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Chapter 2

ABSORPTION

2.1 Routes of drug administration: Emphasis on

Oral, parenteral and Extravascular routes (Self
study) [2 hrs]
2.2 Factors affecting drug absorption:
Physicochemical factors (Emphasis on pH
partition theory and solubility) [3 hrs]
2.3 Factors affecting drug absorption:
Physiological factors (Emphasis on physiology
of GIT) [3 hrs]
2.4 Factors affecting drug absorption:
Formulation and Dosage form factors (Self
study) [2 hrs]
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Factors affecting drug

absorption/ bioavailability

Biopharmaceutical consideration
in dosage form design

Desired
therapeutic effect

Drug must be
delivered from the
drug product at

Optimal rate Optimal amount

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Events occurring after oral

administration of a solid dosage form

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 Rate Determining Step (RDS) – the rate at

which the drug reaches the systemic
circulation is determined by the slowest of
the various steps involved in the sequence.
This is known as the RDS.
 This can get affected by various factors

Factors affecting
absorption/ BA

Pharmaceutical Patient related

factors factors

Dosage
Drug
form
related
related
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Solubility
and

Depends on physico-chemical
dissolution
Stereoche rate Particle
mical size and
nature of surface
properties of the drug the drug area

Polymorphis
Drug m and
stability Drug amorphism
related
factors

Pseudopoy
Lipophilicit morphism
y

pKa of the
drug Salt form

Drug in Solid
Solid drug
Drug in body solution at the dosage
particles
absorption site form

Permeation Dissolution Disintegration

Rate limiting step for Rate limiting step for

hydrophilic drug lipophilic drug

1. Drug solubility and dissolution rate

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Orally administered
drug

Absorption process

Drug permeation
Dissolution through
biomembrane

RDS for poorly water RDS for poorly

soluble drugs eg. permeable drug eg
Griseofulvin, neomycin, cromolyn
spironolactone sodium 11

Maximum absorbable dose [MAD]

Dose [mg/ kg] Desired solubility values (mg/ml) for drugs with
High permeability Medium permeability Low permeability
0.1 1 5 21
1 10 52 210
10 100 520 2100

𝑀𝐴𝐷 = 𝐾𝑎 𝑆𝐺𝐼 𝑉𝐺𝐼 𝑡𝑟

Where:
Ka – intrinsic absorption rate
SGI – the solubility of the drug in the GI fluid
Dose > MAD – drug
VGI – the volume of GI fluid present absorption is not a
tr – residence of the drug in GI limiting factor for efficacy
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Biopharmaceutical Classification
System

Class I Class II
Solubility Solubility
Permeability Permeability
e.g. Paracetamol, e.g. Cinnarizine,
metoprolol Famotidine
BCS
classification e.g. Griseofulvin,
e.g. Atenolol, ranitidine
spironolactone
Class III Class IV
Solubility Solubility
Permeability Permeability 13

BCS Solubility Permeati Absorptio Rate Examples

Class on n limiting of drug
step in
absorptio
n
I High High Good Gastric Diltiazem
emptying
II Low High Variable Dissolutio Nifedipine
n
III High Low Variable Permeabil Insulin
ity
IV Low Low Poor Case by Taxol
case

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Solubility and dissolution

 An important prerequisite for the absorption of a drug by all
mechanism except endocytosis is that the drug must be
present in aqueous solution.
 This depends on drug’s absolute solubility and dissolution rate

Absolute solubility Dissolution rate

The amount of solid substance that goes into
Maximum amount of solute dissolved in a given
solution per unit time under standard
solvent under standard conditions of
conditions of temperature, pH, solvent
temperature, pressure and pH.
composition and constant solid surface area

It is a static property It is a dynamic process

15

 Several drugs have poor aqueous solubility which

has a bearing on dissolution rate
 It is important especially when the solubility is less
than 1 – 2 mg/ml in the pH range of 2 – 8.
 Exception: Cisapride – low aqueous solubility but
sufficient oral bioavailability.
 There can be 2 reasons for this:
1. Rapid rate of dissolution despite low aqueous solubility
2. The therapeutic dose of drug must be so small that the GI
transit time is sufficient for adequate dissolution and
absorption to occur.
 Thus in contrast to absolute solubility the dynamic
process of dissolution is better related to drug
absorption and bioavailability
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Theories of dissolution

17

Theories of dissolution

 Dissolution – it is a process in which a solid

substance solubilises in a given solvent i.e. mass
transfer from solid surface to the liquid phase.
 Several theories describe the process of
dissolution
1. Diffusion layer model/ film theory
2. Danckwert’s model/ Penetration or surface
renewal theory
3. Interfacial barrier model/ double barrier model
or limited solvation theory

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Theory I
Diffusion layer model/ film theory
 Simplest and most common theory
Saturated Forms a thin
Interphase of
solution of drug film or layer at
solid and liquid
is formed the interphase

Known as
Diffusion of
Rapid step stagnant film or
soluble solute
diffusion layer

From stagnant
Hence rate
layer to bulk of Slower step
limiting step
the solution

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Dissolving solid drug GI lumen GI barrier Blood

Solid-liquid
interphase Stagnant diffusion layer of thickness “h”
and concentration “Cs”

Solid
drug
particle

Diffusion of
molecules

Bulk of solution with concentration “Cb”

Diffusion layer model for drug dissolution

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The earliest equation to explain the rate of dissolution when

the process is diffusion controlled and involves no chemical
reaction was given by Noyes and Whitney in 1897

Arthur A. Noyes with Willis R. Whitney studied the

dissolution of two sparingly soluble compounds, benzoic
acid and lead chloride.

The materials were laid around glass cylinders which were

submerged into vessels containing water. The cylinders were
rotated at constant speed and under constant temperature.

The authors noticed that the rate of dissolution is

proportional to the difference between the instantaneous
concentration, C at time t, and the saturation solubility, CS

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 This statement can be formulated

mathematically as follows:
𝑑𝐶 𝐴 𝐶𝑠 −𝐶𝑏

𝑑𝑡
∝ ℎ
𝑑𝐶 𝐷𝐴 𝐶𝑠 −𝐶𝑏
 =
𝑑𝑡 ℎ
𝑑𝐶

𝑑𝑡
= 𝑘(𝐶𝑠 − 𝐶𝑏)

 Where;
 dc/dt = dissolution rate of the drug
 k = dissolution rate constant (first order) =
DA/h
 Cs = concentration of drug in the stagnant
layer (also known as saturation or
maximum drug solubility)
 Cb = concentration of drug in the bulk of
the solution at time t
 This is based on Fick’s second law of
diffusion

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 Nernst and Brunner incorporated Fick’s first law

of diffusion and modified the Noyes-Whitney
equation to:
𝑑𝐶 𝐷𝐴𝑘𝑤/𝑜 (𝐶𝑠 −𝐶𝑏 )
 =
𝑑𝑡 𝑉ℎ
 Where;
 D = diffusion coefficient (diffusivity) of drug
 A = surface area of dissolving solid
 Kw/o = partition coefficient of the drug
 V = volume of dissolution medium
 h = thickness of stagnant layer
 (Cs-Cb) = concentration gradient for diffusion of drug
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Influence of some factors on

dissolution rate of drug
Parameters Symbo Influence on drug dissolution
l
Diffusion coefficient D Directly proportional
Diffusion decreases as viscosity of dissolution medium
increases
Surface area of solid A Directly proportional
Can be improved by micronisation
Water/oil partition Kw/o Higher the value faster dissolution in aqueous fluids
coefficient
Concentration (Cs-Cb) Directly proportional.
gradient Can be increased by increasing drug solubility and
volume of medium
Thickness of h Inversely proportional
stagnant layer Can be decreased by agitation
Volume of the V Inversely proportional 25
dissolution medium Can be enhanced by taking minimum volume of solvent

Sink condition
 In vivo dissolution is always rapid
than in vitro dissolution
 The moment the drug dissolves it
is absorbed into the systemic
circulation
 As a result Cb = o
 Maximum concentration gradient
is maintained
 No concentration built-up hence
the process does not slow down
 At any point Cs >> Cb
 This is known as sink conditions

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Non-Sink condition

 First order dissolution rate process – normally

 (Cs-Cb) = concentration gradient is the
driving force
 If in vitro dissolution is carried out in limited
volume of medium
 After sometime the concentration gradient
decreases and hence the process slows down
 This is know as non-sink condition

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 Under sink condition if the volume of medium and

surface area of solid are kept constant, the equation
changes to
𝑑𝐶
 = 𝑘𝐶𝑠
𝑑𝑡
 Where k incorporates all the constants
 This equation represents that dissolution rate is
constant under sink conditions and follows zero
order kinetics i.e. yields a linear plot
 The in vitro sink conditions are so maintained that
Cb is always less than 10% of Cs

The term sink conditions is defined as the volume

of medium at least greater than three times that
required to form a saturated solution of a drug
substance – As per WHO guidelines
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The Noyes-Whitney’s equation assumes that the surface area of

the dissolving solid remains constant during dissolution, which is
practically not possible for dissolving particles.

Hence, dissolution methods that involves use of constant surface

area discs are employed to determine the rate of dissolution.

To account for the particle size decreases and change in the surface area
accompanying dissolution, Hixson and Crowell’s cubic root law of
dissolution is used:

Wo1/3– W1/3= K.t W = mass of drug remaining to be dissolved at

Where, time t
K = dissolution rate constant

Wo = original mass of the drug

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Theory II
Danckwert’s model/ Penetration or surface
renewal theory

Danckwert did not approve of the existence of a

stagnant layer

He suggested that turbulence in the dissolution

medium exists at the solid/ liquid interphase

Thus the agitated fluid consists of macroscopic

mass of eddies or packets

These reach the solid/ liquid interphase in a

random fashion due to eddy currents

They absorb the solute by diffusion

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Such solute containing packets are

continuously replaced with new packets of
fresh solvent

Thus drug concentration at solid/ liquid

interphase never reaches Cs

It has a lower limiting value of Ci

Since solvent packets are exposed to new solid

surface each time

Theory is known as surface renewal theory

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 Danckwert’s model is expressed by the

equation:
𝑑𝐶 𝑑𝑚
𝑉 = = 𝐴(𝐶𝑠 − 𝐶𝑏 ) 𝛾𝐷
𝑑𝑡 𝑑𝑡
where,
m = mass of solid dissolved
γ = rate of surface renewal or interfacial
tension

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Theory III
Interfacial Barrier Model (double barrier or
limited solvation theory)
 The diffusion layer model and Danckwert’s model were
based on two assumptions:
1. The rate determining step that controls dissolution is the mass
transport.
2. Solid-solution equilibrium is achieved at the solid/liquid
interphase.

 According to the interfacial barrier model, an intermediate

concentration can exist at the interphase 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
crystal will have a different interfacial barrier.

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 Such a concept is given by the following

equation :
 𝐺 = 𝐾𝑖 𝐶𝑠 − 𝐶𝑏
 Where,
 G = dissolution rate per unit area
 Ki = effective interfacial transport constant
 In this theory the diffusivity D may not be
independent of saturation concentration Cs.

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Predicting dissolution from

solubility
𝑑𝐶
 𝑅= = 2.24𝐶𝑠
𝑑𝑡
 Where, R = dissolution rate

 It has been observed that drugs with a

minimum aqueous solubility of 1% does not
normally have bioavailability problems

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2. Particle size and

effective surface area
They are inversely
related

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Absolute surface area: Total area of solid surface of any particle

Effective surface area: The area of solid surface exposed to the

dissolution medium

As per Noyes Whitney equation, larger surface area gives higher

dissolution rate.

Thus to improve BA particle size can be reduced

Micronisation – particle size reduction leads to increase in EFA

generally.

Can help in reduction of dose of some drugs:

• Eg. Griseofulvin – dose reduced to half
• Spironolactone – dose reduced 20 times

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Drug

Micronisation

Decrease in
particle size

Increase in Increase in
absolute surface effective surface
area area

Solubility and
No net increase
dissolution rate
in solubility
improves 39

Faster
dissolution
Intimate contact
between solid
Increase in surface and
effective surface aqueous
area medium

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Particle size
below 0.1 µ

Increase in
intrinsic
solubility and
dissolution rate
41

Size < 0.1 µ

Higher surface
This is true for
area non-hydrophobic
drugs
Higher surface
free energy Examples
Griseofulvin
Chloramphenicol
Increased
interaction with Tetracyclines
solvent

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Micronisation of
hydrophobic drugs

Decrease in effective
surface area

Fall in dissolution rate

- 3 reasons

Generation of surface
Hydrophobic surface Higher surface free
charges leading to
of drug adsorbs air. energy, thus particles
electrically induced
Thus no wetting reaggregate.
agglomeration
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How to convert absolute surface

area of hydrophobic drugs into
effective surface area
Use of Adding
surfactants as hydrophilic
wetting agents diluents

They coat the

Decreases surface of
interfacial tension hydrophobic
drugs

Displaces Render the

adsorbed air with surface
solvent hydrophilic

Eg polysorbate 80
Eg PEG, PVP,
increases the BA
Dextrose
of phenacetin
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When is
micronisation When drugs are unstable and degrade
unadvisable? in solution form (penicillin G and
erythromycin)

When drugs produce undesirable

effects (gastric irritation caused by
nitrofurantoin)

When a sustained effect is desired.

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3. Polymorphism and
amorphism
Substance exists in more than one crystalline form

Molecule

Crystalline Amorphous
form form

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Drug

Internal structure

Crystalline Amorphous

Polymorphs (single
Molecular adducts
molecules)

Stoichiometric
Nonstoichiometric
Monotropic Enantiotropic complexes
complexes
(pseudopolymorphs)

Hydrates Amorphous Organic solvates

47

Polymorphism

 When a substance exists in more than one

crystalline form, the different forms are
designated as polymorphs and the phenomena is
known as polymorphism

 Polymorphs are of 2 types:

1. Enantiotropic polymorph: it can reversible
change into another form by altering the
temperature or pressure eg. Sulphur
2. Monotropic polymorph: one which is unstable
at all temperatures and pressures eg. Glyceryl
stearates
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Prepared by: crystallizing the drug from

different solvents under diverse conditions

Differing properties How to identify?

 Melting point  Optical crystallography
 Density  X-ray diffraction
 Hardness  Differential scanning
 Compression calorimetry
characteristics
 Solubility
 Stability

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Stable polymorph
One polymorph

Lowest energy
state
Highest melting
point
Least aqueous
solubility
Highest physical
stability
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Metastable polymorph

Other polymorphs Higher energy state

Cannot call it
Lower melting point
“Unstable” –
it remains
Higher aqueous solubility stable for
years if kept
Low physical stability in dry
conditions
Thermodynamic tendency
to convert to stable form
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 Examples
1. Chloramphenicol palmitate – 3 forms. A, B
and C.
 B form – best BA
 A form – biologically inactive
2. Riboflavin – 3 forms. I, II and III
 Form III 20 times more water soluble than form I

53

 Only 10% of drugs are present in metastable

form
 Because of their poor thermodynamic
stability aging of dosage forms containing
such metastable forms usually result in
formation of less soluble, stable polymorph

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Formulation with
Conversion of
metastable On aging
polymorph
polymorph

After years
Which has less
converted to
solubility
stable polymorph

Example: Form II of cortisone acetate in an aqueous suspension

on aging converts to less soluble form V, this leads to caking
Prevention of conversion:
1. Dehydrating the molecule environment
2. Adding viscosity builders like PVP or CMC
3. Adding pectin or gelatin which adsorb onto the surface of
crystals and prevent conversion 55

Amorphism

Amorphous form have no internal structure

Highest energy state

Considered as supercooled liquid

Highest aqueous solubility

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Amorphous form of
Crystalline form of drug
drug

More energy required to transfer Less energy required to transfer a

a molecule from crystal lattice molecule from crystal lattice

Lesser aqueous solubility Greater aqueous solubility

Examples:
Solubility of amorphous form of novobiocin is 10 times
more than its crystalline form
Chloramphenicol palmitate, cortisone acetate,
phenobarbital
57

Order of dissolution of
different solid forms of
drugs is:
Stable form

Metastable
form

Amorphous
form

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4. Pseudopolymorphism

The stoichiometric type of adducts where the solvent

molecules are incorporated in the crystal lattice of the solid are
known as solvates
The trapped solvent is known as solvent of crystallization

They can also exist in different crystalline forms, hence known

as pseudopolymorphism

If the solvent in association with the drug is water, the solvate

is known as hydrate

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Hydrate form of drug

Already in interaction with water

Have less energy for crystal breakup

as compared to anhydrous form

Thus lesser interaction with bulk

water

Lesser solubility
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 Examples:
 Amorphous forms of theophylline and
ampicillin have higher aqueous solubility,
dissolve at a faster rate and show better
bioavailability than their monohydrate and
trihydrate forms respectively

61

Solvates show greater solubility than non-solvate forms

Eg. glibenclamide has been isolated as pentanol and

toluene solvates, and these solvates exhibited higher
solubility and dissolution rate than two nonsolvated forms

Eg. Chloroform solvate of griseofulvin is more soluble

than griseofulvin

It is undesirable to use solvates for drugs and

pharmaceuticals as the presence of organic solvent
residues may be toxic.
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5. Salt form of the drug

Most drugs are
weak acids or
bases

Improve
solubility by
making salt form

Weakly acidic Weakly basic

drug drug

Make strong acid

Make strong
salt
base salt

Eg. Atorvastatin
Ranitidine HCl,
Na, Losartan K,
ephedrine HCl
Warfarin Na 63

Mechanism – phase I
Consider pH of
Diffusion layer
interfacial layer not Eg. weak acid
theory
the bulk layer

If salt of weak acid Thus solubility of pH of diffusion layer

is used the drug decreases is acidic

pH of diffusion layer The solubility of the Similar case seen in

becomes basic parent compound case of weakly
(buffering effect) increases basic drug
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 Thus,
 For salts of weak acids, [𝐻 + ]𝑑 < [𝐻 + ]𝑏
 For salts of weak bases, [𝐻 + ]𝑑 > [𝐻 + ]𝑏

65

Mechanism – phase II

Soluble ionic form

pH of bulk
of acidic drug in Diffuses into bulk
solution is low
diffusion layer

Free acid form of

Forms fine Solubility
the drug
particles decreases
precipitates

Increase in surface Rapid dissolution

area and absorption

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 Eg. Buffered tablets of aspirin, penicillin etc

Aspirin

3 problems

Sodium salt of
Gastric irritation
Poorly solubility aspirin has poor
and ulcerogenic
hydrolytic stability
67

Promotes dissolution

Increase pH of Gastric irritation is reduced

Buffered tablets of aspirin
microenvironment due to faster absorption

In situ salt formation,

hence stability of salt form
not important

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 Factor the influences the solubility of salt

form of drug – size of the counter ion

Smaller size of
counter ion

Greater
solubility of
salt 69

 Examples:
 The BA of novobiocin from its sodium salt,
calcium salt and free acid form was in the
ration 50:25:1
 If counter ion is very large, the salts have
lesser solubility than parent compound eg.
Stearates and palmitates have lesser
solubilities than free base.

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 Advantages of salt form

1. Improve solubility eg novobiocin
2. Prolong duration of action eg. Steroidal salts
3. Overcome bad taste eg chloramphenicol
palmitate
4. Enhance GI stability – erythromycin estolate
5. Decrease local and systemic side effects eg
aspirin

71

 Limitation of salt form – Common Ion Effect

 Free phenobarbital has better BA than
sodium salt of phenobarbital
 Free bases of tetracycline and papaverine
have better BA than their HCl analogs

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6 and 7. Drug pKa and

Lipophilicity
 Drug pKa ,Lipophilicity and GI pH—pH
Partition Hypothesis

 Proposed by Brodie et al

 Explains the process of drug absorption from

the GIT and its distribution across all
biological membranes

73

pH partition hypothesis
statement
 The theory states that for drug compounds of
molecular weight greater than 100, which are
primarily transported across the
biomembrane by passive diffusion, the
process of absorption is governed by:
1. The dissociation constant (pKa) of the drug.
2. The lipid solubility of the unionised drug (a
function of drug Ko/w).
3. The pH at the absorption site.
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 The above statement of the hypothesis was

based on the assumptions that:
1. The GIT is a simple lipoidal barrier to the
transport of drug.
2. Larger the fraction of unionised drug, faster
the absorption.
3. Greater the lipophilicity (Ko/w) of the
unionised drug, better the absorption.

75

1. Drug pKa and GI pH

 The amount of drug that exists in unionised

form is a function of dissociation constant
(pKa) of the drug and pH of the fluid at the
absorption site

 For acidic drugs – lower pKa – strong acids

 For basic drugs – higher pKa – strong bases

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 Henderson-Hasselbach equations
 From the knowledge of pKa of drug and pH at
the absorption site (or biological fluid), the
relative amount of ionised and unionised
drug in solution at a particular pH and the
percent of drug ionised at this pH can be
determined

77

Henderson – Hasselbach equations for weak acids and bases

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 For acidic drugs

 For basic drugs

79

 If there is a membrane barrier that separates

the aqueous solutions of different pH such as
the GIT and the plasma, then the theoretical
ratio R of drug concentration on either side of
the membrane can be given by equations
derived by Shore et al
 For weakly acidic drugs

 For weakly basic drugs

80

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Some generalizations

 pH range in the GIT – 1 to 8

 pH of stomach – 1 to 3

 pH of intestine – 5 to 8

81

Acidic Drugs
Drugs pKa absorption
Strong acids <2.5 Ionised at all pH
Disodium 2 values, poorly
cromoglycate absorbed from GIT

Moderately weak 2.5 - 7.5 Unionised in

acids gastric and ionised
Aspirin 3.5 in intestinal pH,
Ibuprofen 4.4 better absorbed
from stomach
Very weak acids >8 Unionised at all
Pentobabital 8.1 pH, absorbed
Hexobarbital 8.2 along entire length
of GIT 82

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Basic Drugs
Drugs pKa absorption
Very weak bases <5 Unionised at all
Theophylline 0.7 pH, absorbed
Caffeine 0.8 along entire length
of GIT
Moderately weak 5 – 11 Ionised in gastric
bases and unionised in
Heroin 7.8 intestinal pH,
Codeine 8.2 better absorbed
from intestine
Strong bases > 11 Ionised at all pH
Mecamylamine 11.2 values, poorly
Guanethidine 11.7 absorbed from GIT
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Lipophilicity and Drug

Absorption
Absorbed into
pH of area systemic
circulation

Optimum lipid
pKa of drug
solubility

Drug ionises Unionised drug

85

Thus even if the dru exists in the unionised form it has no guarantee
that it would get absorbed

The unionised form of the drug should have enough lipid solubility

Ideally, for optimum absorption, a drug should have sufficient

aqueous solubility to dissolve in the fluids at the absorption site and
lipid solubility (Ko/w) high enough to facilitate the partitioning of the
drug in the lipoidal biomembrane and into the systemic circulation

A perfect hydrophilic-lipophilic balance (HLB) should be there in the

structure of the drug for optimum bioavailability.

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The lipid solubility of a drug is measured by a

parameter called as log P where P is oil/water
partition coefficient (Ko/w) 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)
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
87

Drug Ko/w % absorbed

Thiopental 3.3 67
Aspirin 0.03 21
Phenylbutazone 100 54

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 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

 For basic drugs

89

Limitations of pH –
partition hypothesis
 The pH-partition hypothesis over-simplified the
otherwise complicated process of drug
absorption and therefore has its own limitations.
Some of the deviations from the theory are:
1. Presence of virtual membrane pH
2. Absorption of ionised drug
3. Influence of GI surface area and residence time
of drug
4. Presence of aqueous unstirred diffusion layer

90

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Presence of Virtual Membrane

pH
The pH-partition hypothesis suggested that only the
unionised drug at a given GI lumen pH is absorbed .

differences in the extent of absorption of salicylic acid

has been observed at a given GI pH than that
predicted by pH-partition hypothesis

The experimental pH-absorption curves are less steep

and shift to the left (lower pH values) for a basic drug
and to the right (higher pH values) for an acidic drug.

91

pH-absorption curve for acidic and basic drugs.

Dotted lines indicate curves predicted by pH-
partition hypothesis and bold lines indicate the
practical curves.
92

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 This led to the suggestion that a virtual pH,

also called as the microclimate pH, different
from the luminal pH exists at the membrane
surface.
 This virtual membrane pH actually
determines the extent of drug ionisation and
thus, drug absorption.

93

Absorption of Ionised Drugs

An important assumption of the theory was that only unionised

form of the drug is absorbed

Theory also states that the permeation of the ionised drug is

negligible since its rate of absorption is 3 to 4 times less than
that of unionised drug
This is called as principle of non-ionic diffusion.

The principle is true to a large extent as ionised drugs have low

lipid solubility and relatively poor permeability.

94

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 However, the pH-absorption curve shift

suggested that ionised forms of some drugs
also get absorbed to a considerable extent.
 Possible reasons for the absorption of the
ionised form:
1. If such drugs have a large lipophilic group in their
structure, despite their ionisation, they will be
absorbed passively—for example, morphinan
derivatives.
2. Other mechanisms are also involved in the
absorption of ionised drugs such as active
transport, ion-pair transport and convective flow.

95

Influence of GI Surface Area

and Residence Time of Drug
 According to the pH-partition theory drugs
are best absorbed from the site in which
conditions they are unionised to a large
extent.
 Acidic drugs are best absorbed from stomach
(acidic pH); and
 Basic drugs from intestine (alkaline pH)

96

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It thus Once an acidic drug reaches the

means intestine, the remaining fraction
that: will be poorly absorbed

Unless a basic drug reaches the

intestine and gets absorbed
considerably, it may not be able
to attain its therapeutic level
97

 But, irrespective of the GI pH and the degree

of ionisation, both acidic and basic drugs are
more rapidly absorbed from the intestine
 Reasons for that:
1. Large surface area
2. Long residence time of the drug in the
intestine

98

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Presence of Aqueous
Unstirred Diffusion Layer
 The pH-shift in the absorption of acidic and
basic drugs, also accounts for the fact that
the bulk of the luminal fluid is not in direct
contact with the membrane but a barrier
called as aqueous unstirred diffusion layer is
interposed between them.

99

Such a layer has a real thickness and is a barrier to

absorption of drugs

As per pH-partition theory, the rate-limiting step in

the absorption of drugs is the partitioning in the lipid
barrier.

With the incorporation of unstirred aqueous diffusion

layer, a drug must diffuse first through this aqueous
barrier and then through the lipoidal barrier

100

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 Thus, drugs having large partition coefficient

can rapidly penetrate the lipid membrane but
diffusion through unstirred water layer is the
rate-limiting step in their absorption.
 Eg. high molecular weight fatty acids and bile
acids

101

8. Permeability and
absorption
 Most orally administered drugs enter the
systemic circulation by passive diffusion and
their absorption is expressed mathematically by
equation
M = Peff A Capp tres
 Where,
 M = amount of drug absorbed
 Peff = effective membrane permeability
 A = surface area available for absorption
 Capp = apparent luminal drug concentration
 tres = residence time of drug in GI lumen

102

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 The three major drug characteristics that

determine the passive transport or
permeability of drugs across intestinal
epithelium are

1. Lipophilicity of drug expressed as log P.

2. Polarity of drug
3. Molecular size

103

 The net effect of the above three properties of

drug on its permeability across intestinal
epithelium is given as Rule of Five by Lipinski et
al
1. Molecular weight of drug < 500
2. Lipophilicity of drug, log P < 5
3. Number of H-bond acceptors < 10
4. Number of H-bond donors < 5
5. For a given drug, if any two of these values is
greater than that specified above, then oral
absorption may be significant problem

104

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9. Drug stability

 A drug for oral use may destabilize either

during its shelf-life or in the GIT
 2 stability problems that leads to a decrease
in BA are:
1. Degradation of drug into inactive form (shelf
life)
2. Interaction with other components eg.
Tetracycline combining with calcium in milk
leading to decreased BA
105

10. Stereochemical Nature of

Drug
Chiral drugs constitute approximately 60% of the drugs in
current use.

Majority of these are marketed as racemic mixtures.

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 elimination.
106

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 Most of the biological processes which are

passive in nature do not display selectively for
one isomer over another
 However some biological processes are
affected by the stereochemical nature of the
drug:
1. Protein binding which require interaction of
a drug with a macromolecule
2. Absorption by a carrier-mediated process
107

Patient related factors

affecting drug absorption

108

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Gastrointestinal Tract

• Secretion
Function • Digestion
• Absorption

Length • 40 cm

Functional • Stomach
• Small intestine (duodenum, jejunum and ileum)
components • Large intestine (colon)

109

110

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Anatomical and Functional Differences

Between the Important Regions of the GIT

111

Stomach

The stomach is a bag like structure having a smooth mucosa

and thus small surface area

Its acidic pH, due to secretion of HCl, favours absorption of

acidic drugs if they are soluble in the gastric fluids since they
are unionised to a large extent in such a pH

The gastric pH aids dissolution of basic drugs due to salt

formation and subsequent ionisation which are therefore
absorbed to a lesser extent from stomach because of the
same reason
112

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 The stomach is not the principal region for drug

absorption because:
1. The total mucosal area is small
2. The epithelium is dominated by mucus-
secreting cells rather than absorptive cells
3. The gastric residence time is limited due to
which there is limited opportunity for gastric
uptake of drug

113

Small intestine
 It is the major site for absorption of most drugs
due to its special characteristics
1. Large surface
area:

The folds in the

intestinal Vili Microvili
mucosa

Folds of Finger like Protrude from

Kerckring projections surface of vili

3 fold increase 30 folds 600 times

in surface area increase increase
114

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2. Great length of small intestine – approx 285

cm - more than 200 square meters of surface
3. Greater blood flow – 6 to 10 times that of
stomach
4. Favourable pH range - 5 to 7.5 which is
favourable for most drugs to remain
unionised
5. Slow peristaltic movement - prolongs the
residence time
6. High permeability - intestinal epithelium is
dominated by absorptive cells

115

Large intestine
Length and mucosal surface very small

Vili and microvili are absent

Contents are neutral or alkaline

Absorption of water and electrolytes

Insignificant absorption of drugs

However, because of the long residence time (6 to 12 hours), colonic transit may
be important in the absorption of some poorly soluble drugs and sustained
release dosage forms
116

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117

Age
First pass Gastric
effect emptying

Contact
time with
Patient Intestinal
transit
GI mucosa
related
GI factors GI pH
contents

Blood flow Disease

to GIT states

118

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1. Age
Elderly
Infants
persons

Gastric pH is Altered gastric

high emptying

Decreased
Intestinal
intestinal
surface is low
surface area

Blood flow to Decreased GI

the GIT is low blood flow

Higher
incidents of
achlorhydria

Bacterial
overgrowth in
small intestine
119

2. Gastric emptying
 Gastric emptying – it is the passage of
contents from stomach to small intestine

 Along with dissolution and permeation,

gastric emptying can also be a RLS

120

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 Gastric emptying is a first-order process.

 Several parameters are used to quantify gastric
emptying:
1. Gastric emptying rate is the speed at which the
stomach contents empty into the intestine.
2. Gastric emptying time is the time required for
the gastric contents to empty into the small
intestine
3. Gastric emptying t½ is the time taken for half the
stomach contents to empty

121

 In vivo gastric emptying

can be studies by:
1. Using radio-opaque
contrast materials like
barium sulphate
2. Tagging the drug with
a radioisotope and
scanning the stomach
at regular intervals of
time
122

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Volume
of meal
Composi
Drugs tion of
meal

Physical
Disease
state of
state
meal

Gastric
emptying Tempera
Exercise ture of
meal

Emotion
GI pH
al state

Body Electrolyt
posture es
123

Volume of meal

Larger volume Longer GE

of meal time

124

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Composition of meal

High fats diet promotes the absorption of griseofulvin

125

Physical state of meal

Solid foods
(6 - 7 hrs)

Liquid foods
(< 1 hr)
126

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Higher
viscosity of
contents

Slower gastric
emptying rate

127

Temperature of meal

Decrease
emptying
rate

128

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Gastrointestinal pH

High pH – Low pH –
increased emptying
emptying retarded
129

Chemicals also affect gastric emptying as they may

influence gastric pH
1. Inhibitory effects of various acids is as follows:
HCl
Acetic
Lactic
Tartaric
Citric

2. Inhibitory effect of bases: Low base conc increases

emptying rate more than high base conc

130

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Electrolytes and osmotic pressure

Higher electrolyte
content

Water, isotonic and

low electrolyte
content

131

Body posture

Lying on left
side

Standing up of
lying on right
side
132

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Emotional state

Depression

Anxiety and
stress
133

Exercise

Rigorous
exercise

Decreases
emptying
134

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Disease state

Gastroenteritis,
gastric ulcer, pyloric
stenosis, diabetes,
hypothyroidism

Duodenal ulcer,
hyperthyroidism,
partial or total
gastrectomy
135

Drugs

Metoclopramide,
domperidone,
cisapride

Aluminium hydroxide,
atropine, morphine,
imipramine,
amitriptylline

136

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1. Rapid onset of action is desired eg.

Rapid Sedatives
gastric 2. Dissolution of drug occurs in intestine
eg. Enteric coated tablets
emptying 3. Drugs not stable in GI pH eg. Penicillin
desired G, erythromycin
4. Drugs best absorbed from distal part of
small intestine eg. Vitamin B12

How to achieve this – take medicines on an empty stomach

137

1. Food promotes drug dissolution or

absorption eg. Griseofulvin
2. Drugs that dissolve slowly eg.
Griseofulvin
Delayed 3. Drugs that irritate mucosa eg. Aspirin,
gastric phenylbutazone and nitrofurantoin
emptying 4. Drugs absorbed from proximal part of
desired small intestine eg. Vitamin B2 and C
5. Drugs degraded in small intestine eg.
captopril

How to achieve this - co-administering food

138

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Oesophageal transit

 Drug passage through oesophagus

 Important in people swallowing solid dosage
form lying down in supine position with little
or no water
 As a result:
 Dosage form remains lodged in oesophagus
 Disintegrates slowly
 Delayed absorption
 Local damage to mucosa from a drug like NSAIDs
139

3. Intestinal transit

 As small intestine is the major site for drug

absorption for most drugs, long intestinal
transit time is desirable for complete drug
absorption

140

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1. Drugs that dissolve or release slowly

from their dosage form (sustained-
release products) or when the ratio of
dose to solubility is high e.g.
chlorothiazide
Delayed 2. Drugs that dissolve only in the
intestinal intestine (enteric-coated formulations)
emptying 3. Drugs which are absorbed from
desired specific sites in the intestine (several B
vitamins, lithium carbonate, etc.)
4. When the drug penetrates the
intestinal mucosa very slowly e.g.
acyclovir
5. When absorption of drug from the
colon is minimal
141

What does delayed intestinal

transit do
Mixing movements
in intestine

Promotes
absorption

Increasing drug- Enhancing drug

intestinal dissolution by
membrane contact agitation
142

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4. Gastrointestinal pH
6–8 GI pH
Rectum

Large Disintegration
intestine
Dissolution
Small
intestine Absorption

Stomach Stability
1–3

143

Disintegration Dissolution
Maybe pH sensitive eg. Enteric  Weakly acidic drugs – faster
coated tablets dissolution in intestine
 Weakly basic drugs – faster
dissolution in stomach

Absorption Stability
 Strongly acidic/ basic drugs – not
 Some drugs get degraded in GI pH
absorbed from GIT
 Drugs degrading in stomach –
 Very weakly acidic/ basic drugs –
penicillin, erythromycin
absorbed throughout GIT
 Drugs degrading in intestine -
 Moderately acidic drugs –
captopril
absorbed from stomach
 Moderately basic drugs –
absorbed from intestine
144

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5. Disease states

 3 classes of disease can affect bioavailability

of some drugs
1. Gastrointestinal diseases
2. Cardiovascular diseases
3. Hepatic diseases

145

GI diseases

Affect drug
absorption

Diseases
GI infections
affecting GI GI surgery
and conditions
motility
146

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Diseases altering motility

Gastroenteritis, gastric
ulcer, pyloric stenosis,
diabetes,
hypothyroidism

Duodenal ulcer,
hyperthyroidism, partial
or total gastrectomy

147

GI infections and conditions

• Increase gastric pH
Achlorhydria • Decreased absorption of acidic drugs like aspirin

• increased gastric emptying rate and GI permeability

Celiac • altered intestinal drug metabolism
• steatorrhea (impaired secretion of bile thus affecting
disease absorption of lipophilic drugs and vitamins)
• reduced enterohepatic cycling of bile salts

Crohn’s • Altered gut wall microbial flora

• Decreased gut surface area
disease • Intestinal transit rate

148

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• Shigellosis, gastroenteritis, cholera

GI infections and food poisoning
• Result in malabsorption

• Colitis, amoebiasis and

Colonic constipation
diseases • Also alter drug absorption

• Induced by drugs such as

antineoplastics and alcohol
Malabsorption • Increase permeability of agents not
normally absorbed
149

GI surgery

• Drug dumping in the intestine

Gastrectomy • Osmotic diarrhoea
• Reduced intestinal transit time

• Intestinal transit time is

Intestinal reduced
surgery • Surface area is reduced

150

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CV Diseases
Congestive Cardiac Failure
It cause changes in GIT – edema of intestine, decreased
blood flow to GIT, altered GI pH and decreased gastric
emptying – thus BA of drugs changes

Hepatic Diseases
Affects BA of drugs undergoing extensive first
pass metabolism eg. Propranolol
Liver cirrhosis – enhanced BA of such drugs

151

6. Blood flow to GIT

GIT

Extensively
supplied by

Blood capillary Lymphatic

network system
152

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Systemic Lymphatic
circulation circulation
500 to 1000 times
Less than blood
(28% of cardiac
flow
output)

Most drugs reach

Only a few drugs
the systemic
are removed by
circulation via
lymphatic system
blood

Lipid soluble
compounds are
removed by
lymphatic system
153

Other characteristics of
blood flow to GIT
• Maintains high conc gradient for
Sink condition
drug absorption

• For absorption of highly lipid soluble

RLS
drugs

Needed for actively • Supplies oxygen and energy needed

absorbed drugs for active transport

• After meals – perfusion rate

Food
increases
154

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7. GI contents

Drug – food
interaction

Drug – natural
GI
Fluid volume GI contents
contents
interaction

Drug – drug
interaction

155

Drug – Food interactions

Influence of food on drug absorption

General rule
“Drugs are better absorbed under fasting conditions and
presence of food retards or prevents it. “

Delayed Decreased Increased Unaffected

Aspirin Penicillin Griseofulvin Methyldopa

Paracetamol Erthromycin Diazepam Propylthiouracil
Diclofenac Ethanol Nitrofurantoin Sulphasomidine
Nitrofurantoin Tetracyclines Actively absorbed
Digoxin Levodopa water soluble
Iron vitamins

156

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Why does food delayed or

decreased drug absorption?
1. Delayed gastric emptying, affecting drugs
unstable in the stomach e.g. penicillins, or
preventing the transit of enteric coated
tablets into the intestine which may be as
long as 6 to 8 hours
2. Formation of a poorly soluble, unabsorbable
complex e.g. tetracycline-calcium
3. Increased viscosity due to food thereby
preventing drug dissolution and/or diffusion
towards the absorption site
157

Why is there an increased drug

absorption following a meal?
1. Increased time for dissolution of a poorly
soluble drug
2. Enhanced solubility due to GI secretions like
bile
3. Prolonged residence time and absorption
site contact of the drug e.g. water-soluble
vitamins
4. Increased lymphatic absorption e.g. acitretin

158

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Influence of specific meal

components on drug absorption

High • Aids solubilisation of poorly

aqueous soluble drugs e.g.
fats isotretinoin

High • Inhibits absorption of levodopa

• Increased oral availability of
proteins propranolol

159

Drug – normal GI contents interactions

Normal GI contents – mucin, bile salts, enzymes

etc

1. Mucin + streptomycin = retards absorption

2. Bile salts + vitamins A/ D/ E/ K = promotes
absorption
3. Bile salts + griseofulvin = promotes absorption
4. Bile salts + neomycin = retards absorption
5. Bile salts + kanamycin = retards absorption

160

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Drug – Drug interactions

Physico-
Physiological
chemical

161

Physicochemical interactions

• Anti diarrhoeal eg. Pectin/ kaolin +

Adsorption promazine = decreased absorption of
promazine

• Antacids like NaHCO3 + tetracycline =

elevation in pH = decreased absorption
pH change of tetracycline due to decreased
dissolution rate or precipitation of
drug

162

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• Ca/ Al containing antacids +

tetracycline = decreased absorption of
tetracycline
• Mineral substitutes containing Al, Ca,
Fe, Mg, Zn etc retard absorption of
Complexation tetracyclines
• Anion exchange resins eg
cholestyramine, cholestipol etc binds
bile salts and number of drugs and
prevents their absorption

163

Physiological interactions

• Anticholinergics like
propanthelin + ranitidine/
digoxin = promotes
Decreased absorption
GI Transit • Propanthelin + paracetamol/
sulphamethoxazole = retards
absorption

164

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• Metoclopramide +
tetracycline/
Increased pivampicillin/ levodopa
GE = enhanced absorption
• Metoclopramide
promotes GI motility

165

• Antibiotics inhibits bacterial

metabolism of drugs - Erythromycin +
digoxin = enhanced efficacy
• Decreased enterohepatic cycling of
Altered GI steroid conjugates which otherwise
metabolism are hydrolysed by gut bacteria after
biliary excretion Antibiotic + oral
contraceptives (ethinyl estradiol) =
decreased absorption of
contraceptives

166

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Fluid volume
Large fluid Better
volume dissolution

Enhanced Rapid gastric

absorption emptying

Eg. erythromycin is better absorbed when taken with a

glass of water under fasting condition than when taken
with meals
167

8. Contact time with GI

mucosa
• Severe diarrhea
Less contact • Less absorption of drugs

Delayed
• Delays rate of absorption as majority of drugs are absorbed
gastric from intestine
emptying

• Increases residence time and hence contact time

Food • Stimulates secretion of endogenous surfactants – bile salts
• Lipophilic drugs are better absorbed when given with food

168

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9. Presystemic metabolism/
first pass effect

 The loss of drug through biotransformation

by eliminating organs during its passage to
systemic circulation

Destroyed Destroyed Destroyed

Drug
in gut in gut wall in liver

169

Drug metabolism

Gut enzyme Gut wall enzyme

(Luminal (mucosal Hepatic enzyme
enzymes) enzymes)

Digestive Bacterial
enzymes enzymes

170

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Digestive enzymes

 These are the enzymes present in the gut

fluids
 include enzymes from intestinal and
pancreatic secretions
 Examples
1. Hydrolases which hydrolyse ester drugs like
chloramphenicol palmitate into active
chloramphenicol
2. Peptidases which split amide linkages and
inactivate protein/polypeptide drugs eg insulin

171

Bacterial enzymes
 The GI microflora is scantily present in stomach
and small intestine and is rich in colon
 The colonic microbes generally render a drug
more active or toxic on biotransformation
 Example sulphasalazine, a drug used in ulcerative
colitis, is hydrolysed to sulphapyridine and 5-amino
salicylic acid by the microbial enzymes of the colon
 Intestinal microflora play an important role in
enterohepatic cycling
 Example Their enzymes hydrolyse the conjugates of
drugs actively secreted via bile such as glucuronides of
digoxin and oral contraceptives. The free drugs are
reabsorbed into the systemic circulation.
172

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Gut wall enzymes

 They are present in stomach, intestine and colon

1. Stomach mucosal enzyme example: Alcohol
dehydrogenase (ADH) is an enzyme that inactivates
ethanol
2. Intestinal mucosal enzymes examples: contains both
phase I and phase II (predominant) enzymes, e.g.
sulphation of ethinyl oestradiol and isoprenaline
3. Colonic mucosa also contain both phase I and phase
II enzymes
 However, it is only the enzymes of the proximal
small intestine that are most active
173

Hepatic enzymes

 Many drugs undergo first pass hepatic

metabolism such as propranolol, nifedipine,
lidocaine, morphine

174

87