Oral Drug Absorption

Influence of Physicochemical Factors

By
Dr. Ch. D. S. Prasad
Drug Delivery
System

Site of


Action

Sufficient Concentration
Desired
Pharmacological
Activity
Local Delivery
Distribution
Delivery
Systemic Delivery
Systemic
Circulation
Site of
Action
Intravascular
Peroral
Buccal
Transdermal
Rectal
Intrauterine
Intramuscular
Several Cellular
Membranes
Oral Absorption is the process of Penetration of the Drug
across the intestinal membrane and its appearance,
unchanged in the blood draining the GIT.
Oral Absorption
Intestinal membrane is not a unicellular membrane, instead a
number of unicellular membrane in parallel to each other.
Abs orption
Drug
from
GI fluids
Extracellular
Compartments
Structure of Membrane
Mechanisms of Membrane Transport
Nonionic Diffusion
Convective Transport
Ionic Diffusion
Facilitated Diffusion
Active Transport
Pinocytosis
Passive or Nonionic Diffusion

Down the electrochemical gradient

Does not require expenditure of metabolic energy


Rate of diffusion increases linearly with increase in
concentration


Concentration
Convective Transport
Absorption of low molecular wt. Drugs (<100 Daltons)
Water soluble drugs
Driving force is Hydrostatic or Osmotic Pressure
Transports through water filled Channels
Membrane
outside
Inside
Facilitated Diffusion
Carrier-mediated
Down the electrochemical gradient
Does not require expenditure of
metabolic energy
eg Vitamin B
12
glucose and Amino Acids are transported by
facilitated diffusion
Ionic Diffusion
+
+
+
+
+
+
+
_
_
_
_
_
M
+
M
+
M
+
M
-
M
-
M
+
M
-
M
-
Membrane
Anions > Cations
Active Transport
Carrier Mediated
Against the electrochemical gradient
Require expenditure of metabolic energy
Inhibited by Metabolic poison
Endogenous Substances (Ions: Na, K, Ca; Vitamins Pyridoxine,
Ascorbic Acid)
Drugs with structural similarities (Levodopa (L-amino acid),
5-Florouracil (Pyrimidine)
Transposition of Drug from Oral Dosage Form into
General Circulation
Site of
Absorption
Drug in
Solution
Dosage Form
Transport
Across
Membrane
General Circulation
Factors Influencing Oral Absorption of Drugs
Physicochemical Properties of Drug Substance
ex. Solubility, pKa, log P, Particle size etc.

Dosage Form Related
Ex. Ingredients, Manufacturing variables etc.

Physiological and Patient Related Factors
Ex. Gastric emptying, Intestinal Transit time, Disease state etc.

Transposition of Drug from Oral Dosage Form into
General Circulation
Site of
Absorption
Drug in
Solution
Dosage Form
Transport
Across
Membrane
General Circulation
Slowest of all the four determines the absorption rate
Drug in
solution
Dosage form
Systemic
circulation
GI tract
GI
membrane
Dissolution Rate
Limited Absorption
Permeability Rate
Limited Absorption
Graphical Representation of Permeability Rate-limited Absorption
and Dissolution Rate-limited Absorption
Drug in
solution
Systemic
circulation
GI
membrane
Physicochemical factors Influencing Oral
Absorption (Drug in Solution)
Permeability and Partition Coefficient (K
o/w
)
Extent of Ionization in biological fluids (pK
a
)
pH of the GIT fluid in which it is dissolved
Molecular weight (or) Molecular Volume of the drug
Permeability and Partition Coefficient
Permeability is the ability of a molecule to cross the
biological membranes
Major Constituent of biomembranes are Lipid and they are
Amphipathic in nature
Enroute to its biophase the drug has to partition between lipid
biomembrane and the aqueous biological fluids
The drug molecule should have a balance between
hydrophilic and lipophillic properties
Octanol/water Partition coefficient is the physical property
extensively used to describe the hydrophilic and lipophillic
balance of a molecule
Partition Coefficient (K
octanol/water
)
Partition coefficient is the ratio of the unionized compound in
mutually saturated Octanol and water system (Denoted as P)
Solubility parameters of Octanol are very close to the
biological membrane
Logarithm of P (log P) is used for convenience
Small Molecules (<0.8nm)
Polar (Water Filled Channels)
Molecules Polar
0
3
Partition Coefficient Permeability Relationship
Log P values Increases
Membrane is the
barrier to diffusion
Aqueous layer surrounding
Membrane is the barrier to diffusion
Membrane
Partition Coefficient Permeability Relationship
Molecules Weight > 4000
Impermeable
Same Log P value
(Sufficient Lipophylicity)
Membrane
Molecules Weight > 1500 < 4000
Almost Impermeable
Molecules Weight > 750 < 1500
Poorly permeable
Molecules Weight > 450 < 750
permeable
Molecules Weight < 450
Highly permeable
Partition Coefficient Permeability Relationship
Nearly Same Log P values
and
Nearly Same Mol. Weight
Membrane
Straight Chain Molecules
Branched Chain Molecules
Drug pK
a
and gastrointestinal pH
The amount of drug that exits in unionized form is a
function of dissociation constant (pKa) of the drug and
pH of the fluid at the site of absorption
pK
a
is the ve logarithm of dissociation constant K
a

pK
a
is the pH at which half of the molecules are
dissociated
Week Acid
Strong Acid
pK
a
Strong Base
Week Base
For Acidic Drugs
pH < pKa
Unionized
Ionized
For Basic Drugs
pH > pKa
Unionized
Ionized
Best Absorbed from
Stomach
Best Absorbed from
Intestine
ion Concentrat Drug Unionized
ion Concentrat Drug Ionized
pKa pH log
ion Concentrat Drug Ionized
ion Concentrat Drug Unionized
pKa pH log
100
10 1
10
%

pKa pH
pKa pH
Ionized Drug
For Acidic Drugs
For Basic Drugs
100
10
10 1
%

pH pKa
pH pKa
Ionized Drug
Determination of Ionization (Henderson-Hasselbach Eq.)
Drug pKa Examples Stomach Intestine
Very week acids > 8.0
Phenytoin
Barbiturates
Unionized Unionized
Moderately week
acids
2.5 to 7.5
Aspirin
Phenylbutazone
Unionized Ionized
Strong acids < 2.5 Cromolyn Na Ionized Ionized
Very week bases < 5.0
Theophylline
Diazepam
Unionized Unionized
Moderately week
Bases
5.0 to 11.0
Reserpine
Codeine
Ionized
Relatively
unionized
Strong Bases > 11
Mecamylamine
Guanethidine
Ionized Ionized
Influence of Drug pKa and GI pH on Drug Absorption


Apparent first order absorption rate constant
Stomach Stomach Intestine
pH 3 pH 6 pH 6
Acids
Salicyclic acid 0.015 0.0053 0.085
Barbital 0.0029 0.0026 0.037
Sulfaethiodole 0.004 0.0023 0.022
Bases
Prochlorperazine <0.002 0.0062 0.030
Haloperidol 0.0028 0.0041 0.028
Aminopyrine <0.002 0.0046 0.022

Drug in
solution
Dosage form
GI tract
Factors Influencing Drug Dissolution
Diffusion Layer Model Theory of Dissolution
(Noyes-Whitney)
) (
b S
C C S
h
D
dt
dQ

Q = amount of drug dissolved
T = time
D = diffusion coefficient of drug
S = effective surface area
h = thickness of stationary layer of solvent around the drug particle
C
S
= saturated solubility of the drug in the stationary layer
C
b
= concentration of drug in the bulk fluids of the GIT
Factors Affecting Rate of Dissolution
Effective Surface of the Drug
Saturation Solubility of the drug
Concentration of the Dissolved Drug in
Bulk Solution
Diffusion coefficient
Thickness of the Diffusion layer
Effective Surface of the Drug
Particle Size
Absolute surface area is the
total area of the solid surface
of a particle

Effective surface area is the
area of solid particle exposed
to the dissolution medium

Non-hydrophobic Drugs: Effective Surface Area = Absolute Surface Area

Hydrophobic Drugs: Effective Surface Area Absolute Surface Area
Saturation Solubility of Drug
Salt Form of the Drug
Polymorphism
Solvate Formation
Complexation
Solid-Solid Interaction
Effect of Salt Form of a Drug
Dissolution from a week acid Dissolution from salt of week acid
A B
Acidic Basic
XNa X
-
+ Na
+
HX X
-
+ H
+
pH of the stagnant layer determines the solubility and diffusion
of the drug into bulk of the solution
If pH of Bulk Solution is Acidic
If pH of Bulk Solution is Basic
Polymorphism
Polymorphism is the existence of molecules in
more than one crystalline form
Solvate Form
Stoichiometric adducts where the solvent molecules are
incorporated into the crystal lattice
The solvent of crystallization is water, it is called
hydrates
Generally hydrates are less soluble in water; they are
already in interaction with water therefore have less
energy for crystal break-up (Theophylline and Ampicillin)
Solvates are more soluble in water than nonsolvates
(chloroform solvate of Griseofulvin)


Diffusion Coefficient

6
kT
D
D = diffusion coefficient
k = Boltzmans Constant
T = absolute temperature
r = radius is molecule in solution
= Viscosity of the fluid

Concentration of the Drug in Bulk Solution
) (
b S
C C S
h
D
dt
dQ

Concentration
Gradient
Volume of the Boundary layer
<
Volume of the Bulk Fluid
Thickness of the Diffusion Layer
) (
b S
C C S
h
D
dt
dQ

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