Unit 1 (Part 2)

Factors Influencing Drug

Absorption
 II. PHARMACEUTICAL FACTORS

1. Disintegration time (tablets/capsules):

➢Rapid disintegration is important to have a rapid absorption so lower
disintegration time is required.
➢Disintegration time of tablet is directly proportional to amount of
binder & Compression force.
➢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.
➢E.g. COATED TABLETS: they have long disintegration time.
➢Fast dispersible tablets have short disintegration time
 2) Dissolution time:
➢Dissolution is a process in which a solid substance solubilizes in a given
solvent i.e. mass transfer from the solid surface to the liquid phase.
➢Dissolution time is also an important factor which affect the drug
absorption.

3) Manufacturing variables:
➢Several manufacturing processes influence drug dissolution from solid
dosage forms.
For example: For tablet it is
✓Method of granulation
✓Compression force
Method of granulation:
➢The wet granulation process is the most conventional technique
➢The tablets that dissolve faster than those made by other granulation
methods.
➢But wet granulation has several limitations like formation of crystal
bridge or chemical degradation.
➢The method of direct compression force has been utilized to yield the
tablets that dissolve at a faster rate
Compression force:
➢The compression force employed in tableting process influence
density, porosity, hardness, disintegration time and dissolution rate of
tablets.
➢Higher compression force increases the density and hardness of the
tablet, decreases porosity and hence penetrability of the solvent into
the tablet and thus in slowing of dissolution and absorption.
➢On the other hand, higher compression force causes deformation,
crushing or fracture of drug particles into smaller ones and causes a
large increase in effective surface area. This results in an increase in
dissolution rate of tablets.
 4) Pharmaceutical ingredients (excipients/adjuvants):
➢More the number of Excipients in the dosage form, more complex it is
& greater the potential for absorption and Bioavailability problems.
➢Commonly used excipients in various dosage forms are,

a) Vehicle:
➢Rate of absorption– depends on its miscibility with biological fluid
➢Miscible vehicles causes rapid absorption e.g. propylene glycol.
➢Immiscible vehicles– Absorption depends on its partitioning from oil
phase to aqueous body fluid
b) Diluents:
➢Hydrophilic diluents – Imparts Absorption
➢Hydrophobic diluents – Retards Absorption
➢Also, there is a drug-diluent interaction, forming insoluble complex and
retards the absorption. E.g. Tetracycline-DCP

c) Binders & granulating agent:

➢Hydrophilic binders– Imparts hydrophilic properties to the granule surface–
gives better dissolution properties. E.g. Starch, Gelatin. PVP.
➢More amount of binder increases the hardness of the tablet and retards the
absorption rate.

d) Disintegrants:
➢Mostly hydrophilic in nature.
➢Decrease in amount of disintegrants– significantly lowers bioavailability.
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 un-absorbable 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.
➢e.g. Griseofulvin, steroids
➢It may decrease absorption when it forms the un-absorbable complex with
drug above CMC.
h) Coating:
➢In general, deleterious effects of various coatings on the drug
dissolution from a tablet dosage form are in the following order.
Enteric coat > sugar coat > non-enteric coat
➢The dissolution profile of certain coating materials change on aging;
e.g. shellac coated tablets, on prolonged storage, dissolve more slowly
in the intestine. This can be however, be prevented by incorporating
little PVP in the coating formulation.

i) Buffers:
➢Buffers are sometimes useful in creating the right atmosphere for drug
dissolution as was observed for buffered aspirin tablets.
➢However, certain buffer systems containing potassium cations inhibit
the drug absorption as seen with Vitamin B2 and sulfanilamide
j) Colorants:
➢Even a low concentration of water soluble dye can have an inhibitory effect
on dissolution rate.
➢The dye molecules get absorbed onto the crystal faces and inhibit the drug
dissolution.
➢For example: Brilliant blue retards dissolution of sulfathiazole.

k) Complexing agents:
➢Complex formation has been used to alter the physicochemical &
biopharmaceutical properties of a drug.
Example
1)Enhanced dissolution through formation of a soluble complex. E.g.
ergotamine tartarate-caffeine complex & hydroquinone digoxin complex.
2)Enhanced lipophilicity for better membrane permeability. E.g. caffeine-PABA
complex.
 5) Nature & type of dosage form:
➢ Apart from the proper selection of the drug, clinical success often
depends to a great extent on the proper selection of the dosage form
of that drug.
➢ As a general rule, the bio-availability of a drug form various dosage
forms decrease in the following order:

Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated
Tablets > Enteric Coated Tablets > Sustained Release Products.
 6)Product age & storage condition:
➢ Product aging and storage conditions can adversely affect the bio-
availability by change in especially the physico-chemical properties of
the dosage forms.

For example:
➢[Link] of the drug in solution
➢[Link] of tablet
➢[Link] in particle size of suspension
 B. PATIENT RELATED FACTORS
1. Age:
• In infants, the gastric pH is high and intestinal surface and blood flow
to the GIT is low resulting in altered absorption pattern in compare to
adults.
• In elderly persons, gastric emptying altered, decreased intestinal
surface area and GI blood flow, higher incidents of achlorhydria so
impaired drug absorption.
2. Gastric emptying time:
• The process by which food leaves the stomach and enters the
duodenum.
• Rapid gastric emptying is required when the drug is best absorbed
from distal part of the small intestine.
• Delayed gastric emptying is required when drugs are absorbed from
proximal part of the small intestine and prolonged drug absorption
site contact is desired.

Rapid gastric emptying 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:
• 1. The food promotes drug dissolution and absorption e.g.
griseofulvin.
• 2. Disintegration and dissolution of dosage form is promoted by
gastric fluids.
• 3. The drugs dissolve slowly e.g. griseofulvin.
• 4. The drugs irritate the gastric mucosa e.g. aspirin, phenylbutazone
nitrofurantoin. and
• 5. The drugs are absorbed from the proximal part of the small
intestine and prolonged drug-absorption site contact is desired e.g.
vitamin B2 and vitamin C
Factors influence gastric emptying
3. Intestinal transit time:
• Intestinal transit time is the major site of absorption of most of drugs.
• The mixing movement of the intestine that occurs due to peristaltic
contractions promotes drug absorption, firstly, by increasing the drug
intestinal membrane contact and secondly by enhancing drug
dissolution of especially of poorly soluble drugs, through induced
agitation.
• Delayed intestinal transit is desirable for
• A)Drugs that dissolve or release slowly from their dosage form (sustained
release products)
• B)Drugs that dissolve only in intestine (enteric coated formulations)
• C) Drugs absorbed from specific sites in the intestine (several B vitamins
• Intestinal transit time is influenced by various factors such as food,
diseases and drugs.
• E.g. metoclopramide which promotes intestinal transit, enhance
absorption of rapidly soluble drugs while anticholinergic retards
intestinal transit and promotes the absorption of poorly soluble drugs.
4. Gastrointestinal pH:
5. Disease states

1. Gastric diseases (Achlorhydric patients):

• They may not have adequate production of acids in the stomach;
stomach HCl is essential for solubilizing insoluble free bases.
• Two disorders related with malabsorption syndrome are celiac
disease (characterized by destruction of villi and microvilli) and
Crohn’s disease. Abnormalities associated with celiac disease include
increased gastric emptying rate and GI permeability, altered intestinal
drug metabolism.
• Crohn’s disease altered gut wall microbial flora, decreased gut
surface area and intestinal transit rate.
• Malabsorption is also induced by drugs such as antineoplastics and
alcohol. GI infections like shigellosis, gastroenteritis, cholera and food
poisoning also result in malabsorption.
2. Cardio-vascular diseases:
• Several changes associated with congestive cardiac failure influence
bio-availability of a drug viz., edema of the intestine, decreased blood
flow to the GIT and gastric emptying rate and altered GI pH, secretions
and microbial flora.

3. Hepatic diseases:
• Disorders such as hepatic cirrhosis influence bioavailability mainly of
drugs that undergo considerable first-pass hepatic metabolism e.g.
propranolol; enhanced bioavailability is observed in such cases.
6. Blood flow through the GIT:
• It plays a major role in absorption by continuously maintain the
concentration gradient across the epithelial membrane.
• The GIT is extensively supplied by blood capillary network.
• Blood flow is imp for actively absorption of drugs.
• Absorption of polar molecules doesn’t depends on the blood flow
but lipid soluble molecules highly depends on the blood flow.
• Food influences blood flow to the GIT. Perfusion increases after
meals & persist for few hours but absorption is not affected
7. Gastrointestinal contents:
• 1) Food- drug interactions: The presence of food in the GI tract can
affect the bioavailability of the drug .
• Digested foods contain amino acids, fatty acids, and many nutrients
that may affect intestinal pH and solubility of drugs.
• Some effects of food on the bioavailability of a drug from a drug
product include:
• Delay in gastric emptying
• Stimulation of bile flow
• A change in the pH of the GI tract
• An increase in splanchnic blood flow
Presence of food will affect absorption in following way
a)Decreased absorption: ex. Penicillin, erythromycin, ethanol,
tetracycline, levodopa etc.
b)Increased absorption: ex grieseofulvin, diazepam, vitamins etc
2) Fluid volume:
• Large fluid volume results in better dissolution, rapid gastric
emptying and enhanced absorption
• Ex. Erythromycin is better absorbed when taken with a glass of
water under fasting condition than when taken with meals.

3) Interaction of drug with normal GI constituents:

• The GIT contains a number of normal constituents such as mucin
which is a protective mucopolysaccharides that lines the GI mucosa,
interact with streptomycin
8. Presystemic metabolism:
• The loss of drugs through bio-transformation by such eliminating
organs during the passage to systemic circulation is called as first pass
or pre-systemic metabolism.
• complete absence of the drug in plasma after oral administration is
indicative of the first-pass effects. The four primary systems which
affect the pre-systemic metabolism of a drug
1) Lumenal Enzymes
2) Gut wall enzymes/mucosal enzymes
3) Bacterial enzymes
4) Hepatic enzymes