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ABSTRACT
Excipients play an important role in formulating a dosage form. These are the ingredients which along with
Active Pharmaceutical Ingredients make up the dosage forms. Excipients act as protective agents, bulking
agents and can also be used to improve bioavailability of drugs in some instances, the following review
discusses the various types and sources of excipients along with their uses, and these can be used for different
activities. Specific excipients are best suited for a particular dosage form; the selection criterion for excipients
and various interactions that an excipient can undergo during its course of stay in formulation has been
discussed in this review. Some excipient interactions can be detrimental and need to be avoided. This has been
detailed out in the interaction section. Excipients as like other active pharmaceutical ingredients need to be
stabilized and standardized; the following review gives brief information about standardization and
stabilization process alongwith the safety evaluation parameters of the excipients.
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Vegetable source: - Starch, Peppermint, Turmeric, characteristics, segmental absorption behavior,
Guar gum, Arginates, Acacia etc. drug delivery platform, intellectual property
issues etc while selecting an excipient for
Mineral source: - Calcium phosphate, Silica, Talc, formulation development, this may help in
Calamine, Asbestos, Kaolin, Paraffin, etc. determining the absorption challenges and desired
Synthetic: - Boric acid, Saccharin, Lactic acid, delivery platform for active pharmaceutical
Polyethylene glycols, Polysorbates, Povidone etc. ingredients.
The concept of quality by design (QbD) helps in
2. The following tables gives a classification of understanding excipients normal variability and
various excipients used in pharmaceutical dosage its potential impact on the processes of
forms: (table no 1,2,3) formulation development can be achieved.
Excipient compatibility tests allows us to
3. Classification of excipients based on their determine drug excipient interactions which can
functions 10-13:- be either avoided or can be modified to utilize in
Excipients are classified on the basis of the functions an efficient manner which helps in minimizing the
they perform such as:- risk associated with the excipients. Excipient
Various excipients used in solid dosage forms selection also depends on various routes of
perform various functions like:- administrations. Excipient selection must be done
Binders, diluents, lubricants, disintegrating agent’s on the basis of characteristics an excipient offers.
plasticizers etc, e.g.: when 5% starch is used in
formulation it acts as a binder for tablet The ideal characteristics of an excipient are given as
formulations where as when it is used in dry form under:-
it can perform the function of a disintegrant. An excipient must be:-
Excipients that are used in liquid dosage forms are:- Chemically stable
Solvents co- solvents, buffers anti-microbial agents Non reactive
emulsifying agents sweetening agents, flavors, etc Low equipment and process sensitive
Some excipients have therapeutic values which are Inert to human body
classified as under:- Non toxic
Anesthetics 10:- chloroform, etc Acceptable with regards to organoleptic
Laxatives: - bentonite, psyllium, xanthan gum11, characteristics
guar- gum etc.
Economical
Ph modifiers: - citric acid.
Having efficiency in regards with the intended use.
Astringent: - cinnamon, alum, zinc sulphate.
Excipients even though considered inert substance,
Carminative: - cinnamon13, dill water, anise water.
have the tendency to react with drug components,
Nutrient sources: - agar12, lactose, etc.
other excipients, and also the packaging system.
Excipients may also contain various impurities
Excipient selection 14:-
which may result in decomposition of the active
Excipients can be considered as indispensible
pharmaceutical ingredients in the formulation thus
component of medicinal products and in most of
altering the shelf life of the formulation.
the formulations they are present in greater
The various type of interactions that an excipient can
proportion with regards to active pharmaceutical
undergo are termed as
ingredient, as it forms the bulk of the formulation
it is always necessary to select an excipient which Drug-Excipient interactions
satisfies the ideal properties for a particular Excipient-Excipient interactions
excipient. Excipient selection generally focuses Package-Excipient interactions
on the desirable characteristics of excipients such
as functionality, material consistency, regulatory These interactions are discussed in detail as follows:-
acceptance, cost, availability, and sources. Drug – Excipient interaction15-19
Material properties like micromeritics, chemical In pharmaceutical dosage forms the active
thermal rheological, mechanical etc also play an pharmaceutical ingredients are in intimate
important role in development of drug contact with the excipients which are in
formulation. greater quantity. Excipients and drugs may
Formulators must also consider physicochemical have certain incompatibilities which lead to
properties, stability and compatibility issue, drug –excipient interaction.
pharmacokinetic attributes, permeation
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Excipients affect the physicochemical raise pH of stomach resulting in
characters of the active pharmaceutical breakdown of the enteric coat in stomach
ingredient which may lead to formation of and release of active pharmaceutical
molecular complexes, increase in rate of ingredient in stomach itself, which
chemical degradation etc. results in degradation of drug in stomach.
In case of NSAID’s premature
Drug excipient interactions are further classified breakdown of enteric coat may cause
as side effects like gastric bleeding.
Physical interactions
Chemical interactions 2) Interactions due to adjunct therapy: -
Biopharmaceutical interactions Tetracycline antibiotics form complexes
with calcium and magnesium ions which
a. Physical interactions: - physical are quite common excipients in various
interactions alter the rate of dissolution, formulations which may be administered
dosage uniformity, etc. physical along with tetracycline as adjunct
interactions do not involve chemical therapy the complex so formed is not
changes thus permitting the components absorbed from the G.I.T.
in the formulation to retain their
molecular structure. Physical interactions 3) Increase in gastrointestinal motility: -
are difficult to detect. Physical many of the excipients like sorbital,
interactions can be either beneficial or xylitol, have tendency to increase the
detrimental to the product performance gastrointestinal motility thus reducing
which is dependent on its application. the time available for absorption of drugs
like metoprolol.
Various types of physical interactions are Polyethylene glycol 400 also has
listed as in table no 4. influence on the absorption of
b. Chemical interactions: - active Ranitidine.
pharmaceutical ingredients and
excipients react with each other to form d. Excipient –Excipient interactions [19, 20,
21, 22, 23, 24, 25, and 26]
unstable compounds. Several chemical :- Excipient-Excipient
drugs –excipient interactions have been interactions though observed very rarely,
reported in literature. Generally chemical these are of prime importance in
interactions have a deleterious effect on determining the stability of the dosage
the formulation hence such kind of forms. Excipient –Excipient interactions
interactions must be usually avoided, can be undesirable as well as some
various examples of chemical interactions are used in the formulations
interactions have been listed in table no - to get the desired product attributes.
5. Various excipients undergo such kind of
c. Biopharmaceutical interactions: - these interactions.
are the interactions which are observed Examples of undesirable Excipient-Excipient
after administration of the medication. interactions are listed in table 6 15.
Interaction within the body is between Some excipients are formulated as mixture in
medicine and body fluids which order to obtain desired effect in the product;
influence the rate of absorption. All such Excipient- Excipient interactions are
excipients interacts in physiological way beneficial for improving functional
when they are administered along with performances in the formulation. Such type
active pharmaceutical ingredients, of excipients can be considered as co-
various examples of biopharmaceutical processed excipients.
interactions are stated as follows:-
Co processed excipients: - Tablets are
1) Premature breakdown of enteric coat:- generally considered as a dosage form of
the enteric coating polymers like choice when oral route is preferred, because
cellulose acetate phthalate and hydroxyl of accurate dosing, better patient
propyl cellulose acetate phthalate, are compliance. Excipients such as binders,
soluble more at basic pH, but antacids disintegrants, diluents, glidants, lubricants
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etc are used along with the active are very friable, co processing of
pharmaceutical ingredient in the tablet mannitol with some polyols offer similar
manufacturing, These excipient offer in flowability and compressibility with
enhancing various properties like addition of low friability as compared to
dissolution, absorption etc of active direct compressed mannitol.
pharmaceutical ingredient when in tablet.
Some excipients fail to give the desired f. Added functionality partially
output; hence the need for modified pregelatinized starches:- partially
excipients with enhanced properties is pregelatinized starches are used as filers
developed. in hard gelatin capsules (5-75%) binders
Co processing is a novel concept that has been in wet granulation tabletting (5-20%),
introduced, which alters excipient disintegrants in tablet formulation( 5-
functionality by retaining favorable 10%) and also in direct compression
attributes and supplementing with newer tablets which also provide better particle
ones, by processing parent excipient with size control, decreased friability, narrow
another excipient. The high functionality particle size distribution, and reduced
excipients so formed help improve process levels of fines. Partially pregelatinized
ability such as flow properties, starch particles having compact,
compressibility, and improved disintegration embedded matrix are significantly less
and dissolution profiles. friable than those made of loosely
Introduction of high speed tablet machines and associated ones. Such type of compact
direct compression techniques pose several matrix partially pregelatinized starches
problems with the tablet manufacturing. Co help in rapid dissolution of drugs e.g.
processed excipients aid in solving such acetaminophen.
problems with their multifunctional
properties. Co processing provides a synergy Some examples of such excipients are given
of functionality improvement, as well as in table no 7
masking the undesirable properties of
individual excipients. Co processing is g. Package –Excipient interactions28-31]:-
aimed at improving flow properties, Packaging of pharmaceuticals is a vital
compressibility, disintegration potential and part of the processing steps of product
development of filler binder combination. formulation, hence in pharmaceutical
Many bulk excipients that are used for industry its essential that package
conventional tablets are unsuitable for orally selected adequately preserves the
disintegrating tablets which necessities the integrity of products, the selection of
use of specific excipients and technology to package therefore begins with a
mask drugs unacceptable taste and improve determination of products physical and
the orally disintegrating tablet properties. chemical characteristics, its protective
The quick effect of dispersion is due to the needs, and its marketing requirements.
excipients ability to absorb water quickly. The package thus selected should be
Tablets rapid dispersion on surface of inert in nature, should protect the product
tongue is also facilitated by use of from external environmental conditions,
superdisintegrants like crosspovidone etc.
sodium, starch glycolate, crosscarmellose. Usually the packaging material used is
glass; plastic, metal, rubber closures etc,
e. Added functionality mannitol for orally these containers and closures react to
disintegrating tablets: - directly certain extent with the drug product as
compressible mannitol is generally used well as with the excipient and give
because of its property to prepare robust deleterious effects thus altering the
tablets, spray dried or directly product stability. Such interactions
compressible mannitol are highly porous generally cause loss of product quality.
and friable which upon compression fill These interactions are listed in the
the interstitial spaces between larger following table no 8:-
porous particles. The disadvantage of
orally disintegrating tablets is that they Standardization of excipients 32
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Excipient quality plays a vital role in assuring safety, and standard process which is very effective in
quality and efficacy of dosage forms. saving time. This information helps both users
Standardization of excipient usually assures the and suppliers to manage the information in a
customers and manufacturers that the excipient systematic and efficient manner.
quality will meet the international market, Product regulatory database: - this
therefore the rules for regulation of bulk document has been formed with the main
excipients are stringent and whenever a new objective of providing information about
excipient is to be introduced it is necessary for the important physical properties,
applicant to submit safety and quality data and for manufacturing and regulatory information
an approved excipient the applicant has to provide specific to excipients to the user which
literature reference data. facilitates the use of excipients in drug
The various reasons for which excipients must be formulations. The various sections included
standardized are:-To assure the customer that the are
excipients used are safe and will not alter the General product information:- this includes
formulation and cause undesirable effects. information like product identification ,
To assure the manufacture that he is using product code/name, scope of document, and
a standard quality material for any other information that is necessary,
formulating his dosage form and Manufacturing, packaging, release and
To reduce resources to host frequent supplier information:- this section
customer audits and assure excipient describes the information regarding
GMP audit is conducted against excipient manufacturing site and the
appropriate GMP conformance information related with it, for e.g.:-
expectations. manufacturing processing, packaging,
The standard chosen as framework for quality product release warehousing, laboratory site
management system is ISO 9001. The Iso etc, distribution channels, GMP or GDP
certification has the advantage of assuring the compliance statements, equipment
customers that excipient manufactueres quality information etc.
management system has been verified Physicochemical information:- this section
independently. deals with the information related to the
GMPpractise for excipients assures product integrity, physical and chemical characteristics of the
avoid product contamination etc. product for e.g.:- CAS number, information
IPEC is an international industry association which is about the origin of excipients, their
formed with the main objective of development synonyms, its morphological characteristics,
and harmonization of international excipient processes applied during manufacturing,
standard and development of newer excipients. It mixed excipient information and the country
deals with three kinds of stakeholder groups viz; of its origin if applicable.
suppliers, users and regulatory authorities. It is Regulatory information:- this section
necessary to obtain sufficient data about the describes the regulatory status of an
excipient and the manufacturer or distributer, excipient, it includes information like
usually to get such information and information of compendia compliance (e.g. USP-NF, Food
the excipient in detail the users and customers chemicals codex, BP etc) drug master file,
send questionnaires to the supplier, the or European Directorate for the Quality of
questionnaire consists of large amount of queries Medicines and healthcare (EDQM)
which becomes very difficult to resolve and certificate of suitability, viral safety,
address every individual as lot of time and money allergens, hypersensitivity information,
is wasted during this process, hence in order to residual solvent information, metal catalyst
minimize this stressful process IPEC has put and metal reagent residue information.
forward an standardized excipient package that Kosher/Halal status, bioburden/ pyrogen
comprises of (optional) information etc.
Product regulatory database Miscellaneous product information:- this
Site quality overview and section includes information like lot/batch
Site and supply chain security overview. number, expiry date, use, nutritional
This information is useful in responding to the information (if applicable) packaging
questionnaires and other requests in a simplified information etc.
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Revision:- this section provides information Excipients(s) for the particular API in dosage form
regarding version control for document. under consideration and also those
Contact information:- this section includes Excipients(s) that should be avoided for particular
the contact details of the supplier. API . Excipients are derived from various sources
Site quality overview:- this document gives such as natural and synthetic origins. Natural
information regarding the site of sources of excipients are usually contaminated
manufacturing, and any other areas related with microorganisms and certain impurities that
to the excipient processing or testing, there may render the formulation incompatible and
are various sections that are included in this cannot be used, thus in order to avoid any
document which are as follows:- incompatibilities in formulation the excipients
Site overview:- it describes supplier’s must be tested for their stability.
organization and production capabilities, IPEC with an objective to contribute to the
topics included in this section are site development and harmonization of international
name, address, corporate ownership, excipient standards has laid certain guidelines for
customers audit policy (optional) site the stability testing of excipients. These
details etc. guidelines provide an approach for excipient
Compliance evidence:- this section describes manufacturer to establish a stability study
information of facilities being provided e.g. program for excipients, which will help in
ISO certification, GMP inspection by defining revalidation intervals or expiration date.
competent authority, GMP statements, The primary purpose of excipient stability study
external audit programs like International serves the purpose to retain its stability throught
Pharmaceutical Excipients the manufacturing process, packaging upto the
Auditing(IPEA),AIB international, GMA- point at which the package is opened. The
SAFE, etc. stability studies are designed on the basis of
IPEC-PQG GMP compliance:- this section following factors like 1) utilization of historical
deals with information about how the data about a particular excipient and drawing
suppliers comply with the applicable conclusions about excipient stability.
elements of IPEC-PQG-GMP guide. 2) Conducting stability studies using excipients
Miscellaneous site information:- this packed in commercial packaging placed in
different warehouses where the temperature is
includes any additional information
monitored.
provided( optional).
3) Conducting studies using conditions and
Other information includes the contact details
recommendations as in ICHQ 1A (R2):-
etc.
These guidelines serve the purpose of stability testing
Site and supply chain security overview:- which provides the evidence of the quality of drug
This document deals with information regarding products under influence of various climatic
protection of product and continuity of
conditions. Choice of test conditions are based on
supply as assured by supplier, this document
the analytic effects of climatic conditions in three
includes information about site name,
regions namely Europe, Japan and United states.
address, evaluation of carrier, tamper
Following procedures are followed in accordance to
evident packaging, qualification of the guidelines:-
distributer, broker, intermediate storage 1) Stress testing: - it helps to identify the degradation
location, repackaging, relabeling activities, products within the formulations. Such testing’s
FDA registration information , security, are carried in single batch where the effect of
safety and environmental considerations etc. temperature is tested where the temperature is
Thus these documents help in assuring the user, kept in increments of 100c for e.g. 500c, 600c etc
customer and supplier about the quality of
above which accelerated stability testing is
excipient and may also give assurance that
performed. Humidity is maintained at around 75%
this process will continue to provide RH or greater for the testing procedure. Photo
excipients of good and standard quality. stability testing forms an integral part of stress
testing where the excipients are exposed to
Excipient stability testing33 conditions as mentioned in ICHQ 1B.
The main objective behind the compatibility 2) Specifications:- specifications to analytical
testing is to find out most appropriate procedures are followed as per the guidelines
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mentioned in ICHQ 6A[9] and ICHQ 6B, and for studies, repeat dose toxicity testing and safety
degradation products as in ICHQ 3A. pharmacology studies etc.The documentation
3) Testing frequency:- for long term storage procedure begins with submission of the excipient
conditions testing is carried out every three safety dossier (in Common Technical Document
months over first year, every six months over format) to Product Development Group,which
second year, and annually thereafter. sends it to the NEEC(New excipient evaluation
For accelerated stability studies testing carried out at committee) chairperson, who distributes it to
0 month, 3 month, and 6 month. Testing over other committee members. It is recommended that
period of 6 months is generally recommended. Excipient dossiers be prepared according to
1) Storage conditions:- excipients are tested for IPEC’s Master File Guide. The file guide
the storage conditions for its thermal comprises two parts. The first is the
stability, moisture sensitivity or solvent loss. administrative section, which is region-specific
The specifications for storage testing are based on submission specifics and local
given as under: (Table no 9) requirements. The second is the core technical
Stability indicating test methods: - Excipients document (CTD) that includes all technical details
should be tested for their stability using stability and summaries needed for Excipient acceptance
indicating assay methods, microbiological, in most regions, including CTD P4 requirements.
physical and chemical tests, Reviews are expected to last 1 to 3 months,
Chemical stability can be measured by depending on the quantity of information within
chromatographic techniques, physical stability by (or absent from) the dossiers. In most cases, the
microscopy, particle size analysis, in vitro cost will be based on not more than 50 hours of
dissolution tests etc. review time plus administrative overhead. The
Various analytical tools such as thermal analysis, chairperson or a designee collates the comments
chromatographic techniques, diffuse reflectance of the committee members and drafts a report that
spectroscopy, etc are used in detection and is sent to each member for concurrence or further
characterization of the excipient compatibility. discussion. Once agreement is reached, the final
Stability considerations should also be given to report is sent to the excipient sponsor for review
comparison of composition profile of excipient at and comment. If the expert committee cannot
the limit of its retest/ revaluation intervals if agree on one or more points in the final report, the
appropriate to that of excipients at time zero, the sponsor is told of the disagreements and the
composition should remain unchanged within the reasons for them. The sponsor may discuss the
recommended storage conditions. final report with the expert committee and request
clarifications or explanations. Once everyone is
Excipient safety evaluation34 satisfied, the chairperson signs the final report and
In 2007, the IPEC-Americas Safety Committee sends it to the sponsor, who becomes its sole
developed the IPEC New Excipient Safety owner. The report will contain, at a minimum:
Evaluation Procedure, which is an independent 1. Discussion of chemical and toxicological data and
excipient review procedure. The procedure is human safety concerns based on intended use of
intended to reduce costs stemming from the excipient;
unnecessary testing and the uncertainty related to 2. Opinions on conformance with data needs
using new excipients, thereby encouraging their according to the CDER Guidance; and
use in drug development and boosting innovation 3. Identification of data gaps, if any, and points of
in formulating drug products. In this procedure reviewer disagreement that were not resolved and
Excipients are evaluated for their safety using the reasons for them.
various in-vitro assay methods to screen for The IPEC New Excipient Safety Evaluation
potential toxicity in this process the undesired Procedure provides an excellent method for
toxicity producing material can be eliminated, this independently evaluating the safety of new
program is developed in different tiers of testing, excipients, including co-processed mixtures of
where in first tier the compound is tested for its existing excipients, physical and chemical
genotoxicity, cytotoxicity, metabolism and ability modification of existing excipients, higher use
of compound to cross the biological membrane. levels of existing excipients, and NCEs. The
This step may also include development of QSAR Excipient sponsor can use the NEEC’s report to
studies which can help predict the toxicity of support the use of a new excipient in a drug
compounds. In later cases the other steps can be development approval process. As new excipients
followed, for eg testing for immunotoxicity emerge, it’s important to recognize their potential
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use in various complex delivery systems, and the IPEC procedure helps do that.35.
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Table 2: Excipients used in liquid dosage forms8
Excipient category Function in formulation Working principle Examples
Solvents. Dissolving solute/Active Breaking of bonds and reducing Water, alcohol, acetic acid, acetone, ethyl
pharmaceutical effective charge on ions thus acetates, syrups, etc.
ingredient. increasing Solute-Solvent forces
of attraction which are eventually
greater than Solute-Solute and
Solvent-Solvent forces of
attraction.
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Drugs with substructures like Benzilic carbons, Allylic carbons,
Tertiary carbons, and α position of heteroatoms undergo
oxidation.
3) Racemization Conversion of a chemical into its optical or geometric isomer, Adrenaline has optical 15-20 times greater
having different pharmacological or toxicological biological activity then D –Adrenaline.
activity.(here optically active substance looses its optical
activity without change in chemical composition) .biological
activity of the formulations is hampered as for e.g. biological
effect of a drug in dextro form can be less than that in laevo
form.
4) Polymerization The polymorphic forms possess higher potential energy withAmorphous forms of sodium and potassium
respect to the thermodynamically stable or lowest energy Penicillin-G were unstable to dry heat,
forms. This potential energy is given out during mixing with whereas crystalline forms were stable for
the solvent, in some cases potential energy of compound is several hours.
sufficient to exhibit an apparent solubility greater than more
stable form which may eventually result into reversion of
drug into less soluble form
Maillard reactions Carbonyl group of sugar reacts with amino acid, producing N-Primary amines undergo maillard reactions,
substituted Glycosylamine and water, unstable causes yellow brown coloration of drugs
Glycosylamine undergoes amidroid rearrangement forming like chlorpromazine, etc.
ketosamine which reacts to produce water and reductones orMaillard reaction products found in capsule
produce short chain hydrolytic fission products etc, rate of containing lactose and antidepressant
Maillard reactions increases as the water activity increases. Fluoxetine.
6) Photolysis Decomposition resulting from absorption of radiant energy in theSuch interactions are observed in Riboflavin,
form of light. Reactions like ring alterations, oxidation- Folic acids, Nifedipine, containing
reduction, polymerization etc are catalyzed or accelerated by formulations. Prednisolone and Methyl-
exposure to sunlight. Exposure to light may lead to prednisolone degradation is observed in
discoloration or even decomposition of product alcoholic preparations.
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