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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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
packed in commercial packaging placed in
Miscellaneous site information:- this
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 supply conditions. Choice of test conditions are based on
as assured by supplier, this document includes the analytic effects of climatic conditions in three
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, safety are carried in single batch where the effect of
and environmental considerations etc. Thus
temperature is tested where the temperature is
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 this performed. Humidity is maintained at around 75%
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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ingredient in ointments
5. Gelling agents Form gels Carbomer934, pemulen®, carboxy methyl cellulose,
hydroxy propyl cellulose, xanthan gum etc
6. Emollients Modify vehicle/skin Glycerin, mineral oil, petrolatum, isopropyl palmitate etc
characteristics to assist
penetration of active
ingredient through skin
7. suppository bases Used to form base for dissolving Cocoa butter, glycerin, coconut oil, gelatin, hydrogenated
active ingredient vegetable oil, polyethylene glycol etc
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