INTRODUCTION

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Definition:
The process of movement of unchanged drug from
the site of administration to systemic circulation.
 Factors affecting absorption

A. Pharmaceutical factors:
1. Physicochemical properties of drug
a. Drug solubility and dissolution rate
b. Particle size and effective surface area
c. Polymorphism and amorphism
d. Pseudopolymorphism(hydrates or solvates)
e. Salt form of the drug
f. Lipophilicity of the drug
g. Drug stability
h. Stereochemical nature of the drug
 2. Formulation factors

a. disintegration time
b. manufacturing variables
c. nature and type of dosage form
d. pharmaceutical ingredients (excepients)
e. product age and storage conditions
 B. Patient related factors
a. age
b. gastric emptying time
c. intestinal transit time
d. gastrointestinal pH
e. diseased states
f. blood flow through the GIT
g. gastrointestinal contents
1. other drugs
2.food
3.fluids
4.other normal G.I contents
h. presystemic metabolism by
1. luminal enzymes
2. gut wall enzymes
3.bacterial enzymes
4. hepatic enzymes
a. Drug solubility and dissolution rate

solid dosage form

disintegration

solid drug particles

dissolution (RDS for lipophilic drugs)

drug in solution at absorption site

permeation (RDS for hydrophilic drugs)

drug in the body

 For Hydrophobic drugs

 Dissolution is rate limited step. e.g. Griseofulvin, spironolactone

For Hydrophilic drugs

 Permeation is rate limited step. e.g. cromolyn sodium, neomycin.

b. Particle size and effective surface area
of drug
Smaller the drug particle, greater the surface area.
surface area

absolute surface area effective surface area

total surface area of area of solid surface exposed to

solid surface of particle dissolution medium
 Smaller the particle size (by micronization) greater is the
effective surface area more intimate contact b/w solid surface
and aq solvent higher is the dissolution rate increase in
absorption efficiency.
 Particle size reduction has been used to increase the
absorption of a large number of poorly soluble drugs, such as
bishydroxycoumarin, digoxin, griseofulvin, nitrofurantoin,and
tolbutamide.
 Griseofulvin has extremely low aqueous solubility, and
material of normal particle size gave rise to poor and erratic
absorption.
 Microsize particles improve absorption, but it is improved
even more when it is formulated in ultramicrosize particles as
a monomolecular dispersion in polyethylene glycol.
 c.Polymorphism and Amorphism

Many compounds form crystals with different molecular

arrangements, or polymorphs.
These polymorphs may have different physical properties, such
as dissolution rate and solubility.

polymorphs

enantiotropic monotropic
polymorph polymorph
eg: sulphur eg:glyceryl stearates
 40 % of all organic compounds – exist in various polymorphic
forms.
 70% of barbiturates & 65% of sulphonamides exhibit
polymorphism.

Amorphous form:
These have greater aqueous solubility than the crystaline
forms because the energy required to transfer a molecule from
crystal lattice is greater than that required for non-crystalline
solid .
eg: amorphous form of novobiocin - 10 times more soluble
than crystalline form.
amorphous > metastable> stable
 d.Hydrates or solvates

 The stoichiometric type of adducts where the solvent

molecule are incorporated with the crystal lattice of the
solid are called as solvates.
 Trapped solvent is the solvent of crystallisation.
 The solvates can exist in diff crystalline forms called as
 pseudomorphs and the phenomenon is
pseudopolymorphism.
 When the solvent in association with drug is water, the
solvate is known as hydrate.
eg: anhydrous form of theophylline and ampicillin

high aq solubility

dissolve at a faster rate

more bioavailability than their monohydrate &

trihydrate forms
 e. Salt form of drug
 At given pH, the solubility of drug, whether acidic/basic
or its salt, 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.
For salts of weak acids,
[H+]d < [H+]b

For salts of weak bases,

[H+]d > [H+]b

where [H+]d = [H+] of diffusion layer

[H+]b = [H+] of bulk of the solution
Other approach to enhance the dissolution and absorption rate
of certain drugs is by in – situ salt formation
i.e. increasing in pH of microenvironment of drug by
incorporating buffer agent.
e.g: aspirin, penicillin
But sometimes more soluble salt form of drug may result in
poor absorption.
e.g: sodium salt of phenobarbitone and phenobarbitone

tablet of salt of phenobarbitone swelled

it did not get disintegrate

dissolved slowly & results in poor absorption.

 f.Drug pKa & lipophilicity & GI pH --- pH partition
hypothesis

pH – partition theory states that for drug compounds of molecular

weight more than 100, which are primarily transported across the
biomembrane by passive diffusion,
the process of absorption is governed by
 pKa of drug
 The lipid solubility of the unionized drug
 pH at the absorption site.
Amount of drug that exist in unionized form and in ionized form
is a function of pKa of drug & pH of the fluid at the absorption
site and it can be determined by Hendersonhesselbach equation: -

For, Acidic drugs

pH = pKa + log [ionized form]
[Unionized form]
For, Basic drugs
pH = pKa + log [unionized form]
[Ionized form]
 g.Lipophilicity and drug absorption

Ideally for optimum absorption, a drug should have

sufficient aq solubility to dissolve in fluids at absorption site
and lipid solubility (Ko/w) high enough to facilitate the
partitioning of the rug in the lipoidal biomembrane i.e. drug
should have perfect HLB for optimum Bioavailability.

Ko/w = Distribution of drug in organic phase

(octanol) Distribution of drug in aq
phase
As Ko/w i.e. lipid solubility, i.e. partition
coefficient increases percentage drug
absorbed increases.
 Formulation factor

1. Disintegration time:
Rapid disintegration is important to have a rapid absorption so lower
D.T is required.
Now D.T of tablet is directly proportional to – amount o f binder -
Compression force.
And one thing should be remembered that in vitro disintegration test
gives no means of a guarantee of drugs bioavailability because if the
disintegrated drug particles do not dissolve then absorption is not
possible.
2. Manufacturing variables: -
a) Method of granulation:
Wet granulation yields a tablet that dissolves faster than those made
by other granulating methods. But wet granulation has several
limitations like formation of crystal bridge or chemical degradation.
Other superior recent method named APOC (agglomerative
phase of communition) that involves grinding of drug till
spontaneous agglomeration and granules are prepared with
higher surface area. So tablet made up of this granules have
higher dissolution rate.
b) Compression force:
Higher compression force yields a tablet with greater hardness
and reduced wettability & hence have a long D.T. but on other
hand higher compression force cause crushing of drug particles
into smaller ones with higher effective surface area which in
decrease in D.T.
So effect of compression force should be thoroughly studied on
each formulation.
3. Nature and type of dosage form
Drug formulations are
designed to provide an
attractive, stable, and
convenient method to use
products. Conventional
dosage forms may be broadly
characterized in order of
decreasing dissolution rate as
solutions, solid solutions,
suspensions, capsules and
tablets, coated capsules and
tablets, and controlled release
formulations.
A. Solutions:
Aqueous solutions, syrups,
elixirs, and emulsions do
not present a dissolution
problem and generally
result in fast and often
complete absorption as
compared to solid dosage
forms. Due to their
generally good systemic
availability, solutions are
frequently used as
bioavailability standards
against which other dosage
forms are compared.
B.Solid solutions
The solid solution is a
formulation in which
drug is trapped as a solid
solution or
monomolecular
dispersion in a water-
soluble matrix. Although
the solid solution is an
attractive approach to
increase drug absorption,
only one drug,
griseofulvin, is currently
marketed in this form.
C.Suspensions:
A drug in a suspension is in solid
form, but is finely divided and has a
large surface area. Drug particles
can diffuse readily between the
stomach and small intestine so that
absorption is relatively insensitive
to stomach emptying rate.
Adjusting the dose to a patient’s
needs is easier with solutions and
suspensions than with solid dosage
forms. Liquid dosage forms,
therefore, have several practical
advantages besides simple
dissolution rate.
However, they also have some
disadvantages, including greater
bulk, difficulty in handling, and
perhaps reduced stability.
D. Capsules and tablets:

These formulations differ from

each other in that material in
capsules is less impacted than in
compressed tablets. Once a
capsule dissolves, the contents
generally disperse quickly. The
capsule material, although water
soluble, can impede drug
dissolution by interacting with the
drug, but this is uncommon.
Tablets generally disintegrate in
stages, first into granules and then
into primary particles. As particle size
decreases, dissolution rate increases
due to of increased surface area.
Tablet disintegration was once
considered a sufficient criterion to
predict in vivo absorption.
As a general rule, the bio-
availability of a drug from various
dosage forms decrease in the
following order:

Solutions > Emulsions> Suspensions >

Capsules >Tablets > Coated Tablets >
Enteric coated
Tablets > Sustained Release Products.
 4. Pharmaceutical ingredients /
Excipients
 More the no. of excepients in dosage form, more complex it
is & greater the potential for absorption and Bioavailability
problems.
 Changing an excipient from calcium sulfate to lactose and
increasing the proportion of magnesium silicate, increases
the activity of oral phenytoin.
 Systemic availability of thiamine and riboflavin is reduced by
the presence of Fuller’s earth.
 Absorption of tetracycline from capsules is reduced
by calcium phosphate due to complexation.
 Most of these types of interactions were reported some time
ago and are unlikely to occur in the current environment of
rigorous testing of new dosage forms and formulations.
a) Vehicle:
Rate of absorption – depends on its miscibility with biological
fluid.Miscible vehicles (aq or water miscible vehicle) –rapid
absorption e.g. propylene glycol.
Immiscible vehicles - absorption –depends on its partitioning
from oil phase to aq body fluid.
b) Diluents:
Hydrophilic diluents-form the hydrophilic coat around
hydrophobic drug particles –thus promotes dissolution and
absorption of poorly soluble hydrophobic drug.
c) Binders & granulating agent :
Hydrophilic binders – imparts hydrophilic properties to granule
surface – better dissolution of poorly wettable drug. e.g. starch,
gelatin, PVP. More amount of binder – increases hardness of
tablet – decrease dissolution & disintegration
rate.
 d) Disintegrants
 Mostly hydrophilic in nature.
Decrease in amount of disintegrants – significantly lowers
B.A.
e) Lubricants :
Commonly hydrophobic in nature – therefore inhibits
penetration of water into tablet and thus dissolution and
disintegration.
f) Suspending agents/viscosity agent :
Stabilized the solid drug particles and thus affect drug
absorption.
 Macromolecular gum forms unabsorbable complex with drug
e.g. Na CMC.
Viscosity imparters – act as a mechanical barrier to diffusion
of drug from its dosage form and retard GI transit of drug.
g) Surfactants :
May enhance or retards drug
absorption by interacting with drug
or membrane or both.
Surfactants have been considered
as absorption enhancers, again
mostly in animals.
Polyoxyethylene ethers have been
shown to enhance gastric or rectal
absorption of lincomycin, penicillin,
cephalosporins, and fosfomycin in
rats and rabbits.
However, in humans, oral
polyoxyethylene-20-oleyl ether
resulted in poor and variable insulin
absorption.
In general, unionic surfactants
have little effect on membrane
structure but cationic
Surfactants have been associated
with reversible cell loss and loss of
goblet cells.
Physiologic surfactants – bile
salts – promotes absorption
e.g. Griseofulvin, steroids
It may decrease absorption when
it forms the unabsorbable complex
with drug above CMC.
Colourants:
Even a low concentration of water soluble dye can have
an inhibitory effect on dissolution rate of several
crystalline drugs.
The dye molecules get absorbed onto the crystal faces
and inhibit the drug dissolution.
e.g: Brilliant blue retards dissolution of sulfathiazole.
5. Product age and storage conditions :
Product aging and improper storage conditions
adversely affect B.A.
e.g:precipitation of drug in solution decrease rate of
Change in particle size of suspension drug dissolution
& Hardening of tablet & absorption.
 Patient related factors

Gastric emptying: apart from the dissolution of

drug and its permeation through the bio
membrane,the passage from stomach to small
intestine, called as gastric emptying,can also be a
rate limiting step in absorption because the major
site of drug absorption is intestine.
It is advisable where:
 Rapid onset of drug is desired eg:sedatives
 Drug not stable in gastric fluids eg:pencillin G
Dissolution occuring in intestine eg:enteric coated
forms
Delay in gastric emptying is recommended in particular
where:
Food promotes drug dissolution and absorption
eg: griseofulvin.
The drugs dissolve slowly. Disintegration and dissolution of
dosage form is promoted by gastric fluids.
Gastric emptying is first order process. Several
parameters used to quantify are:
Gastric emptying rate: speed at which stomach contents
empties into intestine.
Gastric emptying time: time required for gastric contents
to empty into small intestine
Gastric emptying t1/2 : time taken for half of the stomach
contents to empty
 Factors influencing gastric emptying
Volume of meal: larger the bulk of meals, longer the gastric
emptying time. An initial rapid rate of emptying observed with
large volume of meal and an initial lag phase in emptying of
small volume of meal.
Since gastric emptying is first order, a plot of volume of
contents remaining in stomach vs time yields a straight line.
Composition of meal:
carbohydrates > proteins> fats
Delayed gastric emptying with fatty meal, is beneficial for the
absorption of poorly soluble drugs like griseofulvin.
Physical state and viscosity of meal:
Liquid meals take less than hour to empty whereas a solid
meal may take as long as 6 to 7 hours.
Temperature:
High or low temperature of injested fluid reduces the gastric
emptying.
Gastro intestinal ph:
Retarded at low stomach ph and promoted at high ph. The
inhibitory effect of various acids on emptying decreases with
increase in mol wt, order is:
Hcl > acetic > lactic > tartaric> citric
Electrolytes and osmotic ph: water, isotonic solutions and of
low salt concentration empty rapidly whereas high electrolyte
conentration decreases gastric emptying.
Drugs that retard gastric emptying include
Poorly soluble antacids: aluminium hydroxide
Anticholinergics: atropine
Narcotic analgesics: morphine
Tricyclic anti depressents: imipramine

Disease state: like gastroenteritis, gastric ulcer, pyloric stenosis

retard gastric emptying rate.
 Intestinal transit
Since small intestine is the major site for absorption of most
drugs, long intestinal transit time is desirable for complete
drug absorption.

Intestinal region Transit time

Duodenum 5 min
Jejunum 2 hrs
Ileum 3to 6 hrs
Caecum 0.5 to 1hr
Colon 6 to 12 hrs
Delayed transit time is desirable for:
 Drugs that dissolve their dosage form.
 Drugs that dissolve only in intestine.
 Drugs absorbed from specific sites in the intestine.
 Laxatives promote the rate of intestinal transit.
Anticholinergic drugs: retard gastric and intestinal transit
promote absorption of poorly soluble drugs
eg:propantheline
 Gastro intestinal pH
The GI ph generally increases as one moves down the stomach
to the colon and rectum.GI ph influence absorption in several
ways.
Disintegration:
Enteric coated formulations: coat dissolves
only in intestine followed by disintegration.
Dissolution:
weakly acidic drugs: dissolve rapidly in alkaline ph of
intestine
Weakly basic drugs: dissolve in acidic ph of stomach
Absorption: depends on drug pKa and whether its an acidic or
basic drug, GI ph influences drug absorption by determining
amount of drug that would exist in unionised form at the site of
absorption.
Stability: acidic stomach ph- affect degradation of pencillin G
and erythromycin

Can be overcome by preparing prodrugs of such drugs .

eg: carindacillin and erythromycin estolate.
 Pre systemic metabolism
For a drug administration orally, the 2 main reasons for its
decreased bioavailability are:
a. Decreased absorption and
b. First pass metabolism
The loss of drug through biotransformation by such
eliminating organs during its passage to systemic circulations
called as first pass or presystemic metabolism.
The 4 primary systems which effect presystemic metabolism
of a drug are:
a. Luminal enzymes b. Gut wall enzymes
c. Bacterial enzymes d. Hepatic enzymes
 Luminal enzymes

These are present in gut fluids and include enzymes from

intestinal and pancreatic secretions. latter contain hydrolases
which hydrolyse ester drugs.
chloramphenicol palmitate active chloramphenicol, and
which split amide linkages and inactivate proteins.

One approach to To deliver them to

effect oral colon which lack
absorption of peptidases
peptides is
 * also called as mucosal enzymes
present in stomach, intestine and colon.
Alcohol dehydrogenase: enzyme of stomach mucosa
inactivates ethanol.
Intestinal mucosa: contains both phase I and phase II
enzymes.
eg: sulphation if ethinyl estradiol .
Colonic mucosa: also contains both phase I and phase II
enzymes.
Bacterial enzymes: colonic generally render a drug more
active or toxic on biotransformation.

hydrolyzation
eg: sulphasalazine sulphapyridine &
(drug in ulcerative colitis) 5-aminsalicylic acid
Enzymes hydrolyse conjugates of drugs actively secreted via bile
such as glucoronides of digoxin and oral contraceptives
Hepatic enzymes:
several drugs undergo first pass hepatic metabolism, the highly
extracted ones being isoprenaline, propranolol, alprenolol,
pentoxyphylline, nitroglycerine, diltiazem, lidocaine, morphine
etc.
Altered GI motility:
Gastrointestinal diseases and infections:
 Two of the intestinal disorders related with
malabsorption syndrome that influence drug availability
are celiac disease and Crohn’s disease.
 Crohn’s disease that can alter absorption pattern are
altered gut wall microbial flora, decreased gut surface
area and intestinal transit rate.
 GI infections like shigellosis, gastroenteritis, cholera
and food poisoning also result in malabsorption.
Gastrointestinal surgery:
Gastrectomy can result in drug dumping in the intestine,
osmotic diarrhea and reduced intestinal transit time.
Cardiovascular diseases:
Several changes associated with congestive cardiac failure
influence bioavailability of a drug.
Hepatic diseases:
Disorders such as hepatic cirrhosis influence bioavailability
mainly of drugs that undergo considerable first-pass hepatic
metabolism.
e.g. propranolol.
 A number of contents can influence drug absorption as follows:
 Food-drug interactions: Presence of food may either delay,
reduce, increase or may not affect drug absorption.
Delayed Decreased Increased Unaffected

Aspirin Pencillins Griseofulvin Methyldopa

Paracetamol Erythromycin Nitrofurantoin Propylthiouracil

Diclofenac Ethanol Diazepam Sulfasomidine

Nitrofurantoin Tetracyclines Actively

Dioxin Levodopa absorbed
Iron vitamins
 Administration of drug with large fluid volume results in
better dissolution, rapid gastric emptying and enhanced
absorption.
e.g: erythromycin
Interaction of drug with normal GI constituents:
The GIT contains a number of normal constituents such as
mucin, bile salts and enzymes which influence drug
absorption.
Mucin a protective mucopolysaccharide that lines the GI
mucosa, interacts with streptomycin and certain quaternary
ammonium compounds and retards their absorption.
 These interactions can be either physicochemical or physiological.

Physicochemical interactions are due to :

Adsorption: antidiarrhoeal preparations containing
adsorbents like attapulgite or kaolin-pectin retard
absorption of number of drugs co-administered with
them.
e.g: promazine, linomycin.
 Complexation: unabsorbable complexes are formed. e.g:
antacids or mineral substances containing
heavy metals such as Al, Ca+2 , Mg+2 retard absorption of
tetracycline by forming unabsorbable complexes.
Physiological interactions are due to :
 Decreased GI transit:
Anticholinergics like propantheline retard GI motility
and promote absorption of drugs like ranitidine and digoxin &
delay absorption of paracetemol and sulphamethoxazole.

 Increased gastric emptying:

Metoclopramide promotes GI motility and enhances
absorption of tetracycline, levodopa.