FACTORS

AFFECTING
ABSORPTION OF
DRUGS

1
 FACTORS AFFECTING
GI ABSORBTION OF
A DRUG FROM ITS
DOSAGE FORM

PATIENT
PHARMACEUTIC RELATED
FACTORS FACTORS

DOSAGE FORM
PHSICOCHEMICAL
CHARACTERISTICS
PROPERTIES OF
&PHARMACEUTICAL
DRUG SUBSTANCES
INGREDIENTS 2
 3
A. PHARMACEUTIC FACTORS

I. PHYISICOCHEMICAL PROPERITES OF DRUG

SUBSTANCES
1. DRUG SOLUBILITY AND DISSOLUTION RATE
2. PARTICLE SIZE AND EFFECTIVE SURFACE AREA
3. POLYMORPHISM AND AMORPHISM
4. PSEUDOPOLYMORPHISM
5. SALT FORM OF THE DRUG
6. LIPOPHILICITY OF THE DRUG
7. Pka OF THE DRUG AND PH
8. DRUG STABILITY
 .
II. DOSAGE FORM CHRACTERISTICS
&PHARMACEUTIC INGREDIENTS:
1. DISINTEGRATION TIME

2. DISSOLUTION TIME

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3. MANUFACTURING VARIABLES

4. PHARMACEUTIC INGREDIENTS

5. NATURE AND TYPE OF DOSAGE FORM

6. PRODUCT AGE AND STORAGE CONDITIONS

B.PATIENT RELATED FACTORS

1. AGE

2. GASTRIC EMPTYING TIME

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3. INTESTINAL TRANSIT TIME

4. GASTRO INTESTINAL PH

5. DISESASE STATES

6. BLOOD FLOW THROUGH THE GIT

7. GASTRO INTESTINAL CONTENTS

8. PRESYSTEMIC METABOLISM
 PHYSICOCHEMIC
AL PROPERTIES
OF DRUG
SUBSTANCES

6
1.Drug Solubility and Dissolution Rate :

For hydrophobic drugs i.e. poorly aqueous soluble drugs

dissolution is the rate determining step (RDS).

Absorption of such drugs is called as dissolution rate limited.

Eg : Griseofulvin, Spironolactone.

For hydrophilic drugs i.e. drugs with high aqueous solubility

permeation through biomembrane is the RDS.

Absorption of such drugs is called as permeation rate limited or

trans membrane rate limited.

Eg: Cromolyn Sodium, Neomycin. 7

THE TWO RDS IN THE ABSORPTION OF DRUGS
FROM ORALLY ADMINISTERED
FORMULATIONS

disintegration or permeation across

deaggregation dissolution the biomembrane

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

RDS for RDS for

hydrophobic hydrophilic
drugs drugs

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 Based on the intestinal permeability and solubility of drugs,
Amidon et al developed Biopharmaceutics Classification System
(BCS).
Class Solubility Permeability Absorption Rate-limiting Examples
pattern Step in absorption

I High High Well Gastric emptying Diltiazem

absorbed

II Low High variable Dissolution Nifedipine

III High Low variable Permeability Insulin

IV Low Low Poorly Case by case Taxol

absorbed
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DEFINITIONS

Absolute/intrinsic solubility
Defined as maximum amount of solute dissolved in a given solvent under
standard condition of temperature pressure and pH static property.

Dissolution
Process in which a solid substance solubilizes in a given solvent i.e.
mass transfer from the solid surface to the liquid phase.

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Rate of dissolution:

The amount of drug substance that goes in solution per unit

time under standardized conditions of temperature, pH,
constant solid surface area and solvent composition.
Dynamic property.

Ex: Cisaparide low solubility- but sufficient oral

bioavailability. This because rapid dissolution rate despite
low intrinsic solubility.

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 THEORIES OF DRUG
DISSOLUTION

 Diffusion layer model/Film theory.

 Danckwert’s model/Penetration or surface renewal

theory.

 Interfacial barrier model/Double barrier or Limited

solvation theory.

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 DIFFUSION LAYER MODEL/FILM
THEORY
It involves two steps :

 Solution of the solid to

form stagnant film or
diffusive layer which is
saturated with the drug at
the solid liquid interface.

 Diffusion of the soluble

solute from the stagnant
layer to the bulk of the
solution, this is RDS in
drug dissolution.

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 The rate of dissolution is given by Noyes and Whitney :

dc
dt = K (Cs- Cb)

Where,
dc/dt= dissolution rate of the drug
K= dissolution rate constant
Cs= concentration of drug in stagnant layer
Cb= concentration of drug in the bulk of the solution at time t
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 MODIFIED NOYES-WHITNEY’S EQUATION :

dc DAKw/o (Cs – Cb)

=
dt Vh

Where,
D= diffusion coefficient of drug.
A= surface area of dissolving solid.
Kw/o= water/oil partition coefficient of drug. intrinsic
dissolution rate constant
V= volume of dissolution medium.
h= thickness of stagnant layer.
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(Cs – Cb )= conc. gradient for diffusion of drug.
 This is first order dissolution rate process, for which the driving force is concentration
gradient.

 This is true for in-vitro dissolution which is characterized by non-sink conditions.

 The in-vivo dissolution is rapid as sink conditions are maintained by absorption of drug
in systemic circulation i.e. Cb=0 and rate of dissolution is maximum.

 Under sink conditions, if the volume and surface area of the solid are kept constant, then

dC
dt
 This represents that the dissolution rate is constant under sink conditions and follows
zero order kinetics.

= K

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Dissolution rate under non-sink & sink conditions

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Hixson-Crowell’s cubic root law
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.
Hixson-Crowell’s cubic root law accounts for particle size
decrease and change in surface area accompanying dissolution.

W01/3 – W1/3 = Kt
Where,
W0=original mass of the drug.
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W=mass of drug remaining to dissolve at time t
 DANCKWERT’S MODEL / PENETRATION OR
SURFACE RENEWAL THEORY
 Danckwert’s did not approve the existence of stagnant layer
because of liquid turbulence.

 Takes into account the eddies or packets that are present in the
agitated fluid which reach the solid-liquid interface, absorb the
solute by diffusion and carry it into the bulk of solution.

 These packets get continuously replaced by new ones and expose

to new solid surface each time, thus the theory is called as surface
renewal theory.
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 The Danckwert’s model is expressed by equation

= dm
dc
V dt = A (Cs - γD
dt Cb).
Where, D= Diffusivity
m = mass of solid dissolved
Gamma (γ) = rate of surface renewal

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Interfacial barrier model/Double barrier or limited solvation
theory
Diffusion layer model and the Danckwert’s model were based on
two assumptions:
The rate-determining step that controls dissolution is the mass
transport.
Solid-solution equilibrium is achieved at the solid/liquid
interface.
An intermediate concentration can exist at the interface as a
result of solvation mechanism
As the activation energy required is more for solid therefore the
rate of solubility of solid in the liquid becomes rate limiting
rather then diffusion of dissolved solids

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 The concept of this theory is explained by following equation
G = Ki (Cs - Cb)
G = dissolution rate per unit area
Ki = effective interfacial transport constant.

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Particle size & Effective surface area

 Particle size and surface area of a solid drug are inversely related.
 Two types of surface area
 Absolute surface area
 Effective surface area
 Absolute surface area which is the total area of solid surface of
any particle.
 Effective surface area which is the area of solid surface exposed to
the dissolution medium.
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Hydrophilic Drugs

Micronisation reduce particle size & surface of such particles have

high energy than the bulk of the solid resulting increased interaction
with the solvent

Micronisation of hydrophilic drugs results in ↑ dissolution rate in

comparison to the simple milled form of these drugs.

Decreased dose, increased absorption efficiency Ex: Griseofulvin

reduced to half and Spironolactone decreased 20 times

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Hydrophobic drugs

Micronisation of hydrophobic drugs (aspirin, phenacetin) decrease

effective surface area of powders resulting fall in dissolution rate

Reasons:

Surface of the drug adsorbs air onto their surface which inhibits
wettability.

The particles re-aggregate to form larger particles due to their high

surface free energy which either float on the surface or settle down

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Overcome

Use of surfactant as a wetting agent, decreases the

interfacial tension & displaces the adsorbed air with the
solvent.

Polysorbate 80 increases the bioavailability of phenacetin

Adding hydrophilic diluents such as PEG, PVP, Dextrose

etc which coat the surface of hydrophobic drug particles and
render them hydrophilic.

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3.Polymorphism
Depending on the internal structure a solid can exist either in a
crystalline or amorphous.

Substance exists in more than one crystalline form, the different

forms are designated as polymorphs and the phenomenon as
polymorphism

Polymorphs are two types

Enantiotropic polymorph is the one which can be reversibly
changed into another form by altering the temperature or pressure.
ex: sulphur

Monotropic polymorph is the one which is unstable at all

temperatures and pressures eg: glyceryl stearates. 27
28
 Polymorphs differs in physical properties, solubility, Melting
point, density, hardness and compression characteristics
POLYMORPHISM
 They are determined by techniques like optical crystallography,
x-ray diffraction, differential scanning calorimetry etc.

 One of the polymorphic forms will be physically more stable than

others such a stable polymorphic represents the lowest energy
state, has highest MP & least aqueous solubility.

 other forms are metastable, low MP have greater solubility they

show better availability and are preferred in formulation

 Ex. chloramphenicol palmitate A,B,C,D. B shows best

bioavailability & A is virtually inactive biologically
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3.1 Amorphous form

 Drugs also exist as amorphous form have greater aqueous

solubility than the crystalline forms energy required to transfer a
molecule from lattice is greater than that required for amorphous

 Ex: Cortisone acetate is 3 times more soluble than crystalline

form

 Order of dissolution is Amorphous>metastable>stable

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4.Pseudopolymorphism
When the solvent molecules are incorporated in the crystal lattice
of the solid - solvates

 Solvates can exist in different crystalline form called as

pseudopolymorphs. The phenomenon is called
pseudopolymorphism.

4.1.Hydrates and Solvates

In case entrapped Solvent is water then it is referred as Hydrate

Anhydrous form of the drug has greater aqueous solubility then

the hydrates. (because already in interaction with water have less
energy for crystal break up in comparison to the anhydrates).

Solvates differ in their physical parameters. 31

5.Salt form of the drug

Most of the drugs are either weak acids or weak bases. One of the
easiest approaches to enhance the solubility and dissolution rate is
convert them into their salt forms.

Weakly acidic drugs, a strong base salt is prepared such as the

sodium and potassium salts of barbiturates and sulphonamides.

Weakly basic drugs a strong acid salt is prepared like the

hydrochloride or sulphate salts of several alkaloidal drugs.

 At a given pH , the solubility of a drug, whether acidic/basic or

its salt form is a constant.While considering the salt form of drug,
pH of the diffusion layer is imp not the pH of the bulk of the
solution 32
Consider the case of a salt of a weak acid.

At any given pH of the bulk of the solution, the pH of the

diffusion layer (saturation solubility of the drug) of the salt
form of a weak acid will be higher than that observable with
the free acid form of the drug (can be practically observed in
the laboratory).
Owing to the increased pH of the diffusion layer, the solubility
and dissolution rate of a weak acid in this layer is promoted;
since it is a known fact that higher pH favours the dissolution
of weak acids.
The hydrogen ion concentration of the bulk is [H+] , is not
equal to hydrogen concentration of the diffusion layer [H+] d .

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[H+] d < [H+] for weak acid. [H+] d >[H+] for weak bases.
 Increases or decrease in the pH of the diffusion layer is due the
buffering action of strong cation or anion, which promotes
ionization hence ↑ solubility and dissolution of weak acid or
base.

 When soluble ionic form moves into the bulk solution the pH is
lower or higher resulting in ppt of weak acid or base in form of
fine particles which has increased surface area resulting in
increased solubility

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 Factor that influences the solubility of salt forms of the drug is
the size of the counter ion. Generally speaking smaller the size
of the counter ion, greater the solubility of the salt

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The principle of in situ salt formation has been utilized to
enhance the dissolution and absorption rate of certain drugs
like aspirin and penicillin from buffered alkaline tablets.

The approach is to increase the pH of the microenvironment of

the drug by incorporating buffer agents and promote
dissolution rate.

Apart from the enhanced bioavailability, buffered aspirin

tablets have two more advantages:
firstly, the gastric irritation and ulcerogenic tendency of the
drug is greatly reduced, and

secondly, the problem with the use of sodium salt of aspirin

(to enhance the solubility) which otherwise has poor hydrolytic36
stability, is overcome by in situ salt formation.
pH PARTITION THEORY :
The theory states that for drug compound of moleculer weight
greater than 100, which are primarily transported across the bio-
membrane by passive diffusion ,the process of absorption is
governed by

Dissociation constant pKa of drug.

Lipid solubility of the unionized drug (KO/W).

pH of absorption site.

Hypothesis was based on the assumptions:

GIT is simple lipoidal barrier.

Larger the fraction of unionized drug, faster the absorption.

Greater the lipophilicity (KO/W) of unionized drug better the

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absorption.
HENDERSON HASSELBATCH EQUATION

Amount of drug that exist in unionized and ionized form is a

function of pKa of drug & pH of the fluid at the absorption site.It
can be determined by Henderson-Hasselbach equation

pH = pKa +log [ionized form] For, Acidic drugs

[Unionized form]

pH = pKa + log [unionized form] For, Basic drugs

[Ionized form]

Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have >
99% of unionized form . Weak base quinine (pKa=8.5) will have
very high ionization in gastric pH . 38
INFLUENCE OF DRUG DISSOCIATION & GI PH ON
ABSORPTION
Drugs
Very weak acids (pKa > 8.0)
Moderately weak acids (pKa 2.5 – 7.5)
Strong acids (pKa <2.5)
Very weak bases (pKa < 5)
Moderately weak bases (pKa 5 – 11 )
Strong bases (pKa >11)
Site of absorption
Unionized at all pH values
Absorbed along entire length of GIT
Unionized in gastric pH
Ionized in intestinal pH
Better absorbed from stomach
Ionized at all pH values
Poorly absorbed from GIT
Unionized at all pH values
Absorbed along entire length of GIT
Ionized in gastric pH
Unionized in intestinal pH
Better absorbed from intestine
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Ionized at all pH values
Poorly Absorbed from GIT
Lipid solubility of drugs:

Some drugs are poorly absorbed after oral administration even

though they are unionized in small intestine. Low lipid solubility may
be the reason.

The best parameter to correlate between water and lipid solubility is

partition coefficient.

Partition coefficient (p) = [ L] conc / [W] conc

 where, [ L] conc is the concentration of the drug in lipid phase. [W]

conc is the concentration of the drug in aqueous phase.

The higher p value, the more absorption is observed

Optimum absorption occurs, if the structure has aqueous solubility to

dissolve & lipid solubility to facilitate partition lipoidal membrane40ie.
HLB in structure for optimum bioavailability
Limitations pH partition hypothesis:

1 Presence of Virtual Membrane

S- shaped pH absorption curves obtained due dissociation for
experimented & predicted are different

 Presence of Virtual Membrane pH or the micro-climate pH,

different from the luminal pH which exists at the membrane
surface.

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2. Absorption of the ionized drug
Despite of the assumption that only un-ionized and lipophilic
drugs are absorbed to a greater extent, some drugs e.g. Morphinan
derivatives which are much more ionized are absorbed passively

Structure has very high lipophilicity.

3. Influence of the GI surface area and residence time of the drug:

 Irrespective of the GI pH and degree of ionization, both acidic
and basic drugs are more rapidly absorbed from the intestine.

Primarily because of its large surface area and secondly, because

of the long residence time of the drug in the intestine. 42
 4. Presence of Aqueous Unstirred Diffusion Layer:
Drugs having a large partition co-efficient can readily penetrate
the lipid membrane.
But the predicted & obtained are different
 Diffusion through the unstirred water layer is the rate limiting
step in their absorption.
Particular true for high molecular weight fatty acids and bile
acids.

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8.Drug stability
A drug for oral use may destabilize either during its shelf-life or in
the GIT resulting in poor bioavailability.

Degradation of drug into inactive form by interaction with one or

more different component(s) to form a complex that is poorly
soluble or is un-absorbable

9.Stereochemical nature of drug:

Enantiomers possess identical physical and chemical properties
despite significant differences in spatial configuration.
Stereoselectivity is not expected effect during passive absorption
of enatiomers.

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 This is not generally true if an active or receptor-mediated
process is involved.

 Absorption may exhibit stereo selectivity , giving rise to the

possibility of competitive interaction between enatiomers.

 Ex. intestinal absorption of D-cefalexin via dipeptide

transport system can be inhibited by its L-enatiomer.

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 DOSAGE FORM
CHARACTERISTICS AND
PHARMACEUTIC
INGREDIENTS

46
1. DISINTEGRATION TIME

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 Solid dosage form should conform to disintegration time,
otherwise leads to slower dissolution resulting in insufficient the
absorption resulting in bioavailability problems

 Rapid disintegration is important in therapeutic success of solid

dosage form.

 Disintegration time of the tablet is directly related to the amount

of binder present and compressional force of the tablet.

 Disintegration can be aided by incorporating disintegrants in

suitable amounts during formulation.

 Dissolution in such fine particles is faster than that from

granules.
2.MANUFACTURING VARIABLES
Solid dosage form related factors that influence dissolution:
Excipients

Manufacturing process

Manufacturing processes
Tablet : method of granulation ,compression force

Capsule: intensity of powder packing

Method of granulation
Wet granulation
Limitations
I.Formation of crystal bridge by the presence of liquid

II.Liquid may cause process like hydrolysis

III. Dry step may effect thermolabile substances

IV.Method & duration of blending

V.Method, time & temperature of drying

Direct compression
Agglomerative phase of communition

Involves grinding of drugs in a ball mill for time long enough to

affect spontaneous agglomeration.
Tablet produced will be stronger and show rapid dissolution

Attributed- increase in internal surface area

Compression force(CF)
CF employed in tableting influences density, porosity, hardness -
DT and dissolution of tablets.
Higher CF increases density & hardness of tablet, decreases
porosity and hence↓ penetrability
 Retards wettability by forming a firmer and more effective
sealing layer by the lubricant

 Promotes tighter bonding between the particles

 Result in slowing of the dissolution rate of tablets

 Higher CF cause deformation, crushing or fracture of drug

particles into smaller ones with a large increase in the effective
surface, results in increased in dissolution rate

51
Influence of compression force on dissolution rate is difficult
to predict

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Intensity of packing of capsule contents

 Packing density of capsule content can either inhibit or promote

dissolution

 Diffusion of GI fluids into the tightly filled capsules creates a high

pressure within the capsule resulting in rapid bursting & dissolution

 Particles having fine size & hydrophobic in nature result in tightly

packed mass with decrease porosity & penetrability

z
Excipients/Pharmaceutic Ingredients:

 Substances which are added to ensure acceptability,

physicochemical stability during the shelf life , uniformity of
composition optimum bioavilability and function-ability of
the drug product.

 Despite their inertness and utility in the dosage form,

excipients can influence the absorption of the drug

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1.Vehicle
 Major component of liquid orals & Parenterals.

 Aqueous vehicles, Nonaqueous water miscible-glycerol,

Nonaqueous water immiscible vehicles-vegetable oils.

 Bioavailability of a drug depends to a large extent on its miscibility

with the biological fluids

 Aqueous vehicles are miscible with body fluid helping in rapid

absorption

 Water immiscible vehicles absorption depends on its partitioning

from oil phase to aqueous body fluids- slower

 Viscosity of the vehicle influence diffusion

2.Diluents/fillers

 Added to increase bulkiness may be organic or inorganic

 Hydrophilic powders promote dissolution of poorly water

soluble drugs(steroids) by forming a coat rendering them
hydrophilic.

 Drug diluent interaction can result in poor bioavilability:

DCP-Tetra

56
3.Binders and granulating agents
 Materials used to hold powders together by promoting
cohesiveness .

 Binders used are polymeric materials eithere natural, semisynthetic

and synthetic like starch, cellulose ,PVP, etc.

57
 Hydrophilic binders promote dissolution of by imparting
hydrophilic properties to granules surface.

 Large amount of binder increases hardness & decrease dissolution &

disintegration rates of tablets.

 PEG 6000 forms complex with phenobarbital ↓ solubility

 Nonaqueous binders like ethylcellulose retard Disso

 4. Disintegrants

 Agents that break cohesive strength of tablet

 A decrease in amount of disintegrant can significantly lower

bioavilability.

 They are hydrophilic in nature

 Adsorbing disintegrants bentonite , veegum , adsorb the low dose

drug ↓ absorption

 Microcrystalline cellulose at high CF retard Disso

5.Lubricants

 Aids flow of granules & reduce interparticulate friction.

 Hydrophobic in nature (metallic stearates and waxes)

59
 known to inhibit wettability ,penetration of water into tablet and
their dissolution/disintegration

 It can be overcome by adding them just before compression

 Use soluble lubricants like carbowaxes & SLS

6.Coatings

 Effect of various coating on dissolution: Enteric coating>sugar

coating>non enteric film coating

 Dissolution profile of coating may change on ageing. Ex: shellac

coated tablets on long storage show slows dissolution.

 Overcome by incorporating PVP

60
7.Suspending agents
 Reduce the settling of particles by increasing viscosity of the
continuous phase

 Macromolecular gums form unabsorbable complex: CMC-

Amphetamine

 Viscosity enhancers act as a mechanical barrier to the diffusion

of the drug from dosage form into GI fluids

 Form a viscid layer on the mucosa

 They also retard the GI transit of the drug.

8.Surfactants
 Used as wetting agents , Solubilizers, emulsifiers

 Increasing absorption
 Promotion of wetting by increasing effective surface area
 Better membrane contact of drug
 Enhance membrane permeability of drug

 Decreasing absorption
 Unabsorbable drug micelle complex formation at conc. greater CMC
 Laxative action –large surfactant concentration

 Synthetic surfactants show their action at pre CMC . But natural

surfactants at CMC
9.Buffers

 Create a right atmosphere for drug dissolution(buffered aspirin

tablets)

 Certain buffers containing potassium ions inhibits the

absorption(vitB2,sulfanamide)r by decresing effective drug
concentrarion

 Overcome buffer system should contain same cation as the drug-

salt.
10.Complexing agents
 Enchance bioavilability

 highly soluble complex :Ergotamine tartarate-caffeine

 ↑ lipophilicity: caffeine-PABA complex membrane
 ↑ permeability by chelation membrane ions -GI absorption of
heparin in presence of EDTA.

 Decreased bioavailability
 Large size complex
 Failure of the complex to dissociate
11.Colourants

 Water soluble dye have inhibitory effect on dissolution rate of

several crystalline drugs.

65
 Dye get adsorbed onto the crystal phase ↓ESA ex :brittle blue
retards dissolution-sulfathiazole

 Inhibit miceller solubilization

 Cation dyes more reactive anion dyes(>adsorption on primary

particles)
12.Crystal growth inhibitors:

Solution with high dissolved conc. of drug tend show

precipitation or crystal formation

Prevent crystal growth or ppt. Eg. PVP , PVG

Increasing the viscosity vehicle

Inhibit conversion of high energy metastable polymorph to

stable, less soluble polymorph

Adsorbing on crystal surface preventing crystal growth 66

NATURE AND TYPE OF DOSAGE FORM
Two to five fold difference in oral bioavailability occurs for a drug
depending on nature & type of dosage form

This is due to variation in release rate from the dosage

Complicated the dosage form greater the rate limiting steps &
bioavailability variation

Bioavilability of the drug from various dosage form decreases in

following order:

Solutions>emulsions>suspensions>capsules>tablets>coatedtablets>
enteric coated tablets>sustained release products.
Drug release from oral dosage forms

68
Solutions

 Factors-nature of solvent ,viscosity ,surfactants, solubilizers,

stabilizers, etc.

69
 Dilution may result in precipitation sometimes.

 Factors that limit drug formulation in solution are stability,

solubility, cost etc.
Emulsions

They present a large surface area of oil to the GIT for absorption
of a drug

Drug administered in oily vehicle emulsified are solubilized in

the GIT by bile salts forming mixed micelles

Drug absorbed directly into the lymphatic system avoiding

first-pass metabolism

Ex: Indoxole dispensed as emulsion increases absorption 3 fold

over its aqueous suspension
70
Suspension

Rate limiting step in absorption of a drug is drug dissolution, due

to large surface area of the particles

Particle size, polymorphism, wetting agents, viscosity,

suspending agents

Powders

Particle size, polymorphism, wetting etc.

Drug formulation in powders is limited due to handling and

palatability problems.
Capsules

 Powders and granules are administered in hard capsules

 Particle size, polymorphism, density, intensity of packing and

nature of diluents

 Hydrophobic drugs of fine particle size tightly pack resulting in

decreased porosity with decreased penetrability

 Incorporating a large amount of hydrophilic diluents (upto 50%), a

small amount of wetting agent as SLS ( upto 1%) counters the said
problem
 Interaction between the drug and the diluents (eg: - tetracycline-
DCP) or gelatin shell.

 Viscous fluids and oils are packed in soft capsules

 Dissolves faster and show better drug availability than hard caps

 High water content in shell (above20%) migrates into capsule &

crystallization occurs during the drying stage resulting in altered
drug dissolution characteristics.

73
Tablets
 Bioavailability problem may arise due to reduction in surface area
due to granulation & compression

 Processing & physicochemical properties of drug & diluents

Coated tablets
 Coating acts as a barrier which must first dissolve to give way to
dissolution and disintegration of tablets

 Sugar coat takes longer time to dissolve than film coat

 Seal coat on aging effect DT

Enteric coated tablets
 Bioavailability problems occur as coat dissolves in intestinal pH
which takes 2 to 4 hours

 This variability in gastric emptying depends on nature of meal &

GI motility

 Thickness & aging of shellac enteric coat

Sustained release products

 Drug release is most unpredictable

 Problems from dose dumping and no drug release.

Product age & storage condition

Solution on storage precipitates altering solubility due conversion

from metastable to stable polymorph

Particle size distribution changes in suspension

Alteration DT for tablets due hardening of excipients(PVP, lactose,

acacia) or softening of binders (CMC)

Shelf-life changes occurs mainly due variation in temperature &

humidity altering physicochemical properties of excipients effecting
DT & Disso
76
PATIENT RELATED FACTORS
AFFECTING
DRUG
ABSORPTION

77
PATIENT RELATED FACTORS
1)Age
2)Gastric emptying
3)Intestinal transit
4)Gastrointestinal pH
5)Disease states
6)Blood flow to GIT
7)Gastrointestinal contents
8)Pre-systemic metabolism/ first pass effects

78
GIT

Stomach shows limited drug absorption

The total mucosal area is small
The epithelium is dominated by mucus- secreting rather than
absorptive cells.
The gastric residence time is limited

Lipophilic, neutral & acidic drugs are absorbed

Small intestine major site for absorption  

Large surface area: The folds in intestinal mucosa (kerckring)↑

3folds . This folds posses finger like projections called as villi(↑ 30
times). From the surface of villi protrude microvilli ( 600 times)
increase in surface area. 79
Length of intestine results in more than 200 square meters of
surface

Blood flow to small intestine is 6 to 10 times that of stomach.

pH range is 5 to 7.5 favors many drugs to remain unionized

Slow peristaltic movement prolongs the residence time

 Large intestine length and mucosal surfaces is very small

absorption of drugs from this region is insignificant.

80
 Absorption of water and electrolytes.

 Long residence time (6-12 hours) may be important in the

absorption of some poorly soluble drugs and sustained release
dosage forms

1. AGE

 In infants the gastric pH is high, intestine surface and blood flow

is low

 In the elderly altered gastric emptying , decreased intestinal

surface area and GI blood flow & bacterial over growth shows
altered absorption 81
2. GASTRIC EMPTYING

The passage of material from stomach to small intestine called as

gastric emptying & is a first order process

Gastric emptying rate: is the speed at which stomach contents

empty into the intestine

Gastric emptying time: is the time required for gastric contents to

empty into the small intestine. Longer the gastric emptying rate
slower the gastric emptying time

Gastric emptying : T1/2 is the time taken to empty the stomach

content by half.
82
 
Rapid gastric emptying is desirable

A rapid onset of action is desired e.g. sedatives

Dissolution of drug occurs in the intestine e.g. enteric coated

Drugs are unstable in gastric fluids e.g: penicillin G,

erythromycin

Drug is best absorbed from distal part of the small intestine e.g.
Vitamin B12

83
Delay in gastric emptying desirable

Food promotes drug dissolution and absorption. Eg: griseofulvin

Disintegration and dissolution of dosage forms is promoted in

gastric fluids

The drug dissolve slowly. e.g: griseofulvin

Drugs are absorbed from the proximal part of small intestine &
prolonged drug-absorption site contact is desired. e.g. Vit B2 & C

84
Factors Influence Gastric Emptying
Volume of meal : larger the bulk of the meal greater is the
emptying time

Temperature of the meal : High or low temperature fluids in

comparison with the body temperature reduces the gastric
emptying rate

Composition of meal
Carbohydrates>proteins>fats
Fats promote secretion of bile which inhibits gastric emptying
Fatty meal is beneficial for absorption of poorly soluble
drugs like Gresiofulvin

Physical state and viscosity of meal: Liquids take about an hour

time & solid meal requires about 4-5 hours for emptying. 85
 GI pH : Gastric emptying is retarded at low gastric pH &
promoted at alkaline pH.

 Body posture: Gastric emptying is favored while standing &

lying on the right side .

 Emotional state: Stress & anxiety promotes gastric motility.

Depression retards gastric motility.

 Drugs: antacids, anticholinergics, narcotic analgesics retard

while metoclopromide, domperidone & cisapride etc. stimulate
GE
86
3. INTESTINAL TRANSIT
The residence time depends on the intestinal motility

Peristaltic movements promote absorption by increasing the drug-

intestinal membrane contact & enhancing the dissolution of poorly
soluble drugs through induced agitation.

Delayed intestinal transit desirable

 Drug that dissolves or releases slowly(sustained release)
 Drugs that dissolve only in intestine (enteric coated formulations)
 Drugs that are absorbed at specific sites in intestine(b vitamins)
 Drug penetrates the mucosa very slowly ex:acyclovir
Food, decreased GI secretions, anticholinergic & pregnancy retard
intestinal transit.
Diarrhoea, metoclopramide, laxatives promotes intestinal transit.
87
4) GASTROINTESTINAL pH
Disintegration: enteric coated tablets made of pH sensitive
polymer like eudragits DT & Disso get effected.

Dissolution
 Most drugs are moderately acidic or basic
 pH that favors formation of salt is desirable
 Weakly acidic drugs dissolve in alkaline pH & weakly basic
drugs dissolve in acidic pH.

Absorption : depending on the drug pka & whether it is an acidic

or basic drug, the GI pH influences its ionization & drug absorption

Stability: acidic stomach pH degrades penicillin G &

erythromycin, counter by preparing pro-drugs carindacillin &
erythromycin estolate. 88
DISEASE STATES

Gastrointestinal

Achlorhydria(decreased GI secretin and high pH): decreases

absorption of acidic drugs like Aspirin

Celiac disease: (destruction of villi & microvilli)

Increased GI emptying rate
Altered intestinal drug metabolism
Steatorrhea: impaired secretion of bile ,affecting absorption of
lipophilic drugs.

 Crohn’s disease: altered gut wall microbial flora, decreased gut

surface area & alter intestinal transit rate 89
 Cardiovascular : there is oedema of the intestine , decreased
blood flow to GIT. It alters gastric emptying rate, gastric pH,
secretions, microbial flora.

 Hepatic: cirrhosis influences the absorption of drugs that

considerably undergo first pass metabolism.

90
6) BLOOD FLOW TO GIT

 The high perfusion rate ensures drug permeated across

membrane is rapidly removed from the absorption site maintaining
sink conditions & concentration gradient.

Lipid soluble drugs, it is the perfusion rate which is the rate

limiting step in absorption.

Food influences blood flow to GIT. The perfusion rate increases

after meal & persists for few hours but drug absorption is not
significantly influenced.

91
7) GASTROINTESTINAL CONTENTS
i. Food-Drug interaction
Food may either delay, reduce, increase or may not affect
absorption of drugs

General rule better absorbed in fasting condition & retarded in

presence of food

Delayed /decreased absorption

 Delayed gastric emptying (enteric coated) & affecting the

drugs unstable in stomach ex: penicillin
 High viscosity of meal prevents dissolution & diffusion of
drug towards absorption site
 Forming of poorly soluble , un-absorbable complexes ex:
tetracycline-calcium 92
 Increased drug absorption

 Increased time for dissolution of poorly soluble drugs

 Enhanced solubility due to GI secretions like bile
 Prolonged residence time & absorption site contact of drug
ex: water soluble vitamins
 Increased lymphatic absorption

ii. Fluid Volume:

 Large fluid volume results in better dissolution, rapid
gastric emptying & enhanced absorption

 Erythromycin is better absorbed when taken with glass of

water under fasting conditions than when taken with meal
93
iii. Interaction of drug with normal GI constituents:

Mucin protective muco polysaccharide interacts with

streptomycin & certain quaternary ammonium compounds
retard their absorption

Bile salts
Aid solubilisation & absorption of lipid soluble drugs ex:
Gresiofulvin & Vit-A D E K
Decreases absorption of Neomycin & Kanamycin by forming
water insoluble complexes

94
 iv. Drug-drug interactions :

a) Physicochemical:

Adsorption: Anti diarrhoeals containing adsorbents (kaolin-pectin)

retard / prevent absorption of drugs co-administered with them ex:
Lincomycin

Complexation: Antacids containing heavy metals like Al, Ca, Fe,

Mg or Zn form un-absorbable complex with Tetracyclin.

pH Change: Basic drugs dissolve in acidic pH. Co-administration

of such drugs Tetracycline with antacids results in elevation of pH
95

hence low dissolution

b)Physiological:

 Decreased GI Transit: Anticholinergics retard GI motility &

promote absorption of drugs like ranitidine whereas delay of
paracetamol absorption.

 Increased Gastric Emptying: Metoclopromide promotes GI

motility & enhance absorption of tetracycline & levodopa.

 Altered GI Metabolism: antibiotics inhibit bacterial meatbolism

of drugs e.g. erthromycin enhances efficacy of digoxin

96
7) FIRST PASS EFFECT/PRESYSTEMIC METABOLISM

Reasons for decreased oral bioavailability:

1)Decreased absorption (precipitation , complexation & poor
solubility)

2)Destruction of the drug

3) First pass/ pre-systemic metabolism

The loss of drug through biotransformation reaching before

reaching systemic circulation after oral administration is first pass
effect.
97
The three enzyme systems which affect pre-systemic metabolism of
drug are
Luminal enzymes
•Digestive enzymes
•Bacterial enzymes
Gut wall or mucosal enzymes
Hepatic enzymes

Digestive enzymes:
Enzymes present in gut fluids including intestinal and pancreatic
secretions.

Pancreatic contain hydrolases which hydolyse ester drugs like

chloramphenicol palmitate to active chloramphenicol

Peptidases which split amide linkages hence inactivate protein drugs.

98
Peptides are delivered into colon (no peptidases)
Bacterial enzymes:
Present in stomach, small intestine & rich in colon. Render a drug
more active or toxic on biotransformation.
E.g. Sulphasalazine (ulcerative colitis) hydrolyzed by these
enzymes to sulphapyridine & 5-amino salicylic acid.

Gut wall/Mucosal enzymes:

Present in stomach, intestine & colon. ADH is an enzyme of
stomach which inactivates alcohol
Intestinal mucosa contains both phase I & II & act on drugs e.g.
sulfation of isoprenaline

Hepatic enzymes:
Present in the liver responsible for first pass effect e.g.
isoprenaline, nitroglycerine, morphine, lidocaine etc. 99
ABSORPTION OF DRUGS FROM
NON-PER OS EXTRA VASCULAR
ROUTES

100
Intraocular Administration

Meant for local effects such as mydriasis, miosis, anesthesia ,

glaucoma, etc

The barrier to penetration of drugs is the cornea which possesses

both hydrophilic and lipophilic characteristics.

 Optimum permeation occurs if drugs possess biphasic solubility.

pH of the formulation influences lachrymal output—higher pH

decreases tear flow and promotes drug absorption & vice versa due
to drug drainage
101
 Instillation of small volume of drug solution in concentrated form
increases its effectiveness than when administered in large volume
in dilute form

 Viscosity imparters in the formulation increase bioavailability by

prolonging drug’s contact time with the eye.

102
Intranasal Administration
Systemic delivery of peptide and protein drugs

Absorption is rapid as observed after parenteral administration

because of its rich vasculature and high permeability

Lipophilic drugs, absorption by diffusion is observed upto 400

Daltons & satisfactory absorption up to 1000 Daltons.

Permeability enhancers (surfactants) added help absorption of drug

with molecular weight of 6000 Daltons

Polar compounds primarily absorbed by pore transport(200 Daltons)

Nasal permeation is effected by pH of nasal secretions (5.5 to 6.5),

103

viscosity, pathological conditions such as common cold and rhinitis

Pulmonary Administration
Large surface area of the alveoli, high permeability of the alveolar
epithelium and rich perfusion permit extremely rapid absorption

Route limited for administering drugs affecting pulmonary system

bronchodilators , anti-inflammatory steroid & antiallergics

Lipophilic drugs are rapidly absorbed by passive diffusion and

polar drugs by pore transport

pH of pulmonary fluids, particle size of the aerosolised droplets

(0.6 microns) from which drug absorption is rapid, penetrate rapidly
but are susceptible to easy exhalation

Patients’ inability to inhale a sufficient amount of drug is the

104

limitation
SUBLINGUAL / BUCCAL ROUTE
Sublingual route: Dosage form is placed beneath the tongue.

Buccal route: Dosage form is placed between the cheek and teeth.

Drugs administered by this route are supposed to produce systemic

action act because as the absorbed drug drains directly into the
general circulation.

Oral mucosal regions are highly vascularized therefore rapid onset

of action is observed.Eg, Nitroglycerin Oxytocin, Fenosterol etc.
105
Factors to be considered:
Lipid solubility should be high for absorption with a low dose

Drug should be soluble in buccal fluid & pH of saliva which is 6

Sublingual absorption is faster than buccal, because mucosa

region is thinner than that of buccal mucosa

Limited mucosal surface area.

Taste of medicament and discomfort.

106
RECTAL ADMINISTRATION
This route of administration is useful in children, old people and
unconscious patients & occurs by passive diffusion.

Drugs may be administered as solutions (microenemas) or

suppositories

Irritating suppository bases such as PEG promotes defecation and

drug loss.

Highly vascularized, absorption is slower because of limited surface

area.

Eg., drugs that are administered are: aspirin, acetaminophen,

107
theophylline, indomethacin, promethazine & certain barbiturates.
VAGINAL ADMINISTRATION

Generally intended to act locally in treatment of bacterial or fungal

infections or prevent conception

Systemic delivery of contraceptives & steroids with no first-pass

metabolism

Buffering, size & shape of dosage a must for better patient

convenience & compliance

pH of lumen fluids (4 to 5), vaginal secretions and the

microorganisms present in the vaginal lumen which may metabolize
the drug may influence absorption 108
Topical Administration

Drugs applied topically are meant to exert their effect locally &
drugs that exert their effects systemically, the mode of administration
is called as percutaneous or transdermal delivery.

Anatomically, the skin is made of 3 distinct layers

Epidermis is the nonvascular, multilayered outer region of the skin.

Dermis or true skin is a highly vascular region; drugs permeating to

this region are taken up into the systemic circulation
subcutaneous fat tissue

Principal barrier to the entry of drugs is the most superficial layer of

epidermis called as stratum corneum
109
Factors influencing absorption

Absorption is very slow from regions such as foot and palm where
the skin has thickened stratum corneum.

Absorption is rapid from regions where numerous hair follicles

exist e.g. scalp.

Rashes, inflammation, mild burns stratum corneum is destroyed,

promote drug absorption.

Hydration of skin promote hydration of skin and drug absorption.

110
Novel techniques: Ionic drugs are not absorbed transdermally,
absorption of such drugs can be affected by the following

Iontophoresis:
Drug delivery into the body by means of an electric current

An ionized drug in solution is placed on the skin and an electrical

potential difference established thus driving the ions into the skin.

Application of a positive current will drive positively charged drug

molecules away from the electrode and into the tissues & vice versa
e.g. Cortisol, methacholine,

Phonophoresis: Defined as the movement of drug molecules through

111
the skin under the influence of ultrasound.
May 2009
1.Write the factors influencing drug absorption through GIT with
examples(15)
2.What is Noyes-Whitney’s equation?(2)

May 2010
1.Explain the Noyes-whitney’s equation(5)
2.Explain the mechanism of drug absorption by passive diffusion(5)
3.Define dissolution and name the theories of drug dissolution (2).
4.List the different mechanisms of drug absorption(2)
5.State the Fick’s law of diffusion and give its mathematical
expression(2)

112
May 2011
1.Describe pH partition hypothesis (5)
2.Explain the Noise-whitney’s equation (5)
3.Explain Fick’s first law of diffusion(2)
4.How does food affect the rate and extent of drug absorption from
GIT?(2)
5.How do bacteria present in the colon influence colonic pH (2)
6.What is endocytosis?(2)
May 2012
1.Define absorption. Explain the various biological, physicochemical
and pharmaceutical factors which affect the drug absorption(15)
2.What is Hasselbalch equation(2)
3.What do you mean by rate-limited step in drug absorption?(2)

113
May 2013
1.Explain the various physic-chemical and biological factors
affecting gastro-intestinal absorption of drugs(15)
2.Fick’s first law of diffusion(2)

114