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Phases in drug developments I: Pre-clinical studies Kausar Ahmad Department of Pharmaceutical Technology Kulliyyah of Pharmacy [email protected] http://staff.iium.edu.my/akausar RM-KAHS 1 Phases in drug development Preformulation • Chemical evaluations Dosage form design • Determination of dosage forms & product formulation Early stage development • Pharmaceutical, animal study and in-vitro evaluation Late stage development • In-vivo and clinical evaluations RM-KAHS 2 Preformulation Understanding physicochemical parameters of a drug • Characterization of drug molecule Application of biopharmaceutical principles Drug delivery system • Dosage form RM-KAHS 3 Physicochemical properties Spectroscopy Solubility pKa Partition coefficient Melting point Crystal properties and Polymorphism Particle size shape surface area microscopy Powder flow Compression properties Stability studies Excipient compatibility RM-KAHS 4 Physicochemical properties • to produce a simple method for analysing the drug • for identifying the best salt to develop and for producing liquid dosage forms • which reflects, for example, crystalline solubility spectroscopy solubility melting point assay development • in solution and in the solid state, alone or with excipients • to determine crystal morphology and particle size and polymorphism • necessary data for capsule & tablet formulation • to ensure that dosage forms perform correctly powder flow & compression properties excipient compatibility stability Microscopy RM-KAHS • necessary for drug stability studies, perhaps employing thin layer- or high pressure liquidchromatography 5 Spectroscopy To confirm drug structure and functional groups • Usually by UV. to quantify amount of drug in a particular solution • use wavelength at λmax • the amount of light absorbed is proportional to concentration (C) and the path length of the solution (L) through which the UV light has passed. • Beer-Lambert’s Law RM-KAHS 6 pKa • Determination of the dissociation constant for a drug - capable of ionization within a pH range of 1 to 10 • This is important since solubility, and consequently absorption, can be altered by changing pH (buffer). RM-KAHS 7 Rate of dissolution • Determination of the rate is important when it is the rate limiting step in the drug absorption process. • If solubility of drug > 10 mg/ml, at pH7, there will be no problem of bioavailability or dissolution (Kaplan,1972) RM-KAHS 8 Partition coefficient Partition coefficient (oil/water) indicates ability of a drug to cross cell membranes. It is defined as the ratio of un-ionized drug distributed between the organic and aqueous phases at equilibrium. Biological membranes are lipoidal in nature. Thus, the rate of drug transfer for passively absorbed drugs is directly related to the lipophilicity of the molecule. Po/w = (Coil/Cwater) equilibrium RM-KAHS 9 Melting Point • Affected by purity • Affected by types of polymorphs RM-KAHS 10 Crystal Properties & Polymorphism Need to determine crystal morphology and particle size A polymorph is a solid material with two or more different molecular arrangements and having a distinct crystal shape. These differences disappear in the liquid or vapour state. Polymorphs generally have different melting points, x-ray diffraction patterns, and solubilities, even though they are chemically identical. • Dissolution rate affects bioavailability • Tensile strength affects compression ability • Different stability at various temperature & pressure In general, the stable polymorph exhibits the highest melting point, the lowest solubility, and the maximum chemical stability RM-KAHS 11 Particle properties Properties of drugs are affected by particle size and shape. Particle size is critical in dose uniformity and dissolution rate of solid dosage forms. • poorly soluble drugs have low dissolution rate & hence low bioavailability. • But bioavailable when administered in a finely subdivided state rather than as a coarse material. Suspensions and creams are more uniform if the ingredients used are in micronised form. RM-KAHS 12 Powder Flow & Compression Properties necessary data for capsule & tablet formulation • Ease of operation • Homogeneity • Uniform unit dose Factors • • • • • Particles sizes distribution Chemical characteristics of substances Differences in polymorphs Drug-excipient interactions Drug-environmental & excipient-environmental interactions RM-KAHS 13 Polyamide: Carrier for insoluble ingredients; Protector for sensitive ingredients; Slow delivery & long lasting effect 7 m, empty spheres 10 m, porous PHM4153 Dosage Design 2 2011/12 14 Excipient: Particle size distribution PHM4153 Dosage Design 2 2011/12 15 Excipient: Pore volume & pore diameter PHM4153 Dosage Design 2 2011/12 16 Chemical Stability of Active Compounds Study of intrinsic stability of the active components allow better approaches to formulation, selection of excipients, use of protective additives and accurate selection of suitable materials and design of packaging. Include both solution and solid state experiments under conditions typical for the handling, formulation, storage, and administration of a drug candidate as well as stability in presence of other excipients. RM-KAHS 17 Excipients & Product Stability • Excipients are important for processing and efficacy – For tablets: binders, disintegrants, lubricants, and fillers. – For liquids: preservatives, thickener, colorants, flavours, sweeteners, buffer and water • Techniques to screen drug-excipient compatibility: – Thin-layer chromatography – Differential thermal analysis – Diffuse reflectance spectroscopy RM-KAHS 18 Incompatibility Chemical Physical pH/dissociation Immiscibility pH/disperse systems Insolubility Packaging Formulation and packaging materials polyvalent cations complexation cationic and anionic compounds of high MW reducing agents (cause fading of dyes) PHM4153 Dosage Design 2 2011/12 19 Detection of Incompatibility Cracked cream Hydrolysis or oxidation Discoloration Precipitation PHM4153 Dosage Design 2 2011/12 20 Other factors to be considered in preformulation Consumer’s preferences Compatibility of packaging materials Facility and equipment capabilities Security/Protection Market needs Child-resistance packaging RM-KAHS 21 Dosage form design Ailment Bio Route of administration Enteral Pharmaceutics Packaging Parenteral Oral Rectal Intravascular Subcutaneous tablets suppositories vaccines Creams RM-KAHS 22 Dosage form Tablets, liquids, capsules, creams, ointments, vaccines Optimise formulation (& processes) Use required excipients • Surfactants • Anti-oxidants • Preservatives • Binders RM-KAHS 23 Formulation Process whereby drugs are combined with other substances (excipients) • e.g. preservative to produce dosage forms • e.g. cream suitable for administration to or by patients. PHM4153 Dosage Design 2 2011/12 24 Formulation requirement: efficacy, safety, and quality Contain accurate dose Convenient to take or administer Retain quality throughout shelf life & usage period Provide drug in a form for absorption or other delivery to the target Manufactured by a process that does not compromise performance and that is reproducible and economical PHM4153 Dosage Design 2 2011/12 25 Categories of excipients Provide essential parts of dosage form & enhance bioavailability • Emulsifiers • Viscosity modifier Prevent degradation of the formulation: protect, improve safety & enhance stability • Anti-oxidants • Anti-bacterials • Preservatives • UV absorbers Aid processing during manufacturing Assist product identification colour PHM4153 Dosage Design 2 2011/12 26 Choosing excipients physiological inertness commercially available at low cost physical and chemical stability absence of pathogenic microbial organisms conformance to regulatory agency requirements no interference with drug bioavailability PHM4153 Dosage Design 2 2011/12 27 Pharmaceutical evaluation Product testing Tablets • Hardness • Disintegration Creams • Viscosity • Microbial • Diffusion Animal study Efficacy of product RM-KAHS 28 Example RM-KAHS 29 Summary RM-KAHS 30 References Aulton, M.E. (2002). Pharmaceutics – The Science of Dosage Form Design (2nd Ed.). Churchill Livingstone. Bugay, D. E. (1999). Pharmaceutical excipients : characterization by IR, Raman, and NMR spectroscopy. Kibbe, A. H. (2000). Handbook of pharmaceutical excipients. Rowe, R. C., Sheskey, P. J. & Owen, S. C. (2006). Handbook of pharmaceutical excipients Rowe, R. C. (2009). Handbook of pharmaceutical excipients. RM-KAHS 31