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Pharmaceutical Excipients: a Review

Pharmaceutical Excipients: a Review

www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______INTERNATIONAL JOURNAL OF ADVANCES IN PHARMACY, BIOLOGY AND CHEMISTRY Review Article

Pharmaceutical Excipients: A review

Shilpa P Chaudhari* and Pradeep S Patil Marathwada Mitra Mandal’s College of Pharmacy, Thergaon, Pune, Maharashtra, India.

ABSTRACT Excipients play an important role in formulating a . 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 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.

Keywords: excipient, Interactions, co-processed excipients, Standardization.

INTRODUCTION1-5 substance (such as aspirin) is not absorbed Many dosage forms formulated today are complex easily by human body in such cases the system containing many other components along active ingredient is dissolved in or mixed with the active pharmaceutical ingredient (API); with an excipient which may either act as these compounds are generally added along with solvent or assist in absorption of the in the active pharmaceutical ingredients in order to human body.  Protect, support or enhance stability of the  Enhance overall safety and effectiveness of formulation:- Most of the times it is the formulation during its storage and use. observed that the active pharmaceutical These components are generally termed as excipients ingredient in its pure form does not retain its and according to the international pharmaceutical stability for long which results in its excipient council, Excipient is defined as “Any denaturation, or sticking to the container substance other than active drug or pro-drug that wall thus rendering it unfit, hence in order is included in the manufacturing process or is to stabilize the API excipients are added contained in finished pharmaceutical dosage which aid in maintaining the stability of the forms”. product and ensures that API retains its The US pharmacopoeia-National formulary (USP- stability for a considerable period of time NF) categorizes excipients according to the thus improving the shelf life of dosage functions they perform in the formulations e.g. formulation. Binders, disintegrants etc.  Bulk up the formulation in case of potent drug Excipients can be classified on the basis of their for assisting in formulation of an accurate origin, use in dosage form, and functions they dosage form. perform as follows  Improve patient acceptance. 5  Help improve bioavailability of active drug: 1. Excipient based on their origin - Excipients usually help in improving the Animal source: - , , , Bees bioavailability of the active pharmaceutical wax, Honey, Musk, Lanolin etc. ingredient for e.g. In many cases an active 21

www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______Vegetable source: - , Peppermint, Turmeric, characteristics, segmental absorption behavior, Guar gum, Arginates, Acacia etc. 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 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, , 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 11  Acceptable with regards to organoleptic Laxatives: - bentonite, psyllium, xanthan gum , characteristics guar- gum etc.  Economical Ph modifiers: - .  Having efficiency in regards with the intended use. Astringent: - cinnamon, alum, zinc sulphate. Excipients even though considered inert substance, Carminative: - cinnamon13, dill , 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  Drug-Excipient interactions it is always necessary to select an excipient which 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:- 15-19 acceptance, cost, availability, and sources.  Drug – Excipient interaction 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 22

www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______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 , 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 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, unstable compounds. Several chemical 21, 22, 23, 24, 25, and 26]:- 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 . 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 like choice when oral route is preferred, because 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 disintegrants, diluents, glidants, lubricants 23

www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______etc are used along with the active are very friable, co processing of pharmaceutical ingredient in the tablet 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 :- 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 24

www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______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. 25

www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______ 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, 0 0 0 kept in increments of 10 c for e.g. 50 c, 60 c 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

33 testing where the excipients are exposed to Excipient stability testing 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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www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______mentioned in ICHQ 6A[9] and ICHQ 6B, and for studies, repeat dose toxicity testing and safety degradation products as in ICHQ 3A. 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 27

www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______use in various complex delivery systems, and the IPEC procedure helps do that.35.

Table 1: Excipients used in solid dosage forms6,7 Excipient category Function in formulation Working principle Examples Diluents Fillers Make up the bulk of solid unit Lactose, Directly compressible dosage forms when drug Starches, Dextrose, , itself is inadequate to Microcrystalline cellulose, produce the bulk. Dibasic Calcium phosphate dehydrate. Binders and Adhesives Impart cohesive qualities to Improves free flow qualities by Acacia, Gelatin, Starch paste, powdered material. formulation of granules to Polyvinyl pyrrolidone, desired hardness and size. Glucose, , Povidone. Lubricants Reduce inter-particular , Interpose a film of low shear Talc, Stearic acid, Magnesium prevent adhesion of tablet strength that interface stearate, Calcium stearate, material to the surface of dies between the tabletting mass Polyethylene glycol, and punches facilitate easy and die wall Surfactants, vegetable oil. ejection of tablet from die cavity and improve the rate of flow tablet granulation Glidants Improve flow characteristics of Added in dry state prior Colloidal Silicone dioxide mixture. compression, it reduces (Carbosil), Asbestos free friction between particles. starch, Corn starch. Disintegrants Facilitate breakup or disintegration Function by drawing water into Starches, Clays, Cellulose, Cross after administration the tablet, swelling it and linked polymers, Modified causing the tablet to burst starches such as Primogel apart. and Explotab, Veegum HV. Improved disintegrant efficacy Crosscarmalose, Cross Povidone, Superdisintegrants resulting in decreased use Sodium starch glycolate. levels when compared to traditional disintegrants Coloring agents Impart aesthetic appearance to FD and C, D and C dyes and ( these must be approved and dosage form, disguising off lakes. certified by F.D.A) color drugs, product identification. Flavors Limited to chewable tablets/ tablets Mask unpleasant taste Spray dried and other flavors, intended to dissolve in mouth. syrups etc. Sweeteners Impart sweet taste to the Mannitol, Saccharin.etc formulation; use is limited to chewable tablets. Sorbents Moisture proofing Limits the fluid sorbing, taking , activated carbon, clay up of liquid or gas either by etc or absorption in dry state. Coating materials Protect tablet ingredients from Hydroxypropylmethyl cellulose detoriation by moisture, help (HPMC), Synthetic swallowing unpleasant tasting polymers, , Corn tablets protein Zein, , Capslues coated by Gelatin, Povidone, Ethyl cellulose. Plasticizers For soft gelatin Produce elasticity and flexibility , Diacetylated preparation, gelatin based to the coating materials in Monoglycerides, suppositories, film coated case of tablets, determine Polyethylene glycol, tablets etc. hardness of capsule shell in Polypropylene glycol, case of soft gelatin capsule . and impart softness and resilience to suppositories.

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www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______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, , 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.

Co solvents Increase the solubility of , Sorbitol, Glycerin, solute in solvents. Co-solvent system works by reducing etc. the interfacial tension between predominantly aqueous solutions and hydrophobic solutes. Buffers Maintain pH of the Act by binding hydrogen ions in acids Phosphate buffers, Acetate buffers, Citric formulation. and donating hydrogen ions in acid Phosphate buffers etc bases Antimicrobial Prevent microbial growth Bacteriostatic action Benzyl alcohol, Butyl , Phenol, . in formulations. Thiomersal etc. Control oxidation. Act by getting preferentially oxidized Ascorbic acid, Sodium bisulphate, Thiourea, or by blocking an oxidative chain Butyl Hydroxy Toluene (BHT), reaction. Tocopherols.etc Wetting agents Aid wetting and Act by reducing interfacial tension Sodium Lauryl Sulphate (SLS), Tween 80, dispersion of between solids and liquids in Spans, Lecithins etc. hydrophobic active suspensions. pharmaceutical ingredients. Antifoaming agents Discourage formation of Lowers surface tension and cohesive Simethicone, Organic phosphates, Alcohols, stable foam. binding of liquid phase. Paraffin oils, Sterates and glycols. Thickening agents. Prevent settling/sedime- Work by entrapment of solid particles. , Hydroxyethyl cellulose, ntation, modify Microcrystallince cellulose etc. viscosity. Humectants Retard evaporation of They are hygroscopic in nature which Propylene glycols, Glycerol, Polyethylene aqueous vehicles helps in preventing evaporation of glycol etc. from dosage forms solvent. Chelating agents. Protect drug from Chelating agents form complexes with Disodium EDTA, Dihydroxy ethyl glycine, catalysts that metal ions inactivating their Citric acid and Tartaric acid. accelerate the catalytic activity in oxidation of oxidative reaction. medicaments. Emulsifying agents Prevent coalescence of Forms barriers at interface, and Sodium Lauryl Sulphate, Cetrimide, the dispersed reduces interfacial tension. esters, Sorbitan esters etc. globules. Flocculating agents. Prevent caking Addition of an electrolyte reduces the Starch, Sodium alginate, Carbomer.etc. magnitude of zeta potential of dispersed particles. Sweetening agents Impart sweetness , Sorbitol, Saccharin, Aspartame, Sucralase Colors. Impart color Amaranth, Erythrosin, Eosin, Tartarazine etc. Flavors Impart Aromatic , Syrup etc Excipient used in Developing pressure in Trichloromonofluoromethane, aerosol container which Dichlorodifluoromethane, Propellant expels the product Etc.

Table 3: Excipients used in semisolid dosage forms9 Excipient category Function in formulation Examples 1. Structure forming Form gel like structure Cetosterly alcohol, sorbiton and other hydrophilic excipients surfactants , fluid hydrocarbons like mineral oils etc 2. Preservatives For preserving the formulation Benzyl alcohol, proply paraben, methyl paraben, chlorocresol, imidazolidinyl , sodium benzoate etc 3. Antioxidants Prevent oxidation Butyl hydroxy toulne , butyl hydroxy anisole, ascorbic acid etc 4. Solubilizers Enhance solubility of the active Lanolin, cholesterol or cholesterol esters 29

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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, , 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

Table 4: Physical interactions Interaction Beneficial effect examples Detrimental effect examples Complexation:- 1) Cyclodextrin is often used to improve1) Tetracycline formed insoluble complex with Usually binds reversibly with drugs to form bioavailability of poorly water soluble drugs. leading to slower complex, sometimes insoluble complexes This increases bioavailability and increases dissolution and decreased absorption. are formed which lead to slower rate and extent of drug dissolution by dissolution and decreased absorption of increasing mucosal permeability or drug. increasing stability of drug. Result observed in such cases is detrimental

2) Complexation of Cyclodextrin with2) Formulation of chlorpromazine with Complexing agents can also be used to ursodeoxycholic acid increased polysorbate 80 and sodium lauryl sulphate increase bioavailability of poorly water bioavailability caused by increased decreased membrane permeability of drug. soluble drugs dissolution. Result observed in such case is beneficial Adsorption:- Formulation of Indomethacin (NSAID) using 1) Cetyl Pyridinium chloride cations get Adsorption of drug by excipient can lead to kaolin as adsorbent increased its adsorbed on the surface of magnesium reduced bioavailability as the drug is not dissolution rate which leads to increase stearate which acts as a lubricant in tablet available for dissolution. in bioavailability of drug. containing Cetyl Pyridini8um chloride. This leads to marked reduction in the Adsorption of drug on excipient surface can antibacterial activity of the drug. assist in increasing surface area of drug 2) Decrease in absorption of dicumarol in the available for dissolution which eventually formulations containing excipients like increases bioavailability. Aluminum hydroxide, Starch, Talc, owing to the adsorbing properties of excipients Solid dispersion:- Improved dissolution rates of drugs like Solid dispersion product formed due to This kind of interactions improves the Piroxicam, Norfloxacin, Nifedipine and interaction between Povidone and Stearic dissolution and bioavailability of Ibuprofen were observed when these acid in a capsule showed slow dissolution hydrophobic drugs. drugs were formulated into solid of drugs. dispersions using Polyethylene glycol of Sometimes solid dispersion interactions can different molecular weights. result in slow dissolution of drugs.

Table 5: Chemical interactions Interaction Effect observed Examples of drugs undergoing such interactions 1) Hydrolysis Drugs with functional groups like esters, amides, lactones,Anestheti cs , antibiotics, vitamins, and undergo hydrolysis, in presence of water, low or high pH, in barbiturates, presence of alkaline metals, acids, acids i.e. anion and hydrogen ion, alkali etc. 2) Oxidation Oxidative reactions are catalyzed by oxygen, light, heavy metalSteroids, Vitamins, Antibiotics, Epinephrine, ions, fumed metal oxides, fumed silica, fumed, zirconia etc. Aldehydes, Alcohols, Phenols. Oxidation process involves removal of an electropositive atom or electron or radical, or addition of oxygen atom, generally the interactions of the active pharmaceutical ingredients are with oxidizing impurities in excipients or oxidative degradation products of excipients. 30

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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 reacts with , 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.

Table 6: Excipient –Excipient Interactions Excipient Incompatible with excipients like, Effect observed Acacia. 1) Ethanol (95%) 1)Precipitate organic salts of Acacia 2) Ferric and other salts Mucilage of acacia becomes gelatinous. 3) initiate coagulation 3)Trivalent salts 4)Form coacervates 4) Aqueous solutions (having negative charge) react with gelatin. 5) Soaps in case of emulsions and suspensions. Alcohol. 1) Acidic solution. 1) React vigorously with oxidizing agents. 2)Alkali mixtures 2) Darken color of preparation owing to reaction with residual amount of aldehyde.

Bentonite 1) Acids. 1) Aqueous suspensions precipitated, acid washed bentonite 2) Alcohol. does not have suspending properties. 3) Cationic antimicrobial preservatives 2) Precipitation of bentonite primarily due to dehydration by lattic structure. 3) Antimicrobial efficacy reduced. Butylated Hydroxy Toluene1) Oxidizing agents like Peroxides and Permanganates.1) Cause spontaneous combustion. (BHT) 2) Ion salts 2) Discoloration with loss of activity. 3) Acids 3) Heating with catalytic amount of acids causes rapid decomposition with release of flammable gas Isobutane Crosscarmellose Sodium Hygroscopic excipients like Sorbitol Efficacy as disintegrant reduced. Gelatin 1) Aldehyde. 1) Gelatin film hardens resulting in hard gelatin capsule shell. 2) Viscosity is altered. 2) Cationic and anionic polymers. Isopropyl Myristicate. Hard paraffin Produces granular mixture.

Table 7: Co-processed excipients Co-processed Excipient Combination of Use Ludipress Lactose, Povidone and Crosspovidone. Used for direct compression process in tablet manufacturing. Prosolv Microcrystalline cellulose and fumed silica. Orally disintegrating excipient matrix 31

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Starlac Starch and Lactose Used for orodispersible tablets and chewable tablets where palatability is of prime importance. Microcellac Microcrystalline cellulose and Lactose For improving flow property. Cellactose Powdered cellulose and Lactose. Better flow property Opadryl and Opadry HPMC, Titanium dioxide, PEG. Formulation of easily dispersible film coating system. Excipient Interaction with Benefit gained Xanthum gum Ceratonia Viscosity increased. HPMC and hydroxypropyl ethyl cellulose. Sodium Lauryl Sulphate Viscosity increased. Gelatin Plasticizer Produced Soft gelatin capsule.

Table 8: Package- excipient interactions Materials Interactions observed Effect observed 1) leaching of alkali Change in pH of the formulation 2) adsorption/absorption of excipients:- Inactivation of formulation resulting in instability. 3) Glass containers possess oxides of Alter physical and chemical stability of the formulation. E.g.:- sulphate Boron, Sodium, Potassium, 2) Glass salts react with barium and calcium to form inorganic insoluble Calcium, Iron and Magnesium salts. which interact with formulation. Iron and Manganese oxide cations catalyze oxidative reactions, these 4) Oxidative reactions. ions are extracted from glass and cause decomposition. 1) Moisture uptake associated with disintegrants in tablet form micro- cracks due to disintegrant swelling. 2) Capsule becomes soft and sticky and undergoes chemical reactions that affect dissolution behavior. 1) Moisture uptake 3) Change in the hardness of tablets is observed. 4) Strength change in lactose-corn starch tablets’ observed in strip 2) Plastic packaging. 5) Discoloration of sugar coated tablets of Ascorbic acid.

1) Water in oil type of emulsions have tendency to migrate and diffuse 2) Migration. into hydrophobic plastic containers. 2) Tocopherols may be absorbed into plastic. 1) Dyes migrate into parentrals and cause toxic effects. 2) Release of a constituent from plastic results in contamination. 3) Leaching of antioxidants from polyolefinic plastics into oleginious 3) Leaching. containers anti-oxidants like Pentaerythrityl tetrakis (3, 5-di-tert- butyl-4-hydroxyphenyl) propionate (Irganox) and tris (2, 4- di-tert- butylphenyl) phosphate (Igrafos) showed release into oily vehicles which affects content quality. Preservatives are sorbed into the containers leading to the loss of 4) sorption activity. 1) Tin tubes can be corroded by chlorides or acidic conditions. 1) corrosion 2)Sodium lauryl suphates are mildly corrosive to steel, copper, brass, 3) metals bronze, and aluminium Aluminium reacts with fatty alcohol emulsions to form a white 2) reactivity encrustation, unstable for mercury containing compounds. Antimicrobial preservatives like phenyl mercuric acetate are known to 1) sorption partition into rubber during storage reducing formulation 4) rubber concentration below effective antimicrobial levels Permeation of water through closures affects the overall stability of 2 Water permeability formulation. Presence of rubber closure extractives in the vial solutions could affect toxicity pyrogeneticity of injectable preparations, interaction with 3) Leaching preservatives to cause inactivation or loss of stability and causes physical instability of preparation. 1) Ethyl oleate dissolves certain types of rubber and causes others to swell. 4) dissolution 2) When Isopropyl myristicate comes in contact with rubber there is drop in viscosity with concomitant swelling and partial dissolution of the rubber.

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Table 9: Storage conditions In general case Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C/60% RH ± 5% RH. or 12 months 30°C ± 2°C/65% RH ± 5% RH. Intermediate 30°C ± 2°C/65% RH ± 5% RH. 6 months Accelerated 40°C ± 2°C/75% RH ± 5% RH. 6 months Drug substances intended for storage in a refrigerator Study Storage condition Minimum time period covered by data at submission Long term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C/60% RH ± 5% RH 6 months Drug substances intended for storage in a freezer Study Storage condition Minimum time period covered by data at submission Long term - 20°C ± 5°C 12 months 2. Lakshmana Pramod et.al” globalregulatory perspective of bulk pharmaceutical excipients” CONCLUSION available on www.pharmainfo.net/ review/global- Excipients being an indispensible component of medicinal products, must be evaluated for their safety and stability. The various excipent interactions regulatory perspective-bulk-pharmaceutical – like drug- excipient interactions, excipient-excipient excipients. interactions and package- excipient interactions may 3. Patrick J Crowley, Luigi G Martini “ excipients render the excipient harmful for use in formulation. for pharmaceutical dosage forms” Encyclopedia In order to avoid the use of incompatible excipients of pharmaceutical technology 02 oct 2006. and to assure that that the excipients are safe and Available at www.informaworld.com. stable for use in the designing of the formulation, 4. Lokesh Bhattacharyya, Stefan Schuber, Catherine various stability testing procedures are carried out Sheehan, and Roger William “Excipients: where the excipients are subjected to extreme background/introduction” Excipient development conditions of temperature ,humidity etc. if the for pharmaceutical biotechnology and drug stability testing data is in favor of the use of excipient delivery systems; Ashok Katdare , Mahesh V. in formulation the excipients are further tested for Chaubal (ed) ©by Informa Healthcare USA, Inc, assuring safety, which is the most important feature 2006;1-2. of any formulation intended to be used in humans or 5. Giorgio Pifferi, Patrizia Restani” the safety of animals. As new excipients emerge, it’s important to pharmaceutical excipients” farmaco 58 (8) 541- recognize their potential use in various complex 550 (2003). delivery systems, and the IPEC procedure subjects 6. Herbert A Liberman, Leon Lachman, and Joseph new excipients for potential use in humans to a B Schwart, Pharmaceutical dosage thorough safety assessment. forms- tablets, Informa Healthcare vol –I, second The safety assurance of excipients helps the edition, pg -88-120. formulator to design an effective and safe dosage 7. http://www.pharmpedia.com/Tablet. form with the use of efficient and safe excipients. 8. Leon Lachman, Herbert A Lieberman, Joseph Thus for an excipient to be in a formulation it must .L.Kanig, “the theory and practice of industrial be highly stable, safe and efficacious, and above all it pharmacy”, , Varghese publishing house, third must comply with the expected performance in the edtion 1990; 457-471. formulation. 9. Prashant Srivastava “Excipients for Semisolid Formulations”excipient development for REFERENCES pharmaceutical biotechnology and drug delivery 1. Dorothy Chang, Ron Kun Chang” review of systems; Ashok Katdare , Mahesh V. Chaubal current issue in pharmaceutical excipients” may 2 (ed) ©by Informa Healthcare USA, Inc, 2007, available on www.pharmtech 2006;197-207. findpedia.com. 10. www.inchem.org/document/pims/chemical/pim12 1.htm (chloroform) 33

www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______11. www.webmd.com/vitamins- Chemistry today. Vol 24 nr5, sept/Oct 2006, page supplements/ingredients.mono-340-xanthan 64-66. 12. www.sciencebuddies.shtml.org/microbio agar. 26. Ashish A Joshi and Xavier Duriez “added 13. www.herbco.com/p-785-cinnamon chips. functionality excipients; an answer to challenging 14. Sari Airaksinen et.al” excipient selection can formulations” pharmaceutical technology significantly affect solid state phase excipients, solid dosage forms 2004, transformation in formulation during wet www.pharmtech.com granulation” apps pharmscitech, 2005, 6(2), E 27. Md Zaki Ahmad, et. al” drug excipient 311-E 322, DOI10.12081 pt 060241 interactions and compatibility study; a review” j 15. Md Zaki Ahmad, et. al” drug excipient pharm res; 2010, 3 (9), 2092-2095. interactions and compatibility study; a review” J 28. Kenneth C Waterman, Bruce C Macdonald Pharm Res 2010, 3 (9), 2092-2095. “package selection for moisture protection for 16. Patrik Crowley, Dr Luigi G Martini “drug solid oral drug product” J Pharm Sci, excipient interactions” 2010;99(11):4437-4452. www.callumconsultancy.com/article/drug 29. Dennis Jenke” evaluation of chemical excipient interaction.pdf compatibility of plastic contact material and 17. D.D Wireth et.al” maillard reaction of lactose and pharmaceutical products; safety and fluoxetime hydrochloride, a secondary amine” J considerations related to extractable and Pharm Sci, 87, 31-39 (1998). leachable” J Pharm Sci, 2007;96(10): 2566-2581. 18. www.informahealthcare .com “excipient 30. B Marcato, S Guerra, et.al” migration of development for pharmaceutical biotechnology additives from various polyolefinic and drug delivery systems” page 93-124 plastics into oleaginous vehicles” Int j Pharmceut, 19. Fenghe Qiu” identification of drug excipient 2003;257(1-2):217-225. interaction products using stress testing assisted 31. Thomas Gonyon et.al “container effects on the approach” boehringer Ingelhein pharmaceuticals physicochemical properties of parentral lipid INC. available on www.americanpharmaceutical emulsions” Int j app basic nutri sci, 2008;24, (11) review.com. :1182-1188. 20. Raymond C Rowe, Paul J Sheskey and Paul J 32. The IPEC excipient information package (EIP) Weller; Handbook of Pharmaceutical Excipients, template and user guide 2009. www.ipec- Pharmaceutical press, American Pharmaceutical europe.org/UPLOADS/Excipients_Insight_nov09 Association, 4th ed, 2003 _final(1).pdf 21. M.C Gohel “a review of coprocessed directly 33. EMEA, ICH Topic Q1 A (R2) , stability testing of compressible excipients”, j.pharm pharmaceut sci new drug substance and products. Aug 2003, (www.cspscanada.org) 8(1) 26-93, 2005 CPMP/ICH/2736/99. Available at 22. Ashish A Joshi and Sergio Neves” from www.ema.europa.eu/docs/en_GB/document_libra commodities to specialized excipients” available ry/Scientific_guideline/2009/09/WC500002651.p on www.pharmquality.com df 23. Minakshi Marwaha et.al” co processing of 34. Christopher DeMerlis, Jay Goldring, Ranga excipients; a review on excipient development for Velagaleti, William Brock, and Robert Osterberg, tableting performance” Int j app pharmceut, regulatory update; the IPEC novel excipient safety 2010;2 (3), 41-47. evaluation procedure, Nov 2009, Volume 33, 24. Mahesh Kreer et.al” application of novel Number 11. excipients in the allopathic and herbal 35. Christopher DeMerlis ;Elaine V. Knight ;R. formulations” j.chem.pharm.res, 2010, 2(4), 851- Christian Moreton ;Robert E. Osterberg, “Eye on 860. Excipients”, Tablets and capsules -formulation 25. Hans Leuenberger “ from functionality excipients production and packaging vol 9, number 3, april towards drug carrier system”Chimi Caoggi. 2011, 33-41.

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