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 surface area microscopy shape Powder flow Compression properties Stability studies

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Excipient compatibility

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Physicochemical properties

• to produce a simple method for analysing the drug • for identifying the best salt to develop and for producing liquid dosage forms

spectroscopy solubility

• which reflects, for example, crystalline solubility

melting point

• necessary for drug stability studies, perhaps employing thin layer- or high pressure liquid chromatography

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

stability Microscopy powder flow & compression properties

RM-KAHS • to ensure that dosage forms perform correctly

excipient compatibility

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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.

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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

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m, porous

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m, empty spheres

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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.

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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 pH/disperse systems polyvalent cations Immiscibility Insolubility Packaging complexation cationic and anionic compounds of high MW reducing agents (cause fading of dyes) PHM4153 Dosage Design 2 2011/12 Formulation and packaging materials 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 Market needs Facility and equipment capabilities Security/Protection Child-resistance packaging RM-KAHS 21

Dosage form design

Oral Ailment Route of administration Enteral Parenteral Rectal Intravascular Subcutaneous Bio Pharmaceutics Packaging tablets suppositories vaccines RM-KAHS Creams 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.

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Formulation requirement: efficacy, safety, and quality Contain accurate dose Convenient to take or administer Provide drug in a form for absorption or other delivery to the target Retain quality throughout shelf life & usage period 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 no interference with drug bioavailability PHM4153 Dosage Design 2 2011/12 conformance to regulatory agency requirements 27

Pharmaceutical evaluation Product testing

Tablets • Hardness • Disintegration

Animal study

Creams • Viscosity • Microbial • Diffusion Efficacy of product RM-KAHS 28

Example

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Summary

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References

Aulton, M.E. (2002). Pharmaceutics – The Science of Dosage Form Design (2 nd 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