EFFECT OF PHYSICO-CHEMICAL PROPERTIES OF DRUG ON ABSORPTION

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EFFECT OF PHYSICO-CHEMICAL PROPERTIES OF DRUG ON
ABSORPTION

• By
• Dr. A. S. Adebayo

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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
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Noyes-Whitney equation

• 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.

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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).

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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
• To understand the physical-chemical factors which
  affect the oral absorption of drug products
• To understand the pH-partition theory and Ficks
  law as they apply to drug absorption
• 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

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pH of git plasma fluid

• control 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
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Trans-membrane transfer
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pH-pKa Relationship with proportion unionized.
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
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
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END OF PRESENTATION

• QUESTIONS/DISCUSSION