What is Excipient ? The term comes from Latin word excipiens which means to receive or to take out .

IT IS AN INERT SUPPORT OF THE ACTIVE PRINCIPLE According to International Pharmaceutical Excipient Council (IPEC) : These are the process aids or any substances other then the Active Pharmaceutical Ingredient (API) or prodrug that is included in pharmaceutical dosage forms. Selection of excipients for solid oral dosage forms: Ideal characteristics. Nontoxic Pharmacologically inert. Physically and chemically stable. Acceptable to the Regulatory agencies in all countries. Commercially available. Have pleasing organoleptic properties. Must be colour compatible. Economical Basic requirements of a modern pharmaceutical Excipients: API vs. Excipients: For both safety and quality. For API therapeutic efficacy. For Excipients functionality. What are the functionalities of Excipient? Impart weight, consistency and volume: Its allow accuracy of dose. Improve solubility. Increase stability. Enhance bioavailability. Modifying drug release. Assist in product identification. Increase patient acceptability. Facilitate dosage form design. Classification of excipients Primary Excipients Diluents (Filler) Binders (Adhesives) Disintegrants Lubricants Antiadhesives Glidents Excipients Secondary excipients Colouring agents Flavours Sweeteners Coating agents Plasticizers Wetting agents Miscellaneous Excipients Buffers Adsorbents Waxes Diluents (Filler): Diluents are used to increase the bulk volume of a tablet or capsule when the drug dosage itself is inadequate to produce tablets of adequate weight and size. Usually the range of diluent may vary from 5-80% . The tablet size should be kept above 2-3 mm . Minimum tablet weight is typically ~50mg . Actual API doses can be as low as ~20 g. Functions of diluent: To facilitate tablet handling during manufacture. To achieve targeted content uniformity. To provide improved cohesion. To allow direct compression manufacturing. To enhance flow. To adjust weight of tablet as per die capacity. DISINTEGRANT AND SUPER-DISINTEGRANT Disintegrants cause rapid break up of the tablet compact upon exposure to moisture. Superdisintegrant: the simplest way to achieve quick disintegration. Used intragranulerly or extragranularly or both for better action . Mode of action : Swelling : e.g.- Cellulose and its derivatives Porosity and Capillary Action (Wicking): e.g.- Microcrystalline cellulose Deformation By enzymatic reaction: enzymes destroy the binding action of binder and helps in disintegration. ENZYMES BINDER Amylase Starch Protease Gelatin Cellulase Cellulose derivatives Invertase Sucrose TRADE NAME OF DILUENTS COMPOSITION Fast Flo lactose Crystalline -lactose monohydrate and amorphous lactose. Microcellac 75% lactose and 25% MCC Ludipress 93% - lactose monohydrate, 3.5% polyvinylpyrrolidone, and 3.5% crospovidone. Nu-Tab Sucrose 95-97%, invert sugar 3-4% and magnesium- stearate 0.5% Di-Pac Sucrose 97% and modified dextrins 3% Sugartab Sucrose 90-93% and invert sugar 7-10%. Emdex Dextrose 93-99% and maltose 1-7% Cal-Tab Calcium sulfate 93% and vegetable gum 7% Cal Carb Calcium carbonate 95% and maltodextrins 5% Calcium 90 Calcium carbonate 90-91% and Starch 9-10% SUPERDISINTEGRANTS EXAMPLE OF MECHANISM OF ACTION Crosscarmellose Ac-Di-Sol Vivasol Primellose Crosslinked cellulose -Swells 4-8 folds in < 10 seconds. -Swelling and wicking both. Crosspovidone Crosspovidon M Kollidon Polyplasdone Crosslinked PVP -Swells very little and returns to original size after compression but act by capillary action Sodium starch glycolate Explotab Primogel Crosslinked starch -Swells 7-12 folds in <30 seconds Alginic acid NF Satialgine Crosslinked alginic acid -Rapid swelling in aqueous medium or wicking action Soypolysaccharides Emcosoy Natural super disintegrant Swelling Calcium silicate -Wicking action LIST OF SUPERDISINTEGRANTS COATING AGENTS : COATING TYPE POLYMERS TRADE NAME Enteric Coatings Cellulose Acetate Phthalate HPMC Aquacoat CPD Sepifilm LP Polymer Extenders Hydroxypropylcellulose Klucel EF and LF Immediate Release Coatings HPMC Ethylcellulose Microcrystalline Cellulose Carrageenan Methylcellulose Sepifilm LP Aquacoat ECD Lustre Clear Metolose SM-4 Sustained Release Coatings Ethylcellulose Aquacoat ECD Aqualon Subcoat Hydroxypropylcellulose Klucel Pellet Coating Methylcellulose Metolose SM-4 PLASTICIZERS FOR COATING Used for physical modification of coating polymer . Plas II : composed of: Glyceryl Monostearate Polysorbate 80 Triethylcitrate Methyl Parabens Propyl Parabens Citrate Esters Triethyl citrate Acetyltriethyl Citrate Acetyltri-n-butyl Citrate Dibutyl Sebacate Diethyl phthalate Triacetin

Physicochemical Tests for Excipients Flow rate Gel strength (binders) Lubricity (frictional) Microbiological status Moisture sorption Particle hardness Particle size distribution: (1) sieve analysis (2) air permeability Porosity Shear rate Tensile strength Bulk volume Water absorption STANDERDIZATION OF EXCIPIENTS NEED:- After invention of any new component to be used as an Excipient. To verify the particular use of an Excipient. To establish the standards for newly invented Excipient. STANDERDIZATION OF EXCIPIENTS: IPEC (International Pharmaceutical Excipient Council)Significant Change Guidance: Two areas of concern to excipient makers and users have been those of significant change and certificates of analyses. Any change by the manufacturer of an excipient that alters excipients physical or chemical property from the norm or that is likely to alter the excipients performance in dosage form is considered significant. The types of changes that might be considered include: Site Scale Equipment Process Packaging Specifications. EVALUATION CRITERIA:- The evaluation criteria in the guideline include: Changes in the chemical properties of excipients owing to the change. Changes in the physical properties of excipients. Changes in the impurity profile of excipients. Changes in the functionality of excipients. Changes in the moisture level of excipients. Changes in the bioburden of excipients. IMPURITY PROFILE:- The IPEA-Americas profile addresses the following guide:- All specific organic impurities. Undefined organic impurities at or above 0.1% whether specified or not. Residual solvents. Inorganic impurities. Toxic impurities. PRECLINICAL TESTING OF EXIPIENTS: Essentially, a new (novel) excipient is a material that has not been previously used in a pharmaceutical formulation. New proposed excipients cover a range of functions from conventional use to active roles of enhanced drug uptake and specific drug delivery. Indeed, the activating of older drug formulations by inclusion of new excipients for a range of pharmaceutical classes is an ongoing process. The preclinical safety evaluation of a new excipient commences after initial in vitro pharmacy work to demonstrate the materials proposed role. Additionally, some in vivo investigations may occur, for example, comparing the new proposed material in a drug formulation versus a marketed drug formulation. Enhanced drug exposure and/or a reduced toxicity profile may be a study end point. A possible approach in toxicity studies is to add groups of animals that receive the excipient alone as well as the drug-treated groups, as mentioned in the FDA guidance. However, this approach can make the size of the study enormous, especially if more than one excipient-only group is included. Thus, a case-by-case approach is needed for the safety evaluation of new excipients. GUIDELINES:- As mentioned earlier, the testing strategies proposed by IPEC and the FDA offer a useful starting point for preclinical excipient testing. Proposed study types are given for a range of dose routes, including oral, topical, parenteral and inhalational. The FDA has divided testing requirements into those needed to support maximum clinical duration of up to 14 consecutive days (short-term use), more than two weeks but three months or less (intermediate use), and more than three months of use (long-term use). The final FDA guidance now also suggests a high limit dose of 2000 mg/kg/day (or 2% in the diet), which is more sensible than the draft FDA document, which suggested consideration of a heroic high-dose level of 5000 mg/kg/day (or 5% in the diet). The latter level of testing is unnecessary because very high doses of materials by oral gavages. Additional considerations for inhalation/intranasal route: acute inhalation, application site, and pulmonary sensitization studies. For parenteral route: acute parenteral toxicity and application site studies. For mucosal use: application site evaluation For transdermal and topical drugs: application site and photo toxicity/ photoallergy evaluation. ARRANGEMENT DURING STANDERDIZATION:- Although it was originally intended that each monograph contain only information about a single excipient, it rapidly became clear that some substances or groups of substances should be discussed together. This gave rise to such monographs as Coloring Agents and Hydrocarbons. In addition, some materials have more than one monograph depending on the physical characteristics of the material, e.g. Starch versus Pregelatinized Starch. Regardless of the complexity of the monograph they are all divided into 22 sections as follows: Nonproprietary Names Synonyms Chemical Name and CAS Registry Number Empirical Formula and Molecular Weight Structural Formula Functional Category Applications in Pharmaceutical Formulation or Technology 8. Description 9. Pharmacopeial Specifications 10.Typical Properties 11. Stability and Storage Conditions .Incompatibilities 13.Method of Manufacture 14.Safety 15.Handling Precautions 16.Regulatory Status 17.Related Substances 18.Comments 19.Specific References 20.General References 21.Authors 22.Date of Revision 1:Nonproprietary Names Lists the excipient names used in the current British Pharmacopoeia, European Pharmacopeia, Japanese Pharmacopeia, and the United States Pharmacopeia/National Formulary. Section 2:Synonyms Lists of other names for the excipient, including trade names used by suppliers (shown in italics).

3:Chemical Name and CAS Registry Number Indicates the unique Chemical Abstract Services number for an excipient along with the chemical name. Sections 4 and 5:Empirical Formula and Molecular Weight and Structural Formula Are self-explanatory. Section 6:Functional Category Lists the function(s) that an excipient is generally thought to perform, e.g., diluent, emulsifying agent, etc. 7:Applications in Pharmaceutical Formulation or Technology Section 8:Description Includes details of the physical appearance of the excipient , e.g., white or yellow flakes, etc. Section 9:Pharmacopeial Specifications Briefly presents the compendial standards for the excipient . Information included is obtained from BP, USP, IP, PhEup , JP,etc . 10:Typical Properties Describes the physical properties of the excipient which are not shown in Section 9. All data are for measurements made at 20C unless otherwise indicated. Where the solubility of the excipient is described in words, the following terms describe the solubility ranges: 22 Very soluble 1 part in less than 1 Freely soluble 1 part in 110 Soluble 1 part in 1030 Sparingly soluble 1 part in 30100 Slightly soluble 1 part in 1001000 Very slightly soluble 1 part in 100010 000 Practically insoluble or insoluble 1 part in more than 10 000 11:Stability and Storage Conditions Describes the conditions under which the bulk material as received from the supplier should be stored. In addition some monographs report on storage and stability of the dosage forms that contain the excipient. Section 12:Incompatibilities Describes the reported incompatibilities for the excipient either with other excipients or with active ingredients. 13: Method of Manufacture Describes the common methods of manufacture and additional processes that are used to give the excipient its physical characteristics. Section 14:Safety Describes briefly the types of formulations in which the excipient has been used and presents relevant data concerning possible hazards and adverse reactions that have been reported. 15:Handling Precautions Indicates possible hazards associated with handling the excipient and makes recommendations for suitable containment and protection methods. Section 16:Regulatory Status Describes the accepted uses in foods and licensed pharmaceuticals where known. 17:Related Substances Lists excipients similar to the excipient discussed in the monograph. Section 18:Comments Includes additional information and observations relevant to the excipient. Where appropriate, the different grades of the excipient available are discussed. 19:Specific References Is a list of references cited within the monograph. Section 20:General References Lists references which have general information about this type of excipient or the types of dosage forms made with these excipients. 21:Authors Lists the current authors of the monograph in alphabetical order. Section 22:Date of Revision Indicates the date on which changes were last made to the text of the monograph. THE CHALLENGE:- It is clear that although useful as a starting point for development, such proposed packages of studies are extensive and generally no different from that of a new drug substance itself. Thus, they should not be viewed as a concrete list of preclinical studies that must be submitted to regulatory bodies but a series of topics that should be examined. The challenge to the toxicologist is what is the minimal,yet most scientifically robust, set of studies needed to support safe inclusion of an excipient in a drug formulation to be used in humans. An interesting challenge will be the design of such studies to support the expanding use of drug delivery systems. CONCLUSION:- Overall, a wide range of testing considerations are needed for new excipient materials, although the actual package of study types still remains a case-by-case approach. On some occasions, a full program of studies may be needed to confirm a risk benefit situation, whereas in others (e.g., lifesaving therapy), it may be acceptable to have reduced toxicity data. Similarly, the extent of studies needed to support the safe use of essentially new excipients, and indeed well-known materials, needs careful consideration based on available knowledge.