Pharmaceutical Formulation

and Biopharmaceutics

Aniruddha Roy
Dosage form design:
Biopharmaceutical
consideration
For a drug to exert its biological effect, it must be
o Transported by the body fluids,
o Traverse the required membrane
biological barriers,
o Escape widespread distribution to unwanted areas,
o Endure metabolic attack,
o Penetrate in adequate concentration to the sites of
action,
o Interact in a specific fashion,
o Causing an alteration of cellular function.
 General principles of drug absorption
Body membranes are generally classified as three
main types:
- those composed of several layers of cells, as the
skin,
- those composed of a single layer of cells, as the
intestinal epithelium,
- those of less than one cell in thickness, as the
membrane of a single cell.

In most instances a drug substance must pass

more than one of these membrane types before it
reaches its site of action.
 Drugs are thought to penetrate these
biologic membranes in two general
ways:

1. By passive diffusion
2. By active transport
 Passive diffusion
• Passive diffusion is used to describe the passage of
(drug) molecules through a membrane which behaves
inertly in that it does not actively participate in the
process.
• The absorption process is driven by the concentration
gradient existing across the membrane, with the
passage of drug molecules occurring from the side of
high drug concentration.
• A major source of variation is membrane permeability,
which depends on the lipophilicity of the drug molecule
(logP). The lipid solubility of a drug, therefore, is a
very important physicochemical property governing the
rate of transfer through a variety of biologic
membrane barriers.
 Fick’s law: the rate of diffusion or transport across a
membrane (dc/dt) is proportional to the difference in
drug concentration on both sides of the membrane.

=dc/dt=P(C1-C2)
Where dc/dt = rate of diffusion,
C1 and C2 refer to the drug concentrations on each side of the
membrane
P is a permeability coefficient or constant.

For practical purposes the value of C1-C2 may be taken

simply as that of C1 and the equation written in the
standard form for a first order rate equation:

-dc/dt=PC1
 The gastrointestinal absorption of most drugs
from solution occurs in this manner in accordance with
first order kinetics in which the rate is dependent on
drug concentration.

The magnitude of the permeability constant, depends on

• the diffusion coefficient of the drug
• the thickness and area of the absorbing membrane
• the permeability of the membrane to the
particular drug.
 Biologic Membrane
• GI membrane is consists of a bimolecular lipoid layer covered
on each side by protein, with the lipid molecule oriented
perpendicular to the cell surface, approximately 70 to 100 Å
in thickness.
• The lipid layer is interrupted by small, water-filled pores with
a radius of approximately 4 Å. A molecule with a radius of 4
Å or less can easily pass through these water-filled pores
known as “convective absorption.”
• When permeation through the membrane occurs, the
permeating substance is considered to have transferred from
solution in the luminal aqueous phase to the lipid membrane
phase, then to the aqueous phase on the other side of the
membrane.
• Biologic membranes have a hydrophilic exterior and a
hydrophobic interior.
• Because of the lipoid nature of the cell membrane, it
is highly permeable to lipid soluble substances.
• Aqueous pores vary in size from membrane to
membrane and thus in their individual permeability
characteristics for certain drugs and other
substances.
Carrier-Mediated or Active Transport
• Although most drugs are absorbed from the
gastrointestinal tract by passive diffusion, some
drugs of therapeutic interest and some chemicals of
nutritional value, such as amino acids, dipeptides and
tripeptides, glucose, and folic acid, are absorbed by
the action of transporter proteins (i.e., a carrier-
mediated transport mechanism).
• The usual requirement for active transport is
structural similarities between the drug and the
substrate normally transported across the membrane.
Active transport
Active transport differs from passive diffusion in the
following ways:

1) The transport of the drug occurs against a concentration

gradient;

2) Limited to drugs structurally similar to endogenous

substances (eg, ions, vitamins, sugars, amino
acids).

3) Requires energy

4) The transport mechanism can become saturated at high

drug concentration; and

5) A specificity for a certain molecular structure can

promote competition in the presence of a similarly
structured compound. This, in turn, can decrease the
absorption of a drug.
Gastrointestinal Physiology

• Drugs, via drug delivery systems, are often

most
administered to human by the oral
subjects Compared to drug administration,
route.
other
especially the
routes
intravenous
of route, the oral route is unusually
complex with respect to the physicochemical conditions
existing at the absorption site. Therefore, before we
discuss how the biopharmaceutical properties of a drug in
a dosage form can affect the availability and action of
that drug, it is prudent to review gastrointestinal
physiology.
o If dissolution is rapid or if the drug is
administered as a solution the rate at which the
drug becomes absorbed depends mainly on its
ability to traverse the membrane barrier.
o If dissolution slow because of the
physicochemical characteristics of the drug
substance or dosage form, dissolution is a
rate-limiting step in absorption.
o Drug remain in stomach :2 to 4 hours.
o In small intestine: 4 to 10 hours.
Anatomy of GI tract
Oral cavity
• Saliva is the main secretion of the oral cavity
• pH 7
• Contains ptyalin which digests starch.
e.g fentanyl citrate, nitroglycerin etc (lipid soluble
drug)
Esophagus
• It connects the pharynx and the cardiac orifice of
stomach
• pH 5-6
• Very little drug dissolution occurs in it
 Stomach
• Fasting pH 2-6
• pH in presence of food is 1.5-2
• Intrinsic factor enhances vit B-12 absorption &
gastric enzymes initiate digestion.
• Basic drugs are solubilized rapidly in presence
of acid
• pH may be increased due to certain drugs e.g
omeprazole.
• Ethanol easily crosses cell membrane & efficiently
absorbed from the stomach.
• e.g ibuprofen, aspirin etc absorbed here.
 Intestine
• pH 5-7.5
• Large area for drug absorption due to presence of
villi, faster drug absorption.
• pH is optimum for enzymatic digestion of protein and
peptide containing food. Hence protein type drug
(e.g insulin) can’t be administered orally.
• The influence of absorptive surface area is much
prominent than pH.
• Most of the drugs absorb here.
 Colon and Rectum
• pH 5.5-7
• Colon promotes melting of oily drugs to form
emulsion.
• Rectums pH is 7 and virtually has no buffer
capacity
• Oral sustained release drug delivery system are well
absorbed in colon (e.g theophylline)
• Suppositories are well absorbed in rectum
normal
 Gastric Emptying Time
o The gastric emptying time for a drug is rapid with
fasting stomach.
o Slower as food content is increased, temperature and viscosity
of food also influence. Fats inhibit gastric secretion and gastric
emptying.
o Anticholinergic drug slows gastric emptying. Which increases
drugs absorption from stomach and reduce drugs absorption from
small intestine.
o Drugs that enhance gastric motility, for example, laxatives,
reduce amount of drug absorbed.
o Aging decrease absorption (geriatrics)

o Decrease in gastric emptying rate is advantageous for drugs

absorbed from stomach but disadvantage for drugs prone to
acid degradation, like penicillins and erythromycin, or inactivated
by stomach enzymes, like L-dopa.
o If acidic drugs remain for long time into stomach,
they get absorbed at a faster rate.
o If basic drug remains for a short time in
stomach and being more time in small intestine,
they get easily absorbed.
o For acidic drug gastric emptying time should
be more and for basic drug less.
o Example: penicillin is unstable in acid and
decomposes if stomach emptying is delayed. Other
drugs, such as aspirin, may irritate the gastric
mucosa during prolonged contact.
 Factors Influencing Gastric Emptying Time
Factors Influence on Gastric Emptying
Volume The larger the starting volume, the greater the initial
rate of emptying, after this initial period, the larger
the original volume, the slower the rate of emptying.
Type of meal Reduction in rate of emptying to an extent directly
dependent upon concentration of carbohydrate, lipid
and protein type food
Osmotic Reduction in rate of emptying dependent upon
concentration for salts and nonelectrolytes
pressure
Physical state Solutions or suspensions of small particles empty
of gastric more rapidly
contents
Body position Rate of emptying is reduced in a patient lying on
left side.
Viscosity Rate of emptying is lower for viscous solutions.
 Contd.
Factors Influence on Gastric Emptying

Temperature Increase in temperature, increase in empyting

of Food rate
Emotional Aggressive or stressful emotional states increase
states stomach contractions and emptying rate; depression
reduces stomach contraction and emptying.

Disease Rate of emptying is reduced in some diabetics and in

states patients with local pyloric lesions and
hypothyroidism; gastric emptying rate is increased in
hyperthyroidism.
Drugs Anticholinergic, narcotic analgesic etc decrease
emptying; Metoclopramide, Domperidone,
Erythromycin, Bethanchol increase emptying.
Interaction between drugs and GI components

Different enzymes affect drug absorption in different ways –

o Esterase transform ester drugs into parent compounds
o Pancreatic enzymes convert Chloromycetin palmitate into
chloromycetin
 Various proteins reduce activity of aluminum antacids by
complexation
 Bile salts enhance dissolution of sparingly soluble drugs and improve
absorption
 Bile salts can also decrease absorption of Neomycin and
Kanamycin by forming insoluble complex
 Mucin, the polysaccharide covering of the GI tract can also alter
absorption
o During trauma or irritation, mucin layer thickness increases
leading to decrease in absorption.
o They can form complex with different drugs – quaternary
ammonium compounds, anticholinergic and hypotensive drugs. Also
streptomycin.
 Effect of Food
The presence of food in the GI tract affects the bioavailability
of oral drugs.

Some effects of food on the bioavailability of the oral drugs

include:
• Delay in gastric emptying time
• Stimulation of bile flow
• Change in the pH of GI tract
• Increase in splanchnic blood flow
• Change in luminal metabolism of drug substances
• Physical/chemical interaction of metal with drug
substances
o Absorption of some antibiotics decreases when
administered with food (e.g. penicillin, tetracycline)
o Absorption of some lipid soluble drugs increases when
administered with food. e.g. metazalone.
o The presence of food in the GI lumen stimulates the flow of
bile which increases the solubility of fat soluble drugs by
forming micelle.
o The presence of food in the stomach lowers the pH which causes
acidic drugs to remain in non-ionized form – helps in
absorption. They may help some basic drug in dissolution as well.
o Drugs irritating to GI mucosa (e.g: erythromycin, aspirin,
NSAIDs etc) given with food to reduce the irritation
by decreasing the rate of drug absorption.
o In the presence of food, enteric coated and non disintegrating
drug products can not reach the duodenum rapidly, thus they
delay drug release & systemic drug absorption.
Effect of nutrients on drug absorption
• Absorption of water soluble vitamins (e.g. B-12, folic
acid) in the stomach are facilitated by forming
complex with intrinsic factors.
• Absorption of calcium in the duodenum is facilitated
by vitamin-D by increasing calcium binding protein
which binds calcium in the intestinal cell & transfer it
to the blood circulation.
• Grape juice contains various flavonoids e.g.
naringin which inhibits cytochrome P-450 enzymes.
Thus it increases bioavailability of certain drugs.
Age
In children & infants: Gastric pH is high,
membrane permeability & BBB permeability is
high, protein binding is less therefore it helps
drug absorption.

While in elderly patient there is altered gastric

emptying, decrease intestinal surface area,
decrease gastric blood flow & higher incidence
of achlorhydria so it inhibits drug absorption.
Effect of Disease States
• Drug absorption differs in any disease which causes
changes in –
• 1. Intestinal blood flow
• 2. Gastrointestinal motility
• 3. Changes in stomach emptying time
• 4. Gastric Ph
• 5. Intestinal pH
• 6. Permeability of gut wall
• 7. Bile secretion
• 8. Digestive enzyme secretion
• 9. Alteration of normal GI flora
• Patient with Parkinson’s disease have difficulty
swallowing & greatly diminished GI motility
• Patient on tricyclic antidepressants & antipsychotic
drugs reduce GI motility which delay drug absorption
• In achlorhydric patient weak-base drugs remain
undissolved in stomach because no adequate acid
• In patient with acid reflux disorder, Proton Pump
Inhibitor such as omeprazole, render stomach
achlorhydric, may affect drug absorption
• HIV-AIDS patients are prone to a number of GI
disturbances e.g. increased gastric transit time,
diarrhea
• Crohn’s disease causes impaired absorption due to
reduce surface area & thicker gut wall e.g. higher plasma
propranolol conc. observe in crohn’s disease
• Patient with Celiac disease increase rate of stomach
emptying & permeability of small intestine
• Cephalexin absorption increase in Celiac disease
• Cardio-vascular diseases: Several changes associated
with congestive cardiac failure influence the bio-
availability of the drug viz., edema of the intestine,
decreases blood flow to GIT, etc.
• Hepatic diseases: Disorders such as hepatic cirrhosis
influence bio-availability mainly of drugs that undergo
considerable first-pass hepatic metabolism e.g.
Propranolol
 Drugs that Affect Absorption of other Drugs
• Metoclopramide (antiemetic) stimulates stomach contraction
& increases intestinal peristalsis : Decrease the peak drug
conc. by reducing effective time for absorption
• Anticholinergic drug (propantheline bromide) may slow
stomach emptying &motility of small intestine
• Tricyclic antidepressants & phenothiazines with
anticholinergic side effects cause slower peristalsis &
stomach emptying may delay in drug absorption
• Cholestyramine is a non-absorbable ion- exchange resin for
the treatment of hyperlipemia : It binds warfarin, thyroxine,
thereby reducing absorption of these drugs.
• Erythromycin inhibits the hepatic metabolism of a number of
drugs e.g. Digoxin. : Antibiotic eliminates a species of
intestinal flora that inactivates digoxin, thus leading to
greater reabsorption of drug from the enterohepatic
circulation.