramyxoviris 3 aviarii inactivatum ad
meleagrem ....................................................................... 8.1-3693
Vaccinum parotitidis vivum ..................................................... 879
Vaccinum parvovirosis caninae inactivatum ......................... 950
Vaccinum parvovirosis caninae vivum ................................... 951
Vaccinum parvovirosis inactivatum ad suem ...................... 1004
Vaccinum pasteurellae inactivatum ad ovem ......................... 999
Vaccinum pertussis ex cellulis integris adsorbatum ............... 883
Vaccínum pertussis sine cellulis copurificatum adsorbatum .. 882
Vaccinum pertussis sine cellulis ex elementis praeparatum
adsorbatum .............................................................................. 880
Vaccinum pestis anatis vivum .................................................. 963
Vaccinum pestis classicae suillae vivum ex cellulis .............. 1019
Vaccinum pneumococcale polysaccharidicum ........................ 887
Vaccinum pneumococcale polysaccharidicum coniugatum
adsorbatum .............................................................................. 885
Vaccinum pneumoniae enzooticae suillae inactivatum ...... 1001
Vaccinum poliomyelitidis inactivatum ................................... 889
Vaccinum poliomyelitidis perorale .......................................... 891
Vaccinum pseudopestis aviariae inactivatum ........................ 995
Vaccinum pseudopestis aviariae vivum .................................. 997
Vaccinum rabiei ex cellulis ad usum humanum ........... 8.2-3952
Vaccinum rabiei inactivatum ad usum veterinarium ......... 1008
Vaccinum rabiei perorale vivum ad vulpem et
nyctereutem ........................................................................... 1011
Vaccinum rhinitidis atrophicantis ingravescentis suillae
inactivatum ............................................................................ 1005
Vaccinum rhinotracheitidis infectivae bovinae vivum .......... 983
Vaccinum rhinotracheitidis infectivae vivum ad
meleagrem .. ............................................................................ 1022
Vaccinum rhinotracheitidis viralis felinae inactivatum ........ 976
See the information section on general monographs (caver pages)
EUROPEAN PHARMACOPOEIA 8.2
Vaccinum rhinotracheitidis viralis felinae vivum .................. 977
Vaccinum rotaviri vivum perorale ..................................... ,... , 898
Vaccinum rubellae vivum ......................................................... 900
Vaccinum Salmonellae Enteritidis inactivatum ad
pullum .. '" .................. ,................................ ,........................... 1012
Vaccinum Salmonellae Enteritidis vivum perora le ad
pul/um ........... ,............ ,........................................................... 1013
Vaccinum Salmonellae Typhimurium inactivatum ad
..... ,.... ' .... ,..... " ........ "" ................................................. 1015
Salmonellae Typhimurium vivum perora le ad
pullum ...... ,,, .. ,................................................................ ,, ...... 1016
Vaccinum tenosynovitidis viralis aviariae vivum .................. 935
Vaccinum tetani adsorbatum ................................................... 907
Vaccinum tetani ad usum veterinarium ............................... 1021
Vaccinum tuberculosis (BCG) cryodesiccatum ....................... 819
Vaccinum varicellae vivum ...................................................... 913
Vaccinum variolae gallinaceae vivum ................................... 981
Vaccinum variolae vivum ......................................................... 903
Vaccinum vibriosidis aquae frigidae inactivatum ad
salmonidas ......... ,.................... ,..... ,................................. ,...... 1023
Vaccinum vibriosidis inactivatum ad salmonidas .............. 1024
Vaccinum viri parainfluenzae bovini vivum .......................... 938
Vaccinum viri syncytialis meatus spiritus bovini vivum ....... 940
Vaccinum yersiniosidis inactivatum ad salmonidas ............ 1025
Vaccinum zonae vivum ............................................................ 902
Vaginalia ..... ,.............................................................................. 812
Valacicloviri hydrochloridum anhydricum .......................... 3517
Valacicloviri hydrochloridum hydricum ........................ 8.2-4109
Valerianae extractum aquosum siccum ................................ 1412
Valerianae extractum hydroalcaholicum siccum .......... 8.2-3974
Valerianae radix .................... ,................................................. 1413
Valerianae radix minutata ......... " ........................ " ................ 1415
Valerianae tinctura ... ,............................... " ....................... " ... 1416
Valinum.,.,., ......... ,....... ,.... ,.... " ................................................. 3520
Valnemu/ini hydrochloridum ad usum veterinarium " ..... " 3521
Valsartanum ... ,...... ,., ... ,................ ,.... ,.... ,............................. ,., 3524
Vancomycini hydrochloridum .............................. ,................ , 3525
Vanillinum ,...... ,..... " ... " ...... " ............. "." ............................. " .. 3527
Vardenafili hydrochloridum trihydricum ...................... 8.2-4111
Vaselinum album ................... ,... " ......... "." ......... " .................. 2966
Vaselinum flavum ........ " ............................... " ................... " .. , 2967
Vecuronii bromidum .............................................................. 3528
Vedaprofenum ad usum veterinarium .................................. 3529
Venlafaxini hydrochloridum .................................................. 3530
Verapamili hydrochloridum ................................................... 3532
Verbasci flos .... ,........................ ,........................................ " ..... 1325
Verbenae citriodorae folium .......................... " ............... " ..... 1293
Verbenae herba ........................................................................ 1417
Vía praeparandi stirpes homoeopathicas et potentificandi" 1431
General Notices (1) apply to all monographs and other texts
Index
Vigabatrinum., .......... ,...... o............ ,.......... ........................... 0.... 3534
Vinblastini sulfas ..................................................................... 3535
Vincristini sulfas ..................................... 0................... 0.. 0......... 3536
Vindesini sulfas ... o......................................... o.......................... 3537
Vinorelbini tartras.o ... o...... o...................................................... 3539
Vinpocetinum .......................................................................... 3541
Violae herba cumflore ............................................................ 1420
Vitamini synthetici densati A pulvis ..................................... 3546
Vitaminum A ........... 0............. 0............... '0 ................ 0............... 3544
Vitaminum A syntheticum densatum oleosum .................... 3545
Vitaminum A syntheticum, solubilisatum densatum in aqua
dispergibile ............... ,.................... ,.............. 0......................... 3547
Voricanazolum ... 0... ' ................... ,......................... 000 ....... '0 ....... 3548
W
Warfarinum natricum ............................................. ,....... 8.1-3829
Warfarinum natricum clathratum ................................. 8.1-3830
X
Xanthani gummi ..................................................................... 3575
Xenoni ( 133Xe) solutio iniectabilis ............................ 1113
0 .............
Xylazini hydrochloridum ad usum veterinarium ......... 8.1-3835
Xylitolum .................... ,." ................................................. ,.. ,.... 3577
Xylometazolini hydrochloridum ............................................ 3579
Xylosum ............................ ,.................................. ,.................... 3580
y
Yohimbini hydrochloridum ...................................... ,............. 3585
Z
Zidovudinum .. o .................................................................8.2-4115
Zinci acetas dihydricus .................................... 0.............. 0....... 3590
Zinci acexamas ................................................ 0....................... 3591
Zinci chloridum ......................... '0 .......... 0....... ' ....... ' .. 0...... 0....... 3592
Zinci glucanas ,.............. 00.000 ..... 0.................... 00.0 ... 0................... 3593
Zinci oxidum ........................................................ 0.. 0............... 3594
Zinci stearas ............... 0.0 .. 00 ............................. '0 ........................ 3594
Zinci sulfas heptahydricus ..... 00 .................. 0............................ 3595
Zinci sulfas hexahydricus ....................... 0............. 0.... 0...... 0.... ' 3595
Zinci sulfas monohydricus ...... o..................................... o......... 3595
Zinci undecylenas .................................................................... 3596
Zingiberis rhizoma 0........................................ 0.0 ...................... 1256
Ziprasidoni hydrochloridum monohydricum ....... oo .............. 3596
Ziprasidoni mesilas trihydricus .................................... 0.8.1-3839
Zolpidemi tartras ..... 0.................................. ,........................... 3598
Zopiclonum ................ ,.................................. 0.. 0...................... , 3600
Zuclopenthixoli decanoas .................. 0...... 0..... 0....................... 3601
4171
 KEY TO MONOGRAPHS

Carbimazole EUROPEAN PHARMACOPOEIA 8.2

Version date of the text I 01/2008:0884 of this solution to 10.0 mL with a mixture of 20 volumes
I corrected 8.2 of acetonitrile R and 80 volumes of water R.
Referenee solution (b). Dissolve 5.0 mg of thiamazole R in
Text reference I CARBIMAZOLE a mixture of 20 volumes of aeetonitri/e R and 80 volumes
number of water R and dilute to 10.0 mL with the same mixture of
1 Carbimazolum solvents. Dilute 1.0 mL of this solution to 100.0 mL with
Modification to be a mixture of 20 volumes of aeetonitri/e R and 80 volumes
taken into account from F\ ofwater R.
the publication date of H3C /NyNyO~CH3 Column:
Supplement 8.2 O
S - size: 1= 0.15 m, 0 = 3.9 mm,
I ,C,HION,O,S stationary phase: oetadeeylsi/yl si/iea gel for
ehromatography R (5 ¡.¡m).
'-----_C_:A._S_n_u_m_b_e_r-----,[-1 [22232-54-8 JI M,186.2
Mobile phase: acetonitrile R, water R (10:90 V/V).
DEFINITION
Flow rate: 1 mL/min.
Chemical name UEthyI3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1- I Deteetion: spectrophotometer at 254 nm.
in accordance 11 carboxylate.
withIUPAC Content: 98.0 per cent to 102.0 per cent (dried substance). Injeetion: 10 ¡.¡L.
nomenclature rules Run time: 1.5 times the retention time of carbimazole.
CHARACTERS
Appearanee: white or yellowish-white, crystalline powder. Retention time: carbimazole = about 6 min.
Solubi/ity: slightly soluble in water, soluble in acetone and in System suitabi/ity: reference solution (a):
ethanol (96 per cent). - resolution: minimum 5.0 between the peaks due to
Application of the impurity A and carbimazole.
first and second IDENTIFICATION
identification is 11 First identifieation: B. Limits:
defined in the HSeeond identifieation: A, C. I
General Notices
A. Melting point (2.2.14): 122 oC to 125 oc.
(chapter 1)
B. Infrared absorption spectrophotometry (2.2.24).
Preparation: discs.
r--;-.,-----,---==-=-
Reference standard ComtJarison:lcarbimazole CRS.I
available from C. Thin-Iayer chromatography (2.2.27). Loss on drying (2.2.32): maximum 0.5 per cent,
the Secretariat Test solution. Dissolve 10 mg of the subs determined on 1.000 g by drying in a desiccator over
(see www.edqm.eu) examined in methylene ehloride R and diphosphorus pentoxide R at a pressure not exceeding
with the same solvent. 0.7 kPa for 24 h.
Referenee solution. Dissolve 10 mg of earbimazole CRS in Sulfated ash (2.4.14): maximum 0.1 per cent, determined
methylene ehloride R and dilute to 10 mL with the same on 1.0 g.
solvento ASSAY
Dissolve 50.0 mg in water R and dilute to 500.0 mL
Reagent described with the same solvent. To 10.0 mL add 10 mL of di/u te
r-----C""""""i-f¡'Ti7r"'-'-'-'-'-'-'-'--=.J' methylene ehloride R hydroehloric acid R and dilute to 100.0 mL with water R.
in chapter 4
Measure the absorbance (2.2.25) at the absorption
Applieation: 10 ¡.¡L. maximum at 291 nm.
Development: over a path of 15 cm. CaIculate the content of C,H¡ON,O,S taking the specific
Further information absorbance to be 557.
Drying: in air for 30 min.
available on
Deteetion: examine in ultraviolet light at 254 nm. IMPURITIES
www.edqm.eu
(Knowledge) Results: the principal spot in the chromatogram obtained Speeified impurities: A.
with the test solution is similar in position and size to Other detectable impurities (the following substances
the principal spot in the chromatogram obtained with would, if present at a sufficient leve!, be detected by one
the reference solution. or other of the tests in the monograph. They are limited
by the general acceptance criterion for other/unspecified
Reference to a TESTS impurities and/or by the general monograph Substanees
general chapter Related substances. Liquid chromato
for pharmaeeutieal use (2034). It is therefore not
necessary to identify these impurities for demonstration
Test solution. Dissolve 5.0 mg of the substance to be of compliance. See also 5.10. Control of impurities in
Line in the examined in 10.0 mL of a mixture of20 volumes of substanees for pharmaeeutical use): B.
margin aeetonitri/e R and 80 volumes of water R. Use this solution
within 5 min of preparation. /\
indicating
where part of
the text has
Referenee solution (a). Dissolve 5 mg of thiamazole R and
0.10 g of earbimazole CRS in a mixture of20 volumes of
H3C "'- yN
N

aeetonitri/e R and 80 volumes of water R and dilute to SH

been modified
(technical 100.0 mL with the same mixture of solvents. Dilute 1.0 mL A. 1-methyl-1H-imidazole-2-thiol (thiamazole),
modification)

See the information section on general monographs (caver pages)

General Notices (1) apply to all monographs and other texts