Transcript effect of physico-chemical properties of drug on absorption

EFFECT OF PHYSICOCHEMICAL PROPERTIES OF
DRUG ON ABSORPTION
By
Dr. A. S. Adebayo
April 13, 2015
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Effect of drug dissolution
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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
Granules
De-aggregation
Disintegration
Tablet
ENDODISINTEGRANT
EXO-DISINTEGRANT
Fine particles
DISSOLUTION
Drug in
solution
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Noyes-Whitney equation
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dC DS

 C s  Ct 
dt
h
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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
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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.
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The thickness of the diffusion layer, h,
will be influenced by the agitation
experienced by drug particles due
to gastric and/or intestinal
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motility.
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Factors affecting drug
dissolution (Cont.)
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The concentration of drug, C,
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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
dC DSC s

dt
h
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Continuous,
unidirectional
flow from g.i.t.
to blood
First order
kinetic process.
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Physico-chemical properties of
drug
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Particle size
Crystal form
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Polymorphism –Drugs exhibiting
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polymorphism include chloramphenicol
palmitate, cortisone acetate, tetracyclines,
sulphathiazole and paracetamol.
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Armophous form-. Armophous form of
novobiocin is effective while its crystalline forms
are ineffective.
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Physico-chemical properties of
drug
(Cont)
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Solvates and hydrates –
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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–
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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.)
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Ester form – Chloramphenicol,
erythromycin &
Pivaloyloxymethylester of ampicillin
(Pivampicillin).
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Pro-drugs
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Rationale:
I. A drug may be too water insoluble for i.v. dosage
form.
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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
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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.)
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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
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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
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he drug normally exists as monomolecular dispersion in
the clathrate complex.
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Clathrate form (Cont.)
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On exposure to water or dissolution medium,
clathrate-forming vehicle dissolves rapidly
and exposes the drug molecule to dissolution
medium.
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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
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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
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Objectives:
To understand the physical-chemical factors which
affect the oral absorption of drug products
To understand the pH-partition theory and Fick’s
law as they apply to drug absorption
Apply pH-partition principle to predict drug absorption
along git
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pH - partition theory
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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:
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the pKa of the drug
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the pH of the fluid in the GI tract
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the pH of the blood stream
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pH of git & plasma fluid
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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
T otalconc.in blood
D
T otalconc.in theg.i.t.

U b  I b
D
U g  I g
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Trans-membrane transfer
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pH-pKa Relationship with
proportion unionized.
For weak acidic drugs:


I
A
pH  pK a  log
 log
U 
HA
For weak basic drugs:


U
B
pH  pK a  log
 log

I 
HB 
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Effect of pKa on Drug Distribution
between Stomach and Blood
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Illustrative example
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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
D  A  CS  Cb 
Rate of Dissolutio n 
h
when Cs » Cb, the
equation reduces to:
D  A  C S 
Rate of dissolutio n 
h
Dissolution under sink condition is a
1st order process
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Surface area, A
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A is the surface area per gram (or per dose) of a
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A can be changed by altering the particle size.
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solid drug
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
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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.
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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
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The value of D depends on the:
 size of the molecule
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viscosity of the dissolution
medium
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Drug solubility, Cs
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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
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