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April 20, 2023 1
EFFECT OF PHYSICO-CHEMICAL PROPERTIES OF DRUG ON ABSORPTION
ByDr. A. S. Adebayo
April 20, 2023 2
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.
April 20, 2023 3
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
April 20, 2023 4
Noyes-Whitney equation
s t
dC DSC C
dt 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).
April 20, 2023 5
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.
April 20, 2023 6
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.
April 20, 2023 7
Sink condition
Continuous, unidirectional flow from g.i.t. to blood
First order kinetic process.
sDSCdC
dt h
April 20, 2023 8
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.
April 20, 2023 9
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.
April 20, 2023 10
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.
April 20, 2023 11
April 20, 2023 12
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.
April 20, 2023 13
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.
April 20, 2023 14
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.
April 20, 2023 15
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.
April 20, 2023 16
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.
April 20, 2023 17
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
April 20, 2023 18
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.
April 20, 2023 19
April 20, 2023 20
Distribution coefficient
g.i.t. in the conc. Total
bloodin conc. TotalD
gIU
IUD
g
bb
April 20, 2023 21
Trans-membrane transfer
April 20, 2023 22
pH-pKa Relationship with proportion unionized.
HA
A
U
IpKpH a loglog
HB
B
I
UpKpH a loglog
For weak acidic drugs:
For weak basic drugs:
April 20, 2023 23
Effect of pKa on Drug Distribution between Stomach and Blood
April 20, 2023 24
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 ??
April 20, 2023 25
Effect of fraction unionized on absorption rate constant
April 20, 2023 26
Stagnant Layer
April 20, 2023 27
Diffusion gradient/Concentration Gradient
April 20, 2023 28
Noyes-Whitney Equation for particle dissolution
h
Cb SCAD
n 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
April 20, 2023 29
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.
April 20, 2023 30
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
April 20, 2023 31
Reduction of stagnant layer thickness by reactive medium
April 20, 2023 32
Diffusion coefficient, D
The value of D depends on the: size of the molecule
viscosity of the dissolution medium
April 20, 2023 33
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).
April 20, 2023 34
Effect of salt form on solubility
April 20, 2023 35
Effect of salt form on dissolution rate
April 20, 2023 36
Effect of Crystalline/polymorphic form on dissolution rate of Chloramphenicol palmitate
***END OF PRESENTATION***
QUESTIONS/DISCUSSION
April 20, 2023 37