pH partition theory of drug absorption, 2nd semester M pharmacy

1. DRUG ABSORPTION FROM THE GASTROINTESTINAL TRACT
TOPIC : pH partition theory of drug absorption
PRESENTED BY,
Aravinda P N
I M Pharma
Department of Pharmaceutics
GCP
SUBMITTED TO,
Dr.Vijaya G Joshi,
Department of Pharmaceutics
GCP

2. Contents:
 Introduction
pH-Partition theory
Drug pKa and GI pH
Lipophillicity and drug Absorption
Limitations of pH-partition Hypothesis
Conclusion
References

3.  Introduction
A drug injected Intravascular directly enters the systemic
circulation and exerts its pharmacological effects.
But, Majority of drugs are administered orally which is
intended to act systemically.
Such drugs can exert their pharmacological actions only when
they enter into systemic circulation by the process of absorption.
Drug absorption is defined as the process of movement of
unchanged drug from the site of administration to systemic
circulation.

4. pH- PARTITION THEORY
Understanding of the interrelationships between the rate of drug
absorption, the dissociation constant (pKa) and the pH of the
absorption site is known as the pH-partition theory.
The theory states that for drug compounds of molecular weight
greater than 100, which are primarily transported across the bio
membrane by passive diffusion.
The process of absorption is governed by:
1. The dissociation constant (pKa) of the drug.
2. The lipid solubility of the unionized drug.
3. The pH at the absorption site.

5. Brodie proposed the partition theory to explain the
influence of GI pH and drug pKa on the extent of drug
transfer or drug absorption.
• pH partition theory of drug absorption is based on the
GIT is a simple lipid barrier to the transport of drugs and
chemicals.
• Accordingly the unionized form of an acid or basic
drug, if sufficient lipid soluble, is absorbed but the
ionized form is not.
• The larger the fraction of drug is in the unionized form
at a specific absorption site, the faster is the absorption.

6. DRUG pKa and GI pH
• The fraction of drug in solution that exist in the unionized
form is a function of both dissociation constant of the drug
and the pH of the solution.
• The dissociation constant is often expressed for both acids
and bases as pKa (the basic logarithm of the acidic
dissociation constant).
• It is customary to express the dissociation constants of both
acidic and basic drugs by pKa values.
• The lower the pKa of an acidic drug, the stronger the acid
i.e., greater the proportion of ionized form at a particular pH.
The higher the pKa of a basic drug, the stronger the base.

7. Thus from the knowledge of pKa of the drug and pH at the absorption
site (or biological fluid), the relative amount of ionized and unionized
drug in solution at a particular pH and the percent of drug in solution at
this pH can be determined by Henderson- Hasselbach equation,
i.e., for weak acids:
𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔
[𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔]
[𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔]
%𝐷𝑟𝑢𝑔 𝐼𝑜𝑛𝑖𝑧𝑒𝑑 =
10(𝑝𝐻−𝑝𝐾𝑎)
1+10(𝑝𝐻−𝑝𝐾𝑎)100
For weak bases:
𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔
[𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔]
[𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔]
%𝐷𝑟𝑢𝑔 𝐼𝑜𝑛𝑖𝑧𝑒𝑑 =
10(𝑝𝐾𝑎−𝑝𝐻)
1+10(𝑝𝐾𝑎−𝑝𝐻)100

8. When the concentration of ionized drug becomes equal,
(since log1=0) and thus pH= pka. The pka is the
characteristic of the drug.
𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔
[𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔]
[𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝐷𝑟𝑢𝑔]
𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔
[50]
[50]
𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔1
𝑝𝐻 = 𝑝𝐾𝑎 + 0
𝑝𝐻 = 𝑝𝐾𝑎

9. A membrane barrier that separates the aqueous solutions of different pH such as
GIT and plasma then the theoretical ratio R of drug concentration on either
side of the membrane can be given by the equation,
For weak acids:
𝑅𝑎 =
𝐶𝐺𝐼𝑇
𝐶𝑝𝑙𝑎𝑠𝑚𝑎
=
1 + 10(𝑝𝐻𝐺𝐼𝑇−𝑝𝐾𝑎)
1 + 10(𝑝𝐻𝑃𝑙𝑎𝑠𝑚𝑎−𝑝𝐾𝑎)
For weak bases:
𝑅𝑏 =
𝐶𝐺𝐼𝑇
𝐶𝑝𝑙𝑎𝑠𝑚𝑎
=
1 + 10(𝑝𝐾𝑎−𝑝𝐻𝐺𝐼𝑇)
1 + 10(𝑝𝐾𝑎−𝑝𝐻𝑃𝑙𝑎𝑠𝑚𝑎)
pH Range In GIT
• The pH range in GIT from 1-8
stomach is from 1-3
Intestine (from duodenum to colon) 5-8,
• then certain generalization regarding ionization and absorption of drugs can
be made, as predicted from pH partition hypothesis.

10. For Weak Acids For Basic Drugs
1. Very weak acids (pKa > 8) are
essentially unionized at all pH values
and therefore their absorption is rapid
and independent of Gl pH.
1. Very weak bases (pKa, < 5.0) are
essentially unionized at all pH values
and there fore their absorption is
rapid and pH-independent.
2.Moderately weak Acids in the pKa,
range 2.5 to 7.5 are greatly affected by
changes in pH and therefore their
absorption is pH-dependent. Such
drugs are better absorbed from acidic
conditions of stomach (pH <pKa) where
they largely exist in unionized form.
2.Moderately weak Bases in the pKa,
range 5 to 11.0 are greatly affected by
changes in pH and hence their
absorption is pH-dependent. Such drugs
are better absorbed from the relatively
alkaline conditions of the intestine where
they largely exist in unionized form.
3. Stronger acids with pKa, < 2.5 are
ionized in the entire pH range of GIT
and therefore remain poorly absorbed
3. Stronger bases with pKa, > 11.0 are
ionised in the entire pH range of GIT and
therefore poorly absorbed

11. Drugs pKa pH site of absorption
Very weak acids (pKa,> 8.0)
Pentobarbital
Phenytoin
Ethosuximide
8.1
8.2
9.3
Unionised at all pH values Along the entire length of GIT
Moderately weak acids(pKa, 2.5 to 7.5)
Cloxacillin
Aspirin
Ibuprofen
2.7
3.5
4.4
Unionised in gastric pH &
Ionised in intestinal pH
Better absorbed from stomach
Stronger acids (pKa < 2.5)
Disodium cromoglycate 2.0 Ionised at all pH Poorly absorbed from GIT
Very weak bases (pKa<5.0)
Theophylline
Caffeine
Diazepam
0.7
0.8
3.7
Unionised at all pH values Absorbed along the entire length
of GIT
Moderately weak bases (pKa 5 to 11.0)
Reserpine
Codeine
Amitriptyline
6.6
8.2
9.4
Ionised at gastric pH
relatively unionised at
intestinal pH
better absorbed from intestine
Stronger bases (pKa > 11.0)
Guanethidine 11.7 Ionised at all pH values poorly absorbed from GIT
Influence of Drug pKa and GI pH on Drug Absorption

12. LIPOPHILICITY (𝑲𝒐/𝒘) AND DRUG ABSORPTION
• The unionised drug -> if sufficiently lipid soluble-> is
absorbed into the systemic circulation.
• If it has poor lipid solubility ->it will be poorly
absorbed.
• Therefore for optimum absorption -> a perfect HLB
should be required.
• The lipid solubility of a drug is determined
from its oil/water partition coefficient (𝑲𝒐/𝒘) value.

13. Limitations of pH-partition Hypothesis:
1. Presence of virtual membrane pH
2. Absorption of ionized drug
3. Influence of GI surface area and residence time of
drug
4. Presence of aqueous unstirred diffusion layer.

14. 1. Presence of virtual membrane pH:
pH-absorption curve for Acidic and basic drugs.
Dotted lines – Curves predicted by pH-partition hypothesis (only
unionised drug absorbed)
Bold lines – the practical curves (less sleep and shifted)
The Virtual pH also called as the microclimate pH, is different from the
luminal pH exists at the membrane surface.

15. 2. Absorption of ionized drugs :
• As per hypothesis – only unionised form of drug
absorbed and ionised drug is negligible ( 3to4 times less)
– Principle of non-ionic diffusion.
• pH absorption curve shift suggested that ionised forms of
some drugs also get absorbed to a some extent.
• If such drugs have large lipophilic group in their
structure, despite their ionization , they will be absorbed
passively or by active transport , ion pair transport and
convective flow.

16. 3.Influence of GI surface area and residence time of drug
• According to theory – (condition of unionized form in large extent)
Acidic drugs are best absorbed from stomach
Basic drugs are best absorbed from intestine
• But Surface area of Stomach and intestine is different.
• Once a Acidic drug reaches the intestine, the remaining fraction will
be poorly absorbed .
• It may not be attain its therapeutic level.
• But irrespective of GI pH and degree of ionization both acidic and
basic drugs are more rapidly absorbed from intestine, because of its
large surface area , long residence time.

17. 4. Presence of aqueous unstirred diffusion layer
• The bulk of the luminal fluid is not in direct
contact with the membrane but a barrier called
as aqueous unstirred diffusion layer present in
between them.
• Such layer has thickness and it acts as barrier to
absorption of drugs.
• As per pH- partition theory the rate limiting step
in the absorption was partitioning in the lipid
barrier.
• Presence of aqueous unstirred diffusion layer, a
drug must diffuse first through this barrier and
then through the lipoidal barrier.
• Thus , drugs having large Partition coefficient
can rapidly penetrate the lipid membrane but
diffusion through aqueous unstirred layer is the
rate limiting step.

18. CONCLUSION
• In many cases, the ionized and unionized forms of a drug are
appreciably transported across lipophilic membrane.
• But the extension of pH partition theory to incorporate the
effects of the unstirred layer and microclimate pH provides a
far more satisfactory rationalization of the experimental data.
• Despite its limitation the pH –Partition theory is still useful in
the basic understanding of drug absorption and movement of
drug between various body compartments

19. REFERENCE
1. D.M.Brahmankar And S.B.jaiswal, Textbook of
Biopharmaceutics and Pharmacokinetics A treatise, Sixth
edition,Vallabh Prakashan.
2. Jollow .D.J and Brodie B.B, Mechanism Of Drug
Absorption And Of Drug Solution.

20. THANK YOU