ADV BIOPHARMACEUTICS AND PHARMAKINETICS

1. COPS DSU
DEPARTMENT OF PHARMACEUTICS
PRESENTED BY:
SAGAR.G
M. PHARM, 2nd SEM
DEPARTMENT OF PHARMACEUTICS
SUBMITTED TO :
Dr. JOSEPHINE LENO JENITHA
ASST. PROFESSOR
DEPARTMENT OF PHARMACEUTICS
PH PARTITION HYPOTHESIS

2. COPS DSU
DEPARTMENT OF PHARMACEUTICS
It explain drug absorption from GIT and its distribution across
biomembranes.
Drug (>100 daltons) transported by passive diffusion depend
upon:
dissociation constant, pKa of the drug
lipid solubility, K o/w
pH at absorption site.
Most drugs are either weak acids or weak bases whose degree
of ionization is depend upon pH of biological fluid.
PH PARTITION THEORY

3. COPS DSU
DEPARTMENT OF PHARMACEUTICS
For a drug to be absorbed, it should be unionised and the
unionised portion should be lipid soluble.
The fraction of drug remaining unionised is a function of both
Dissociation constant (pKa) and pH of solution.
The pH partition theory is based on following assumption:
GIT acts as a lipoidal barrier to the transport of the drug
The rate of absorption of drug is directly proportional to its
fraction of unionised drug
Higher the lipophilicity of the unionised degree, better the
absorption.

4. COPS DSU
DEPARTMENT OF PHARMACEUTICS
Henderson Hasselbach equation
For acid,
pKa -pH= log [Cu/Ci]
For base,
pKa–pH= log [Ci/Cu]
Ex: Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have
> 99%of unionised form so gets absorbed in stomach
Weak base quinine (pKa=8.5) will have very negligible
unionisation in gastric pH so negligible absorption
Several prodrugs have been developed which are lipid soluble
to overcome poor oral absorption of their parent compounds.

5. COPS DSU
DEPARTMENT OF PHARMACEUTICS
EX: Pivampicilin, the pivaloyloxy-methyl ester of ampicilin is
more lipid soluble than ampicilin.
Lipid solubility is provided to a drug by its partition coefficient
between An organic solvent and water or an aq. Buffer (same pH
of ab. Site)
Ex: Barbital has a p.c. of 0.7 its absorption is 12 %
Phenobarbital ( p.c = 4.8 absorption= 12 %)
Secobarbital (p.c =50.7 absorption= 40 %)

6. COPS DSU
DEPARTMENT OF PHARMACEUTICS
Influence of Drug pKa and GI pH on drug absorption

7. COPS DSU
DEPARTMENT OF PHARMACEUTICS
Drug Solubility and pH
Drug Solubility
The absorption of drug requires that molecule be in
solution at absorption site.
Dissolution, an important step, depends upon
solubility of drug substance.
• pH solubility profile:
pH environment of GIT varies from Acidic in
stomach to slightly Alkaline in a small
intestine.
soluble
1)Basic drug 1) Acidic medium( stomach)
2)Acidic drug 2) basic medium( intestine)

8. COPS DSU
DEPARTMENT OF PHARMACEUTICS
Improvement of solubility:
Addition of acidic or basic excipient
• Ex: Solubility of Aspirin (weak acid) increased by addition
of basic excipient.
For formulation of CRD , buffering agents may be added to
slow or modify the release rate of a fast dissolving drug.

9. COPS DSU
DEPARTMENT OF PHARMACEUTICS
LIPOPHILICITY AND DRUG ABSORPTION:
• The gastro intestinal cell membrane are essentially lipoidal.
Highly lipid soluble drugs are generally absorbed while decidedly
lipid insoluble drugs are in general poorly absorbed.
• Certain drugs are poorly absorbed after oral administration even
though they are largely unionised in the small intestine, low lipid
solubility of the uncharged molecule may be the reason.
• A guide to the lipophilic nature of a drug is its partition
coefficient between a fat like solvent and water or an aqueous
buffer.
• The critical role of lipid solubility in drug absorption is a guiding
principle in drug development. Polar molecules such as gentamicin,
ceftriaxone, heparin and streptokinase are poorly absorbed after oral
administration and must be given by injection.
• Lipid soluble drugs with favorable partition coefficient are usually
well absorbed after oral administration. The selection of a more lipid
soluble compound from a series of research compounds often result in
improved pharmacologic activity.

10. COPS DSU
DEPARTMENT OF PHARMACEUTICS
• Occasionally the structure of an existing drug can be modified to
develop a similar compound with improved absorption.Eg: The
development of clindamycin, which differs from lincomycin by the
single substitution of chloride for a hydroxyl group. Even slight
molecular modification, however runs the risk of also changing the
efficacy and safety profile of the drug. For this reason, medicinal
chemists prefer the development of lipid soluble prodrugs of a drug
with poor oral absorption characteristics.
example: cefuroxime (cefuroxime axetil - acetoxy ethyl ester)
• The lipid solubility of a drug is determined from its oil/water
partition coefficient (ko/w) value.
• This value is a measure of the degree of distribution of drug
between one of the several organic, water immiscible, lipophilic
solvents and an aqueous phase.
• In general, the octonal /pH 7.4 buffer partition coefficient value in
the range of 1 to 2 of a drug is sufficient for passive absorption across
lipoidal membranes.

11. COPS DSU
DEPARTMENT OF PHARMACEUTICS
DEVIATIONS FROM pH-PARTITION THEORY
• The pH-partition theory provides a basic frame work for
understanding drug absorption, but it is an over simplification of a
more complex process.
• The theory indicates that the relationship between pH and
permeation or absorption rate is described by an S- shaped curve
corresponding to the dissociation curve of the drug.
• For a simple acid or base, the inflection point of the pH- absorption
curve should occur at a pH equal to the pka of the drug. This is rarely
observed experimentally.
In general pH absorption curves are less steep then expected and are
shifted to higher pH values for acids and to lower pH values for bases.
The conditions for deviations of the pH-absorption curve from the
course predicted by the simple pH-partition theory are investigated
theoretically. The deviations are an elevation of the asymptotic section
usually approaching zero and/or a shift of the intermediate section,
more exactly of the inflection point, in the direction of the abscissa and/
or the ordinate. In the absence of a special pH at the surface of the
barrier (microclimate pH), the elevation of the asymptotic section can
be attributed to a permeability of the barrier to the ionized form of the
permeating substance.

12. COPS DSU
DEPARTMENT OF PHARMACEUTICS
REFERENCES
1. Milo Gibaldi, biopharmaceutics and clinical pharmacokinetics, fourth edition,
2005, pg:40-45.
2. Leon shargel, Susanna WV-Pong and Andrew B.C.Yu, Applied
biopharmaceutics and pharmacokinetics, fifth edition, 2005, pg:375-379.
3. Alfred Martin, physical pharmacy, fourth edition, 2005, pg:342-346.
4. D.M.Brahmankar, Sunil B Jaiswal, biopharmaceutics and pharmacokinetics a
treatise, first edition, 1995, pg:32-39.
5. G.R. chatwal, biopharmaceutics and pharmacokinetics,first edition ,2003,
pg: 22-24.
6. Leon Lachman, Herbert A.Lieberman, Joseph L. kanig, The theory and
practice of industrial pharmacy, third edition, pg; 222
7. M.E.Aulton, pharmaceutics,The science of dosage form design, second edition,
pg:241-244.
8. Ansels pharmaceutical dosage forms and drug delivery systems, eighth
edition by Loyd V.Allen, Jr. Nichollas G. popovich, Howard C.Ansel.pg:144-147
9. www.boomer.com

13. COPS DSU
DEPARTMENT OF PHARMACEUTICS
THANK YOU