BIOPHARMACEUTICS

Institute of Pharmaceutical Research

 Content
1
• Correlation of in vivo data with in vitro dissolution data.

2 • Transport model : Permeability-Solubility-charge state

3 •The pH partition Hypothesis

4 • pH Microclimate Intracellular pH Environment

5 • Tight-Junction Complex.

6 • References

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Correlation of in vivo data with in vitro dissolution
data

3
 IVIVC - Definition
• FDA :
A predictive mathematical model describing the relationship
between an in vitro property of dosage form (usually the
rate or extent of drug dissolution or release) and a relevant
in vivo response, e.g., plasma drug concentration or amount
of drug .
• USP :
The establishment of a relationship between a biological
property or a parameter derived from a biological property
(Cmax, AUC) produced by a dosage form, and a
physicochemical characteristic (in vitro release) of the same
dosage form.

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• Fick’s first law applied to a membrane shows that passive
diffusion of a solute is the product of the diffusivity and the
concentration gradient of the solute inside the membrane. For
an ionizable molecule to permeate by passive diffusion most
efficiently, the molecule needs to be in its uncharged form at the
membrane surface.
• Consider a vessel divided into two chambers, separated by a
homogeneous lipid membrane. The left side is the donor
compartment, where the sample molecules are first introduced;
the right side is the acceptor compartment, which at the start
has no sample molecules.
 Figure - Transport model diagram, depicting two aqueous cells
separated by a membrane barrier.
.
 drug permeation

Hydrophilic drugs permeates by Intercellular pathway and Lipophilic

drugs permeates by Intracellular (Transcellular) mechanism.
 pH - Partition Theory:
- 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.

- As most drugs are weak electrolytes, the unionized form

of weakly acidic or basic drugs (the lipid-soluble form) will
pass across the gastrointestinal epithelia, whereas the
gastrointestinal epithelia is impermeable to the ionized
(poorly-lipid soluble) form of such drugs.

- Consequently, the absorption of a weak electrolyte will be

determined by the extent to which the drug exists in its
unionized form at the site of absorption.
pH - Partition Theory (Cont.):

Diagram Showing Transfer Across Membrane

 pH - Partition Theory (Cont.):
- The extent to which a weakly acidic or basic drug ionizes in
solution in the gastrointestinal fluid may be calculated
using Henderson - Hasselbach equation.
** Weak acids (e.g. aspirin):

Dissociation Constant equation - Weak Acids

taking the negative log of both sides

 pH - Partition Theory (Cont.):

Rearranging gives the following equation:

Henderson - Hasselbach Equation - Weak Acids

 pH - Partition Theory (Cont.):

Rearranging gives the following equation:

Henderson - Hasselbach Equation - Weak Acids

 pH - Partition Theory (Cont.):
**Weak Bases:

Henderson - Hasselbach Equation - Weak Bases

Limitations of the pH-partition hypothesis:

-Despite their high degree of ionization, weak acids are highly
absorbed from the small intestine and this may be due to:
1- The large surface area that is available for absorption in
the small intestine.
2- A longer small intestine residence time.
 pH - Partition Theory (Cont.):
3- A microclimate pH, that exists on the
surface of intestinal mucosa and is lower
than that of the luminal pH of the small
intestine.
 pH Microclimate :
The absorption of short-chain weak acids in the rat intestine, as a
function of pH, does not appear to conform to the pH partition
hypothesis . Similar anomalies were found with weak bases . The
apparent pKa values observed in the absorption– pH curve were
shifted to higher values for acids and to lower values for bases,
compared with the true pKa values. Such deviations could be
explained by the effect of an acid layer on the apical side of cells,
the so-called acid pH microclimate.

 Intracellular pH environment :
Intracellular pH (pHi) is the measure of the acidity or basicity
(i.e., pH) of intracellular fluid. The pHi plays a critical role in
membrane transport and other intracellular processes.
Physiologically normal intracellular pH is most commonly
between 7.0 and 7.4. Intracellular pH is typically lower than
extracellular pH due to lower concentrations of HCO3−.
Tight junction also known as occluding junction.tight
junction are composed of branching network of sealing
strands, each strand acting independently from the other.The
function of tight junction is to hold the cell together & also
the tight junction are help to maintain the polarity of cell by
preventing the lateral diffusion of integral membrane
protein between apical and lateral/basal surface.
1. Leon Shargel, Andrew B.C.YU “Applied biopharmaceutics
and pharmacokinetics”Seventh edition,Mc Graw Hill
Education, pg no.390-393,429-431.
2. Avdeef alex “Absorption and drug development ’’A john
Wiley & sonc Inc publication, pg no.7-18.
Introduction to 32
Liposome