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UNIT-I (1) Biopharmaceutics and Pharmacokinetics

INTRODUCTION TO BIOPHARMACEUTICS
INTRODUCTION
• Biopharmaceutics and pharmacokinetics are two important aspects of pharmacology that deal with
the study of the interaction between drugs and the body.
• Biopharmaceutics refers to the study of the physical and chemical properties of drugs, the dosage
forms in which they are administered, and how they are absorbed, distributed, metabolized, and
eliminated by the body.
• Pharmacokinetics refers to the study of how drugs are absorbed, distributed, metabolized, and
eliminated by the body over time, including factors such as dose, route of administration, and patient
characteristics.
• Drug absorption
➢ Drug absorption is the process by which a drug enters the bloodstream from its site of
administration.
➢ Factors that affect drug absorption include the physicochemical properties of the drug, the
dosage form, the route of administration, and the presence of food or other drugs in the body.
➢ Understanding drug absorption is important for determining a drug's appropriate dosage and
formulation.
• Drug distribution
➢ Drug distribution refers to the process by which a drug is transported from the bloodstream to
its site of action in the body.
➢ Factors that affect drug distribution include the drug's physicochemical properties, the patient's
physiological characteristics, and the presence of other drugs in the body.
➢ Understanding drug distribution is important for determining the appropriate dosage and route
of administration of a drug.
• Drug metabolism
➢ Drug metabolism refers to the process by which a drug is transformed by the body into other
compounds, often to facilitate its elimination from the body.
➢ The liver is the primary site of drug metabolism, although other organs such as the kidneys and
lungs can also play a role.
➢ Understanding drug metabolism is important for determining the appropriate dosage and
frequency of administration of a drug.
• Drugs and their metabolites are removed from the body through elimination.
➢ The primary routes of drug elimination are through the kidneys (in the form of urine) and the
liver (in the form of bile).
➢ Understanding drug elimination is important for determining a drug's appropriate dosage and
dosing interval.
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Pharmacokinetic parameters
Pharmacokinetic parameters are numerical values that describe the time course of drug
absorption, distribution, metabolism, and elimination.
Some common pharmacokinetic parameters include bioavailability, clearance, half-life, and
volume of distribution.
These parameters can be used to predict the efficacy and safety of a drug, as well as to optimize
its dosage and dosing regimen.
• Drug distribution is the movement of a substance from one compartment to another, typically
between blood and extravascular tissues.
• Pharmacokinetics is the study of the ADME of a drug over time and how it relates to its
therapeutic and harmful effects. Pharmacokinetics, to put it simply, are the kinetics of ADME or
KADME.
• Clinical pharmacokinetics is the application of pharmacokinetic principles to optimize drug
dosage for individual patients and achieve maximum therapeutic effectiveness.
The four phases or processes of drug administration and therapy are as follows:
Pharmaceutical phase: Preparation of the drug in a suitable form for administration.
Pharmacokinetic phase: Absorption, distribution, metabolism, and elimination of the drug in the
body.
Pharmacodynamic phase: Study of the drug's mechanism of action and effects on the body.
Clinical phase: Use of the drug in clinical practice including selection, dosage determination,
and monitoring of patient's response.

Applications of biopharmaceutics and pharmacokinetics

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Biopharmaceutics and pharmacokinetics have many practical applications in drug development and
clinical practice.
These include predicting drug efficacy and safety, optimizing drug dosing regimens, developing new
drug formulations and delivery systems, and studying drug-drug
interactions.
By better understanding the biopharmaceutical and pharmacokinetic properties of drugs, we can
improve the effectiveness and safety of pharmacotherapy.

ABSORPTION
Absorption is the process of movement of drugs form its site of administration to the blood stream, the
therapeutics response of the drug depends on the rate as extent of drug absorption on and its concentration
at the site of action.

Transport of drug across biological barriers

For systemic absorption, a drug must pass from the absorption site through one or more layers of cells to
gain access to the general circulation. For absorption into the cells, a drug must traverse the cell
membrane.
1. Structure of cell membrane
The contents of a cell are completely surrounded by its cell membrane or plasma membrane and act
as a boundary between the cell and interstitial fluid. They are primarily composed of phospholipids in
the form of bilayers. Some carbohydrates and proteins are interdispersed within this lipid bilayer.
The cell membrane acts as a selective barrier to the passage of molecules. it is a porous membrane
(with pores) that permits the movement of selective substances in and out of the cell. Water, some
small molecules, and lipid-soluble molecules pass through such a membrane.
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2. Movement of Substances Across Cell Membrane

These cell membranes serve two important functions:
• It must retain the dissolved materials of the cell so that they do not simply leak out into the
environment.
• It should also allow the necessary exchange of materials into and out of the cell.
There are two major methods for moving molecules across a membrane, and it is related to whether or not
cell energy is used. Passive mechanisms, such as diffusion, require no energy to function, whereas active
transport does.
Molecules can be divided into four categories in terms of their ability to cross the plasma membrane.
• The first category is nonpolar molecules. These hydrophobic molecules can easily cross the
membrane because they interact favorably with nonpolar lipids.
• The second category is small polar molecules. Although they don’t interact with the lipids, their small
size allows them to pass through small temporary holes in the membrane.
• The third category is large polar molecules. These have difficulty crossing the membrane because of
their size and poor interaction with the lipids.
• The last category is ionic compounds. Their charge interacts unfavorably with the lipids, making it
difficult for them to cross the membrane.
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MECHANISMS OF DRUG ABSORPTION THROUGH GIT

The principal mechanisms of transport of drug molecules across the cell membrane are :
1. Passive diffusion
2. Carrier-mediated transport
A. Facilitated transport
B. Active transport
3. Vesicular transport
A. Pinocytosis
B. Phagocytosis
4. Pore transport
5. Ion pair formation Pore transport

Passive Diffusion
It is defined as the difference in the drug concentration on either side of the membrane. Drug movement
is a result of the kinetic energy of molecules. Since no energy source is required, the process is called as
passive diffusion. Also called non-ionic diffusion, it is the major process for the absorption of more than
90% of the drugs. The driving force for this process is the concentration or electrochemical gradient.
During passive diffusion, the drug present in the aqueous solution at the absorption site partitions and
dissolves in the lipid material of the membrane and finally leaves it by dissolving again in an aqueous
medium, this time at the inside of the membrane.
Drugs diffuse across a cell membrane from a region of high concentration (eg, gastrointestinal fluids) to
one of low concentration (eg, blood). The diffusion rate is directly proportional to the concentration
gradient but also depends on the molecule’s lipid solubility, size, degree of ionization, and the area of the
absorptive surface. Because the cell membrane is lipoid, lipid-soluble drugs diffuse most rapidly. Small
molecules tend to penetrate membranes more quickly than larger ones.
Most drugs are weak organic acids or bases, existing in un-ionized and ionized forms in an aqueous
environment. The un-ionized form is usually lipid soluble (lipophilic) and diffuses readily across cell
membranes. The ionized form has low lipid solubility (but high water solubility—ie, hydrophilic) and
high electrical resistance and thus cannot penetrate cell membranes easily.
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Passive diffusion is best expressed by Fick’s first law of diffusion, which states that the drug molecules
diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained
and that the rate of diffusion is directly proportional to the concentration gradient across the membrane.
It can be mathematically expressed by the following equation:

where,
dQ/dt = rate of drug diffusion (amount/time). It also represents the rate of appearance of drugs in blood
D = diffusion coefficient of the drug through the membrane (area/time)
A = surface area of the absorbing membrane for drug diffusion (area)
Km/w = partition coefficient of the drug between the lipoidal membrane and the aqueous GI fluids (no
units)
(CGIT – C) = difference in the concentration of drug in the GI fluids and the plasma, called as the
concentration gradient (amount/volume)
h = thickness of the membrane (length)
Certain characteristics of passive diffusion:
1. The rate of drug transfer is directly proportional to the concentration gradient between GI fluids and
the blood compartment.
2. The greater the area and the lesser the thickness of the membrane, the faster the diffusion; thus, the
more rapid is the rate of drug absorption from the intestine than from the stomach.
The process is rapid over short distances and slower over long distances.
3. Equilibrium is attained when the concentration on either side of the membrane becomes equal.
4. The greater the membrane/water partition coefficient of the drug, the faster the absorption; since the
membrane is lipoidal in nature, a lipophilic drug diffuses at a faster rate by solubilizing in the lipid
layer of the membrane.
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5. The drug diffuses rapidly when the volume of GI fluid is low; conversely, dilution of GI fluids
decreases the drug concentration in these fluids (CGIT) and lowers the concentration gradient (CGIT
– C).
6. drugs having molecular weights between 100 to 400 Daltons are effectively absorbed passively. The
diffusion generally decreases with an increase in the molecular weight of the compound.
7. Dilution and distribution of the absorbed drug into a large pool of body fluids and its subsequent
binding to various tissues are other reasons for elimination being slower than absorption.

2. CARRIER MEDIATED TRANSPORT

Some polar molecules cross the membrane more readily than can be predicted from their concentration
gradient and partition coefficient values. This suggests the presence of some specialized transport
mechanisms without which many essential water-soluble nutrients like monosaccharide’s, amino acids
and vitamins will be poorly absorbed. The mechanism is thought to involve a component of the
membrane called as the carrier that binds reversibly with the solute molecules to be transported. This
carrier-solute complex traverses across the membrane to the other side where it dissociates and discharges
the solute molecule. The carrier then returns to its original site to complete the cycle by accepting a fresh
molecule of solute. The carrier may be an enzyme or some other component of the membrane.

Important characteristics of carrier-mediated transport are:

• A carrier protein always has an uncharged (non-polar) outer surface which allows it to be soluble
within the lipid of the membrane.
• The carriers have no directionality; they work with same efficiency in both directions.
• The transport process is structure-specific i.e. the carriers have special affinity for and transfer a drug
of specific chemical structure only (i.e. lock and key arrangement); generally, the carriers have
special affinity for essential nutrients.
Since the system is structure-specific, drugs having structure similar to essential nutrients, called as
false nutrients, are absorbed by the same carrier system.
• As the number of carriers is limited, the transport system is subject to competition between agents
having similar structure.
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• Since the number of carriers is limited, the system is capacity-limited i.e. at higher drug
concentration; the system becomes saturated and approaches an asymptote. Such a capacity-limited
process can be adequately described by mixed order kinetics, also called as Michaelis-Menten,
saturation or non-linear kinetics. The process is called mixed-order because it is first-order at sub-
saturation drug concentrations and apparent zero-order at and above saturation levels. Moreover, the
capacity-limited characteristics of such a system suggest that the bioavailability of a drug absorbed
by such a system decrease with increasing dose—for example, vitamins like B1, B2 and B12.
• Specialized absorption or carrier-mediated absorption generally occurs from specific sites of the
intestinal tract which are rich in number of carriers. Such an area in which the carrier system is most
dense is called as absorption window. Drugs absorbed through such absorption windows are poor
candidates for controlled release formulations.

Two types of carrier-mediated transport systems have been identified.

A. Facilitated transport
• The process of the movement of molecules across the cell membrane via special transport proteins
that are embedded within the cellular membrane is known as facilitated diffusion or called carrier-
mediated diffusion.
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• Facilitated diffusion is similar to simple diffusion but requires a carrier molecule and is saturable. A
carrier molecule is a transmembrane protein that binds one or more molecules or ions, changes its
conformation and then releases them on the other side of the membrane. Carrier molecules facilitate
entry and exit of physiologically important molecules (e.g. sugars, amino acids, neurotransmitters) in
the direction of their electrochemical gradient.
• Many large molecules, such as glucose, are insoluble in lipids and too large to fit into the proton
therefore, it will bind with its specific carrier proteins, and the complex will then be bonded to a
receptor site and moved through the cellular membrane.
• Facilitated diffusion is of limited importance in the absorption of drugs. Examples of such a transport
system include of passive facilitated diffusion is the GI absorption of vitamin B12. An intrinsic factor
(IF), a glycoprotein produced by the gastric parietal cells, forms a complex with vitamin B12 which
is then transported across the intestinal membrane by a carrier system.

B. Active transport
Active transport is energy-dependent and requires ATP molecules to transport molecules across the cell
membrane from a low concentration to a high concentration. This type of transport is facilitated by
proteins present in the cell membrane, known as transport proteins and pumps. These protein pumps
allow only selected molecules to pass across the membrane.
Active transport allows drugs to cross membranes against a concentration gradient. Examples of non-
specific carriers include organic anion transporters (OAT) and organic cation transporters (OCT), and
P-glycoprotein (PGP), which plays an important role in the blood-brain barrier and in the kidneys.
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Active secretion of weak acids, such as penicillin and uric acid, and weak bases, such as histamine,
into the renal tubular lumen greatly enhances the rate of excretion of these drugs by comparison with
those that enter the tubule after glomerular filtration.

Active transport is a more important process than facilitated diffusion in the absorption of
nutrients and drugs and differs from it in several respects:
1. The drug is transported from a region of lower to one of higher concentration i.e. against the
concentration gradient (in the case of ions, against an electrochemical gradient) or uphill transport,
without any regard for equilibrium.
2. The process is faster than passive diffusion.
3. Since the process is uphill, energy is required in the work done by the carrier.
4. As the process requires the expenditure of energy, it can be inhibited by metabolic poisons that
interfere with energy production like fluorides, cyanide and dinitrophenol and lack of oxygen, etc.
Endogenous substances that are transported actively include sodium, potassium, calcium, iron,
glucose, certain amino acids and vitamins like niacin, pyridoxin and ascorbic acid. Drugs having
structural similarity to such agents are absorbed actively, particularly the agents useful in cancer
chemotherapy. Examples include absorption of 5-fluorouracil and 5- bromouracil via the pyrimidine
transport system, absorption of methyldopa and levodopa via an L-amino acid transport system and
absorption of ACE inhibitor enalapril via the small peptide carrier system. A good example of
competitive inhibition of drug absorption via active transport is the impaired absorption of levodopa
when ingested with meals rich in proteins. Active transport is also important in renal and biliary
excretion of many drugs and their metabolites and secretion of certain acids out of the CNS.
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Active transport is of two types: primary and secondary active transport.

a) Primary Active Transport
Transmembrane proteins aid in the detection of the molecule that has to be conveyed during the
primary active transport. Afterward, these molecules are pushed, using chemical energy called
ATP, to the target place. In this process, there is a direct ATP requirement. Moreover, the process
transfers only one ion or molecule in only one direction and hence is called a uniporter e.g.
absorption of glucose. Example: Sodium-potassium pump, which helps to maintain the cell
potential.
Carrier proteins involved in primary active transport are of two types –
(i) Ion transporters – are responsible for transporting ions in or out of cells. A classic example of
ATP-driven ion pump is proton pump. Two types of ion transporters which play important role in
the intestinal absorption of drugs have been identified.
(a) Organic anion transporter – which aids absorption of drugs such as pravastatin and
atorvastatin.
(b) Organic cation transporter – which aids absorption of drugs such as diphenhydramine.
(ii) ABC (ATP-binding cassette) transporters – are responsible for transporting small foreign
molecules (like drugs and toxins) especially out of cells (and thus called as efflux pumps) which
make them clinically important. A classic example of ABC transporter is P-glycoprotein (P-gp).
The latter is responsible for pumping hydrophobic drugs especially anticancer drugs out of cells.
Presence of large quantity of this protein thus makes the cells resistant to a variety of drugs used in
cancer chemotherapy, a phenomenon called as multi-drug resistance. It is for this reason that P-gp
is called as multi-drug resistance (MDR) protein. ABC transporters present in brain capillaries
pump a wide range of drugs out of the brain.
b) Secondary Active Transport
In these processes, there is no direct requirement of ATP i.e. it takes advantage of previously
existing concentration gradient. The energy required in transporting an ion aids transport of
another ion or molecule (co-transport or coupled transport) either in the same direction or in the
opposite direction. In this kind of transport, molecules are transported along a channel created by
electromagnetic current. Co-transporters, or two additional transport systems, make up secondary
active transport.
i. Symport (co-transport) – involves movement of both molecules in the same direction e.g. Na+-
glucose symporter uses the potential energy of the Na+ concentration gradient to move glucose
against its concentration gradient. A classic example of a symporter is a peptide transporter called
an H+-coupled peptide transporter (PEPT1) which is implicated in the intestinal absorption of
peptide-like drugs such as -lactam antibiotics.
ii. Antiport (counter-transport) – involves movement of molecules in the opposite direction e.g.
expulsion of H+ ions using the Na+ gradient in the kidneys.
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3. VESICULAR TRANSPORT
Vesicular transport is the process of engulfing particles or dissolved materials by the cell. It is a minor
transport mechanism that involves engulfing extracellular materials within a segment of the cell
membrane to form a saccule or a vesicle (hence also called corpuscular or vesicular transport) which is
then pinched off intracellularly. This phenomenon is responsible for the cellular uptake of
macromolecular nutrients like fats and starch, oil-soluble vitamins like A, D, E, and K, water-soluble
vitamins like B12, and drugs such as insulin. Another significance of such a process is that the drug is
absorbed into the lymphatic circulation thereby bypassing first-pass hepatic metabolism.
Both pinocytosis and phagocytosis are types of endocytosis, which is a general term for engulfing
materials from outside the cell.
A. Pinocytosis: (cell drinking): uptake of fluid solute
B. Phagocytosis: (cell eating): adsorptive uptake of solid particulates,

A. Pinocytosis
• Pinocytosis, “cell drinking,” allows the cell to consume solutions. An infant’s intestinal lining ingests
breast milk by pinocytosis, allowing the mother’s protective antibodies to enter the baby’s
bloodstream. While phagocytosis involves the ingestion of solid material, pinocytosis is the ingestion
of surrounding fluid. This type of endocytosis allows a cell to engulf dissolved substances that bind
to the cell membrane prior to internalization. Pinocytosis is a “drinking” mechanism wherein a cell
actively engulfs external fluids over time.
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• pinocytosis primarily occurs when cells absorb nutritional or waste droplets suspended in external
fluid. The nutritional molecules that can activate pinocytosis include fats, sugars, proteins, ions or
other small molecules.
• This process begins when a soluble substrate binds to the surface of a cell. After a substrate binds to
the cell membrane, the cell continues pinocytosis by gathering external fluid into a membrane-bound
pocket called a pinosome.
• This pinosome continues to pinch off from the cell membrane within the cell until it is fully
internalized. Once the cell fully internalizes this cellular pocket, the newly formed compartment can
swap its material with specialized vesicles that can break down substrate into smaller molecules.
Pinocytosis vesicles are typically 100-200 nanometers in diameter.
B. Phagocytosis
• Phagocytosis is a specialized process by which cells engulf relatively large, solid material. These
particles, generally larger than 0.5 μm in diameter, may include apoptotic cells or foreign substances.
phagocytosis vesicles are typically larger than 500 nanometers in diameter.
• Phagocytosis is primarily used by immune system cells to destroy viruses and break down damaged
cells.
• Among these cells, certain types are capable of greater efficiency in the phagocytic process, such as
monocytes or macriophages. Other, like epithelial cells, are capable of phagocytosis, but at a less
efficient rate.
• Activation of phagocytosis causes the cell membrane area in contact with the target material to
rearrange into a cavity called the phagocytic cup. This process begins when the material-stimulated
receptors send molecular signals that prepare the cell for target material intake.

4. Pore transport
Very small molecules (such as urea, water, and sugars) can rapidly cross cell membranes as if the
membrane contains channels or pores. It is also called as convective transport, bulk flow or filtration. A
certain type of protein called transport protein may form an open channel across the lipid membrane of
the cell. e.g. Drug permeation through aqueous pores is used to explain the renal excretion of drugs and
the uptake of drugs into the liver.
The following are the characteristics of pore transport –
1. The driving force is hydrostatic pressure or the osmotic differences across the membrane due to
which bulk flow of water along with small solid molecules occurs through such aqueous channels.
Water flux that promotes such a transport is called solvent drag.
2. The process is important in the absorption of low molecular weight (less than 100), low molecular
size (smaller than the diameter of the pore), and generally water-soluble drugs through narrow,
aqueous-filled channels or pores in the membrane structure—for example, urea, water, and sugars.
3. Chain-like or linear compounds of molecular weight up to 400 Daltons can be absorbed by filtration.
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5. Ion pair formation Pore transport

Strong electrolyte drugs are highly ionized or charged molecules, such as quaternary nitrogen compounds
with extreme pKa values. Strong electrolyte drugs maintain their charge at all physiologic pH values and
penetrate the membrane very poorly. When ionized drugs is linked up with an oppositely charged ion, an
ion pair is formed in which the overall charge of the pair is neutral. This neutral drug-complex diffuses
more easily across the membrane.
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FACTORS INFLUENCING DRUG ABSORPTION THROUGH GIT

The rate and extent of drug absorption from its dosage form can be influenced by several factors in all
these steps.
A. PHARMACEUTICAL FACTORS: include factors relating to the physicochemical properties of the
drug, and dosage form characteristics and pharmaceutical ingredients
I. Physicochemical Properties of Drug Substances
1. Drug solubility and dissolution rate
2. Particle size and effective surface area
3. Polymorphism and amorphism
4. Pseudo polymorphism (hydrates/solvates)
5. Salt form of the drug
6. Lipophilicity of the drug
7. pKa of the drug and gastrointestinal pH
8. Drug stability
9. Stereochemical nature of the drug
II. Dosage Form Characteristics and Pharmaceutical Ingredients
(Pharmaco-technical Factors)
1. Disintegration time (tablets/capsules)
2. Dissolution time
3. Manufacturing variables
4. Pharmaceutical ingredients (excipients/adjuvants)
5. Nature and type of dosage form
6. Product age and storage conditions
B. PATIENT RELATED FACTORS: include factors relating to the anatomical, physiological, and
pathological characteristics of the patient
1. Age
2. Gastric emptying time
3. Intestinal transit time
4. Gastrointestinal pH
5. Disease states
6. Blood flow through the GIT
7. Gastrointestinal contents:
a. Other drugs
b. Food
c. Fluids
d. Other normal GI contents
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8. Pre systemic metabolism by:

a. Luminal enzymes
b. Gut wall enzymes
c. Bacterial enzymes
d. Hepatic enzymes
A. PHARMACEUTICAL FACTORS:
I. Physicochemical Properties of Drug Substances
1. Drug solubility and dissolution rate
Orally administered solid dosage forms are first disintegrated or disaggregated, then the solid particles are
dissolved drugs in solution then permeate across biomembrane to be absorbed in the body.
Absolute or intrinsic solubility is defined as the maximum amount of solute dissolved in a given solvent
under standard conditions of temperature, pressure and pH. It is a static property.
Dissolution rate is defined as the amount of solid substance that goes into solution per unit time under
standard conditions of temperature, pH, solvent composition, and constant solid surface area. It is a
dynamic process. Several drugs have poor aqueous solubility to have a bearing on dissolution rate.
There are two critical processes in the absorption of orally administered drugs:
1. Rate of dissolution,
2. Rate of drug permeation through the biomembrane
There are several theories to explain drug dissolution they are following;
1. Diffusion layer model/Film theory,
2. Danckwert’s model/Penetration or Surface renewal theory, and
3. Interfacial barrier model/Double-barrier or Limited solvation theory.
1. Diffusion layer model :it involves two steps
(1) Solution of the solid to form stagament film or diffusion layer which is saturated with the drug
(2)Diffusion of the soluble solute form the stagment layer to the bulk of the solution this is rate determine
step in drug dissolution
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The rate of dissolution is given by Noyes –Whitney s constant

Dc/dt=(Cs-Cb) (1)
Where,
dc/dt= dissolution rate of
drug K= dissolution constant
Cs=Concentration of drug in stamgent layer
Cb= Concentration of drug in the bulk of the soln at time t
Equation (1) was based on ficks second law of diffusion Nernst and brinier incorporated ficks First law of
diffusion and modified the Noyes Whitney
Noyes-Whitney’s equation of dissolution:

D= diffusion coefficient or diffusivity of the drug molecule

A = surface area of the dissolving solid exposed to the dissolution medium
Ko/w = water/oil partition coefficient of the drug
V= volume of dissolution medium
h= thickness of the stagnant layer
Cs – CB = concentration gradient of the diffusing drug molecule
This equation repent first order dissolution

2. Danckwert’s model/Penetration or Surface renewal theory

Danckwert 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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Danckwert’s model is expressed by equation:

V. dC/dt= dm/dt = A ( Cs-Cb). √(γ.D)
where,
m =mass of solid dissolved
γ=rate of surface renewal
3. Interfacial barrier model/Double-barrier or Limited solvation theory
According to the interfacial barrier model, an intermediate concentration can exist at the interface as a
result of solvation mechanism and is a function of solubility rather than diffusion.
When considering the dissolution of a crystal, each face of crystal will have a different interfacial
barrier.
Interfacial barrier model is expressed by equation
G = Ki (Cs-Cb)
where,
G=dissolution rate per unit area
Ki =effective interfacial transport constant

2. Particle size and effective surface area

Particle size and surface area of a solid drug are inversely related to each other. Smaller the drug particle,
greater the surface area. Two types of surface area of interest can be defined:
1. Absolute surface area which is the total area of solid surface of any particle, and
2. Effective surface area which is the area of solid surface exposed to the dissolution medium.
From the modified Noyes-Whitney equation, it is clear that larger the surface area, higher the dissolution
rate. Since the surface area increases with decreasing particle size, a decrease in particle size, which can
be accomplished by micronisation, will result in higher dissolution rates. However, it is important to note
that it is not the absolute surface area but the effective surface area that is proportional to the dissolution
rate. Greater the effective surface area, the more intimate the contact between the solid surface and the
aqueous solvent and the faster the dissolution. However, it is only when micronization reduces the size of
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particles below 0.1 microns that there is an increase in the intrinsic solubility and dissolution rate of the
drug.
In the case of hydrophobic drugs like aspirin, phenacetin and phenobarbital, micronisation actually results
in a decrease in the effective surface area of such powders and thus, a fall in the dissolution rate.
Three reasons have been suggested for such an outcome —
1. The hydrophobic surface of the drug adsorbs air onto its surface which inhibits its wettability.
2. The particles re-aggregate to form larger particles due to their high surface free energy, which either
float on the surface or settle at the bottom of the dissolution medium.
3. Electrically induced agglomeration owing to surface charges prevents intimate contact of the drug with
the dissolution medium.
The net result of these effects is that there is a decrease in the effective surface area available to the
dissolution medium and therefore a fall in the dissolution rate.
The absolute surface area of hydrophobic drugs can be converted to their effective surface area by:
1. Use of surfactant as a wetting agent that -
➢ Decreases the interfacial tension, and
➢ Displace the adsorbed air with the solvent.
For example, polysorbate 80 increases the bioavailability of phenacetin by promoting its wettability.
2. Adding hydrophilic diluents such as PEG, PVP, dextrose, etc. which coat the surface of hydrophobic
drug particles and render them hydrophilic.
3. Polymorphism and amorphism
• Depending on the internal structure, a solid can exist either in a crystalline or amorphous form.
• When, a substance exists in more than one crystalline form, the different forms are designated as
polymorphs and the phenomenon as polymorphism.
• Various polymorphs can be prepared by crystallizing the drug from different solvents under diverse
conditions. Depending on their relative stability, one of the several polymorphic forms will be
physically more stable than the others. Such a stable polymorph represents the lowest energy state,
has highest melting point and least aqueous solubility. The remaining polymorphs are called
metastable forms which represents higher energy state, the metastable forms have a thermodynamic
tendency to convert to the stable form. A metastable form cannot be called unstable because if it is
kept dry, it will remain stable for years. So the metastable forms have higher aqueous solubility and
hence higher bioavailability than the stable polymorphs. e.g. Chloramphenicol palmitate has three
polymorphs A, B and C. The B -form shows best bioavailability and A form is virtually inactive
biologically.
• e.g. Polymorphic form-III of riboflavin is 20 times more water soluble than the form-I.
• Some drugs can exist in amorphous form (i.e. having no internal crystal structure). Such drugs
represent the highest energy state and can be considered as supercooled liquids. They have greater
aqueous solubility than the crystalline forms because the energy required to transfer a molecule from
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crystal lattice is greater than that required for non-crystalline (amorphous) solid—for example, the
amorphous form of novobiocin is 10 times more soluble than the crystalline form.
4. Pseudo polymorphism (hydrates/solvates)
The crystalline form of a drug can either be a polymorph or a molecular adduct or both. The
stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the
solid are called as the solvates, and the trapped solvent as solvent of crystallization. The solvates can
exist in different crystalline forms called as pseudo-polymorphs. This phenomenon is called as pseudo-
polymorphism. When the solvent in association with the drug is water, the solvate is known as a
hydrate. Hydrates are most common solvate forms of drugs.
Generally, the anhydrous form of a drug has greater aqueous solubility than the hydrates. This is
because the hydrates are already in interaction with water and therefore have less energy for crystal
break-up in comparison to the anhydrates (thermodynamically higher energy state) for further
interaction with water. The anhydrous form of theophylline and ampicillin have higher aqueous
solubilities, dissolve at a faster rate and show better bioavailability in comparison to their monohydrate
and trihydrate forms respectively.
5. Salt form of the drug
• Most drugs are either weak acids or weak bases. One of the easiest approaches to enhance the
solubility and dissolution rate of such drugs is to convert them into their salt forms. Generally, with
weakly acidic drugs, a strong base salt is prepared such as the sodium and potassium salts of
barbiturates and sulphonamides. In case of weakly basic drugs, a strong acid salt is prepared like the
hydrochloride or sulphate salts of several alkaloidal drugs.
• The influence of salt formation on the drug solubility, rate of dissolution and absorption can be
explained by considering the pH of the diffusion layer and not the pH of the bulk of the solution
(refer diffusion layer theory of drug dissolution). 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.
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.
Thus, if dissolution is faster, absorption is bound to be rapid. In case of salts of weak bases, the pH of
the diffusion layer will be lower in comparison to that found with the free base form of the drug.
Consequently, the solubility of a basic drug at this lower pH is enhanced.
 21

• The increase and decrease in pH of the diffusion layer by the salts of weak acids and bases have been
attributed to the buffering action of strong base cation and strong acid anion respectively.
6. Drug pKa and lipophilicity and GI pH (pH partition theory)
The pH partition theory (Brodie et.al.) states that for drug compounds of molecular weight greater
than 100, which are primarily transported across the biomembrane by passive diffusion.
The process of absorption is governed by
dissociation constant (Ka) of the drug
lipid solubility of the unionized drug (Ko/w)
the pH at the absorption site
The above statement of the hypothesis was based on the assumptions that:
The GIT is simple lipoidal barrier to the transport of drug.
Larger the fraction of unionized drug, faster the absorption.
Greater the lipophilicity (Ko/w) of the unionized drug, better the absorption.
Handerson-Hasselbach equation
The amount of drug that exists in unionized form is a function of dissociation constant (pKa) of the
drug and pH of the fluid at the absorption site.
To express the dissociation constants of both acidic and basic drugs by pKa values. The lower the
pKa of an acidic drug, stronger the acid i.e. greater the proportion of ionised form at a particular pH.
Higher the pKa of a basic drug, stronger the base. Thus, from the knowledge of pKa of drug and pH
at the absorption site (or biological fluid), the relative amount of ionised and unionised drug in
solution at a particular pH and the percent of drug ionized at this pH can be determined by
Henderson-Hasselbach equations:

The pKa of the drug determines the degree of ionization at a particular pH and that only the
unionized drug, if sufficiently lipid soluble, is absorbed into the systemic circulation.
 22

Lipophilicity and Drug Absorption

only unionised form of the drug is absorbed and permeation of the ionised drug is negligible since its
rate of absorption is 3 to 4 times less than that of unionised drug. This is called as principle of non-
ionic diffusion. The principle is true to a large extent as ionised drugs have low lipid solubility and
relatively poor permeability.
Ideally, for optimum absorption, a drug should have sufficient aqueous solubility to dissolve in the
fluids at the absorption site and lipid solubility (Ko/w) in the lipoidal biomembrane and into the
systemic circulation.
In other words, a perfect hydrophilic-lipophilic balance (HLB) should be there in the structure of the
drug for optimum bioavailability. The lipid solubility of a drug is measured by a parameter called as
log P where P is oil/water partition coefficient (Ko/w or simply P) value of the drug. This value is a
measure of the degree of distribution of drug between lipophilic solvents such as n-octanol and an
aqueous phase (water or a suitable buffer).

7. Drug stability
A drug for oral use may destabilize either during its shelf-life or in the GIT. Two major stability
problems resulting in poor bioavailability of an orally administered drug are—degradation of the drug
into inactive form, and interaction with one or more different component(s) either of the dosage form
or those present in the GIT to form a complex that is poorly soluble or is unabsorbable.
 23

8. Stereochemical nature of the drug

The stereochemical nature of a drug refers to how the atoms in a drug molecule are arranged in three
dimensions. This arrangement affects the drug's properties and how it interacts with the body.
Stereoisomers are molecules with the same molecular formula but different three-dimensional
arrangements of atoms. Stereoisomers can be classified as geometric isomers or asymmetric center
isomers. Enantiomers are a pair of mirror-image molecules that are non-superimposable. They have the
same chemical composition but different 3D structures. Enantiomers possess identical physical and
chemical properties despite significant differences in spatial configuration. As majority of drugs are
absorbed passively, they do not display stereoselectivity. Conversely, demonstration of stereoselective
absorption would be strong evidence that a drug is absorbed by a carrier-mediated process.

II. Dosage Form Characteristics and Pharmaceutical Ingredients (Pharmaco-technical Factors)

1. Disintegration time (tablets/capsules)
Disintegration time (DT) is of particular importance in case of solid dosage forms like tablets and
capsules. In vitro disintegration test is by no means a guarantee of drug’s bioavailability because if the
disintegrated drug particles do not dissolve, absorption is not possible. Coated tablets, especially sugar
coated ones have long DT.
Rapid disintegration is thus important in the therapeutic success of a solid dosage form. DT of a tablet
is directly related to the amount of binder present and the compression force (hardness) of a tablet. A
harder tablet with large amount of binder has a long DT. Disintegration can be aided by incorporating
disintegrants in suitable amounts during formulation.
2. Dissolution time
After disintegration of a solid dosage form into granules, the granules must deaggregate into fine
particles, as dissolution from such tiny particles is faster than that from granules.
A drug's oral bioavailability is determined by several properties, including drug dissolution rate,
solubility, intestinal permeability, and pre-systemic metabolism. Frequently, the rate-limiting step in
drug absorption from the gastrointestinal tract is drug release and drug dissolution from the dosage
form.
3. Manufacturing variables
Drug dissolution is the single most important factor in the absorption of drugs, especially from the
most widely used conventional solid dosage forms, tablets and capsules. The dosage form related
factors that influence dissolution and hence absorption of a drug from such formulations are:
1. Excipients (formulation ingredients apart from the active principles)
2. Manufacturing processes.
The influence of excipients such as binders, lubricants, disintegrants, etc. on drug dissolution.
Several manufacturing processes influence drug dissolution from solid dosage forms. Processes of
such importance in the manufacture of tablets are:
 24

a) Method of granulation : The wet granulation process is the most conventional technique in
the manufacture of tablets and was once thought to yield tablets that dissolve faster than those
made by other granulation methods. The method of direct compression has been utilized to
yield tablets that dissolve at a faster rate.
b) Compression force: higher compression force increases the density and hardness of tablet,
decreases porosity and hence penetrability of the solvent into the tablet, retards wettability by
forming a firmer and more effective sealing layer by the lubricant, promotes tighter bonding
between the particles, all of which result in slowing of the dissolution rate of tablets.
4. Pharmaceutical ingredients (excipients/adjuvants)
Commonly used excipients in various dosage forms are vehicles, diluents (fillers), binders and
granulating agents, disintegrants, lubricants, coatings, suspending agents, emulsifiers, surfactants,
buffers, complexing agents, colorants, sweeteners, crystal growth inhibitors, etc. Excipients are added
to ensure acceptability, physicochemical stability during the shelf-life, uniformity of composition and
dosage, and optimum bioavailability and functionality of the drug product. The more the number of
excipients in a dosage form, the more complex it is and greater the potential for absorption and
bioavailability problems.
5. Nature and type of dosage form
The proper selection of drug, clinical success often depends to a great extent on the proper selection of
dosage form of that drug. the oral bioavailability of a drug depending upon the nature and type of
dosage form. Such a difference is due to the relative rate at which a particular dosage form releases the
drug to the biological fluids and the membrane.
 25

6. Product age and storage conditions

A number of changes, especially in the physicochemical properties of a drug in dosage form, can result
due to aging and alterations in storage conditions which can adversely affect bioavailability. With
solution dosage form, precipitation of drug due to altered solubility, especially due to conversion of
metastable into poorly soluble, stable polymorph can occur during the shelf life of the product.
Changes in particle size distribution have been observed with a number of suspension dosage forms
resulting in decreased rate of drug dissolution and absorption. In case of solid dosage forms, especially
tablets, disintegration and dissolution rates are greatly affected due to aging and storage conditions.

B. PATIENT RELATED FACTORS: include factors relating to the anatomical, physiological, and
pathological characteristics of the patient
1. Age
In infants, the gastric pH is high, and intestinal surface and blood flow to the GIT is low resulting in an
altered absorption pattern in comparison to adults. In elderly persons, causes of impaired drug absorption
include altered gastric emptying, decreased intestinal surface area and GI blood flow, higher incidents of
achlorhydria, and bacterial overgrowth in the small intestine.
2. Gastric emptying time
Gastric emptying, the process of drug transit from the stomach to the small intestine, can be a rate-
limiting step in drug absorption. This is because the small intestine is the primary site of drug absorption,
and is affected by drug dissolution and permeation of the biomembrane.
Gastric emptying rate is the speed at which the stomach contents empty into the intestine.
Gastric emptying time is the time required for the gastric contents to empty into the small intestine. The
longer the gastric emptying time, the lesser the gastric emptying rate.
For better dissolution and absorption, gastric emptying can be promoted by taking the drug on an empty
stomach. It is recommended to...
Rapid onset of the drug is desired eg: sedatives
Drug not stable in gastric fluids eg: penicillin G
Dissolution occurring in the intestine eg: enteric coated forms
Gastric emptying is altered by several factors due to which large intersubject variations are observed.
Volume of meal: The larger the bulk of the meals, the longer the gastric emptying time.
Composition of meal: Predictably, the rate of gastric emptying for various food materials is in the
following order: carbohydrates >proteins > fats.
Physical state and viscosity of meal: Liquid meals take less than an hour to empty whereas a solid meal
may take as long as 6 to 7 hours.
Electrolytes and osmotic pressure: Water, isotonic, and solutions of low salt concentration empty the
stomach rapidly.
Gastrointestinal pH: Gastric emptying is retarded at low stomach pH and promoted at higher or alkaline
pH.
 26

Disease states: Diseases like gastroenteritis, gastric ulcer, pyloric stenosis, diabetes, and hypothyroidism
retard gastric emptying.
3. Intestinal transit time
Since small intestine is the major site for the absorption of most drugs, long intestinal transit time is
desirable for complete drug absorption.
Delayed intestinal transit is desirable for:
• Drugs that dissolve or release slowly from their dosage form (sustained-release products) or when the
ratio of dose to solubility is high e.g. chlorothiazide.
• Drugs that dissolve only in the intestine (enteric-coated formulations).
• Drugs which are absorbed from specific sites in the intestine (several B vitamins, lithium carbonate,
etc.).
• When the drug penetrates the intestinal mucosa very slowly e.g. acyclovir.
• When absorption of drug from the colon is minimal.
Like gastric emptying, intestinal transit is influenced by several factors like food, drugs and diseases.
Food, decreased digestive secretions and pregnancy retard intestinal transit whereas diarrhoea promotes
it. Drugs like metoclopramide that promote gastric emptying and intestinal transit enhance absorption of
rapidly soluble drugs. Laxatives also promote the rate of intestinal transit
4. Gastrointestinal pH
GI fluid pH influences drug absorption in several ways:
Disintegration: Some dosage forms' disintegration is pH-sensitive. With enteric-coated formulations, the
coat dissolves only in the intestinal pH, followed by the tablet's disintegration.
Dissolution: A large number of drugs are either weakly acidic or weakly basic whose solubility is greatly
affected by pH. A pH that favours the formation of salt of the drug enhances the dissolution rate. e.g.
Weakly acidic drugs dissolve rapidly in the alkaline pH of the intestine whereas basic drugs dissolves in
the acidic pH of the stomach.
Absorption: Depending upon the pKa of the drug and the pH of the GI fluid some amount of the drug
remain in ionized state and some in unionized state. The unionized form will be absorbed through GIT
quickly than the ionized form.
Stability: GI pH influences the chemical stability of drugs. e.g. The acidic stomach pH is known to affect
degradation of Penicillin-G and erythromycin.
5. Disease states
Gastrointestinal diseases and infections: The influence of achlorhydria (decreased gastric acid secretion
and increased stomach pH) on gastric emptying and drug absorption, especially that of acidic drugs
(decreased absorption, e.g. aspirin) has been studied. Two of the intestinal disorders related with
malabsorption syndrome that influence drug availability 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, steatorrhea
 27

(impaired secretion of bile thus affecting absorption of lipophilic drugs and vitamins) and reduced
enterohepatic cycling of bile salts, all of which can significantly impair drug absorption.
Cardiovascular diseases: Several changes associated with congestive cardiac failure influence
bioavailability of a drug viz. oedema of the intestine, decreased blood flow to the GIT and gastric
emptying rate and altered GI pH, secretions and microbial flora.
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
The absorbed drug can thus be taken up by the blood or the lymph. Since the blood flow rate to the GIT is
500 to 1000 times more than the lymph flow, most drugs reach the systemic circulation via blood whereas
only a few drugs, especially low molecular weight, lipid soluble compounds are removed by lymphatic
system. The high perfusion rate of GIT ensures that once the drug has crossed the membrane, it is rapidly
removed from the absorption site thus maintaining the sink conditions and concentration gradient for
continued drug absorption.
7. Gastrointestinal contents:
A number of GI contents can influence drug absorption as
a. Other drugs:
b. Food: Presence of food may either delay, reduce, increase or may not affect drug absorption. drugs are
better absorbed under fasting conditions and presence of food retards or prevents it. Food does not
significantly influence absorption of a drug taken half an hour or more before meals and two hours or
more after meals.

c. Fluids: Administration of a drug with large fluid volume results in better dissolution, rapid gastric
emptying and enhanced absorption—for example, erythromycin is better absorbed when taken with a
glass of water under fasting condition than when taken with meals.
d. Other normal GI contents: 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. It also acts as a barrier to diffusion of drugs. The bile salts aid solubilisation and
absorption of lipid soluble drugs like griseofulvin and vitamins A, D, E and K on one hand and on the
other, decreases absorption of neomycin and kanamycin by forming water insoluble complexes.
8. Pre systemic metabolism by:
For a drug administered orally, the 3 main reasons for its decreased bioavailability are:
1. Decreased absorption (owing to adsorption, precipitation, complexation and poor solubility).
 28

2. Destabilisation or destruction of drug.

3. First-pass/presystemic metabolism
Before a drug reaches blood circulation, it has to pass for the first time through organs of elimination
namely the GIT and the liver. The loss of drug through biotransformation by such eliminating organs
during its passage to systemic circulation is called as first-pass or presystemic metabolism. The
diminished drug concentration or rarely, complete absence of the drug in plasma after oral administration
is indicative of first-pass effects.
a. Luminal enzymes: the metabolism by these enzymes are further categorised into two –
(i) Digestive enzymes: These are the enzymes present in the gut fluids and include enzymes from
intestinal and pancreatic secretions. The latter contains hydrolases which hydrolyse ester drugs like
chloramphenicol palmitate into active chloramphenicol, and peptidases which split amide linkages and
inactivate protein/polypeptide drugs.
(ii) Bacterial enzymes: These are the enzymes present in the gut fluids and include enzymes from
intestinal and pancreatic secretions. The latter contains hydrolases which hydrolyse ester drugs like
chloramphenicol palmitate into active chloramphenicol, and peptidases which split amide linkages and
inactivate protein/polypeptide drugs.
b. Gut wall enzymes: Also called as mucosal enzymes, they are present in stomach, intestine and colon.
Alcohol dehydrogenase (ADH) is an enzyme of stomach mucosa that inactivates ethanol. The colonic
mucosa also contain both phase I and phase II enzymes. However, it is only the enzymes of the proximal
small intestine that are most active.
c. Hepatic enzymes: Several drugs undergo first-pass hepatic metabolism, the highly extracted ones
being isoprenaline, propranolol, alprenolol, pentoxifylline, nitroglycerine, diltiazem, nifedipine, lidocaine,
morphine, etc.

ABSORPTION OF DRUG FROM NON-PER-ORAL EXTRA-VASCULAR ROUTES

Drugs administered via intravenous (IV) injection or infusion do not need to be absorbed, as they are
delivered directly into the bloodstream. However, there are several other types of non-oral
administration routes that must be absorbed through cell membranes to reach systemic circulation. These
include buccal, sublingual, intramuscular, subcutaneous, rectal, topical, transdermal, and inhaled.
Drug absorption from all non-oral extravascular sites is governed by the same factors that influence
absorption from GIT viz. the physicochemical properties of the drug, formulation factors, and the patient's
anatomic, physiologic, and pathologic characteristics. This is so because the barrier to drug transport into
the systemic circulation from all such sites is a lipoidal membrane similar to the GI barrier. The major
mechanism in the absorption is passive diffusion. One of the major advantages of administering drugs by
non-invasive transmucosal routes such as nasal, buccal, rectal, etc. is that greater systemic availability is
attainable for drugs normally subjected to extensive presystemic elimination due to GI degradation and/or
hepatic metabolism. Moreover, peptide and protein drugs can also be delivered by such routes. Some of
 29

the more important biopharmaceutic and pharmacokinetic principles must be considered for non-oral
absorption.
Buccal/Sublingual Administration
The two sites for oral mucosal delivery of drugs are:
1. Sublingual route: The drug is placed under the tongue and allowed to dissolve.
2. Buccal route: The medicament is placed between the cheek and the gum.
The barrier to drug absorption from these routes is the epithelium of oral mucosa. Passive diffusion is the
major mechanism for absorption of most drugs; nutrients may be absorbed by carrier-mediated processes.
Some of the advantages of these routes are:
1. Rapid absorption and higher blood levels due to high vascularisation of the region and therefore
particularly useful for administration of antianginal drugs.
2. No first-pass hepatic metabolism.
3. No degradation of drugs such as that encountered in the GIT
4. Presence of saliva facilitates both drug dissolution and its subsequent permeation by keeping the oral
mucosa moist.
Notable factors to be considered in the oral mucosal delivery of drugs are:
1. Lipophilicity of drug: Slightly higher lipid solubility than that required for GI absorption is necessary
for passive permeation.
2. Salivary secretion: In addition to high lipid solubility, the drug should be soluble in aqueous buccal
fluids i.e. biphasic solubility of the drug is necessary for absorption; absorption is delayed if the mouth is
dry.
3. pH of the saliva: Usually around 6, the buccal pH favours absorption of drugs which remain unionised.
4. Binding to oral mucosa: Systemic availability of drugs that bind to oral mucosa is poor.
5. Storage compartment: For some drugs such as buprenorphine, a storage compartment in the buccal
mucosa appears to exist which is responsible for the slow absorption of drugs.
6. Thickness of oral epithelium: Sublingual absorption is faster than buccal since the epithelium of former
region is thinner and immersed in a larger volume of saliva.
Examples of drugs administered by oral mucosal route include antianginals like nitrites and nitrates,
antihypertensives like nifedipine, analgesics like morphine and bronchodilators like fenoterol. Certain
steroids like oestradiol and peptides like oxytocin can also be administered.
Rectal Administration
The rectal route of drug administration is still an important route for children and old patients. The drugs
may be administered as solutions (microenemas) or suppositories. Absorption is more rapid from
solutions than from suppositories but is more variable in comparison to oral route. Irritating suppository
bases such as PEG promotes defecation and drug loss. Presence of faecal matter retards drug absorption.
The pH of rectal fluids (around 8) also influences drug absorption.
 30

Absorption of drugs from the lower half of rectum bypasses presystemic hepatic metabolism. Drugs
administered by this route include aspirin, paracetamol, theophylline, few barbiturates, etc.
Topical Administration
Majority of drugs applied topically are meant to exert their effect locally. When topically applied drugs
are meant to exert their effects systemically, the mode of administration is called as percutaneous or
transdermal delivery. Percutaneous absorption occurs only if the topically applied drug permeates the
dermal capillaries and enters the blood stream.
Anatomically, the skin is made of 3 distinct layers—the epidermis, the dermis and the subcutaneous fat
tissue. Epidermis is the nonvascular, multilayered outer region of the skin. The dermis or true skin is a
highly vascular region; drugs permeating to this region are taken up into the systemic circulation and sink
conditions are maintained.
Several factors influence passive percutaneous absorption of drugs:
1. Thickness of stratum corneum: absorption is very slow from regions such as foot and palm where the
skin has thickened stratum corneum.
2. Presence of hair follicles: absorption is rapid from regions where numerous hair follicles exist e.g.
scalp.
3. Trauma: cuts, rashes, inflammation, mild burns or other conditions in which the stratum corneum is
destroyed, promote drug absorption.
4. Hydration of skin: soaking the skin in water or occluding it by using emollients, plastic film or
dressing, promote hydration of skin and drug absorption.
5. Environment humidity and temperature: higher humidity and temperature increase both the rate of
hydration as well as local blood flow and hence drug absorption.
6. Age: gross histological changes take place as the skin ages. Aged skin is more prone to allergic and
irritant effects of topically contacted chemicals as a result of hardening of blood vessels. Infants absorb
drug through skin as efficiently as adults.
7. Permeation enhancers: incorporation of certain chemicals such as DMSO, propylene glycol, azone,
etc. in the topical formulations aid drug penetration.
8. Chronic use of certain drugs: long term use of cortisol or keratolytics like salicylic acid results in
enhanced drug penetration.
Intramuscular Administration
Absorption of drugs from i.m. sites is relatively rapid but much slower in comparison to i.v. injections.
Factors that determine rate of drug absorption from i.m. sites are:
1. Vascularity of the injection site: the decreasing order of blood flow rate to muscular tissues in which
drugs are usually injected in Arm (deltoid) > Thigh (vastus lateralis) > Buttocks (gluteus maximus).
Since blood flow rate is often the rate-limiting step in absorption of drugs from i.m. sites, most rapid
absorption is from deltoid muscles and slowest from gluteal region.
 31

2. Lipid solubility and ionisation of drug: highly lipophilic drugs are absorbed rapidly by passive
diffusion whereas hydrophilic and ionised drugs are slowly absorbed through capillary pores.
3. Molecular size of the drug: small molecules and ions gain direct access into capillaries through pores
whereas macromolecules are taken up by the lymphatic system. There is some evidence that small
peptides and fluids can cross the endothelial tissue of blood capillaries and lymph vessels by transport in
small vesicles that cross the membrane, a process called as cytopemphis.
4. Volume of injection and drug concentration: a drug in concentrated injection and large volume is
absorbed faster than when given in dilute form and small volume.
5. pH, composition and viscosity of injection vehicle: a solution of drug in acidic or alkaline pH (e.g.
phenytoin, pH 12) or in a nonaqueous solvent such as propylene glycol or alcohol (e.g. digoxin) when
injected intramuscularly result in precipitation of drug at the injection site followed by slow and
prolonged absorption. Viscous vehicles such as vegetable oils also slow drug absorption.
Subcutaneous Administration
The rate of absorption of a drug from subcutaneous site can be increased in 2 ways:
1. Enhancing blood flow to the injection site: by massage, application of heat, co-administration of
vasodilators locally, or by exercise, and
2. Increasing the drug-tissue contact area: by co-administering the enzyme hyaluronidase that breaks
down the connective tissue and permits spreading of drug solution over a wide area.
Absorption can be slowed down by causing vasoconstriction through local cooling or co-injection of a
vasoconstrictor like adrenaline or by immobilization of limb.
Pulmonary Administration
In principle, all drugs intended for systemic effects can be administered by inhalation since the large
surface area of the alveoli, high permeability of the alveolar epithelium and rich perfusion permit
extremely rapid absorption just like exchange of gases between the blood and the inspired air. However,
the route has been limited for administering drugs that affect pulmonary system such as bronchodilators
(salbutamol), anti-inflammatory steroids (beclomethasone) and antiallergics (cromolyn). Lipid soluble
drugs are rapidly absorbed by passive diffusion and polar drugs by pore transport. Absorption of drugs
whose ionisation is pH sensitive is dependent upon pH of pulmonary fluids. The drugs are generally
administered by inhalation either as gases (volatile/gaseous anaesthetics) or aerosol.
Intranasal Administration
The nasal route is becoming increasingly popular for systemic delivery especially of some peptide and
protein drugs. Drug absorption from nasal mucosa is as rapid as observed after parenteral administration
because of its rich vasculature and high permeability. The route is otherwise used for drugs to treat local
symptoms like nasal congestion, rhinitis, etc.
Two mechanisms for drug transport across the nasal mucosa have been suggested—
➢ A faster rate that is dependent upon drug lipophilicity, and
➢ A slower rate which is dependent upon drug molecular weight.
 32

In case of lipophilic drugs, rapid absorption by diffusion is observed up to 400 Daltons and satisfactory
absorption up to 1000 Daltons. By use of permeability enhancers such as surfactants, even a drug with
molecular weight of 6000 Daltons shows reasonable bioavailability.
Intraocular Administration
Topical application of drugs to the eyes is mainly meant for local effects such as mydriasis, miosis,
anaesthesia or treatment of infections, glaucoma, etc. Sterile aqueous solutions of drugs are widely used
ophthalmic formulations and administered in the conjunctival cul-de-sac. The barrier to intraocular
penetration of drugs is the cornea which possesses both hydrophilic and lipophilic characteristics. Thus,
for optimum intraocular permeation, drugs should possess biphasic solubility. The pH of lachrymal fluid
influences absorption of weak electrolytes such as pilocarpine. On the other hand, pH of the formulation
influences lachrymal output—higher pH decreases tear flow and promotes drug absorption whereas lower
pH solutions increase lachrymation and subsequent drug loss due to drainage. Rate of blinking also
influences drainage loss. The volume of fluid instilled into the eyes also affects bioavailability and
effectiveness of the drug.
Vaginal Administration
Drugs meant for intravaginal application are generally intended to act locally in the treatment of bacterial
or fungal infections or prevent conception. The route is now used for systemic delivery of contraceptives
and other steroids, without the disadvantage of first-pass metabolism. Controlled delivery and termination
of drug action when desired, is possible with this route. Factors that may influence drug absorption from
intravaginal site include pH of lumen fluids (4 to 5), vaginal secretions and the microorganisms present in
the vaginal lumen which may metabolise the drug.