BIOPHARMACEUTICS

Biopharmaceutics is the science

that examines the interrelationship
of the physicochemical properties
of the drug, the dosage form in
which the drug is given, the route
of administration and the rate and
extent of systemic drug absorption.
GASTRO-INTESTINAL
ABSORPTION
&
PHYSICOCHEMICAL
CONSIDERATIONS
CONTENTS
 Introduction of absorption
 Forces involved in transmembrane
movement
 Anatomical and physiological
factors
influencing absorption of drugs
 Physicochemical properties of drugs
affecting absorption
 Absorption of different oral dosage
forms
Absorption

Drug absorption is defined as:

“the process of movement of unchanged drug
from the site of administration to the systemic
circulation.”
OR
“the process of movement of unchanged drug
from the site of administration to the site of
measurement.”
– Absorption requires that drug must be:

• Soluble in the aqueous lining of the GIT

• Able to cross the barrier of intestinal epithelial
cells
• Able to reach the systemic circulation
• Should NOT undergo first pass effect
• Must be WITHOUT pre-systemic losses
Absorption process
• Absorption process requires 2
steps
• Formation of an aqueous
solution of drug in GIT fluids
(which depends on
disintegration & dissolution)
• Crossing of drug molecules
across the membranes
that constitute the GIT
(partitioning)
Nature of cell membrane
 Absorption of drugs occurs through the barrier between
site of administration and systemic circulation.
 The barrier is made up of cell and drug has to pass the
cell membrane to get absorbed. So, it is important to
understand the structure and physiology of cell
membrane.
 Biological membranes potentially pose a significant
barrier to drug delivery and act as a boundary between
the cell and the interstitial fluid.
Nature of cell membrane
 The cell membrane is the barrier that separates the inside
of the cell from the outside.
 The cell membrane is made up of phospholipids, proteins,
and other macromolecules.
 The phospholipids make up a bilayer. It
contains hydrophilic and hydrophobic molecules.
 The proteins in the cell membrane are located within the
phospholipid bilayer.
 So, the biologic membrane is mainly lipid in nature but
contains small aqueous channels or pores.
 The proteins usually span from one side of
the phospholipid bilayer to the other (integral
proteins), but can also sit on one of the
surfaces (peripheral proteins).
 Transmembrane proteins are integral proteins
that cross the membrane and can act as path
ways for ions and molecules. (transportation)
 Proteins on the outside surface of cell
membranes can act as receptors by having a
specific binding site where hormones or other
chemicals can bind.
• .
 Functionally, cell membranes are semipermeable partitions
that act as selective barriers to the passage of molecules.
 Water, some selected small molecules, and lipid soluble
molecules pass through such membranes whereas highly
charged molecules and large molecules, such as protein
and protein bound drugs, do not.
 Transcellular absorption is the process of drug
movement across a cell.
 Some polar molecules may not be able to traverse the cell
membrane but, instead, go through gaps or tight
junctions between cells, a process known as paracellular
drug diffusion.
Passage of drug across cell membrane
 Drug can be transported by both carrier mediated and
non-carrier mediated system.
 In carrier mediated system drug pass through by the help
of carrier.
 The principle mechanisms for transport of drug through
cell membrane are:
a. Passive diffusion
b. Facilitated passive diffusion*
c. Active transport*
d. Carrier mediated intestinal absorption*
e. (Vesicular transport, Pore transport, Ion-pair transport)
* = Carrier-mediated transport
Non-Carrier Mediated Transport

a. Passive diffusion
“Passive diffusion is the movement of the molecules
from high concentration to low concentration due to
the concentration gradient.”

 This process is passive because NO external energy is

expended.
 The driving force for passive diffusion is the difference in
drug concentrations on either side of the cell
membrane.
 The lipid cell membrane is not a barrier to drug diffusion
and absorption in case of:
 lipophilic drug,
 drug with low molecular weight.
 Passive diffusion is the major absorption process for
most drugs.
 If two sides have the same drug concentration,
forward moving drug molecules are balanced by
molecules moving back, resulting in no net transfer
of drug.
 The rate of transfer of drug molecules is called flux
 The rate of transport of drug across the membrane
(rate of diffusion) can be described by Fick’s first law
of diffusion.
Fick’s law of diffusion
According to Fick’s law of diffusion, drug molecules diffuse
from a region of high drug conc. to a region of low drug conc.

(1)

Where
dQ/dt= rate of diffusion
D= diffusion coefficient
K= lipid water partition coefficient of drug in the biologic membrane that
controls drug permeation
A= surface area of membrane
h= membrane thickness
CGI – Cp= difference b/w the conc. of drug in the GI tract & in the plasma
Factors affecting passive diffusion
- D = diffusion coefficient
-K = lipid water partition coefficient of drug in the
biologic membrane that controls drug permeation
- A = surface area of membrane
- h = membrane thickness
-C GI – Cp = difference b/w the conc. of drug in the
GI tract & in the plasma
 D (diffusion coefficient):

 It is a constant for each drug.

 It is defined as:
“the amount of a drug that diffuses across a membrane
of a given unit area per unit time”
e.g. cm square/sec
 K (lipid water partition coefficient of drug in the biologic
membrane that controls drug permeation):

 Degree of lipid solubility of the drug influences the rate of drug

absorption.
 The partition coefficient, K, represents the lipid-water partitioning of a
drug across the hypothetical membrane in the mucosa.
K= Coil/Cwater
 Hence, drugs that are more lipid soluble have a large value of K.
 A (surface area of membrane):

 The surface area, A of the membrane also influences

the rate of absorption.
 Duodenal area of the small intestine shows the most
rapid drug absorption, due to such anatomic
features as villi and microvilli, which provide a large
surface area.
 These villi are less abundant in other areas of the
gastrointestinal tract.
 h (thickness of the hypothetical
model membrane):
 It is a constant for any particular absorption site.
 Drugs usually diffuse very rapidly through capillary plasma
membranes in the vascular compartments, in contrast to
diffusion through plasma membranes of capillaries in the
brain.
 In the brain, capillaries are densely lined with glial cells, so a
drug diffuses slowly into the brain as if a thick lipid
membrane existed.
 Because D, A, K and h are constants under usual conditions
for absorption, a combined constant P or permeability
coefficient may be defined:

(2)

 Drug concentration in the plasma, Cp is extremely small

compared to that in the gastrointestinal tract, CGI
 If Cp is negligible and P is substituted in equation (1), the
following relationship for Fick's law is obtained:
 (3)

Equation 3 is an expression for a first order

process
(i.e. the rate of transfer is directly proportional
to the concentration of drug at absorption
and/or measurement sites).
In short….
 The driving force for passive diffusion is higher drug
concentration on the mucosal side compared to
the blood.
 The concentration of drug in the blood initially will be
quite low with respect to concentration at the site of
drug absorption.
 If the drug is given orally then, C GI >> Cp and a large
concentration gradient is maintained until most of the
drug is absorbed, thus driving drug molecules into
the plasma from GIT.
 Many drugs have both lipophilic and hydrophilic
chemical substituents.
 Those drugs that are more lipid soluble tend to
traverse cell membranes more easily than less lipid
soluble or more water soluble molecules.
 For drugs that act as weak electrolytes, such as
weak acids and bases, the extent of ionization
influences the rate of drug transport.
As we know….
Disintegration-breaking down of solid unit dosage form (tablet, capsule, etc)
into smaller particles
 Gives a dispersion of particles
 Increase surface area leads to increase in rate of dissolution
 Influenced by the excipients

Dissolution-formation of a solution of drug from the fragments of disintegrated

unit in GIT fluid
 Depends on:
 Disintegration-as discussed above
 Ionization-favors rapid dissolution of solid drug
Henderson-Hasselbalch equation
 The extent of ionization influences the rate
of drug transport for weak electrolyte drugs.
 The ionized specie of drug is more water
soluble than the unionized one.
 Degree on ionization depends on both pka
of drug and pH of the medium

pH = measure of acidity or basicity of the medium,

pKa = measure of acid strength of the drug
Important point to note…..
Weak ACID Weak BASE
• Increasing pH of a weak acid • Decreasing pH of a weak
increases ionization base increases ionization

Increase solubility

• Decreasing pH favors Increasing pH favors

• unionized form
unionized form
Increase partitioning
 [𝐈]
[𝐔]

[𝐈]
[𝐔]

Where, [H+] and [A–] are the concentrations of the ionized form of the acid,
[HA] is the concentration of the unionized form, and vice versa
 The substance with the proton is the acid and the substance without
the proton is the salt.
 Remember that the base is the one WITHOUT the proton and the acid
is the one WITH the proton.
 However, the salt of a weak acid is a base (and the salt of a weak base
is an acid).
 The pKa of water is 15.7. Any value higher than this pKa value increases
basicity, while values which decrease from this value are increasing in
acidity. For example, the pKa values for strong acids such as HCl can
even go into the negative values with a pKa of -8. While, a strong base
such as ammonia (NH3) has a pKa of 38.
 THE RELATIONSHIP BETWEEN PH AND PKA IS
DESCRIBED BY
THE HENDERSON-HASSELBALCH EQUATION
Start with a weak acid, + - HA H +A
According to the law of
dissociation, the acid [H+] [A-]
dissociation constant Ka can K
a = [HA
be given as Arrange to get
]
[HA]
[H+] = Ka
Multiply each side [A-]
by log
[HA]
Log[H+] = Log K a+ Log
[A-]
Multiply by -1
[HA]
Substitute -Log[H+] = -Log Ka- [A-]
pH = -Log[H+]
Log [HA]
pKa = Log Ka
pH = pKa - Log
[A-]
Remove (-) and
invert last
[A-] term
pH = pKa + Log
[HA]
Henderson -Hasselbalch
 This equation is useful for certain reactions and
important for absorption, distribution and
excretion of drugs.
 The Henderson-Hasselbalch equation gives you
information of the abundance of ionized and
unionized fractions of molecules within a given
solution.
Handerson Haselbalch equation
conclusion:
 Carrier Mediated Transport
 If the drug has low molecular weight & is lipophilic, the
lipid cell membrane is not a barrier to drug diffusion &
absorption.
 Numerous specialized carrier mediated transport systems
are present in the body, especially in the intestine for
the absorption of ions & nutrients required by the body.
Carrier Mediated Transport
b. Active transport
c. Facilitated passive diffusion
d.Transporters (carrier mediated intestinal
absorption)
 b. Active transport
Active transport is the movement of all types of molecules
across a cell membrane against its concentration gradient with
the help of energy and carrier.

 Active transport is characterized by the transport of drug against

a concentration gradient that is from regions of low drug
concentration to region of high concentration.
 Therefore, this is an energy consuming process.
 In addition active transport is a specialized process requiring a
carrier that binds the drug to form a carrier-drug complex that
shuffles the drug across the membrane & then dissociates the
drug on the other side of the membrane.
 c. Facilitated passive diffusion
Facilitated diffusion is the process of spontaneous passive transport (as
opposed to active transport) of molecules or ions across a biological
membrane via specific transmembrane integral proteins.

 Differing from active transport in that the drug moves along a

concentration
gradient and hence does not require energy input.
 Because this system is carrier mediated, it is
saturable & structurally selective for the
drug.
 It shows competition kinetics for drugs of
similar structure.
 In terms of drug absorption it seems to play
a very minor role.
d. Transporters and Carrier mediated
intestinal absorption
 Various carrier mediated systems (transporters) are present at the
intestinal brush border for absorption of specific ions &
nutrients essential for body.
 The transporters may be:
a) Influx transporters (increase drug absorption)
b) Efflux transporters (decrease drug absorption)
– A transmembrane protein, P-glycoprotein (Pgp) has been identified in
the intestine
– Pgp appears to reduce apparent intestinal epithelial cell permeability
from lumen to blood for various lipophilic or cytotoxic drugs and hence
protects the body from influx of undesirable toxic substances
 For many GI transporters, the transport of drug is often
bidirectional.
OTHERS:

Vesicular transport
 It is a minor mechanism of
absorption which involves
engulfing particles/ dissolved
materials by the cell.
 It includes following two
process:
 Pinocytosis: refers to the
engulfment of small
molecules or fluid.
 Phagocytosis: refers to the
engulfment of larger particles
or macromolecules,
generally by macrophages.

Endocytosis and exocytosis

are the processes of
moving specific
macromolecules into and
out of a cell
Examples
 Vesicular transport is the proposed process
for the absorption of orally administered
Sabin polio vaccine and various large
proteins
 An example of exocytosis is the transport
of protein such as insulin from insulin
producing cells of pancreas into the
extracellular space
Pore (convective) transport
Very small molecules (such as urea, water and
sugars) are able to cross cell membranes rapidly
as if the membrane contained channels or
pores.
A certain type of protein called a transporter
protein may form an open channel across
the lipid membrane of the cell
Small molecules including drugs move through
the channel by diffusion more rapidly than at
the other parts of the membrane
Ion-pair formation
 When the ionized (strong electrolyte) drug 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.
 E.g. formation of ion pairs to facilitated drug absorption
has been demonstrated by propranolol a basic drug
that forms an ion pair with oleic acid.
Passage of drug across cell membrane-
Summary

PASSAGES OF DRUG TRANSPORT

NON-Carrier
Carrier Medicated Others
Mediated

Passive Active Facilitate Intestinal Vesicular Pore Ion pair

Diffusion Transpor d transport transport
t diffusion transport transport
 pH Partition Theory:
• Lipid membranes are preferentially permeable to the unionized
molecules. Thus, an increase in fraction of drug that is unionized will
increase the rate of drug transport across the lipid membrane.
• This concept of absorption by partitioning processes of a drug between
water and lipid at different pH is known as the “pH-partition theory” of
drug absorption, and it addresses relationships among three different
factors affecting partition processes of oral absorption of a compound:
the dissociation constant and lipophilicity of the compound and the
pH at the absorption site.
• The pH-partition hypothesis, states that: the absorption of a weak
electrolyte will be determined chiefly by the extent to which the drug
exists in its un-ionized form at the site of absorption.
• Based on the Handerson-Hasselbalch equation, the degree of ionization
of a drug will depend on both its pKa and pH of the solution.
• The extent to which a weakly acidic or basic drug ionizes in solution
in the gastrointestinal fluid is determined by:
 its pKa & the pH at the absorption site and may be calculated using the
appropriate form of the Henderson-Hasselbach equation
• Brodie proposed the pH partition theory to explain the influence of
GI pH and drug pka on the extent of drug transfer or drug
absorption.
• Ph partition theory of drug absorption is based on the assumption
that the GIT is a simple lipid barrier to the transport of drugs and
chemicals.
• Accordingly the unionized form of an acid or basic drug, is
sufficiently lipid soluble, is absorbed but the ionized form is not.
• The larger the fraction of drug is in the unionized form at a specific
absorption site, the faster is the absorption
 Theory states that:
 non ionized form of a drug partitions into membrane and
ionization depends on pH of environment
 For weak acidic or basic drugs, pKa of drug, pH of GI fluid
controls drug solubility and thereby absorption rate through
membranes lining the GI tract.
 This means that, according to the pH-partition hypothesis, a
weakly acidic drug is more likely to be absorbed from the
stomach where it is unionized, and a weakly basic drug from
the intestine where it is predominantly unionized.
 However, in practice, other factors need to be taken into
consideration.
DIAGRAM SHOWING THE TRANSFER
OF DRUG ACROSS THE
MEMBRANE:
• pKa is the pH where a drug exists as 50%
ionized and 50% unionized
• Weak acids:
• pKa=2.5-7.5
 Predominantly unionized in stomach thus,
show absorption in stomach
• Strong acids:
 Ionized throughout GIT thus, are poorly
absorbed
• Weak bases:
• pKa 5-11
 Predominantly ionized in stomach thus, poorly
absorbed in stomach
 However, absorbed from small intestine
• Strong bases:
 Ionized throughout the GIT thus, poorly
absorbed
pH Partition Theory:
Interpretation:
• Provides a basis for:
 Absorption of drugs from GIT
 Distribution of drugs into body tissues
• Weak acids and bases: relatively non polar,
particularly in their unionized states
• Acidic drugs: unionized at low pH are
more soluble in lipids than in water, more
readily absorbed at low pH
• Basic drugs: maximum absorption at high
pH
pH Partition Theory:
Applications
 Helps predicting absorption by changing
pH of GIT and fraction non ionized
 Explains the absorption of drugs
 Applicable to elimination of drugs
(reabsorption)
pH Partition Theory:
Limitations
• Must be viewed as an approximation.
• Although the pH partition theory is
useful, it often does not hold true.
The discrepancies arise because the
theory does not take into account
certain factors, illustrated by the
following examples:
1. Despite of unfavorable ratio of unionized to ionized drug,
aspirin and most weak acids are well absorbed in the small
intestine.
• A large surface area and a relatively long residence time in
the small intestine are contributing factors.
These factors minimize the need for a large fraction of the drug to
be in an unionized form in the small intestine and hence compensate
for the ionization effect.
2. The pH -partition hypothesis cannot explain the fact that
certain drugs (e.g. tetracyclines) are readily absorbed
despite being ionized over the entire pH range of the
gastrointestinal tract.

One suggestion for this is that such drugs interact with

endogenous organic ions of opposite charge to form an
absorbable neutral species - an ion pair - which is capable of
partitioning into the lipoidal GIT barrier and be absorbed via
passive diffusion.
3. The quaternary ammonium drugs elicit systemic pharmacologic
effects after oral administration, suggesting that the restriction
to ionized forms of a drug by the GI barriers may not be
absolute. Several in vitro studies support this idea.
4. The absorption of organic anions and cations does take place in
the small intestine but at a much slower rate than the
corresponding unionized form of the drug.
 Effect of sink conditions in kinetic
process:
 The passively absorbed drug enters blood, rapidly swept
away and distribute into larger volume of body fluids.
Hence, the concentration of drug at absorption site, CGIT
is maintained greater than the concentration in plasma.
Such a condition is termed as sink condition for drug
absorption.
 Small amount of unionized drug will be rapidly absorbed
followed by re-equilibrium from ionized to unionized
(equilibrium restoration is driven by sink conditions).
• Similarly small concentration of ionized drug will result
in
further dissolution of solid drug.
• The relationship b/w solid & dissolved and ionized vs
non ionized drug is not static- dynamic
In short….
 Absorption process dependents
on:
 Solubility
 Ionization
 Lipophilicity
 Driving force for absorption is
sink condition resulting from
constant blood flow in GI
FACTORS INFLUENCING ABSORPTION OF DRUGS

Drug related Patient

1 factors 2 related factors

a) Physicochemical
properties of a) Physiological
drug factors
substances

b) Formulation/ b) Clinical factors

Pharmaceutical
Factors
 1 Drug related factors
1. Drug solubility and
dissolution rate
2. Particle size and effective
surface area
3. Polymorphism and
a) Physicochemical properties of drug amorphism
substances 4. Solvates/hydrates

5. Salt form of drug

6. Ionization state
1. Disintegration time
7. Drug pKa & lipophilicity & GI
b) Ph
Pharmaceutical 2. Manufacturing variables
/Formulation 8. Drug stability
3.Pharmaceutical
Factors ingredients/Excipients
4. Product age and storage
conditions
5. Nature and type of
dosage
 2 Patient related factors
(1) A. Nature of cell membrane
Membrane
B. Transport processes
physiology
A. Gastric emptying rate
B. Intestinal motility
A)
C. Drug stability in GIT
(2)
Physiological factors
Gastro-
D. pH of GIT
Intestinal E. Surface area of GIT
motility
F. Intestinal transit
(3) G. Blood flow to GIT.
Age
H. Effect of food
 2 Patient related factors

1. Diseases
B) Clinical factors
2. Drugs
 1 Drug related factors

a) Physicochemical properties of drug substances

1. Drug solubility and dissolution rate:

 Many drugs are given in solid dosage forms and therefore

must dissolve before absorption can take place.

 Except controlled released formulations disintegration

and disaggregation occurs rapidly.

Solution > Suspensions > Capsules > Compressed Tablets > Coated Tablets
 The rate determining steps in absorption of orally administered drugs
are:
 Rate of dissolution
 Rate of drug permeation through the biomembrane.
 Important prerequisite for the absorption of a drug is that it must
be present in aqueous solution & this depends on drug’s aqueous
solubility & its dissolution rate.

 Absolute Solubility or intrinsic solubility is defined as:

“ The maximum amount of solute dissolved in the given solvent
under standard conditions of temperature, pressure & pH. ”
 If solubility, Cs increases dissolution rate also increases.
 In order to avoid bioavailability problems, the drug must have a
minimum aqueous solubility of 1%.
 If dissolution is the slow then factors affecting dissolution will
control the overall process. (i.e. rate determining step; the step
controlling the overall rate)
 There are a number of factors which affect drug dissolution, as
given by Noyes Whitney’s equation.
H

L H
 1 Drug related factors

a) Physicochemical properties of drug substances

2. Particle size and effective surface area:
 Particle size plays a major role in drug absorption & this case is important
when the drug is poorly soluble (aqueous solubility).

Smaller the particle size (by micronization),

greater is the effective surface area,

more intimate contact between solid

surface and
aqueous solvent,

higher is the
dissolution rate,

increase in
“ Dissolution rate of solid particles α Surface Area “

Example:
 Griseofulvin, has extremely low aqueous solubility, and material of
normal particle size gave rise to poor and erratic absorption.
 Micro-size particles improve absorption, but it is improved
even more when it is formulated in ultramicro-size particles as
a monomolecular dispersion in polyethylene glycol.

 Particle size reduction has been used to increase the absorption of a

large number of poorly soluble drugs, such as bis-
hydroxycoumarin, digoxin, chloramphenicol, nitrofurantoin and
tolbutamide.
 one of the most important thing to be kept in mind that what type of
drug is need to be micronized, i.e. whether the drug is:
a) HYDROPHILIC OR b) HYDROPHOBIC

a) HYDROPHILIC DRUGS:

In hydrophilic drugs, it was found that the absorption efficiency was highly
increased after micronisation (increased interaction with the solvent).

 Examples:

1. Griseofulvin – Dose reduced to half due to micronisation.

2. Spironolactone – the dose was decreased to 20 times.
3. Digoxin – the bioavailability was found to be 100% in micronized
tablets.
 b) HYDROPHOBIC DRUGS:
 In this, micronization techniques results in decreased effective surface
area* & thus fall in dissolution rate.
 Such problems can be prevented by:
a) Use of surfactant as a wetting agent which
- decreases the interfacial tension.
- displaces the absorbed air with the solvent. (Example: Phenacetin)

b) Add hydrophilic diluents like PEG, PVP, etc.

(which coat the surface of hydrophobic drug particles.)

* Effective surface area is the one that is available for dissolution and is suitable for contact with gastric
fluid, whereas Absolute surface area is the total surface area of a particle.
 1 Drug related factors

a) Physicochemical properties of drug substances

3. Polymorphism and amorphism
 Polymorphism is the arrangement of a drug substance in various crystal
forms or polymorphs.
 Drugs exist in different crystalline forms i.e. polymorphs which possess same
chemical structure but different physical properties such as hardness,
dissolution rate and solubility.

 Example:
 Chloramphenicol, the beta-polymorph is more soluble and better absorbed
 The vitamin riboflavin exists in several polymorphic forms, and these have a
20-fold range in aqueous solubility.
 Polymorphs that no crystal structure, or amorphic
have (non-crystalline forms have different physical properties
forms), crystalline forms. from the

 Amorphous forms generally dissolve faster than crystalline forms because

no energy is needed to break up the crystal lattice.

 For this reason, the amorphous form (non-crystalline form) is often

preferred over the crystalline form and several drugs, including
hydrocortisone and prednisolone, are marketed in the amorphic form.

• Amorphous form • Crystalline form

– More soluble – Less soluble
– Rapidly dissolving – Slower dissolving
– Readily absorbed – Not absorbed to significant
extent
 1 Drug related factors

a) Physicochemical properties of drug substances

4. Solvates/ hydrates
 During their preparation, drug crystals may incorporate one or more
solvent molecules to form solvates (or Hydrate if the solvent is water).

 Solvates: If the drug is able to associate with solvent molecules to produce

crystalline forms.
 Hydrates: drug associates with water molecules.

 The greater the solvation of the crystal, the lower is the solubility
and
dissolution rate (in a solvent identical to the solvation molecules.)

“ Solvation 1/α Solubility or Dissolution “

 1 Drug related factors

 Hydrates are most common solvate forms of drugs.

 If water molecules are already present in a crystal structure, water could
hydrogen bond between 2 drug molecules and tie the lattice together, this
would give a much stronger, more stable lattice and thus a slower rate of
dissolution.
 The difference between hydrates and anhydrous form= pseudopolymorphism
 Anhydrous form has faster rate of dissolution.
 Example:
 Ampicillin trihydrate shows less absorption than its anhydrous form
 Faster dissolution in case of Erythromycin
anhydrate, when compared with its monohydrate and dehydrate
forms
 Theophylline
 1 Drug related factors

a) Physicochemical properties of drug substances

5. Salt form of drug
 It is a method of converting a drug into its salt form by virtue of which its
solubility, dissolution & thereby absorption increases to many folds
comparatively.
 The dissolution rate of a particular salt is usually different from that of the
parent compound.
 Sodium or potassium salts of weak acids dissolve more rapidly than the
free acid, regardless of the pH of the medium.
 While considering the salt form of drug, pH of the diffusion layer is
important not the pH of the bulk of the solution.
 1 Drug related factors

a) Physicochemical properties of drug substances

6. Ionization state

 Unionized state is lipid-soluble state of a drug which is important

for passive diffusion through membrane and ultimately for its
absorption.
 Ionized state is water-soluble form of a drug and is important for
drug’s solubility.
 1 Drug related factors

a) Physicochemical properties of drug substances

7. Drug pKa & lipophilicity & GI pH --- pH partition hypothesis:

 pH – partition theory states that for drug compounds of molecular weight

more than 100, which are primarily transported across the biomembrane
by passive diffusion, the process of absorption is governed by
– pKa of drug
– lipid solubility of the unionized drug i.e. partition coefficient (Ko/w).
– pH at the absorption site.
 1 Drug related factors

a) Physicochemical properties of drug substances

8. 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
Example: Penicillin G (enzymatic degradation)
 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.
 NOTE: The stability profile of drugs in GI conditions must be studied
before selecting a particular drug for improved dissolution.
 1 Drug related factors

b) Formulation/Pharmaceutical factors
1. Disintegration time
 Disintegration time (DT) is of particular importance in case of solid
dosage forms.
 However, if a solid dosage form does not conform to the DT ,it portends
bioavailability problems because the subsequent process of dissolution
will be much slower and absorption may be insufficient
 Rapid disintegration is important to have a rapid absorption so lower DT
is required.
 DT of tablet is directly proportional to
 Amount of binder
 Compression force (hardness)
 1 Drug related factors

 Coated tablets, especially sugar coated ones have long DT.

 A harder tablet with large amount of binder has a long DT.
 It should be remembered that in vitro disintegration test does not
guarantees of drug’s bioavailability because if the disintegrated drug
particles do not dissolve then absorption is not possible.
 1 Drug related factors

b) Formulation/ Pharmaceutical factors

3. Pharmaceutical excipients
 Drugs are rarely administered in their original form. A number of excipients (non-drug
component of a formulation) are added to the drug to formulate the drug in a
desired dosage form.
 Excipients are added to ensure acceptability, physicochemical stability during the shelf-
life, uniformity of composition and dosage, and optimum bioavailability and function-
ability of the drug product.
 Excipients can influence absorption of drugs. More the number of excipients in dosage
form, more complex it is & greater the potential for absorption and bioavailability
problems.
Examples:

– Absorption of tetracycline from capsules is reduced by calcium phosphate

due
to complexation.
 1 Drug related factors

h) COATINGS & COLORANTS:

 In general, the deleterious effect of various coatings on drug dissolution

from a tablet dosage form is in the following order:
enteric coat> sugar coat> non-enteric film 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.
 In case of colorants, even a low concentration of dye can have an
inhibitory effect on dissolution rate of several crystalline drugs.
 The dye molecules get absorbed onto the crystal faces and inhibit the
drug dissolution.
Example:
Brilliant blue retards dissolution of sulfathiazole.
 1 Drug related factors

b) Formulation/ Pharmaceutical factors

5. Nature and type of dosage form
 The passage of drug from the gut into the blood is influenced by biologic
and physicochemical factors and by the dosage form.
 For most drugs, 2-5 fold differences in the rate or extent of gastrointestinal
absorption can occur, depending on the dosage form.
 These two characteristics, rate and completeness of absorption,
comprise bioavailability.
 Generally, the bioavailability of oral drugs follows the order:
Solution > Suspension > Capsule > Tablet > Coated Tablet
• @

Bio-availability risk and absorption of various

dosage forms
Absorption of different oral
dosage forms
 Several factors, especially the excipients which influence
bioavailability of a drug from its dosage form, have
been discussed earlier.
 Now we will discuss about the how absorption varies in
case of different type of dosages forms:
• Solutions
• Emulsions
• Suspensions
• Capsules
• Tablets
• Sustained Release Products
 SOLUTIONS
 Drugs are absorbed more rapidly when given as solution than in any other
oral dosage form.
 A drug in a solution (syrups, elixirs, etc.) is most rapidly absorbed since drug
dissolution is absent.
 Factors that influence bioavailability of a drug from solution dosage form
include
 the nature of solvent (aqueous, water miscible, etc.),
 Chemical stability of drug in GIT,
 Complexation,
 viscosity,
 Surfactant, etc.
 EMULSIONS
 Emulsion dosage forms have been found to be superior to suspensions in
administering poorly aqueous soluble lipophilic drugs.
 Example:
- when indoxole (an NSAID) is dissolved in a vegetable oil and emulsified in
water, absorption increases 3 fold over its aqueous suspension.
 Emulsion dosage forms present a large surface area of oil to the GIT for
absorption of a drug.
 SUSPENSIONS
 A well formulated aqueous suspension is second in efficiency only to the
solution dosage form.
 The major rate-limiting step in the absorption of a drug from suspension
dosage form is drug dissolution which is generally rapid due to the
large surface area of the particles.
 Factors that affect the absorption from suspension include the following:
 Particle size and effective surface area of the dispersed phase.
 Crystal form of the drug.
 Complexation.
 Inclusion of surfactant as a wetting or flocculating agent.
 Viscosity of the suspension.
 Inclusion of colorants
 CAPSULES
 Better absorption profile as compared to compressed tablets.
 Factors :
 Dissolution rate of gelatin shell
 The rate of penetration of the GI fluids into the encapsulated mass
 The rate at which the mass deaggregates in the GI fluids and
 The rate of dissolution of the dispersed drug particles
 Packing density of capsule contents
 Nature and quantity of added excepients
 TABLET
S
1)Uncoated/ compressed tablets:
 Compressed tablets are the most widely used convenient and cost effective
dosage form.
 The bioavailability problems with tablets arise from the reduction in the
effective surface area due to granulation and subsequent compression into
a dosage form.
 Since dissolution is most rapid from primary drug particles due to their large
surface area, disintegration of a tablet into granules and subsequent
disaggregation of granules into fine particles is very important.
 A number of formulation and processing factors influencing these steps and
also the physicochemical properties of drug substance that influence
bioavailability.
 TABLET
S
 Factors :
 wettability,
 effective surface area,
 crystal form and chemical stability.
 The nature and quantity of diluent, binder, disintegrant, lubricant and
any wetting agent.
 The drug excipients interactions,
 size of the granules and their method of manufacture.
 The conditions of storage and age of the tablet.
 TABLET
S
2) Coated Tablets :
 The coating acts as additional barrier which must first dissolve to release the
drug molecule.
 Of the two types of coatings, the film coat, which is thin, dissolves rapidly and
does not significantly affect drug absorption.
 The sugar coat which though soluble but tough and takes longer to dissolve.
 Factors :
 Thickness of coating
Ex: studies with quinine tablets coated with cellulose acetate phthalate
showed a decrease in both rate and extent of absorption with increasing
thickness of coating.
Other factors are more or less similar to compressed tablets.
 SUSTAINED RELEASE PRODUCTS
 Drug release from such products is most unpredictable, the problems ranging
from dose dumping to unsatisfactory or no drug release at all.
 However, with the development of newer innovations and technologies,
it is becoming increasingly reliable and the results reproducible with little
intersubject variations.
 2 Patient related factors
(1) A. Nature of cell membrane
Membrane
physiology B. Transport processes
A. Gastric emptying rate
B. Intestinal motility
(2)
C. Drug stability in GIT
A) Gastro-
Physiological factors Intestinal D. pH of GIT
motility
related
E. Surface area of GIT
F. Intestinal transit
(3)
G. Blood flow to GIT.
Age
H. Effect of food
(4) Pre-systemic Metabolism
GIT Physiology

 The enteral system consists of the

alimentary canal from the mouth to the
anus. The major physiologic processes
that occur in the GI system are secretion,
digestion, and absorption.
 Secretion includes the fluid, electrolytes,
peptides, and proteins into the lumen of
the alimentary canal. Enzymes in saliva
and pancreatic secretions are also
involved in the digestion of
carbohydrates and proteins. Other
secretions, such as mucus, protect the
linings of the lumen of the GI tract.
 Digestion is the breakdown of food
constituents into smaller structures in
preparation for absorption. Food
constituents are mostly absorbed in the
proximal area (duodenum) of the small
intestine.
 The process of absorption is the entry of
constituents from the lumen of the gut
into the body. Absorption may
be
considered as the net result of
both
 Drugs administered orally pass through various parts of the enteral canal, including
the oral cavity, esophagus, and various parts of the gastrointestinal tract. Residues
eventually exit the body through the anus.
 Total transit time (gastric emptying, small intestinal transit, and colonic transit) =
12 hrs to 5 days.
 Small intestine transit time (SITT) = 3 to 4 hrs.
 If absorption is not completed by the time a drug leaves the small intestine,
absorption may be erratic or incomplete.
 The normal physiologic processes of the alimentary canal may be affected by diet,
contents of the gastrointestinal (GI) tract, disease, and drugs. Thus, drugs given by
the enteral route for systemic absorption may be affected by the anatomy,
physiologic functions, and contents of the alimentary tract.
 Moreover, the physical, chemical, and pharmacologic properties of the drug itself
will also affect its own absorption from the alimentary canal.
 1 Patient related factors

A) Physiological factors

3. Gastro-Intestinal motility

A. Gastric emptying
“The passage of the ingested material from stomach to the small intestine is called
gastric emptying.”

 Normal range = 5 minutes - 2 hours

 Several parameters are used to quantify gastric emptying such as:
 Gastric emptying time:
which is the time required for the gastric contents to transverse the stomach and
enter the small intestine.
 Gastric emptying rate:
which is the speed at which the stomach contents empty into the intestine.
 Gastric emptying half-life:
which is the time taken for half the stomach contents to empty.
 It is the rate limiting step in drug absorption for almost
all drugs.
 Main role of stomach is dissolution not absorption so the major
site of absorption is intestine.

 In case of slow gastric emptying:

 drug stay in the stomach for maximum time and drug
absorption is less and less bioavailability of the drug
(but increase absorption in case of acidic drugs e.g.
aspirin).

 In general, rapid gastric emptying:

 rapid onset of action,
 enhances the stability of drug in gastric fluid (e.g.:
penicillin) and increases the absorption and
bioavailability of drug.
General facts….

 Liquid emptied faster than solid dosage forms.

 Small particles (1mm) are not retained in stomach but forced in the
intestine. (comparatively higher pressure in stomach)
 Rate of gastric emptying occurs for various ingested food:
carbohydrates
> proteins > fats.
 Gastric emptying is rapid while lying on the right side and slow while lying
on the left side.
(The reason is not entirely clear. One hypothesis holds that right-side
sleeping relaxes the lower esophageal sphincter, between the stomach and the
esophagus. Also, If you lie on the right side, the stomach and pancreas will hang in a
somewhat unnatural position, forcing them to empty their contents prematurely.)
 Anti-cholinergic drugs delay gastric emptying time.
 1 Patient related factors

B. Intestinal motility

 Normal peristalic movements mix the contents of the duodenum,

bringing the drug particles into intimate contact with the
intestinal cells.
 The drug must have sufficient time (residence time= contact time
of particles with absorption membrane) at the absorption site
for optimum absorption.
 If high motility, then brief residence time, inadequate drug
absorption e.g in diarrhea
 1 Patient related factors

A) Physiological factors

C. Drug stability in GIT

 Chemical stability of drugs is highly affected by GI pH.

 Some drugs are acid sensitive and degrade in stomach which affects the
absorption of drug.
 Example: the acidic stomach pH gives a degradation of penicillin G and
erythromycin.
So such drugs can be formulated by preparing prodrugs.
(Carindacillin and erythromycin estolate)
 1 Patient related factors

A) Physiological factors

3. Gastro-Intestinal motility
D. pH of GIT
• The GI pH generally increases gradually from the stomach to the colon
and rectum.
• GI fluid pH affect drug absorption in several ways:
 Disintegration: The Disintegration of some drugs is pH sensitive e.g with
enteric coating the coat dissolves in only the intestine at specific PH.
 Dissolution : A large number of drugs whose solubility is greatly affected
by pH are either weak acids or weak bases.

Weakly acidic drugs dissolves rapidly in alkaline pH of the intestine whereas

basic drugs dissolve in the acidic pH of the stomach.
 1 Patient related factors

A) Physiological factors

3. Gastro-Intestinal motility

E. Surface area of GIT

 For most drugs, the optimum site for drug absorption after oral
administration is the upper portion of the small intestine or
duodenum region.
 The unique anatomy of the duodenum provides a large surface area
which is due to the presence of valve like folds in the mucous
membrane with small projections known as villi and microvilli,
forming a brush border.
 In addition, the duodenal region is highly perfused with a network of
capillaries, which helps to maintain a concentration gradient from the
intestinal lumen and plasma circulation
 1 Patient related factors

A) Physiological factors

3. Gastro-Intestinal motility

F. Intestinal transit
 The drug must have sufficient time (residence time= contact time of
particles with absorption membrane) at the absorption site for optimum
absorption.
 Small intestine transit time (SITT) = 3 to 4 hours
 If absorption is not completed by the time a drug leaves the small
intestine, absorption may be erratic or incomplete.
 Longer intestinal transit time is desirable for complete absorption
of
drugs.
 Like gastric emptying, intestinal transit is influenced by several similar
factors like food, drugs and diseases.
 1 Patient related factors

A) Physiological factors

3. Gastro-Intestinal motility

G. Blood flow to GIT.

 The blood flow to GIT is important in carrying the absorbed

drug to the systemic circulation.
 Local blood flow is a strong determinant of the rate of
absorption because it continuously maintains the
concentration gradient necessary for passive diffusion to
occur.
 1 Patient related factors

Table : Influence of blood flow effect on various types of

drugs

DRUGS BLOOD
FLOW EFFECT
A) For highly lipid soluble drugs More
B) For many lipophilic drugs Intermediate
such as ethanol, glycerol, etc.
C) Polar compounds Less
 1 Patient related factors

A) Physiological factors

H. Effect of food
The presence of food in the GIT can influence the rate and extent of
absorption, either directly or indirectly via a range of mechanisms, some of
these include:

1. Complexation of drugs with components in the diet:

Tetracycline forms non-absorbable complexes with calcium and iron

2. Alteration of pH:
Food tends to increase stomach pH by acting as a buffer
(hence, decrease the rate of dissolution of a weakly basic drug and increase
that of a weakly acidic one.)
3. Alteration of gastric emptying:
Fats and some drugs tend to reduce gastric emptying and thus delay
the onset of action of certain drugs.

4. Stimulation of gastrointestinal secretions:

Gastrointestinal secretions (e.g. pepsin) produced in response to food
may result in the degradation of drugs, and hence a reduction in their
bioavailability.
Fats stimulate the secretion of bile. Bile salts are surface active
agents which
increase the dissolution of poorly soluble drugs (griseofulvin).
(Bile salts can form insoluble and non-absorbable complexes with
some drugs, such as neomycin and kanamycin.)
5. Food-induced changes in presystemic metabolism:
Certain foods may increase the bioavailability of drugs that are
susceptible to presystemic intestinal metabolism by interacting with the
metabolic process.
E.g. Grapefruit juice is capable of inhibiting the intestinal cytochrome
P450 (CYP3A) and thus taken with drugs that are susceptible to CYP3A
metabolism which result in increase of their bioavailability.
6. Food-induced changes in blood
flow: Food serves to increase the bioavailability of some
drugs (e.g.
propranolol) that are susceptible to first-pass metabolism.
Blood flow to the GIT and liver increases after a meal.

(faster the rate of drug presentation to the liver  larger the fraction of
drug that escapes first-pass metabolism. This is because the enzyme
systems become saturated.)

Competition between food components and drugs for specialized

absorption mechanisms as well as the Increased viscosity
of gastrointestinal contents can also effect the GI absorption of drugs.
 1 Patient related factors

A) Physiological factors

3. Age

In infants:
 Infants show altered absorption pattern compared to adult due to:
- Altered gastric pH, - low surface area of GIT, - low blood flow to the GIT.

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 over growth in small intestine.
 1 Patient related factors
A) Physiological factors

4. Pre-systemic Metabolism

-For a drug administered orally,

one of the main reasons for its
decreased bio-availability is
the pre-systemic metabolism
(First- pass effect)
-The four primary systems which
affect the pre-systemic metabolism
of a drug:
 Luminal Enzymes
 Gut wall enzymes/mucosal
enzymes
 Bacterial enzymes
 Hepatic enzymes
-Luminal Enzymes
These are the enzymes present in the gut fluids and include enzymes from
intestinal and pancreatic secretions.
(Pepsin, Lipases, amylases and proteases and hydrolases enzymes)
-Gut wall enzymes/mucosal enzymes
Gut wall enzymes are present in stomach, intestine and colon.
(Alcohol dehydrogenase (ADH), sulfation)
-Bacterial enzymes
The major GI microflora is in colon. The colonic microbes generally render a drug
more active or toxic on biotransformation.
(Their enzymes hydrolyze the conjugates of drugs such as glucuronides of digoxin
and oral contraceptives. )
-Hepatic enzymes
Aminotransferases (ALT, AST) etc.
 2 Patient related factors

1. Diseases
B) Clinical factors
2. Drugs
 1 Patient related factors

B) Clinical factors

1. Diseases
 Local diseases can cause alterations in gastric pH that can affect the
stability, dissolution and absorption of the drug.
 Several disease states can influence the rate and extent of
drug absorption.
 The 3 major classes of states that can influence the
disease bioavailability of a drug
are:
– 1. Gastrointestinal diseases,
– 2. Cardiovascular diseases, and
– 3. Hepatic diseases.
1) Gastric diseases:
-The influence of achlorhydria (decreased gastric acid secretion and increases
stomach pH) on drug absorption, especially that of acidic drugs (decreased
absorption e.g. aspirin) has been observed.

Intestinal diseases:
-Two of the intestinal disorders related with malabsorption syndrome that
influence drug bioavailability are Celiac disease (proximal SI) and Crohn's
disease. (distal SI and colon)
2) Cardio-vascular diseases:
-In Congestive heart failure (CHF) patients with persistent edema have reduced
splanchnic blood flow and develop edema in the bowel wall. In addition, intestinal
motility is slowed. The reduced blood flow to the intestine results in a decrease in
drug absorption.
For example, furosemide (Lasix), a commonly used loop diuretic, has erratic and
reduced oral absorption in patients with CHF.

3) Hepatic diseases:
-Disorders such as hepatic cirrhosis influence bioavailability mainly of
drugs that undergo considerable first-pass hepatic metabolism e.g.
morphine, diazepam, propranolol.
 1 Patient related factors

B) Clinical factors
2. Drugs
 Anticholinergic drugs in general may reduce stomach acid secretion.
 Tricyclic antidepressants and phenothiazines also have anticholinergic
side effects that may cause slower peristalsis in the GI tract. Slower
stomach emptying may cause delay in drug absorption.
 Metoclopramide is a drug that stimulates stomach contraction,
increases intestinal peristalsis, which may reduce the effective time
for the absorption of some drugs.
 For example,
Digoxin absorption from a tablet is reduced by metoclopramide but
increased by an anticholinergic drug.
 Allowing more time in the stomach for the tablet to dissolve
generally helps with the dissolution and absorption of a poorly
soluble drug, but would not be helpful for a drug that is not soluble
in stomach acid.
 Antacids containing aluminum, calcium, or magnesium may complex
with drugs such as tetracycline, ciprofloxacin, and indinavir, resulting in
a decrease in drug absorption.

 As mentioned, proton pump inhibitors, such as omeprazole, render the

stomach achlorhydric, which may also affect drug absorption.

 Cholestyramine is a nonabsorbable ion-exchange resin for the

treatment of hyperlipidemia. Cholestyramine adsorbs warfarin and
thyroxine, similar to activated charcoal, thereby reducing absorption of
these drugs.

 Absorption of calcium in the duodenum is facilitated by vitamin D, with

calcium absorption as much as four times more than that in vitamin D
deficiency states.
It is believed that a calcium-binding protein, which increases after vitamin
D administration, binds calcium in the intestinal cell and transfers it to
the blood circulation.
Double-Peak Phenomenon
 Some drugs such as ranitidine, cimetidine and dipyridamole after oral
administration produce a blood concentration curve consisting two peaks
 This double-peak phenomenon is generally observed after the
administration of a single dose to fasted patients
 The presence of double-peaks has been attributed to variability in
stomach emptying, variable intestinal motility, presence of food,
enterohepatic recycling or failure of a tablet dosage form etc.

 In case of Cimetidine:
 The double peak phenomenon observed for cimetidine may be due to
variability in stomach emptying and intestinal flow rates during the entire
absorption process after a single dose
 For many drugs very little absorption occurs in the stomach
 For a drug with higher water solubility, dissolution of the drug occurs in
the stomach and partial emptying of the drug into the duodenum 
1st absorption peak
References: