It belongs to a syllabus of Pharmacy.

1. FACTORS AFFECTING DRUG
ABSORPTION
Presented by:
Varsha Barethiya
(M.Pharm sem II)
Department of Pharmaceutics
PJLCP, Nagpur

2. • CONTENTS:
• Introduction
• Cell Membrane structure
• Definition
• Classification of factors affecting drug absorption
• References
2

3. Introduction
3
Cell Membrane:
Cell membrane are mainly consist
of :
1) Lipid bilayer
a) phospholipid
b) cholestrol
c) Glycolipids
2) Proteins
a) Integral membrane protein
b) Lipid anchored protein
c) Peripheral Proteins
i)Hydrophobic nature means lipid
loving- good permeability
property.
ii) Hydrophilic nature means water
loving- good solubility property.

4. Definition of Absorption
4
Absorption process of drug
can be defined as, “the
process of movement of
unchanged form of drug
from the site of
administration to the
systemic circulation.”

5. Factors affecting drug absorption are
listed below as:
I) Pharmaceutical factors:
A] Physico-chemical properties of drug substances:
1. Drug solubility and dissolution rate
2. Particle size and effective surface area
3. Polymorphism and amorphism
4. Pseudo polymorphism ( hydrates and solvates)
5. Salt form of drug
6. Lipophilicity of drug
7. Pka of drug and GIPH
8. Drug Stability
9. Stereochemical nature of drug
B] Formulation factors:
1. Disintegration time
2. Manufacturing variables
3. Nature and type of dosage form
4. Pharmaceutical ingredients
5. Product age and storage conditions
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6. 1.Drug solubility and dissolution rate
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7. • Consider the events that occur following oral administration of a solid dosage
form as shown in fig. Except in case of controlled release formulations,
disintegration and deaggregation occurs rapidly if it is a well formulated
dosage form.Thus, the two critical slower rate determining processes in the
absorption of orally administered drugs are:
• 1. Rate of dissolution
• 2. Rate of drug permeation through the biomembrane.
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•Disintegr
ation/
•Deaggreg
ation
Solid
Dosage
Form
•Dissolutio
n
•RDS for
lipophilic
drug
Solid
Drugs
Particle
s
•Permeatio
n across
the
Biomemb
rane
•RDS for
hydrophil
ic drugs
Drug in
solution
at the
absorpti
on site
Drug in
the
body
Two rate determining steps(RDS) in the absorption of drugs.

8. For Hydrophobic drugs:
1. Dissolution is the rate limited step.
2. Eg.Griseofulvin, spironolactone
For Hydrophilic drugs:
1. Permeation is the rate limited step.
2. Eg: cromolyn sodium, neomycin.
Based on the intestinal permeability and solubility of drugs,
Amidon et al developed Biopharmaceutics Classification System(
BCS) which is as shown in table 1:
8
Class Solubility Permeabili
ty
Absorption
pattern
RLS in
absorption
examples
I High High Well
absorbed
Gastric
emptying
Dilitazem
II Low High Variable dissolution Nifedipine
III High Low Variable permeabilit
y
Insulin
IV Low Low Poorly
absorbed
Case by
case
Taxol

9. For every absorption mechanism except endocytosis the drug should be
present in solution form. This depends on drug’s aqueous solubility
and its dissolution rate.
Absolute or intrinsic solubility is defined as the maximum amount of
solute dissolved in a given solution under standard conditions of
temperature, pressure and pH.
Dissolution rate is defined as the amount of solid substance that goes
into a solution conditions of temperature, pressure, solvent
composition, constant solid surface area and pH.
Theories of drug dissolution are :
1.Diffusion Layer Model ( Film Theory)
2. Danckwert’s Model
3. Interfacial Barrier Model
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10. Diffusion Layer Model
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Danckwert’s Model
1. Suggested that there is no stagnant layer and
existence turbulence at the solid liquid
interface.
2. Agitated fluid consist of packets or
macroscopic mass of eddies which absorb
solute by diffusion and carry it to bulk of the
solution.
3. Solute containing packets are continuously
replaced by packets of fresh solvent; so
concentration at interface will never reach
saturation concentration Cs and has a lower
limiting value Ci.
4. As the solvent packets are exposed to new
surface each time hence it is known as
Surface Renewal Theory.
5. V.dC/dt=dm/dt= A(Cs-Ch)yD
6. Where,
7. m = mass of solid dissolved
8. y = rate of surface renewal

12. Interfacial barrier model/ Double barrier/ limited solvation theory
Diffusion layer model and danckwert’s model were based on the
assumptions
a. Rate limiting step is mass transport.
b. solid solution equilibrium is achieved at the solid liquid.
1. In this model it is assumed that the reaction at solid surfaces is
not instanteous i.e. the reaction at solid surface and its diffusion
across the interface is slower than diffusion across liquid film,
therefore the rate of solubility of solid in liquid film becomes the
rate limiting than the diffusion of dissolved molecules.
2. It suggested that there is no stagnant layer and existence
turbulence at the solid liquid interface.
3. According to this theory, an intermediate concentration exist at
the interface as a result of solvation mechanism.
4. It is a function of solubility rather than diffusion.
G=Ki (Cs-Cb)
Where,
G- dissolution rate per unit area
Ki-effective interfacial transport constant
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2. Particle size and effective surface area of drugs:
Smaller the drug particle, greater the surface area.
Surface
Absolute surface area effective surface area
total surface area of solid area of solid surface exposed to
surface of particles. Dissolution medium
Smaller the particle size ( by micronization) greater is the effective surface area more intimate contact
between solidsurface and aqueous solvent higher is the dissolution rate increase in absorption
efficiency.
Particle size reduction has been used to increase the absorption of a large number of poorly soluble
drugs, such as bishydroxy coumarin, digoxin, griseofulvin, nitrofurantoin and tolbutamide.
Microsize particles improve absorption, but it is improved even more when it is formulated in
ultramicrosize particles as a monomolecular dispersion in polyethylene glycol.
Eg.: Griseofulvin has extremely low aqueous solubility , and material of normal particle size gave rise to
poor and erratic absorption.
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14. 1. Larger the surface area, higher will be the dissolution rate.
2. Surface area will increase as the particle size decreases which can be
accomplished by size reduction of particles.
3. Effective surface area is the one proportion to dissolution rate( not absolute
area).
4. More the effective surface area more faster will be the dissolution rate.
5. In the case of hydrophobic drugs like aspirin, phenobarbital, micronisation
will result in fall in dissolution rate.
6. Hydrophobic surface of drug will adsorb air which inhibits wettability.
7. Particles re aggregate to larger particle which will float or settle to the
bottom of the solvent.
8. Electrically induced agglomeration prevent contact of drug with dissolution
medium.
9. Conversion of absolute surface area of Hydrophobic drugs into effective
surface area-
10.Use of surfactant as wetting agent-
11. Decrease the interfacial tension
12. Displaces adsorbed air with solvent
13.Adding hydrophillic diluents such as PEG, PVP, dextrose,etc.
14. Coating on the surface of hydrophobic drug particles and render them
hydrophilic.
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15. Particle size reduction and subsequent increase in surface area and
dissolution rate is not recommended in certain circumstances.
1. When drugs are unstable and degrade in solution
form(PenicillinG).
2. When drug produces undesirable effects (gastric irritation caused
by nitrofurantoin)
3. When sustained effect is desired.
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Internal structure
of Compound
• Crystalline
• Amorphous(
Non crystalline)
Crystalline
1.Polymorphs:
• A substance
exist in more
than one
crystalline
form.
• 2.Molecular
adducts
Polymorphs
1.Enantiotropic
• It can be changed from
one form to another by
altering the temperature
or pressure.
• 2.Monotropic:
• one which
unstable at all
temp or
pressure

16. 3.Polymorphism and Amorphism
Polymorphs form:
a.Many compounds form crystals with different molecular arrangements, or
polymorphs.
b.These polymorphs may have different physical properties , such as dissolution rate
and solubility.
c.Types of polymorphs:
1.Enantiotropic polymorph 2. Monotropic polymorph
Eg sulphur Eg. Glyceryl stearates
d.40% of all organic compounds- exist in various polymorphic forms.
e.70% of barbiturates and 65% of suphonamides exhibits polymorphism.
f. Stable polymorphs represents the lower energy state and has the highest melting
point and least aqueous solubility.
Metastable forms:
Represents polymorphs the higher energy states, have lower melting points and higher
aqueous sollubility.
Amorphous form:
These have greater aqueous solubility than the crystalline forms because the energy
required to transfer a molecule from crystal lattice is greater than that required
for non-crystalline solid.
Eg.: amorphous form of novobiocin – 10 times more soluble than crystalline form.
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17. 4. Hydrates or solvates:
1. The stoichiometric type of adducts where the solvent molecule are
incorporated with the crystal lattice of the solid are called as
‘Solvates’.
2. Trapped solvent is the solvent of crystalllisation.
3. The solvates can exist in different crystalline forms called as
pseudomorphs and the phenomenon is pseudopolymorphism.
4. When the solvent in association with drug is water, the solvate is known
as hydrates.
eg: anhydrous form of theophylline and ampicillin
High aqueous solubility
dissolve at a faster rate
more bioavailability than their monohydrate
and trihydrate forms
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18. 5.Salt form of drug
1. Most of the drugs are acids or bases,one of the easiest method to increase
their solubility and dissolution rate is covert them into their salts forms.
2. Generally, a weak acidic drug is prepared as its strong basic salt.
3. At any pH solubility of a weak acidic/basic drug is constant.
4. Higher absorption rate of a salt form is explained by pH of diffusion layer and
not pH of the salt.
5. At any given pH of bulk the pH of diffusion layer of a salt form of weak acidic
drug will be higher when compared to free acidic form ofdrug.
6. Since higher pH favours solubility of a weak acid, dissolution and absorption
will be faster.
7. pH of dissolution layer will be lower in the case of salt form of weakly basic
drugs when compared to free form of basic drugs.
8. At given pH, the solubility of drug, whether acidic/basic or its
salt,is a constant.
9. While considering the salt form of drug, pH of the diffusion layer is important
not the pH of the bulk of the solution.
10. For salts of weak acids,
11. [H+]d<[H+]b
12. For salts of weak bases,
13. [H+]d>[H+]b
14. Where [H+]d=[H+] of diffusion layer
15. [H+]b=[H+] of bulk of the solution
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19. In- Situ Salt Formation
1. Other approach to enhance the dissolution and absorption rate of
certain drugs is by in-situ salt formation i.e., increasing in pH of
microenvironment of drug by incorporating buffer agent.
2. Eg. Aspirin, penicillin
3. When a soluble ionic form of the weak acidic drug diffuses from
stagnant layer into bulk of the solution whose pH is low, it will
transformed into its free acid forms with lesser aqueous solubility
and will precipitated as fine particles.
4. Dissolution and absorption rate of Aspirin and Penicillin from
buffered alkaline tablets.
5. Gastric irritation and ulcerogenecity of the drug is greatly reduced.
6. Problem with use of sodium salt of aspirin which has poor
hydrolytic stability is overcome by in situ salt formation.
7. But sometimes more soluble salt form of drug may result in poor
absorption.
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21. 6.Drug Pka and lipophilicity and GI pH----pH
Partition hypothesis
pH- partition theory states that for drug compounds of molecular weight
more than 100, which are primarily transported across the biomembrane
by passive diffusion,
The process of absorption is governed by
a) Dissociation constant pka of drug.
b) The lipid solubility of the unionized drug.
c) pH at the absorption site.
Amount of drug that exist in unionized form and in ionized form is a
function of pka of drug and pH of the fluid at the absorption site and
it can be determined by Henderson Hasselbach equation:
For Acidic drugs
pH= pka+log [ionized form]
[unionized form]
For Basic drugs
pH= pka+log [unionized form]
[ionized form]
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7.Lipophilicity and drug absorption:
Ideally for optimum absorption, a drug should have sufficient
aqueous solubility to dissolve in fluids at absorption site and lipid
solubility (ko/w) high enough to facilitate the partitioning of the
rug in the lipoidal biomembrane i.e drug should have perfect HLB
for optimum Bioavailability.
Ko/w= Distribution of drug in organic phase (octanol)
Distribution of drug in aqueous phase
As Ko/w i.e lipid solubility, i.e. partition coefficient increases
percentage drug absorbed increases.
LIMITATIONS:
1. Prescence of virtual membrane pH
From experimental data it was seen that differences in rate
absorption of salicyclic acid at a given pH from that
predicted by pH partition hypothesis.This is led to the
suggestion that a virtual pH different from luminal pH exist
at the membrane surface.
2. Absorption of Ionised drugs
An important assumption of this theory was that permeation of
ionic drugs is negligible since rate of absorption is 3 to
4times less than that of unionised drug.
pH absorption curves suggest that if a drug have a lipophilic
group in their structure, despite their ionisation they will

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3.Influence of GI surface area and Residence time
1. According to this theory, acidic drugs are best absorbed from
stomach and basic drugs from intestine in which conditions they
are unionised in a large extend.
2. This could be true under conditions where surface area of intestine
and stomach are same.
3. It also explains that once the acidic drug reaches intestine the
remaining fraction will poorly absorbed and unless a basic drug
reaches intestine and absorbed considerably therapeutic effect
may not attained.
4. Irrespective of GI pH and degree of ionisation both acidic and basic
drugs are absorbed in the intestine.
5. This is due to the large surface area and more residence time of
the drug in the intestine.
4. Prescence of Aqueous Unstirred Diffusion layer
1. An aqueous unstirred diffusion layer is exist between bulk of
luminal fluid and the membrane.
2. Such a layer has a real thickness and is a barrier to absorption.
3. For a drug to get absorbed first the drughas to diffuse through this
unstirred layer and then though the lipoidal barrier.
4. Thus the drug having good lipophilicity can pass through the
lipoidal barrier veryfast but diffusion through the unstirred layer
will be the rate limiting step.

25. 8.Drug Stability
1.A drug may be destabilized during its shelf life or in GIT.
2.Two major stability problems leading to poor bioavailability include :
a) degeneration of drug into an inactive form and
b) forming complexes with excipients or components of GIT and forming
complexes that are poorly absorbed.
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26. References:
1.Biopharmaceutics and Pharmacokinetics by
Brahmankar.
2.B iopharmaceutics and pharmacokinetics by V.
Venkateswarlu.
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THANK YOU….