A SEMINAR ON

PHYSICOCHEMICAL PROPERTIES OF DRUG

ABSORPTION/BIOAVAILABILITY

at
UGC-Academic staff college, JNTUH, Kukatpally

By
Mr. NIRANJAN PANDA
M.Pharm, (Ph.D), FICCP
Assistant professor
Department of Pharmaceutics

ANWARUL-ULOOM COLLEGE OF PHARMACY

(New Mallepally, Hyderabad, A.P)
Approved by JNTUH, AICTE and PCI
CONTENTS
INTRODUCTION
PHYSICOCHEMICAL FACTORS AFFECTING DRUG ABSORPTION:
A) DRUG SOLUBILTY AND DISSOLUTION RATE
B) PARTICLE SIZE AND EFFECTIVE SURFACE AREA
C) POLYMORPHISM AND AMORPHISM
D) PSEUDOPOLYMORPHISM (HYDRATES/SOLVATES)
E) SALT FORM OF THE DRUG
F) LIPOPHILICITY OF THE DRUG
G) PKa OF THE DRUG AND GASTROINTESTINAL PH
H) DRUG STABILITY
I) STEREOCHEMICAL NATURE OF THE DRUG
CONCLUSION
BIBLIOGRAPHY
INTRODUCTION

Q) WHAT IS ABSORPTION???
WHAT IS BIOAVAILABILITY???

Absorption is the process of movement of unchanged drug from the site of

administration to systemic circulation.
Bioavailability is defined as rate and extent of unchanged drug that reaches to
systemic circulation i.e rate and extent of absorption of unchanged drug to systemic
circulation.

The main objective to study the physicochemical properties of a drug is to generate

the information useful in the formulation in developing the most bio-available
dosage form which gives optimum therapeutic benefit.
PHYSICOCHEMICAL FACTORS AFFECTING DRUG
ABSORPTION
1)DRUG SOLUBILTY AND DISSOLUTION RATE:
Two rate limiting steps in drug absorption are
1) Rate of dissolution, and
2) Rate of drug permeation through the biomembrane
 Estimates of desired drug solubility for good oral absorption

Dose[mg/kg] High Medium Low

permeability permeability permeability
0.1 1 5 21
1 10 52 207
10 100 520 2100

The concept of maximum absorbable dose (MAD) is nowadays used to correlate drug
absorption with its solubility according to following equation:
MAD=Ka SGI V GI t r
Where,
Ka=intrinsic absorption rate constant,
SGI=the solubility of the drug in the GI fluid,
VGI= the volume of GI fluid present,
tr = residence of drug in GI
-.

Amidon et al developed Bio pharmaceutics Classification System (BCS)

CLASS SOLUBILITY PERMEABILI ABSORPTION RATE EXAMPLES

TY PATTERN LIMITING
STEP IN
ABSORPTION
I HIGH HIGH WELL GASTRIC DILTIAZEM
ABSORBED EMPYTING
II HIGH HIGH VARIABLE DISSOLUTION NIFEDIPINE

III LOW LOW VARIABLE PERMEABILIT INSULIN

Y
IV LOW LOW POORLY CASE BY CASE TAXOL
ABSORBED

CLASS I DRUGS (high solubility/high permeability) are well absorbed orally

since they have neither solubility nor permeability limitation.

CLASS II DRUGS (low solubility/high permeability) show variable absorption

owing to solubility limitation.

CLASS III DRUGS (high solubility/low permeability) also show variable

absorption owing to permeability limitation.
CLASS IV DRUGS (low solubility/low permeability) are poorly absorbed orally
owing to both solubility and permeability limitations
 I)ABSOLUTE OR INTRINSIC SOLUBILTY: The maximum amount of solute
dissolved in a given solvent under standard conditions of temperature, pressure and
pH .It is a static property.

II) DISSOLUTION RATE: The amount of solid substance that goes into the solution
per unit time under standard conditions of temperature, pH and solvent composition
and constant solid surface area. It is a dynamic process.
THEORIES OF DRUG DISSOLUTION

DISSOLUTION:A process in which a solid substance solubilises

in a given solvent that is mass transfer from the solid surface to the liquid
phase. Several theories to explain drug dissolution have been proposed. Some
of the important ones are:

1) Diffusion layer model/film theory

2) Danckwert's model/Penetration or Surface renewal theory,

and

3) Interfacial barrier model/Double-barrier or Limited

solvation theory
I DIFFUSION LAYER MODEL/FILM THEORY:
 Noyes-Whitney Equation for particle dissolution

Rate of Dissolutio n (dc/dt) K (Cs Cb)

when Cs Cb, the equation reduces to:

Rate of dissolutio n (dc/dt) K

Dissolution under sink condition is a zero order process

Modified Noyes-Whitney equation postulated by Brunner & Nernst

DAK w / oCS Cb
Rate of Dissolutio n
Vh
Dissolution rate under non-sink and
sink conditions.
zero order dissolution
under sink condition

first order dissolution under

Conc. of dissolved drug

non-sink condition
(pH
plasma

Time

KLECOP, Nipani
19 November 2010 11

November 27, 2017 10

Hixson and Crowell's cubic root law of dissolution is used:
W01/3-W1/3=Kt
Where,
Wo =original mass of the drug,

W=mass of the drug remaining to dissolve at time t,

K=dissolution rate constant

II.DANCKWERT'S MODEL (PENETRATION OR SURFACE
RENEWAL THEORY):

-The Danckwert's model is expressed by equation:

THE FOLLOWING EQUATION WAS GIVEN BY DANCKWERT:

V dC/dt=dm/dt=A (Cs-C b )
Where,
m= mass of solid dissolved,
g=rate of surface renewal (of the interfacial tension)
III.INTERFACIAL BARRIER MODEL (DOUBLE BARRIER OR
LIMITED SOLVATION THEORY):

The diffusion layer model and the Danckwert's model were based on two
assumptions:

a) The rate-determining step that controls dissolution is the mass transport.

b) Solid-solution equilibrium is achieved at the solid/liquid interface.

According to the interfacial barrier model, an intermediate concentration can

exist at the interface as a result of solvation mechanism and is a function of
solubility rather than diffusion. When considering the dissolution of a crystal, each
face of the crystal will have a different interfacial barrier. Such a concept is given by
the following equation:
G= K i (Cs-Cb)

Where, G=dissolution per unit area, and

K i =effective interfacial transport constant.

FACTORS AFFECTING DRUG DISSOLUTION AND DISSOLUTION
RATE

1) Physicochemical properties of the drug, and

2) Dosage form factors.

The various physicochemical properties of drug that affect drug dissolution and its
rate are: particle size, polymorph

R= d C /d t =2.24Cs

Where,
R=dissolution rate of the drug.

It has been shown that a drug should have a minimum aqueous solubility of 1% to
avoid bioavailability problems.
B) PARTICLE SIZE AND EFFECTIVE SURFACE AREA OF THE
DRUG:

Smaller the drug particle, greater the surface area. Two types of surface area of
interest can b defined:

1) ABSOLUTE SURFACE AREA: The total area of solid surface of any particle,

2) EFFECTIVE SURFACE AREA: The area of solid surface exposed to the

dissolution medium.

This is particularly true in case of drugs which are non-hydrophobic, for example,
micronisation of poorly aqueous soluble drugs like griseofulvin, chloramphenicol
and several salts of tetracycline results in superior dissolution rates in comparison to
the simple milled form of these drugs.

Micronisation has in fact enabled the formulator to decrease the dose of certain
drugs because of increased absorption efficiency, for example, the griseofulvin dose
was reduced to half and that of spiranolactone was decreased 20 times following
micronisation
 The net result of these effects is that there is a decrease in the effective surface area
available to the dissolution medium and therefore a fall in the dissolution rate.
The absolute surface area of hydrophobic drugs can be converted to their effective
surface area by:
1) Use of surfactant as a wetting agent that;
ii ) Decreases the interfacial tension ,and
ii) Displaces the adsorbed air with the solvent.
For example, polysorbate 80 increases the bioavailability of phenacetin by
promoting its wettability.

2) Adding hydrophilic diluents such as PEG, PVP, and dextrose etc which coat the
surface of hydrophobic drug particles and render them hydrophilic.

Particle size reduction and subsequent increase in the surface area and dissolution
rate is not advisable under following circumstances:

i) When the drugs are unstable and degrade in solution (from penicillin G and
erythromycin)

ii) When the drugs produce undesirable effects (gastric irritation caused by
nitrofurantoin)

iii) When a sustained effect is desired

 C) POLYMORPHISM AND AMORPHISM:
Some drugs exist in a number of crystal forms or polymorphs. These different
forms may have different solubility properties and thus different dissolution
characteristics.

Chloramphenicol palmitate is one example which exists in three crystalline forms

A, B and C.
A is the stable polymorph
B is the metastable polymorph (more soluble)
C is the unstable polymorph.

1) ENANTIOTROPIC POLYMORPH: The one which can be reversibly changed into

another form by altering the temperature or pressure. e.g., sulphur.
2) MONOTROPIC POLYMORPH: The one in which is unstable at all temperatures
and pressures.e.g, glyceryl stearates

About 40% of all organic compounds can exist in various polymorphic forms.70%
of barbiturates and 65% of sulphonamides exhibit polymorphism. Barbital, methyl
paraben and sulpha pyridine can exist in as many as 6 polymorphic forms and
cortisone acetate in 8 forms.

Amorphous>Meta stable>Stable
 D) PSEUDOPOLYMORPHISM (HYDRATES/SOLVATES):-

The stoichometric type of adducts where the solvent molecules are incorporated in
the crystal lattice of the solid are called as the solvates, and the trapped solvent as
solvent of crystallization. The solvates can exist in different crystalline forms called
as pseudo polymorphs. This phenomenon is called as pseudo polymorphism.

Generally, the anhydrous form of a drug had greater aqueous solubility than the
hydrates. This is because the hydrates are already in interaction with water and
therefore have less energy for crystal break-up in comparison to the anhydrates
(thermodynamically higher energy state) for further interaction with water.

For example,theophylline and ampicillin have higher aqueous solubilities

For example the n- pentanol solvate of fludrocortisone and succinylsulphathiazole

and the chloroform solvate of griseofulvin are more water-soluble than their non-
solvated forms.
 E) SALT FORM OF THE DRUG:

In case of salts of weak bases, the pH of the diffusion layer will be lower in
comparison to that found with the free base form of the drug. Consequently, the
solubility of a basic drug at this lower pH is enhanced. Thus, if:
[H+]d=hydrogen ion concentration of the diffusion layer, and
[H+]d=hydrogen ion concentration of the bulk of the solution, then,
For salts of weak acids [H+]d<[H+]b
For salts of weak bases [H+]d<[H+]b
 a)Firstly, the gastric irritation and ulcerogenic tendency of the drug is greatly
reduced.
b) Secondly, the problem is with the use of sodium salt of aspirin (to enhance the
solubility) which otherwise has poor hydrolytic

For example, the bioavailability of novobiocin from its sodium salt, calcium salt and
free acid form was found to be in the ratio-50:25:1.Where the counter ion is very
large is size and/or has poor ionic strength (as in case of ester form of drugs),the
solubility may be much lower than the free drug itself stability, is overcome by in
situ formation.

For example, the paomates, stearates and palmitates of weak bases have poor
aqueous solubility. These forms are, however, useful in several ways such as to
prolong the duration of action (steroidal salts), to overcome bad taste
(chloramphenicol palmitate), to enhance GI stability (erythromycin estolate) or to
decrease the side effects, local or systemic.

Slower dissolution with sodium salt was observed and the reason attributed to it was
that its tablet swelled but did not disintegrate and thus dissolved slowly. An identical
result was obtained with hydrochloride salts of several tetracycline analogs and
papaverine; better dissolution and bioavailability was observed with the free bases.
The reason for poor solubility and dissolution rate was the suppression action on the
common ion effect.
: F) DRUG pKa AND LIPOPHILICITY AND GI pH (PARTITION
HYPOTHESIS):

The pH partition theory (Brodie et.al) explains in simple terms, the process of
drug absorption from the GIT and its distribution across all biological
membranes. 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:

a)The dissociation constant(pKa)of the drug

b)The lipid solubility of the unionised drug(a function of drug k o/w)
c)The pH at the absorption site
The above statement of the hypothesis was based on the assumptions that:
a) The GIT is a simple lipoidal barrier to the transport of drug.
b) Larger the fraction of unionised drug, faster the absorption.
c) Greater the lipophilicity (K o/w) of the unionised drug, better the absorption

DRUG pKa AND GASTROINTESTINAL pH:

For weak acids:
pH=pKa+ log [ionised drug]/[Unionised drug]
%Drug Ionised=10(pH-pka)/1+10(pH-pKa)*100

For weak bases:

pH =pKa+ log [Unionised drug]/ [Ionised drug]
%Drug Ionised=10(pKa-pH)/1+10(pKa-pH)*100
 For weak acids,

Ra=CGIT/Cplasma= (1+10(pHGIT-pKa))/1+10(pHplasma -pKa)\

For weak bases,

Ra=CGIT/Cplasma= (1+10(pKa -pHGIT))/1+10 (pKa-pHplasma)

For weak acids,

Ra=CGIT/Cplasma= (1+10(pHGIT-pKa))/1+10(pHplasma -pKa)

For weak bases,

Ra=CGIT/Cplasma= (1+10(pKa -pHGIT))/1+10 (pKa-pHplasma

 For acidic drugs,

ST= Sa [1+10(pH-pKa)]
For basic drugs,

ST=Sb [1+10(pKa-pH)]

Certain conclusions and generalizations can now be stated:

FOR WEAKLY ACIDIC DRUGS,

1) When pH> pKa, ST>> Sa because ionisation of drug increases tremendously.
2) When pH=pKa, ST=2Sa, because the drug is 50% ionised.
3) When pH<pKa, ST = Sa since the drug exists predominantly in unionised form

FOR WEAKLY BASIC DRUGS:

1) When pH>pKa , ST= Sb since the drug exists predominantly in unionised form.
2) When pH=pKa , ST=2Sb because the drug is 50% ionised.
3) When pH< pKa ,ST>>Sb because ionisation of drug increases tremendously
G) LIPOPHILICITY AND DRUG ABSORPTION

In general, the octanol/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. For
ionisable drugs where the ionised species does not partition into the aqueous phase,
the apparent partition coefficient (D) can be calculated from following equations-

For acidic drugs,

Log d=log P-log [1+10(pH-pKa)]

For basic drugs,

Log d=log P-log [1+10(pKa-pH)]

In other words, a perfect Hydrophilic-Lipophilic balance (HLB) should be there in

the structure of the drug for optimum bioavailability.

The lipid solubility of a drug is measured by a parameter called as log P where P is

oil/water partition coefficient (Ko/w or simply P) value of the drug. This value is a
measure of the degree of distribution of drug between lipophilic solvents such as n-
octanol and an aqueous phase (water or a suitable buffer).
LIMITATIONS OF pH-PARTITION HYPOTHESIS

1) PRESENCE OF VIRTUAL MEMBRANE pH

2) ABSORPTION OF IONISED DRUGS::

The principle is true to a large extent as ionised drugs have low lipid
solubility and relatively poor permeability. However, the pH-absorption curve shift
suggested that ionised forms of some drugs also get absorbed to a considerable
extent.

If such drugs have a large lipophilic group in their structure, despite their ionisation,
they will be absorbed passively. For example, morphine derivatives. The principle is
Non-ionic diffusion.
 3)INFLUENCE OF GI SURFACE AREA AND RESIDENCE TIME OF DRUG:

According to the pH-partition theory, acidic drugs are best absorbed from
stomach (acidic pH) and basic drugs from intestine (alkaline pH)in which
conditions they are unionised to a larger extent.
Primarily because of its large surface area and,
Secondly because of long residence time of the drug in the intestine

4) PRESENCE OF AQUEOUS UNSTIRRED DIFFUSION LAYER:

DRUG PERMEABILITY AND ABSORPTION
M=P eff A Capp t res
Where,
M=amount of drug absorbed
Peff=effective membrane permeability
A=surface area available for absorption
Capp=apparent luminal drug concentration
t res=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:
a) Lipophilicity of drug expressed as log P,
b) Polarity of drug which is measured by the number of H-bond acceptors and
number of H-bond donors on the drug molecule.
c) Molecular size
i) Molecular weight of drug <= 500,
ii) Lipophilicity of drug, log P <= 5,
iii) Number of H-bond acceptors <= 10,
iv) Number of H-bond donors <= 5.

If any two of these values are greater than specified limits, the oral absorption of a
drug may be a significant problem.
 H) DRUG STABILITY

A drug for oral use may destabilize either during its shelf-life or in the GIT
.Two major stability problems resulting in poor bioavailability of an orally
administered drug are degradation of the drug into inactive form, and interaction
with one or more different components either of the dosage form or those present in
the GIT to form a complex that is poorly soluble or is unabsorbable.

I) STEREOCHEMICAL NATURE OF DRUG:

Chiral drugs constitute approximately 60%of the drugs in current use. Majority of
these are marked as racemic mixtures.

Although it is well established that optical isomers differ in the potency of

pharmacological effect, it is only recently that attention is being paid to influence of
chirality on pharmacokinetic processes like absorption, distribution and eliminaion.

However, biological processes such as protein binding which require interaction of a

drug with a macromolecule may exhibit stereo selectivity.
 CONCLUSION
BIBLIOGRAPHY:

1) D M Bramhankar, Sunil B.JaiswalBio pharmaceutics and Pharmacokinetics.1

edition Vallabh prakashan Delhi;1995.Pg no:27-51

2) Jain, N.K, Controlled and Novel Drug Delivery, first edition, CBS publishers and
distributors, New Delhi.1997 pg 227-245

3) L.Lachman, H.A, Lieberman and J.L.Kanig,Theory and Practice of Industrial

Pharmacy by, Lea and Febieger,Philadelphia latest edition page-143-157
QUESTIONS??
THANK YOU