Transcript File

SALMAN BIN ABDUL AZIZ UNIVERSITY
COLLEGE OF PHARMACY
PHARMACEUTICSIV
(PHT 414 )
Physical-Chemical Factors Affecting
Drug Absorption
Dr. Mohammad Khalid Anwer
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Physical-Chemical Factors Affecting Oral
Absorption

Outline of Physical-chemical factors affecting
oral absorption:
 pH-partition theory
 Lipid solubility of drugs
 Dissolution and pH
 Salts
 Crystal form
 Drug stability and hydrolysis in GIT
 Complexation
 Adsorption
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pH - partition theory


For a drug to cross a membrane barrier it must
normally be soluble in the lipid material of the
membrane to get into membrane, also it has to
be soluble in the aqueous phase as well to get
out of the membrane.
Most drugs have polar and non-polar
characteristics or are weak acids or bases.
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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 dissociation constant (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
biomembrane.
transfer
across
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
Total conc. in blood
D
Total conc. in the g.i.t.

U b  I b
D
U g  I g
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Trans-membrane transfer
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Henderson - Hasselbach equation
 The amount of drug that exists in unionized form is a
function of dissociation constant (pKa) of the drug
and pH of the fluid at the absorption site
 The ratio of un-ionized and ionized drug [U]/[I] is a
function of the pH of the solution and the pKa of the
drug, as described by the Henderson - Hasselbach
equation
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pH-pKa Relationship, Henderson Hasselbach equation
For weak acidic drugs:
where HA is the weak acid and A- is the salt or conjugate base
For weak basic drugs:
where B is the weak base and HB+ is the salt or conjugate acid
pH  pK a
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

U
B
 log
 log

I 
HB 
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For weak acidic drugs:
=
Ionized
unionized
For weak basic drugs
=
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Unionized
Ionized
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For weak acids:
1. Very weak acid (pKa > 8) such as phenytoin, ethosuximide and
several barbiturates are essentially unionized at all pH values
and therefore their absorption is rapid, and independent of GI
pH.
2. Acid in the pKa range 2.5-7.5 are greatly affected by changes
in pH and therefore their absorption is pH dependent, e.g.
several NSAIDs like aspirin, ibuprofen, phenylbutazone and
number of penicillin analogs. Such drugs are better absorbed
from acidic conditions of stomach (pH<pKa) where they largely
exists in unionized form.
3. Stronger acids with pKa < 2.5 such as cromolyn sodium are
ionized in the entire pH range of GIT and therefore remain
poorly absorbed.
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For Basic drugs:
1. Very weak bases (pKa < 5) such as caffeine, theophylin and a
number of benzodiazepines like diazepam, oxazepam, and
nitrazepam are essentially unionized at all pH values and
therefore their absorption is rapid, and independent of GI pH.
2. Bases in the pKa range 5-11.0 are greatly affected by changes
in pH and therefore their absorption is pH dependent, e.g.
several morphine analogs, chloroquine, imipramine and
amitriptyline. Such drugs are better absorbed from the
relatively alkaline conditions of intestine where they largely
exists in unionized form.
3. Stronger bases with pKa > 11 like mecamylamine and
guanethidine are ionized in the entire pH range of GIT and
therefore remain poorly absorbed.
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Lipid solubility of drugs
Some drugs are poorly absorbed after oral
administration even though they are non-ionized in
small intestine.
Low lipid solubility of them may be the reason.
The best parameter to correlate between water and
lipid solubility is partition coefficient.
Partition coefficient (p) = [ L]conc / [W]conc,
where [ L]conc is the concentration of the drug in lipid
phase, [W]conc is the concentration of the drug in
aqueous phase.
The higher p value, the more absorption is observed.
Prodrug is one of the option that can be used to
enhance
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Dissolution, pH
 However, many drugs are given in solid dosage forms
and therefore must dissolve before absorption can take
place.
However, if dissolution is the slow, rate determining
step (the step controlling the overall rate) then factors
affecting dissolution will control the overall process.
This is a more common problem with drugs which
have a low solubility (below 1 g/100 ml) or which are
given at a high dose, e.g. griseofulvin.
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Dissolution, pH
Granules
De-aggregation
Disintegration
Tablet
ENDODISINTEGRANT
EXO-DISINTEGRANT
Fine particles
DISSOLUTION
Drug in
solution
Schematic representation of dissolution of a drug particle
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in the
G.I. fluid
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Theory of dissolution
There are a number of factors which affect drug
dissolution. One model that is commonly used
is to consider this process to be diffusion
controlled through a stagnant layer surrounding
each solid particle.
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Stagnant Layer
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Theory of dissolution


First we need to consider that each particle of drug formulation
is surrounded by a stagnant layer of solution. After an initial
period we will have a steady state where drug is steadily
dissolved at the solid-liquid interface and diffuses through the
stagnant layer.
The earliest equation to explain the rate of dissolution when
the process is diffusion controlled and involves no chemical
reaction was given by Noyes Whitney





dC/dt= dissolution rate of the drug
K= dissolution rate constant
Cs= conc. of drug in the stagnant layer
Cb= conc. of drug in the bulk of the solution
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Diffusion gradient/Concentration
Gradient
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
If diffusion is the rate determining step we can use Fick's first
law of diffusion to describe the overall process.

If we could measure drug concentration at various distances
from the surface of the solid we would see that a concentration
gradient is developed.

If we assume steady state we can used Fick's first law to
describe drug dissolution.

The Noyes and whitney’s equation was based on Fick's second
law of diffusion. Brunner incorporate Fick's first law of diffusion
and modified the Noyes and whitney’s equation.
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Modified 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
A, is the effective surface area of drug particle in contact
with the g.i. fluid,
Kw/o= water/ oil partition coefficient of drug
V= volume of dissolution medium
h= thickness of stagnant layer
(Cs –Cb)= concentration gradient for diffusion of drug
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Influence of some parameters on
dissolution rate of drug


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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
A is the surface area per gram (or per dose) of a

A can be changed by altering the particle size.


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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
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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Dissolution under Sink condition

If Cb is much smaller than Cs then we have so-called "Sink
Conditions" and the equation reduces to
dC DSC s

dt
h


Under sink conditions, if the volume and surface area of
solid are kept constant
dC/dt = K
Dissolution rate is constant, and follows Zero order kinetic
process.
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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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Factor affecting dissolution
(Physicochemical properties of drug )
Drug solubility, Cs, Salt form

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 .

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
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barbiturates.
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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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Physicochemical properties of drug

Crystal form

Polymorphism –

Some drugs exist in a number of crystal forms or polymorphs. These
different forms may well have different solubility properties and thus
different dissolution characteristics.

Drugs exhibiting polymorphism include chloramphenicol palmitate,
cortisone acetate, tetracyclines, sulphathiazole and paracetamol.

Chloramphenicol palmitate is one example which exists in at least
two polymorphs. The B form is apparently more bioavailable.
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Effect of Crystalline/polymorphic form on
dissolution rate of Chloramphenicol
palmitate
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
Amorphous form (noncrystalline form):
Amorphous form of novobiocin is effective while its
crystalline forms are ineffective.

Ester form – Chloramphenicol, erythromycin &
Pivaloyloxymethylester of ampicillin (Pivampicillin).
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Physicochemical properties of drug
(Cont)
Solvates and hydrates:

The stoichiometric type of abducts where the solvent molecules are
incorporated in the crystal lattice of the solid are called as the
solvates .

When the solvents are water then it called as hydrates.

For instance, the hydrous 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.
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Drug stability and hydrolysis in GIT

Acid and enzymatic hydrolysis of drugs in GIT is one of the reasons
for poor bioavailability.

Penicillin G (half life of degradation = 1 min at pH= 1)

Rapid dissolution leads to poor bioavailability (due to release large
portion of the drug in the stomach, pH = 1.2)

Pro-drug ( conversion in the GIT to parent compound is rate limiting
step in bioavailability, either positively or negatively).
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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-brainbarrier.

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.

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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Complex form (Cont.)




Complexation of a drug in the GIT fluids may alter rate and extent of
drug absorption.
Intestinal mucosa + Streptomycin = poorly absorbed complex
Calcium + Tetracycline = poorly absorbed complex
(Food-drug
interaction)
Carboxyl methylcellulose (CMC) + Amphetamine = poorly absorbed
complex (tablet additive – drug interaction)


Polar drugs + complexing agent = well-absorbed lipid soluble
complex ( dialkylamides + prednisone)
Lipid soluble drug + water soluble complexing agent = wellabsorbed water soluble complex ( cyclodextrine)
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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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