Factors affecting drug absorption part ii

1. Dr. Nilesh S. Kulkarni
Associate Professor in Pharmaceutics
PES Modern college of Pharmacy For Ladies Moshi Pune
9/21/2021

2. Physicochemical properties of drug
1. Drug solubility and dissolution rate
2. Particle size and effective surface area
3. Polymorphism and amorphism
4. Pseudopolymorphism (hydrates/solvates)
5. Salt form of the drug
6. Lipophilicity of the drug
7. pKa of the drug and gastrointestinal pH
8. Drug stability
9. Stereochemical nature of the drug
PHARMACEUTICAL FACTOR
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3. Drug pKa and Lipophilicity and GI pH—pH Partition Hypothesis
- According to the pH-partition hypothesis, the gastrointestinal
epithelia acts as a lipid barrier towards drugs which are
absorbed by passive diffusion, and those that are lipid soluble
will pass across the barrier.
Brodie et al.
“The theory states that for drug compounds of molecular weight
greater than 100, which are primarily transported across the
biomembrane by passive diffusion, the process of absorption is
governed by:
dissociation constant (pKa) of the drug,
lipid solubility of the unionised drug (a function of drug Ko/w)
and The pH at the absorption site.
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4. Most drugs are weak electrolytes (weak acids or weak bases), their degree of
ionisation depends upon the pH of the biological fluid.
If the pH on either side on the membrane is different, then the compartment whose
pH favours greater ionisation of the drug will contain greater amount of drug, and
only the unionised or undissociated fraction of drug, if sufficiently lipid soluble, can
permeate the membrane passively until the concentration of unionised drug on
either side of the membrane becomes equal i.e. until equilibrium is attained.
The above statement of the hypothesis was based on the assumptions that:
1. The GIT is a simple lipoidal barrier to the transport of drug.
2. Larger the fraction of unionised drug, faster the absorption.
3. Greater the lipophilicity (Ko/w) of the unionised drug, better the absorption.
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5. Drug pKa and Gastrointestinal pH
The lower the pKa of an acidic drug, stronger the acid
i.e. greater the proportion of ionised form at a particular pH.
Higher the pKa of a basic drug, stronger the base
i.e. greater the proportion of ionised form at a particular pH.
The knowledge of pKa of drug and pH at the absorption site (or biological fluid), the
relative amount of ionised and unionised drug in solution at a particular pH and the
percent of drug ionised at this pH can be determined by Henderson-Hasselbach
equations:
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6. WEAK ACIDS
WEAK BASE
If there is a membrane barrier that separates the aqueous solutions of different pH such
as the GIT and the plasma, then the theoretical ratio R of drug concentration on either
side of the membrane can be given by equations derived by Shore et al:
WEAK ACIDS
WEAK BASE
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7. Drugs pKa pH/site of absorption
Very weak acids
e.g. Pentobarbital
Hexobarbital
>8
Unionized at all pH values; Absorbed along the
entire length of GIT
Moderately weak acids
e.g. aspirin
Ibuprofen 2.5 – 7.5
Unionized in gastric pH & ionized in intestinal pH;
better absorption from stomach
Stronger acids
E.g. disodium Cromogylate < 2.0
Ionized at all pH values; Poorly absorbed from GIT
Very weak bases
e.g. Theophylline
Caffeine
< 5.0
Unionized at all pH values; Absorbed along entire
GIT
Moderately weak bases
e.g. codeine 5 – 11
Ionized at gastric pH, unionized at intestinal pH;
better absorption from intestine.
Stronger bases
e.g. Guanethidine > 11
Ionized at all pH values; Poorly absorbed from GIT
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8. Influence of Drug pKa and absorption
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9. Total aqueous solubility, ST, of an IONISABLE DRUG is an important factor in the passive
absorption of drugs.
It is defined as the SUM OF CONCENTRATION OF IONISED DRUG IN SOLUTION AND
CONCENTRATION OF UNIONISED DRUG IN SOLUTION.
The solubility of unionised form of the drug is known as the intrinsic solubility of the
drug. If Sa is the intrinsic solubility of weakly acidic drugs and Sb that of weakly basic
drugs,
TOTAL AQUEOUS SOLUBILITY
ACIDS
BASE
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10. 9/21/2021

11. Lipophilicity and Drug Absorption
The degree of ionisation at a particular pH and that only the unionised drug, if
sufficiently lipid soluble, is absorbed into the systemic circulation.
if the drug exists in the unionised form, it will be poorly absorbed if it has poor lipid
solubility (or low Ko/w)
Systemic Circulation
GASTROINTESTINAL
TRACT
CELL
MEMBRANCE
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12. ACIDS
BASE
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13. Limitations of the pH-partition hypothesis
1. Presence of virtual membrane pH
2. Absorption of ionised drug
3. Influence of GI surface area and residence time of drug
4. Presence of aqueous unstirred diffusion layer
PRESENCE OF VIRTUAL MEMBRANE pH
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14. PRESENCE OF AQUEOUS UNSTIRRED DIFFUSION LAYER
Aqueous Bulk Fluid of the GIT
Aqueous Unstirred Layer
Lipoidal Layer (Cell Membrane)
Blood
Limitations of the pH-partition hypothesis
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15. ABSORPTION OF IONISED DRUG
INFLUENCE OF GI SURFACE AREA AND RESIDENCE TIME OF DRUG
Limitations of the pH-partition hypothesis
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16. DRUG PERMEABILITY AND ABSORPTION
M = amount of drug absorbed
Peff = effective membrane permeability
A = surface area available for absorption
Capp = Apparent Luminal Drug Concentration
tres = residence time of Drug in GI lumen
The three major drug characteristics that determine the passive transport or
permeability of drugs across intestinal epithelium are
Lipophilicity of drug expressed as log P.
Polarity of drug which is measured by the number of H-bond acceptors and number of
H-bond donors on the drug molecule.
Molecular size.
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17. Rule of Five by LIPINSKI ET AL which is written as –
Molecular weight of drug ≤ 500
Lipophilicity of drug, log P ≤ 5
Number of H-bond acceptors ≤ 10
Number of H-bond donors ≤ 5
For a given drug, if any two of these values is greater than that specified above,
then oral absorption may be significant problem.
DRUG PERMEABILITY AND ABSORPTION
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18. Dosage form, dosage form related, pharmaceutical excipient
(Pharmaco Technical Factor)
1. Disintegration time (tablets/capsules)
2. Dissolution time
3. Manufacturing variables
4. Pharmaceutical ingredients (excipients/adjuvants)
5. Nature and type of dosage form
6. Product age and storage conditions
PHARMACEUTICAL FACTOR
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19. 1. Disintegration Time:
Coated tablets especially sugar coated have longer DT. DT is directly
proportional to the amount of binder present and the
compressional force of the tablet.
2. Manufacturing /Process variables:
Manufacturing process that affects the DT are :
a. Method of granulation.
b. Compressional force.
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20. 3. Pharmaceutical ingredients:
Excipients used to ensure the acceptability, physicochemical stability during the
shelf life, uniformity of composition and dosage, and optimum bioavailability
and functionality of the drug product.
a. Vehicles b. Diluents
c. Binder and granulating agents d. Disintegrants
e. Lubricants f. Coating
g. Suspending Agents h. Surfactants
4. Nature and type of Dosage form:
As a general rule, the bioavailability of a drug from various dosage form
decreases in the following order:
Solution > Emulsion > Suspension > Capsules > Tablets > Coated tablets > Enteric
Coated tablets > Sustained Release products.
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