IJPRD, 2012; Vol 4(05): July-2012 (064 - 074)

International Standard Serial Number 0974 9446

-------------------------------------------------------------------------------------------------------------------------------------------------A REVIEW OF ON PREFORMULATION STUDIES OF DRUGS Pakkir Mohamed Shaik Allaudin*1, Janakiraman Kunchithapatham2
1

Department of Pharmacy, Annamalai University, Annamalai Nagar 608002, Chidambaram, Tamil Nadu, India. Correspondence to Author

ABSTRACT All most all new drugs are marketed as tablets, capsules, although only few drugs are marketed as an injection. The I.V route is always required during early toxicity, metabolic, bioavailability and clinical studies to provide a precise drug and dose deposition. The goals of preformulation studies are to choose the correct form of the drug substance, evaluate its physical and chemical properties, and generate a thorough understanding of the materials stability under the conditions that will lead to the development of a practical drug delivery system. Preformulation is a science that serves as a big umbrella for the fingerprinting of a drug substance or product both at the early and latter stage of development in pharmaceutical manufacturing. Key words: Preformulation, Intrinsic Solubility, pKa from solubility data, Excipient Compatibilty

Pakkir Mohamed Shaik Allaudin Department of Pharmacy, Annamalai University, Annamalai Nagar 608002, Chidambaram, Tamil Nadu, India. Email: sppharmaa@gmail.com

INTRODUCTION Preformulation can be defined as an investigation of physical and chemical properties of a drug substance alone and when combined with excipients1. The overall objective of preformulation testing is to generate information useful to the formulator in developing stable and bioavailable dosage forms which can be mass-produced24. A recommended list of the information required in preformulation is shown in Table 1. This is assembled, recognizing the relative importance and probable existence of only limited quantities of Available online on www.ijprd.com

new bulk drug (mg rather than gm). Investigator must be pragmatic and generate data of immediate relevance, especially if the likely dosage forms are known. Two fundamental properties are mandatory for a new compound: I. Intrinsic Solubility (CO) II. Dissociation constant (pKa) Independent of this pharmaceutical profiling (Table 1), analysts will generate data (Table 2), to confirm structure and purity, and this should be used to complement and confirm pharmaceutical data.

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Their greater training and knowledge in analysis decrease the products time to market (i.e., from will assist in the identification of suitable stabilitydrug substance to drug product). However, prior to indicating assays by high-performance liquid reviewing the various requirements that determine 1 chromatography (HPLC) . the scope of preformulation studies, it is important The Scope of Preformulation Studies to review how the drug discovery models are A detailed understanding of the properties rapidly changing and why there is a need for not of the drug substance is essential to minimize just one, but several levels of preformulation formulation problems in later stages of drug studies18. development, reduce drug development costs, and TABLE: 1 Preformulation Drug Characterization in A Structured Program:S.No Test Method/ Function Characterization Fundamental 1 Spectroscopy UV Simple assay 2 Solubility Phase solubility/ purity a) Aqueous Intrinsic & pH effect b) pKa solubility control , salt formation c) Salt Solubility, hygroscopicity & stability d)Solvents Vehicles & Extraction e) ko/ w Lipophillicity, structure activity f) Dissolution Biopharmacy 3 Melting point DSC-polymorphism, hydrate & solvent 4 Assay development UV, HPLC, TLC 5 Stability In Solution Thermal, hydrolysis, pH In solid state Oxidation, proteolysis metal ion Derived 6 Microscopy Particle size and morphology 7 Bulk density Tablet and capsule formation 8 Flow properties Tablet and capsule formation 9 Compression properties Acid / excipient choice 10 Excipient compatibility Preliminary screen by DSC, Conformation by TLC TABLE: 2 Analytical Preformulation
S.No 1 Attribute Identity Test Nuclear magnetic resonance (NMR) Infrared spectroscopy (IR) Ultra violet spectroscopy (UV) Differential scanning calorimetry (DSC) Optical rotation Moisture (water and solvents) Inorganic elements Heavy metals Organic impurities and DSC Titration UV,HPLC

Purity

Assays

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4 Quality Appearance, odour Solution colour pH of slurry (Saturated solution) melting point

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Steps in Preformulation Process Pharmaceutical Research 1.Organoleptic properties. 2. Partical size shape and surface area. 3. Solubility (Aqueous solubility, Intrinsic solubility, Determination of Solubility, pH solubility profile, pKa from solubility data, Solubilization10, Salts, solvents). 4. Partition coefficient. 5. Dissolution (Intrinsic dissolution rate, Measurement of Intrinsic dissolution rate). 6. Melting point9 (Capillary melting, Hot-stage microscopy, Differential scanning calorimetry and Thermal analysis). 7. Polymorphism and Amorphism (Pseudo polymorphism, True polymorphism, Crystal purity). 8. Drug and product stability (Solid state stability, Elevated Temperature, Hydrolysis, Oxidation. Photolysis, Solvolysis, Chelating agents, Hygroscopicity). 9. Powder flow properties (Bulk density, Angle of repose). 10. Excipient compatibility (Method, Interpretation)1,2,18. Organoleptic Properties A topical preformulation program should begin with the description of the drug substance. The color, odor, and taste of the new drug must be recorded using descriptive terminology. Table No: 3Particle Size, Shape and Surface Area Color Odor Taste Off-white Pungent Acidic Cream yellow Sulfurous Bitter Tan Fruity Bland Shiny Aromatic Intense Odorless Sweet Tasteless

Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes. The effect is not only on the physical properties of solid drugs but also, in some instances, on their biopharmaceutical behavior. E.g: the bioavalability of griseofulvin and phenacetin is directly related to the particle size distribution of these drugs, It is now generally recognized that poorly soluble drugs showing a dissolution rate limiting step in the absorption process will be more readily bioavailable when administered in a finely subdivided state than as coarse material. Very fine materials are difficult to handle but many difficulties can be overcome by creating solid solution of material of interest in a carrier, such as a water soluble polymer. This represent the ultimate in size reduction, since in a (solid) solution, the dispersed material of interest exist as discrete molecules or agglomerated molecular bundles of very small dimensions indeed. Size also plays a role in the homogeneity of the final tablet2. Solubility A drug substance administered by any route must possess some aqueous solubility for systemic absorption and therapeutic response. Poorly soluble compounds (e.g. less than 10mg/ml aqueous solubility) may exhibit incomplete, erratic, and slow absorption and thus produce minimal response at desired dosage. Enhanced aqueous solubility may be achieved by preparing more derivative of the parent compound, such as salts or esters; by chemical complexation; or by reducing the particle size. Estimates of desired drug solubility for good oral absorption depend on the permeability of the compound and the required dose, as illustrated in Table:41.

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International Journal of Pharmaceutical Research & Development TABLE: 4 Desired Solubility Correlated to Therapeutic Doses Desired solubility Values (mg/kg) for drugs with Dose (mg/kg) High Permeability Medium Permeability

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Low Permeability

0.1 1 1 10 10 100 The concept of maximum absorbable dose (MAD) is nowadays used to correlated drug absorption with its solubility according to following equation: MAD=KaSGIVGItr Where, Ka = Intrinsic absorption rate constant SGI = the solubility of the drug in GI fluid VGI= the volume of GI fluid present tr= resistance of drug in GI The above equation provides a useful calculation that includes the key parameter that are generally known to have a limited effect of absorption5. The approximate solubilities of pharmacopeial and national formulary substances are indicated by the descriptive terms in accompanying table: 5. TABLE: 5 Part of Solvents Descriptive Terms Required for 1 Part of Solute Very Soluble Freely soluble Soluble Sparingly Soluble Slightly Soluble Very slightly soluble Insoluble Less than 1 From 1 to 10 From 10 to 30 From 32 to 100 From 100 to 1000 From 1000 to 10000 Form 10000 to over

Aqueous Solubility Kaplan 1972 suggested that unless a compound has an aqueous solubility in excess 1% (10 mg mL-1) over the pH range 1-7 at 370c, potential bioabsorption problems may occur. If the intrinsic dissolution was greater than 1mg cm-2 min Available online on www.ijprd.com

5 21 52 207 520 2100 -1 then absorption was animpeded. Dissolution rates less than 0.1 mg cm-2 min-1 were likely to give dissolution rate-limited absorption. This tenfold difference in dissolution rates translates to a lower limit for a solubility of 1mg mL-1. Under sink conditions, dissolution rate and solubilities are proportional. Intrinsic Solubility (C0)1 Intrinsic Solubility is defined as the maximum amount of solute dissolved in a given solvent under standard conditions of temperature, pressure and pH. When the purity of the drug sample can be assured, the solubility value obtained in acid for a weak acid or alkali for a weak base can be assumed to be the intrinsic solubility (C0), ie, the fundamental solubility when completely unionized. The solubility should ideally be measured at two temperatures: i. 40c to ensure physical stability and extended short-term storage and chemical stability until more definitive data are available. The maximum density of water occurs at 40c. This leads to a minimum aqueous solubility. ii. 370c to support biopharmaceutical evaluation. Determination of Solubility The solubility of material is usually determined by the equilibrium solubility method, which employs a saturated solution of the material, obtained by stirring an excess of material in the solvent for a prolonged until equilibrium achieved :Common solvents used for solubility determination are:Water , Polyethylene Glycols, Propylene Glycol, Glycerin, Sorbitol, Ethyl Alcohol ,Methanol, Benzyl Alcohol, Isopropyl Alcohol, Tweens, Polysorbates, Castor Oil, PeanutOil, Sesame Oil, Buffer at various pHs24. pKa from solubility Data17 67

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A major improvement in solubility can be Seventy five per cent of all drugs are weak achieved by forming a salt. Acceptable bases; 20% are weak acids and only 5% are nonpharmaceutical salt counter-ions are shown in ionic, amphoteric or alcohol. It is therefore Table 6. As an example, the consequence of appropriate to consider the HandersonHasselbalch Equations for weak bases and acids. changing chlordiazepoxide to various salt forms is shown in Table 7. In some cases, salts prepared For weak bases; pH=pKa +log10([B]/[BH+]) For weak acids; pH=pKa +log10([A ]/[HA]) from strong acids or bases are freely soluble but very hygroscopic. This does lead to instability in Above the equation can be used: 1. To determine pKa by following changes in tablet or capsule formulations, as some drug will solubility. dissolve in its own adsorbed films of moisture. It is 2. To predict solubility at any pH provided that often better to use a weaker acid or base to form the intrinsic solubility (Co) and pKa are known. the salt, provided any solubility requirements are 3. To facilitate the selection of suitable saltmet. A less soluble salt will generally be less forming compounds and predict the solubility hygroscopic and form less acidic or basic solution 4 and pH properties of the salts . (Table 7)1. Salts TABLE: 6 Potential Pharmaceutical Salts Basic Drugs Acidic Drugs Anion Hcl Sulphate Salicylate pKa -6.10 -3.00,+1.96 3.00 % Usage 43.0 7.5 0.9 Cation Potassium Sodium Zinc pKa 16.00 14.77 8.96 % Usage 10.8 62.0 3.0

Salt Base Hcl

TABLE: 7 Theoretical Solubility and pH of Salts of Chlordiazepoxide pKa Salt pH Solubility (mg mL-1) 4.80 -6.10 8.30 2.53 2.0 <165a

Acetateb 4.76 4.78 4.1 a=Maximum solubility of chlordiazepoxide Hcl,achieved at pH 2.89,is governed by crystal lattice Energy and common ions b=Chlorodiazepoxide acetate may not form; pKa of acetate too high and too close to that of Drug ion. Solvent Accordingly, water-miscible solvents are used. Oils It is generally necessary to formulate an are used in emulsions,topical (creams and injection even if there is no intention to market. ointments), IM injections and Liquid-fill oral The first choice solvent is obviously water, preparation (soft and hard gelatin capsule) when However although the drug may be freely soluble, aqueous pH and solvent solubility and stability are unattainable Table:8 It may be unstable in aqueous solution. Cholordiazepoxide HCL is such an example.

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TABLE: 8 Recommended Solvents for Preformulation Screening Dielectric Solubility Solvents Application Constsnt() Parameter Water 80 24.4 All Methanol 32 14.7 Extraction,Sepration 0.1M Hcl (pH 1.1) Dissolution,basic extraction 0.1M NaOH (pH 13.1) Acidic extraction Buffer (pH 6-7) Dissolution(intestinal) Ethanol 24 12.7 Formulation 19,21 Where, V is the kinematic viscosity Partition Coefficient W is the angular velocity of a rotating disc of Partition Coefficient (oil/ water) is a drug11. measure of a drugs lipophilicity and an indication of its ability to cross cell membranes. It is defined Common Ion Effect as the ratio of unionized drug distributed between A common ion significantly reduces, the the organic and aqueous phases at equilibrium. solubility of a slightly soluble electrolyte. The P o/w = (C oil / C water) equilibrium. selling out results from the removal of water 13 Dissolution molecules as solvent owing to the completing Dissolution of drug particles is controlled by hydration of other ions. The reverse process several physicochemical properties include salting in qries with large anions e.g. benzoate, chemical form crystal habits, particle size, salivate which open the water structure. These solubility, surface area, and wetting properties. The hydro topics increase the solubility of properly dissolution rate of a drug substance in which water soluble compounds such as diazepam11. Polymorphism and Amorphism surface area is constant during dissolution is Depending upon the internal structure, a described by the modified Noyes-Whitney equation. solid can exist either in crystalline or amorphous form. When as substances exists in more than one = (Cs-C) crystalline form, the different form are designated Where, as polymorphs and the phenomenon as D = Diffusion coefficient polymorphism. h = Thickness of the diffusion layer at the solid Polymorphs are of two types: liquid interface 1. Enantiotropic Polymorph: is the one which can A= surface area of the drug exposed to dissolution be reversibly changed into another form by medium altering the temperature or pressure. E.g V= volume of medium Sulphur. Cs=Concentration of a saturated solution of the 2. Monotropic Polymorph: is the one which is solute in the dissolution medium at the unstable at all temperature and pressure. E.g experimental temperature glyceryl stearates3. C = Concentration of drug in solution at time t. The polymorphs differ from each other with t = Time respect to their physical properties such as Intrinsic Dissolution Rate solubility, melting point, density, hardness and When dissolution is controlled solely by compression characteristics. They can be prepared diffusion the rate of diffusion is directly by crystallizing the drug from different solvents proportional to the saturated concentration of the under diverse conditions. The existence of the drug in solution under these conditions the rate polymorphs can be determined by using technique constant K1 is defined by such as optical crystallography, X-ray diffraction, 2/3 1/6 1/2 K = 0.62 D v w
1

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examples where the amorphous forms exhibit DSC, etc. About 40% of all organic compounds can higher water solubility. Thus, the order for exist in various polymorphic forms. 70% of the dissolution of different solid forms of drugs is barbiturates and 65% of sulphonamides exibit Amorphous > Metastable > Stable5. polymorphism. Barbital, methyl paraben and sulphapyridine can be exist in as many as 6 Stability1,15 Wherever possible, commercial polymorphic forms and cortisone acetate in 8 pharmaceutical products should have a self life of forms. three years. The potency should not fall below 95% Some drugs can be existent in amorphous form (i.e under the recommended storage conditions and having no internal crystal structure). Such drugs the products should still look and perform as it did represent the highest energy state and can be considered as supercooled liquids. They have when first manufactured. greater solubility than the crystalline forms By investigating the intrinsic stability of the drug it because the energy require to transfer a molecule is possible to advice on formulation approaches from crystal lattice is greater than that require for and indicates types of excipients, specific non-crystalline (amorphous) solid. E.g, the productive addictive and packing which are likely amorphous form of novobiocin is 10 times more to improve the integrity of the drug and the than crystalline form. chloramphenicol palmitate, product. Typical stress condition are shown in cortisone acetate and Phenobarbital are other table: 9 TABLE: 9 Stress Conditions used in Preformulation Stability Assessments Test Conditions Solid: Heat (0c) 4, 20, 30 ,40, 40/70% RH, 50 and 75 Moisture uptake 30,45,60,75,and 90% RH at RTa,b Physical Stress Ball milling Aqueous Solution: pH 1 to 9 and 11 at RT & 370c. Reflux in 1 M HCl & 1 M NaOH c Light UV (254&366 nm) c Oxidation Sparging with oxygen with at RT; UV may accelerate breakdown a RT is ambient room temperature. Can vary between 50 and 250c b Saturated solution of MgBr2 KNO2, NaBr,NaCL and KNO3 respectively c At pH of maximum stability in simple aqueous solution. Hydrolysis: Ionic hydrolysis (Protolysis) is quicker than Hydrolytic reaction involve nucleophilic molecular attack of labile bonds, eg; Heat, Light Lactam>ester>amide>imide, by water on the drug Solution, Polarity and ionic strength in solution, and are first order. When this attack is High drug Concentrations. is by a solvent other than water it is known as Oxidation solvolysis. Oxidation is controlled by the environment, A number of conditions catalyse the breakdown: i.e, light, trace metals, oxygen, oxidizing agent. The presence of OHReduction is a complimentary reaction (Redox) and + The presence of H3O there is a mutual exchange of electrons. Oxidation The presence of divalent metal ions is a loss of electron and oxidizing agent must be able to take electrons. In organic-chemistry, Available online on www.ijprd.com 70

International Journal of Pharmaceutical Research & Development oxidation is synonymous with dehydrogenation (the loss of hydrogen) and this is the mode of action of polyhydroxphenol antioxidants, e.g Hydroquinone. Photolysis Oxidation, and the some extant hydrolysis, is often catalysed by light. The energy associated with the radiation increases as wave length decreases, so that the energy of UV visible is greater than that of IR and is independent of temperature (Table 10). When molecules are exposed to electromagnetic radiation they absorb

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light (protons) at characteristic wave lengths which causes an increase in energy, which can;
Causes decomposition Be retained or transferred Be converted to heat Result in light emission at a new wave length (fluorescence, phosphorescence).

Natural sunlight lies in the wavelength range 290780 nm, of which only the higher (UV) range (290320 nm) causes photodegradation of drugs and sunburn5,1.

TABLE: 10 Relationship between wavelength and associated energy of various forms of light Type of Radiation Wave Length (nm) Energy (kcal mol-1) UV 50-400 287-72 Visible 400-750 72-36 IR 750-10 000 36-1 Thus photolysis is prevented by suitable packaging: Tapped Density low actinic amber glass bottles, cardboard outers The tapped volume was measured by and aluminum foil overlaps and blasters. Clear flint tapping the powder to constant volume. It is glass absorbs around 80% in the 290-320 nm expressed in g/ml and is given by ranges, whereas amber glass absorbs more than Dt = M/Vt 90%. Plastic containers, by comparisons absorb Where, M is the mass of powder and Vt is the 50%. tapped volume of the powder. Power Flow Properties:Compressibility Index and Hausner Ratio When limited amounts of drugs are The compressibility index has been available Power flow properties can be evaluated proposed as an indirect measure of bulk density, by measurements of bulk density and angle of size and shape, surface area,moisture content and repose. Changes in particles size, and shape are cohesiveness of materials all this closely related to generally very important an increase in crystal size predicting powder flow characteristics. The or a more uniform shape will lead to a small angle compressibility index (CI) and the hausner ratio 22 or rpose and a smaller Carrs index . (HR) are determined by measuring both volume Bulk Density and the tapped volume of a powder. Taped Density Pored Density It is determined by measuring the volume CI(%) = 100 Tap Density of a known mass of powder sample that has been Taped Density passed through a screen into a graduated cylinder = Pored Density or through a volume measuring apparatus into a Angle of Repose cup. It is expressed in gm/ml and is given by The maximum angle which is formed b/w Db = M/Vo the surface of a pile of powder and horizontal Where, M is the mass of powder and Vo is the bulk 1 surface is called the angle of repose1,2,5. volume of the powder .

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International Journal of Pharmaceutical Research & Development Table:11 Relationship between flow, angle of repose, Carrs index fee power flow Angle of Carrs Index ( Flow Repose %) Excellent <25 5-15 Good Fair to passable a Poor a 25-30 30-40 > 40 12-16 18-21 23-35

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Very Poor 33-38 Extremely Poor >40 a Note: may be improved by glidant, e.g. 0.2% Aerosil. 17,18 Table: 12 Suggested primary candidates as Excipient Compatibilty exicipients for tablet and capsule formutions The successful formulation of a stable and effective solid dosage form depends on the careful Excipients Functionsa selection of the excipients that are added to Lactose F facilitate administration, promote the constants monohytrate release and bioavailability of the drug and protect Maize starch D it from degradation. Polyvinylpyrrolidone B The thermal analysis can be used to Magnesium Stearate L investigate and predict any physicochemical Colloidal silica G a interactions between components in a formulation Note: B: Binder, D: Disintegrant, and can therefore be applied to the selection of F:Filler/Diluent, G:Glidant, L:Lubricant suitable chemically compatible excipients. Primary Interpretation excipients recommended for initial screening for A scheme for interpreting DSC data for tablet and capsule formulations are shown in table individual components and their mixtures is shown 12. in Figure 1.

Figure 1: scheme to identify chemically compatible excipients using DCA with confirmatory TLC. Where confirmation is required by TLC, and stored for either 7 days at 500c or 14 days at samples (50-50 mixtures of drugs and exicipient) 370c. should be sealed in small neutral glasses test tubes It is important to view the results of such incompatibility of testing with caution. For Available online on www.ijprd.com 72

International Journal of Pharmaceutical Research & Development examples, magnesium stearate is notoriously incompatible with a wide ranges of compounds when tested, yet because it is only used at low

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levels-typically 0.5 1 % such as apparent incompatibility rarely produces a problem in practice is longer term storage and use14.

Figure 2: A generic development pathway: the relationship between preformulation and formulation in dosage form development. The formulation stages are shown in boxes and the preformulation stages are unboxed1. 3. Agular,A.J., SUMMARY AND CONCLUSION and This report is a literature review on Zelmer,J.E.:J.Pharm.Sci.,58:983,1969. 4. Bankar GS and Rhodes CT, Modern preformulation studies of drugs. Preformulation Pharmaceutics, 3rd Edn., Mercel Dekker, Inc., studies are very much important in choosing correct form of drug and its dosage form New York , 2000; p,165-180. development. Preformulation studies involve 5. Brahmankar DM and Jaiswal SB, Biodetermination of physico-chemical parameter, pharmaceutics and Pharmacokinetics, 2nd Edn., analytical method development, Determination of Vallabh Prakashan, New Delhi, 1998.p,23. drug excipient compatibility, Stability studies of 6. Dressman,J.B.,Fleisher. D., and Amidon. G.L.: J. drug and dosage form. This report gives details of Pharma.Sci., 73:1274,1984. above studies with respect to principle, 7. El-Shattawy,H.H.: Drug Dev. instrumentation, and general procedure in brief Ind.pharm.,7:605,1981. and interpretation of results. From this report one 8. Hansch, C., and Dunn, W.J.: J. Pharm. Sci., can conclude that no drug or its dosage form can 61:1,1972. be developed without preformulation studies. 9. Jacobson,H.,&Reier,G.:J.Pharm.Sci.,58:631,1969 . REFERENCES 10. Kramer, S.F., and Flynn, G.L.: J.Pharm. Sci., 1. Aulton ME, Pharmaceutics-The science of 61:1897,1972. st dosage form design, 1 (International student) 11. Martin,A., Swarbrick.J., and Cammarata,A.: Edn., Churchill Livingstone , New York, Physical Pharmacy: Physical Chemical Principles 1996.p,113-138. in the pharmaceutical Sciences. 3rd ed. Lea and 2. Ansel HC, Allen, Jr., LV et al, Pharmaceutical Febiger, Philadelphia,1983. Dosage forms Drug Delivery Systems, 7th Edn., 12. Martin A et al, Physical pharmacy, Indian Edn., Lippincott Williams & Wilkins, Philadelphia, PA, New Delhi, 1998. 2000.p,96-141. 13. Mooney.K.G., et al.: J. Pharma.Sci., 70:13 & 70:22,1981. Available online on www.ijprd.com 73

International Journal of Pharmaceutical Research & Development 14. Perry, R.H., and Chilton, C.H.: Chemical Engineers Handbook. 5th Ed. McGraw-Hill, New York, 1973.p.20. 15. Pikal, M.J., et al.: J. Pharma.Sci., 67:767,1978. 16. Gupta MM,1, T.R. Saini 2, et al.: Int. J. Pharma Res . Dev 1(9), vol-1,Nov 2002. 17. Osol,A.(Ed.):Remingtons Pharmaceutical Science.16th Ed. Mack Publishing, Easton, PA,1980,Chap.16. 18. Sarfaraz k.Niazi ,Handbook of preformulation, Pharmaceutical Scientist Inc. 19. Deerfield, Illinois, New York 2007.p,57-86 20. Stephen A. Howard and Jian-Xin Li, Preformulation Considerations for Controlled

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Release Dosage Form, AAPS PharmSciTech, Vol. 9, No. 2, 2008. 21. Suzuki, A., Higuchi, W,I., and Ho. N.F.: J. Pharma.Sci., 59:644.1970. 22. York,P.:Intern.J.Pharm., 6:89,1980. 23. Williams, N.A., and Amidon, G.L.: J. Pharm. Sci., 73:18,1984. 24. www.pharmainfo.net, Vol-6,2008.

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