Transport models : permeability , solubility and charge state

1. TRANSPORT MODELS : PERMEABILITY ,
SOLUBILITY – CHARGE STATE AND THE
PH PARTITION HYPOTHESIS
PRESENTED BY :
Nisha N .
M .Pharm 2nd Sem
Dept . Of Pharmaceutics
SUBMITTED TO :
Prof . H . S . Keerthy
Dept . Of Pharmaceutics
Mallige College of
Pharmacy
1/23

2. CONTENTS :
1) Permeability - solubility charge state
2) Ph partition theory
3) Influence of drug pka on drug absorption
4) Drug solubility and PH
5) Lipophilicity and drug absorption
6) Deviation from Ph partition theory
2/23

3. According to Ficks first law passive diffusion of a solute
is the product of diffusivity and concentration gradient of
the solute inside the membrane.
The membrane/water apparent partition coefficient
relates the latter internal gradient to the external bulk water
concentration difference between the two solutions
separated by 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.
The amount of the uncharged form present at a given
pH, which directly contributes to the flux, depends on
several important factors, such as pH, binding to proteins
and bile acids, self-binding, and solubility
Permeability -Solubility charge state
3/23

4. 4/23

5. Consider a vessel is divided into 2 chambers separated by
lipid membrane ,left side is the donor compartment and right
side is the acceptor compartment.
Fick’s first law applied to homogeneous membranes at steady
state is a transport equation,
J= Dm dCm/dx = Dm [ Cm0 - Cmh ] / h
J = flux
Cm0 – Cmh = are the concentrations in mol/cm3 units,
uncharged form of solute within the membrane at two water
membrane boundaries
h = thickness of the membrane
Dm = diffusivity of the solute within the membrane
At steady state, the concentration gradient, dCm/dx, within
the membrane is linear
5/23

6. The limitation of eq. 1 is that measurement of
concentrations of solute within different parts of the
membrane is very inconvenient.
So we can estimate the distribution coefficients between
bulk water and the membrane, log Kd (the pH dependent
apparent partition coefficient),
we can convert eq. 1 into a more accessible form,
J = Dm Kd (CD - CA)/h……... (2)
where the substitution of
Kd allows us to use bulk water concentrations in the donor
and acceptor compartments,
CD and CA, respectively. ( for ionizable molecules, CA
and CD refer to the concentrations of the solute summed
over all forms of charge state.)
6/23

7. Eq. 2 is still not sufficiently convenient, since we need to
estimate Dm and Kd.
 It is a common practice to lump these parameters and the
thickness of the membrane into a composite parameter,
called “membrane permeability,” Pe,
Pe = Dm Kd / h……… (3)
The relevance of eq. 2 (which predicts how quickly
molecules pass through simple membranes) to solubility
comes in the concentration terms.
Consider “sink” conditions, where CA is essentially zero.
Eq. 2 reduces to the following flux equation
J = Pe C ………(4)
7/23

8. Flux depends on the product of membrane permeability
of the solute times the concentration of the solute (summed
over all charge state forms) at the water-side of the donor
surface of the membrane.
This concentration ideally may be equal to the dose of
the drug, unless the dose exceeds the solubility limit, in
which case it is equal to the solubility.
Since the uncharged molecular species is the permeant,
eq. 4 may be restated as
J = Po Co<Po So……… (5)
8/23

9. Where, Po = the intrinsic permeability
Co= concentration of the uncharged species,
respectively.
The intrinsic permeability does not
depend on pH, but its cofactor in the flux equation, Co,
does. The concentration of the uncharged species is always
equal to or less than the intrinsic solubility of the species,
So.
Note that for the uncharged species, eq. 3 takes on
the form
Po = Dm Kp/h………..(6)
where Kp = Cm(0) / CDo; also, Kp = Cm(h) / CAO;
CDo and CAo are the aqueous solution concentrations of
the uncharged species in the donor and acceptor sides,
respectively.
9/23

10. PH PARTITION THEORY
 It explain drug absorption from GIT and its distribution
across bio-membranes.
 Drug (>100 daltons) transported by passive diffusion
depend upon : dissociation constant, pka of the drug lipid
solubility, 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.
For a drug to be absorbed, it should be unionized and the
unionized portion should be lipid soluble.
10/23

11. 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 unionized drug
 Higher the lipophilicity of the unionized degree, better
the absorption
11/23

12. 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 pro-drugs have been developed which are lipid
soluble to overcome poor oral absorption of their parent
compounds.
HENDERSON HASSELBALCH EQUATION
12/23

13. 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 %)
13/23

14. Influence of drug pKa and GI pH on drug absorption
14/23

15. 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.
1)Basic drug 1) Acidic medium( stomach)
2)Acidic drug 2) basic medium( intestine)
Drug Solubility and pH
15/23

16. 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.
16/23

17. Lipophilicity and Drug absorption
The gastrointestinal cell membrane are essentially
lipoidal. Highly lipid soluble drugs are generally absorbed
while 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
17/23

18. 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.
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
18/23

19. 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.
19/23

20. 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
20/23

21. REFERENCES :
1) www.slideshare.net
2) https://www.slideshare.net/SujithaMary1/transport-
models-biopharamaceutics
3) https://www.slideshare.net/DrxShubhamBadhe/semina
r-advance-biopharmaceutics
.
21/23

22. QUESTIONS :
1) Explain Ph partition hypothesis and its limitations ?
( Jan 2020 )
1) Discuss the Ph partition theory of drug absorption ?
( June 2019 )
22/23

23. 23/23