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Phases in drug developments I: Pre-clinical studies

Kausar AhmadDepartment of Pharmaceutical Technology

Kulliyyah of Pharmacyakausar@iium.edu.my

http://staff.iium.edu.my/akausar

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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

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Preformulation

Understanding physicochemical parameters of a drug• Characterization of drug molecule

Application of biopharmaceutical principles

Drug delivery system

• Dosage form

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Physicochemical properties

Spectroscopy Solubility pKa Partition coefficient

Melting pointCrystal

properties and Polymorphism

Particle size shape

surface area microscopy Powder flow Compression properties

Stability studies

Excipient compatibility

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Physicochemical properties• to produce a simple

method for analysing the drug

spectroscopy

• for identifying the best salt to develop and for producing liquid dosage forms

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

stability

• to determine crystal morphology and particle size and polymorphism

Microscopy

• necessary data for capsule & tablet formulation

powder flow & compression properties

• 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

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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).

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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)

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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

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Melting Point

• Affected by purity• Affected by types of polymorphs

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Crystal Properties & Polymorphism

Need to determine crystal morphology and particle size

• Dissolution rate affects bioavailability• Tensile strength affects compression ability• Different stability at various temperature & pressure

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.

In general, the stable polymorph exhibits the highest melting point, the lowest solubility, and the maximum chemical stability

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Particle properties

Properties of drugs are affected by particle size and shape.

• 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.

Particle size is critical in dose uniformity and dissolution rate of solid dosage forms.

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

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10 m, porous

7 m, empty spheres

Polyamide: Carrier for insoluble ingredients; Protector for sensitive ingredients; Slow delivery & long lasting effect

Excipient: Particle size distribution

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Excipient: Pore volume & pore diameter

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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

Incompatibility

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Chemical

pH/dissociation

pH/disperse systems

polyvalent cations

complexation

cationic and anionic compounds of high MW

reducing agents (cause fading of dyes)

Detection of Incompatibility

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Cracked cream Hydrolysis or oxidation

Discoloration Precipitation

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Other factors to be considered in preformulation

Consumer’s preferences

Compatibility of packaging materials

Facility and equipment capabilities

Market needs

Security/ProtectionChild-resistance

packaging

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Dosage form design

Ailment

Route of administration

EnteralOraltablet

s

Rectalsupp

ositories

ParenteralIntrav

ascularvacci

nes

Subcutaneo

usCreams

BioPharmaceutics Packaging

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Dosage form

Tablets, liquids, capsules, creams, ointments, vaccines

Optimise formulation (& processes)

Use required excipients• Surfactants• Anti-oxidants• Preservatives• Binders

Formulation

PHM4153 Dosage Design 2 2011/12

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

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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

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Categories of excipients

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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

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Choosing excipients

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physiological inertness

physical and chemical stability

conformance to regulatory agency

requirements

no interference with drug bioavailability

absence of pathogenic microbial

organisms

commercially available at low cost

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Pharmaceutical evaluation

Product testing

Tablets• Hardn

ess• Disint

egration

Animal study

Efficacy of product

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Example

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Summary

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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.