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EFFECT OF PHYSICO-CHEMICAL PROPERTIES OF DRUG ON ABSORPTION

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Effect of drug dissolution

Factors affecting rate of release/dissolution and hence, bioavailability from solid dosage forms:

The rate and extent at which the drug in solution reaches the site (s) of absorption in absorbable form

The rate and extent of absorption across the gastro-intestinal barrier

The extent to which the drug is metabolized during passage through the g.i.t. and/or liver.

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Schematic representation of dissolution of a drug particle in the g.i. fluid

Tablet

Disintegration

De-aggregationGranules

Fine particles

Drug in solution

DISSOLUTION

EXO-DISINTEGRANT ENDO-DISINTEGRANT

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Noyes-Whitney equation

s tdC DS C Cdt h

where dC/dt is the rate of dissolution

D is the diffusion coefficient of the drug in solution in g.i. fluid

S is the effective surface area of drug particle in contact with the g.i. fluid,

Cs is the saturation solubility of the drug in the diffusion layer and

Ct is the concentration of drug in solution in the bulk medium (g.i. fluid).

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Factors affecting drug dissolution

Physiological conditions – The diffusion coefficient, D, of a drug in

the g.i. fluid may be decreased by presence of substances which increase the viscosity of the fluids such as food.

The thickness of the diffusion layer, h, will be influenced by the agitation experienced by drug particles due to gastric and/or intestinal motility.

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Factors affecting drug dissolution (Cont.)

The concentration of drug, C, will be influenced by the rate of removal of

dissolved drug by absorption through the g.i./blood barrier and

the volume of fluid available for dissolution (fluid intake).

A low value of C will increase the concentration gradient and this forms the basis for the dissolution under the so called “sink” condition.

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Sink condition Continuous,

unidirectional flow from g.i.t. to blood

First order kinetic process.

sDSCdCdt h

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Physico-chemical properties of drug

Particle size Crystal form

Polymorphism –Drugs exhibiting polymorphism include chloramphenicol palmitate, cortisone acetate, tetracyclines, sulphathiazole and paracetamol.

Armophous form-. Armophous form of novobiocin is effective while its crystalline forms are ineffective.

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Physico-chemical properties of drug (Cont)

Solvates and hydrates – For instance, the anhydrous form of ampicillin showed

greater extent of absorption from hard gelatin capsule or aqueous suspension dosage forms than the less soluble, slower dissolving crystalline form.

Salt form– For example, sodium salt of tolbutamide gave in vitro

dissolution rate significantly greater than the acid form.

Other examples are salt forms of penicillin, novobiocin and barbiturates.

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Physico-chemical properties of drug (Cont.)

Ester form – Chloramphenicol, erythromycin & Pivaloyloxymethylester of ampicillin (Pivampicillin).

Pro-drugs Rationale: I. A drug may be too water insoluble for i.v.

dosage form. Chemical modification may produce significant water

solubility for its i.v. formulation

II. A drug required to alter some CNS function may be too polar and therefore not well absorbed across the lipoidal blood-brain-barrier.

III. Rapid metabolism of a drug at the site of absorption leading to a decrease in systemic bioavailability after oral dosing.

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Complex form Molecular complex consists of

components held together by weak forces such as hydrogen bond

Bonding interaction between the two molecules is rapidly reversible, provided the complex is soluble in biological fluids.

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Complex form (Cont.) Properties of drug complexes such as

solubility, molecular size and lipid-water partition coefficient differ significantly from those of the respective free drugs.

Complexation is often a deliberate attempt in dosage form design to increase solubility or stability of the drug e.g. solid-in-solid complex.

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Clathrate form Clathrates are formed if a substance is

capable of forming channels or cages which can take up another substance into the intra-space of the structure.

Clathrate forming substances are gallic acid urea, thiourea, aminos and zeolites.

Clathrates are formed by crystallization of an organic solution of clathrate forming substance with the drug. T

he drug normally exists as monomolecular dispersion in the clathrate complex.

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Clathrate form (Cont.) On exposure to water or dissolution

medium, clathrate-forming vehicle dissolves rapidly and exposes the drug molecule to dissolution medium.

Drugs that have been presented in clathrate forms include Vitamine A, sulphathiazole, chloramphenicol and reserpine.

Clathrates are stable in the dry form.

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Adsorption Concurrent administration of drugs and medicinal

substances containing solid adsorbents (e.g. antidiarrhoeal mixtures) may result in interference with the absorption of drugs in the git.

Drug may be adsorbed onto kaolin, attapulgite or charcoal with consequent decrease in the rate and extent of its absorption.

Examples of documented interactions are promazine/charcoal, lincomycin/kaopectate, talc/cyanocobolamin.

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Physical-Chemical Factors Affecting Oral Absorption

Objectives:

o To understand the physical-chemical factors which affect the oral absorption of drug products

o To understand the pH-partition theory and Fick’s law as they apply to drug absorption

o Apply pH-partition principle to predict drug absorption along git

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pH - partition theory

For weak acid or basic drug, the solubility of the drug and the rate of absorption through the membranes (lining the GI tract) is controlled by: the pKa of the drug

the pH of the fluid in the GI tract

the pH of the blood stream

pH of git & plasma fluidcontrol the process of its transfer across biomembrane.

This can be explained by the pH partition theory of Brodie (1957).

The theory is based on the assumption that only unionized drug moiety can cross biomembrane.

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Distribution coefficient

g.i.t. in the conc. Total bloodin conc. Total

D

gIU

IUD

g

bb

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Trans-membrane transfer

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pH-pKa Relationship with proportion unionized.

HAA

UIpKpH a loglog

HBB

IUpKpH a loglog

For weak acidic drugs:

For weak basic drugs:

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Effect of pKa on Drug Distribution between Stomach and Blood

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Illustrative example Compare D for a weak acid (pKa =

5.4) from the stomach (pH 3.4) or intestine (pH 6.4), with blood pH = 7.4 ??

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Effect of fraction unionized on absorption rate constant

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Stagnant Layer

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Diffusion gradient/Concentration Gradient

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Noyes-Whitney Equation for particle dissolution

h

Cb SCADn Dissolutio of Rate

h

CADn dissolutio of Rate S

when Cs » Cb, the equation reduces to:

Dissolution under sink condition is a 1st order process

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Surface area, A A is the surface area per gram (or per dose) of

a solid drug

A can be changed by altering the particle size.

Generally as A increases the dissolution rate will also increase.

Improved bioavailability has been observed with griseofulvin, digoxin, etc.

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Diffusion layer thickness, h

This thickness is determined by the agitation in the bulk solution.

In vivo we usually have very little control over this parameter, however factors affecting g.i.t motility/transit time can be important.

Affected by agitation rate which must be controlled when we perform in vitro dissolution studies

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Reduction of stagnant layer thickness by reactive medium

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Diffusion coefficient, D

The value of D depends on the: size of the molecule

viscosity of the dissolution medium

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Drug solubility, Cs

Dissolution rate increases with Cs

Salts of weak acids and weak bases generally have much higher aqueous solubility than the free acid or base

If the drug can be given as a salt the solubility and dissolution rate can be increased (e.g. Penicillin V).

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Effect of salt form on solubility

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Effect of salt form on dissolution rate

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Effect of Crystalline/polymorphic form on dissolution rate of Chloramphenicol palmitate

***END OF PRESENTATION***

QUESTIONS/DISCUSSION

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