2. EXCIPIENTS PROFILES ANNEXURE -2 Excipients profiles of Compritol ATO 888, Gelucire 43/01, HPMC and PVP and have been described in the following section. 2.1. COMPRITOL 888 Non proprietary names BP: Glycerol Dibehenate Ph Eur: Glycerol Dibehenate USP-NF: Glyceryl Behenate Synonyms Glyceryl Behenate; 2,3-dihydroxypropyl docosanoate; docosanoic acid, 2,3- dihydroxypropyl ester; E471; glycerol behenate; glyceroli dibehenas; glyceryl monobehenate. Chemical name and CAS registry number Docosanoic acid, monoester with glycerin [30233-64-8] (glyceryl behenate) Docosanoic acid, diester with glycerin [94201-62-4] (glyceryl dibehenate) Docosanoic acid, triester with glycerin [18641-57-1] (glyceryl tribehenate) Description Compritol 888 occurs as a fine white-yellow powder, as a hard waxy mass or pellet, or as white or almost white unctuous flakes with faint odor. Empirical formula and molecular weight Glyceryl dibehenate is a mixture of glycerol esters. The PhEur 6.0 describes glyceryl dibehenate as a mixture of diacylglycerols, mainly dibehenoylglycerol, together with variable quantities of mono- and triacylglycerols. The USP32 NF27 describes glyceryl behenate as a mixture of glycerides of fatty acids, mainly behenic acid. It specifies that the content of 1-monoglycerides should be 12.0 18.0 %. 189
Structural Formula Functional category Coating agent, tablet binder Tablet and capsule lubricant Thickening agent Viscosity increasing agent Physical properties HLB value = 2 Melting point = 65 770C Solubility = Soluble, when heated, in chloroform and dichloromethane and in many organic solvents; slightly soluble in hot ethanol (96%); practically insoluble in cold ethanol (95%), hexane, mineral oil, and water. Stability and storage conditions Glyceryl behenate should be stored in a tightly closed container, at a temperature less than 35 o C. Safety Glyceryl behenate is used in cosmetics, foods and oral pharmaceutical formulations, and is generally regarded as a relatively non irritant and nontoxic material. The US Cosmetic Ingredients Review Expert Panel evaluated glyceryl behenate and concluded that it is safe for use in cosmetic formulations in present practices of use and concentration. LD50 (mouse, oral): 5 g/kg. Applications in pharmaceutical formulation or technology In pharmaceutical formulations, glyceryl behenate is mainly used as a lubricant in the preparation of oral tablets and capsules. It has good binding properties, it does not 190
affect tablet hardness and is unaffected by mixing or production parameters. Glyceryl behenate has been investigated for the encapsulation of various drugs such as retinoids. It has also been investigated for use in the preparation of sustained-release tablets; as a matrix-forming agent for the controlled release of water-soluble drugs and it can also be used as a hot-melt coating agent sprayed onto a powder or drugloaded sugar beads and granules. It may also be incorporated via extrusion/spheronization into pellets, which can be further compressed into tablets. Glyceryl behenate is used in oral enteric coated pellets, powders and suspensions. It is also used in controlled, extended release and orally disintegrating tablets. For oral preparations, glyceryl behenate forms a lipidic matrix for sustained-release formulations. 2.2. GELUCIRE 43/01 Gelucire are a family of vehicles derived from mixtures of mono-, di- and triglycerides with polyethylene glycol esters of fatty acids. Gelucire 43/01 describes as a gelucire having melting point of 43 o C having HLB value of 1. Chemical name and CAS registry number Semi-synthetic glycerides made of saturated C 8 -C 18 fatty acid glycerides [91052-53- 8]. Description Gelucire is light white waxy solid having light odor except atomized gelucire 70/02 is available as powders Functional category Low HLB gelucire are used as hydrophobic matrix carrier while high HLB gelucire are utilized for enhancement of solubility and dissolution of poorly water-soluble drug. Gelucire 70/02 called as Compritol 888 ATO is also used as lubricant. Structural formula C 12 -C 18 mono-, di- and triglycerides 191
Physical properties Melting point: 42 to 45 o C Flash point: 150 O C Solubility: Insoluble in water, freely soluble in chloroform and methylene chloride and slightly soluble in ethanol. Stability and storage conditions Prevent exposure to air, heat and moisture and store in its original non opened packing. Applications in pharmaceutical formulation or technology Gelucire are a family of vehicles derived from mixtures of mono-, di- and triglycerides with polyethylene glycol esters of fatty acids. Lipids are considered as an alternative to polymer in the design of sustained drug delivery systems due to their advantages such as the low melt viscosity (thus avoiding the need of organic solvents for solubilization), absence of toxic impurities such as residual monomer catalysts and initiators, potential biocompatibility and biodegradability. Gelucire are available with a range of properties depending on their Hydrophilic Lipophilic Balance (HLB 1-18) and melting point (33-70 o C) range. Gelucire 43/01 is used as excipient for hard gelatin capsules especially for drug protection against oxidation and hydrolysis. Gelucire 43/01 is also used for handling of low density products or toxic or low dose drugs. Gelucire 43/01 is also utilized for solid dosage form having liquid drugs. Gelucire 70/02 which is called as Compritol 888 available in powder form is used as lubricant at low concentration and used as binder in hot melt extrusion above 10 % as at this concentration it is used as hydrophobic matrices. The Gelucires containing only PEG esters (Gelucire 55/18) are generally used in preparation of fast release formulations, while Gelucires containing only glycerides or a mixture of glycerides and PEG esters (Gelucire 54/02, 50/13, 43/01) are used in preparation of sustained release formulations. 2.3. HYDROXYPROPYL METHYL CELLULOSE (HPMC) 192
Hydroxypropyl methyl cellulose (HPMC) is mixed hydroxyl alkyl cellulose ether and may be regarded as the propylene glycol ether of methyl cellulose. It is available in many grades of different viscosity range from 5 cps to 100000 cps. Non-proprietary names BP: Hypromellose JP: Hydroxypropyl methylcellulose USP: Hypromellose Chemical name and CAS registry number Cellulose, 2-hydroxypropyl methyl ether [9004-65-3] Description Odorless, tasteless, white or creamy white fibrous or granular powder Empirical formula and molecular weight The PhEur 2002 describes hypromellose as a partly O-methylated and O-(2- hydroxypropylated) cellulose. Grades may be distinguished by appending a number indicative of the apparent viscosity, in mpa s, of a 2% w/w aqueous solution at 20 C. Hypromellose defined in the USP 26 specifies the substitution type by appending a four-digit number to the nonproprietary name: e.g., hypromellose 1828. The first two digits refer to the approximate percentage content of the methoxy group (OCH 3 ). The second two digits refer to the approximate percentage content of the hydroxypropoxy group [OCH 2 CH (OH) CH 3 ], calculated on a dried basis. Molecular weight is approximately 10000-1500000. Structural formula Viscosity (2% aqueous solution) 193
HPMC K100 LV: 100 cps HPMC K4M: 4000 cps HPMC K15M: 15000 cps HPMC K100M: 100000 cps Functional category Coating agent Film-former Rate-controlling polymer for sustained release Stabilizing agent Suspending agent Tablet binder Viscosity-increasing agent Physical properties Acidity/alkalinity: ph = 5.5-8.0 for a 1% w/w aqueous solution. Ash: 1.5-3.0%, depending upon the grade Auto ignition temperature: 360 C Density (bulk): 0.341 g/cm 3 Density (tapped): 0.557 g/cm 3 Density (true): 1.326 g/cm 3 Melting point: browns at 190-200 C; chars at 225-230 C Glass transition temperature is 170-180 C Specific gravity: 1.26 Solubility Soluble in cold water, forming a viscous colloidal solution; practically insoluble in chloroform, ethanol (95%), and ether, but soluble in mixtures of ethanol and dichloromethane, mixtures of methanol and dichloromethane, and mixtures of water and alcohol. Certain grades of hypromellose are soluble in aqueous acetone solutions, mixtures of dichloromethane and propan-2-ol, and other organic solvents. Moisture content 194
Hypromellose absorbs moisture from the atmosphere, the amount of water absorbed depending upon the initial moisture content and the temperature and relative humidity of the surrounding air. Stability and storage conditions Hypromellose powder is a stable material, although it is hygroscopic after drying. Solutions are stable at ph 3-11. Increasing temperature reduces the viscosity of solutions. Hypromellose undergoes a reversible sol gel transformation upon heating and cooling, respectively. The gel point is 50-90 C, depending upon the grade and concentration of material. Aqueous solutions are comparatively enzyme-resistant, providing good viscosity stability during long term storage. However, aqueous solutions are liable to microbial spoilage and should be preserved with an antimicrobial preservative: when hypromellose is used as a viscosity-increasing agent in ophthalmic solutions, benzalkonium chloride is commonly used as the preservative. Aqueous solutions may also be sterilized by autoclaving; the coagulated polymer must be redispersed on cooling by shaking. Hypromellose powder should be stored in a well-closed container, in a cool, dry place. Incompatibilities Hypromellose is incompatible with some oxidizing agents. Since it is non ionic, hypromellose will not complex with metallic salts or ionic organics to form insoluble precipitates. Safety Hypromellose is widely used as an excipient in oral and topical pharmaceutical formulations. It is also used extensively in cosmetics and food products. Hypromellose is generally regarded as a nontoxic and non irritant material, although excessive oral consumption may have a laxative effect. The WHO has not specified an acceptable daily intake for hypromellose since the levels consumed were not considered to represent a hazard to health. LD50 (mouse, IP): 5 g/kg LD50 (rat, IP): 5.2 g/kg Applications in pharmaceutical formulation or technology 195
It is suspending, viscosity enhancing and film forming agent. HPMC is most widely used in hydrophilic matrix sustaining release tablets and other type of controlled release pharmaceutical dosage forms, because of its characteristic namely non-toxic nature, its capacity to incorporate active pharmaceutical, manufacture of tablet by direct compression without previous granulation as well as ph independent nature. 2.4. POLY VINYL PYRROLIDONE (PVP) Non-proprietary names BP: Povidone JP: Povidone PhEur: Povidonum USP: Povidone Synonyms E1201; Kollidon; Plasdone; poly[1-(2-oxo-1-pyrrolidinyl)ethylene]; polyvidone; polyvinylpyrrolidone; PVP; 1-vinyl-2-pyrrolidinone polymer. Chemical name and CAS registry number -Ethenyl-2-pyrrolidinone homopolymer [9003-39-8] Description Povidone occurs as a fine, white to creamy-white coloured, odourless or almost odourless, hygroscopic powder. Empirical formula and molecular weight (C 6 H 9 NO)n 2500 30,00,000 The USP 28 describes povidone as a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing degree of polymerization of which results in polymers of various molecular weights. It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, in the range 10 120. Structural Formula 196
Functional category Disintegrant Dissolution aid Suspending agent Tablet binder. Table I uses of povidone Use Concentration (%) Carrier for drugs 10-25 Dispersing agent Up to 5 Eye drops 2-10 Suspending agent Up to 5 Tablet binder, tablet diluents, or coating agent 0.5-5 Physical Properties Acidity/alkalinity: ph = 3.0 7.0 (5% w/v aqueous solution). Density (bulk): 0.29 0.39 g/cm 3 for Plasdone. Density (tapped): 0.39 0.54 g/cm 3 for Plasdone. Density (true): 1.180 g/cm 3 Flowability: 20 g/s for povidone K-15; 16 g/s for povidone K-29/32. Melting point: softens at 150 ºC. Moisture content: povidone is very hygroscopic, significant amounts of moisture being absorbed at low relative humidity. Particle size distribution: Kollidon 25/30: 90 % >50 mm, 50 % >100 mm. Solubility: freely soluble in acids, chloroform, ethanol (95 %), ketones, methanol, and water; practically insoluble in ether, hydrocarbons, and mineral 197
oil. In water, the concentration of a solution is limited only by the viscosity of the resulting solution, which is a function of the K-value. Stability and storage conditions Povidone darkens to some extent on heating at 1508 ºC, with a reduction in aqueous solubility. It is stable to a short cycle of heat exposure around 110-1308 ºC; steam sterilization of an aqueous solution does not alter its properties. Aqueous solutions are susceptible to mold growth and consequently require the addition of suitable preservatives. However, since the powder is hygroscopic, it should be stored in an airtight container in a cool, dry place. Applications in pharmaceutical formulation or technology Although povidone is used in a variety of pharmaceutical formulations, it is primarily used in solid-dosage forms. In tableting, povidone solutions are used as binders in wet- granulation processes. Povidone is used as a solubilizer in oral and parenteral formulations and has been shown to enhance dissolution of poorly soluble drugs from solid-dosage forms. Povidone solutions may also be used as coating agents. Povidone is additionally used as a suspending, stabilizing, or viscosity-increasing agent in a number of topical and oral suspensions and solutions 198