Bioavailability, Bio-equivalence, Generic drug

and factors affecting biovailability of drugs.

Presented By: Pramila Thapa Magar

M.Pharm, Clinical Pharmacy, 6th Batch

1
Introduction
• The most important property of any non-intravenous dosage
form, intended to treat a systemic condition, is the ability to
deliver the active ingredient to the bloodstream in an amount
sufficient to cause the desired response.

• This property of a dosage form has historically been identified

as physiologic availability, biologic availability or bioavailability.

• Both Bioavailability & Bioequivalence focus on release of drug

substance from its dosage form & subsequent absorption in
circulation

2
• Bioavailability means the rate and the extent to which
the active drug ingredient of therapeutic moiety is
absorbed from a drug product and becomes available
at the site of action.
• Bioavailable fraction (F), refers to the fraction of
administered dose that enters the systemic circulation
where as,
F = Bioavailable dose
Administered dose

3
• The influence of route of administration on
drug’s bioavailability is generally in following
order:
parenteral>oral>rectal>topical
• Intravenous injection of a drug results in 100%
bioavailability as the absorption process is
bypassed.

4
Objectives of bioavailability
• To obtain evidence for therapeutic utility of new drug
and its dosage form.
• Development of new formulation of the existing drugs.
• Determination of influence of excipients, patient
related factors & possible interactions with other
drugs.
• Control of quality of drug products, influence of →
processing factors, storage & stability.
• Comparison of availability of a drug substance from
different form or same dosage form produced by
different manufacturers.
5
 Types of bioavailability
a) Absolute bioavailability
b) Relative bioavailability

c) Absolute bioavailability:
- When the systemic availability of a drug administered orally is
determined in comparison to its intravenous administration, it is
called as absolute bioavailability.
- I.V. dose is standard because the i.v. administered drug directly
reaches to systemic circulation i.e. 100% biovailable.
F (ab) = (AUC)drug
(AUC)IV

6
 b) Relative bioavailability
• When the systemic availability of a drug after oral
administration is compared with that of an oral
standard of the same drug, it is referred to as
relative bioavailability.
F rel = ( AUC) drug
(AUC) standard

7
Bioequivalence:
• Relative term which denotes that the drug
substance in two or more identical dosage
form, reaches the systemic circulation at same
relative rate and extent respectively.
• Plasma concentration-time profiles will be
identical without significant statistical
differences.
• When statistically significant differences are
observed in the bioavailability of two or more
drug products, bio-inequivalence is indicated.
8
Parameters to determine bioavailability
a) Plasma level-time studies
• the area under the blood drug concentration versus time
curve (AUC)
• Maximum blood concentration (Cmax)
• Time to reach maximum concentration (Tmax)
b) Urinary excretion method
• Cumulative amount of drug excreted in urine (Du)
• Rate of drug excretion in urine (dDu/Dt)
• Time for maximum urinary excretion (t)
c) Acute pharmacological response
d) Therapeutic response 9
a) Plasma level-time studies

1) Cmax : The peak plasma concentration that gives an indiction

whether the drug is sufficiently absorbed systematically to
provide the therapeutic response. Cmax will increase with an
increase in the dose, as well as with an increase in the
absorption rate.
2) Tmax : The peak time that gives an indication of the rate of
absorption. It decreases as the rate of absorption increases.
3) AUC : It gives a measure of the extent of absorption or the
amount of drug that reaches the systemic circulation.

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1

11
Urinary Excretion Studies
• It is based on the principle that the urinary
excretion of unchanged drug is directly
propotional to the plasma concentration of drug.
• As a rule of thumb, determination of
bioavailability using excretion data should be
conducted only if atleast 20% of administered
dose is excreted unchanged in the urine.

12
Parameters examined in urinary excretion
a) Maximum urinary excretion rate (dXu/dt)max : It is obtained
from the peak of plot between rate of excretion versus mid point
time of urine collection period. Its value increases as the rate and
extent of absorption increases.
b) Time for maximum excretion rate (tu): it is analogous to tmax of
plasma level data. Its value decreases as absorption rate
increases.
c) Cumulative amount of drug excreted in urine (Xu∞): It is related
to AUC of plasma level data and increases as the extent of
absorption increases.

13
 Acute pharmacological response
When pharmacokinetic methods is not suitable,
inaccurate or non-reproducible for
measurement of bioavailability, an acute
pharmacological response or effect is related to
the time course of given drug.
• Bioavailability can be determined by
construction of pharmacological effect-time
curve as well as dose response graphs.
• The method requires at least 3 biological half-
lives of drug in order to obtain a good estimate
of AUC. 14
 Therapeutic Response method
• It is based on observing the clinical responses to a
drug formulation given to patients suffering from
disease for which it is intended to be used.
• Example: studies of topical antifungal agents,
drugs used in the treatment of acne and agent
such as sucralfate use in ulcer therapy.

15
 Generic drug
• Generic drugs have the same active ingredients as
brand name drugs already approved by the Food
and Drug Administration (FDA).
• It may have different shape, size, color and taste.
• Generics only become available after the patent
expires on a brand name drug.

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• Generic drugs could have different sizes, shapes,
colors or markings. – They have different names.

• They might have different inactive ingredients.

• The generic costs less than the brand name drug.

• Generic drugs may vary by manufacturer.

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Waxman- Hatch Act
• Using bioequivalence as the basis for approving
generic copies in US “Drug Price Competition and Patent
Term Restoration Act of 1984,” also known as the
Waxman-Hatch Act.
• This act, by eliminating the requirement for clinical
safety and efficacy testing for generics of drugs
introduced after 1962, greatly expedited the entry of
generic drugs into the market place.
• It created generic industries and increases their
availability.

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• The purpose of this act was to facilitate
generic competition and thereby reduce
health care costs.
• This act significantly expanded the number of
drugs eligible to be manufactured as generics.

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Factors affecting bioavailability of drugs

a) Pharmaceutical factors
I) Physicochemical properties of drugs
II) Dosage form characteristics and
III) Nature of excipients in the formulations
b) Patient related factors

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a) Pharmaceutical factors
I. Physicochemical Properties of Drug Substances
1. Drug solubility and dissolution rate
2. Particle size and effective surface area
3. Polymorphism and amorphism
4. Pseudopolymorphism (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
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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
 

22
 B. PATIENT RELATED FACTORS: 
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
8. Presystemic metabolism by:
a. Luminal enzymes
b. Gut wall enzymes
c. Bacterial enzymes
d. Hepatic enzymes 23
 A) PHARMACEUTICAL FACTORS
I) PHYSICOCHEMICAL PROPERTIES OF DRUGS
1) Drug solubility and dissolution rate :
•  Except in case of controlled-release formulations,
disintegration and deaggregation occur rapidly if it is a well-
formulated dosage form. Thus, the two critical slower rate-
determining processes in the absorption of orally administered
drugs are:
- Rate of dissolution, and
- Rate of drug permeation through the biomembrane.
• Higher the dissolution rate means greater the absorption and
better bioavailability of drugs

24
• Dissolution is the rate determining step for hydrophobic,
poorly aqueous soluble drugs like griseofulvin and
spironolactone; absorption of such drugs is often said to be
dissolution rate-limited.
• Drug with hydrophilicity and high aqueous solubility – for
example: cromolyn sodium or neomycin, then dissolution is
rapid and RDS in the absorption of such drugs is rate of
permeation through the biomembrane.

Fig 2: The two rate-determining steps in the absorption of drugs from orally

administered formulations
25
• Based on the intestinal permeability and solubility of drugs,
Amidon et al developed Biopharmaceutics Classification
System (BCS) which classifies the drugs into one of the 4 groups
as shown in the table below:

• Class I drugs (high solubility/high permeability) are well absorbed

orally since they have neither solubility nor permeability limitation.
• Class II drugs (low solubility/high permeability) show variable
absorption owing to solubility limitation.
• Class III drugs (high solubility/low permeability) also show
variable absorption owing to permeability limitation.
• Class IV drugs (low solubility/low permeability) are poorly absorbed orally
owing to both solubility and permeability limitations.
26
• Dissolution is a process in which a solid substance solubilises in
a given solvent i.e. mass transfer from the solid surface to the
liquid phase. Several theories to explain drug dissolution have
been proposed.
• Dissolution rate is defined as the amount of solid substance
that goes into solution per unit time under standard conditions
of temperature, pH and solvent composition and constant solid
surface area.
Theories of Drug Dissolution
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.

27
Diffusion Layer Model/Film Theory
• This is the simplest and the most common theory for
dissolution. Here, the process of dissolution of solid
particles in a liquid, in the absence of reactive or chemical
forces, consists of two consecutive steps:
1. Solution of the solid to form a thin film or layer at the
solid/liquid interface called as the stagnant
film or diffusion layer which is saturated with the drug;
this step is usually rapid, and
2. Diffusion of the soluble solute from the stagnant layer to
the bulk of the solution; this step is slower and is therefore
the rate-determining step in drug dissolution. The model is
depicted in Fig below.

28
fig 3: diffusion layer model for drug dissolution.

29
The earliest equation to explain the rate of dissolution when
the process is diffusion controlled and involves no chemical
reaction was given by Noyes and Whitney:

dc/dt = k ( Cs- Cb) (1)

where,
dC/dt = dissolution rate of the drug,
k = dissolution rate constant (first order),
Cs = concentration of drug in the stagnant layer (also called as
the saturation or maximum drug solubility), and
Cb = concentration of drug in the bulk of the solution at time t.

30
Equation 1 was based on Fick's second law of diffusion. Nernst and Brunner incorporated
Fick‘s first law of diffusion and modified the Noyes-Whitney’s equation to:

dc/dt= {DAKo/w (Cs-Cb)}/ Vh (2)

where,
D = diffusion coefficient (diffusivity) of the drug
A= surface area of the dissolving solid
Kw/o = water/oil partition coefficient of the drug considering the fact that dissolution
body fluids are aqueous. Since the rapidity with which a drug dissolves depends on the
Kw/o, it is also called as the intrinsic dissolution rate constant. It is a characteristic of
drugs.
V = volume of dissolution medium.
h= thickness of the stagnant layer.
(Cs – Cb) = concentration gradient for diffusion of drug.

Equation (2) represents first-order dissolution rate process, the driving force for which is
the concentration gradient (Cs – Cb). Under such a situation, dissolution is said to be
under non-sink conditions.

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Influence of Some Parameters on Dissolution Rate of Drug

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• The in vivo dissolution is always rapid than in-vitro dissolution
because the moment the drug dissolves; it is absorbed into the
systemic circulation. As a result, Cb = 0, and dissolution is at its
maximum.
• Thus, under in vivo conditions, there is no concentration build-up in
the bulk of the solution and hence no retarding effect on the
dissolution rate of the drug i.e.Cs>>Cb and sink conditions are
maintained.
• Under sink conditions, if the volume and surface area of solid are
kept constant, then equation 2 reduces to:
dc/dt= k (3)

where K incorporates all the constants in equation 2. Equation 3

represents that the dissolution rate is constant under sink
conditions and follows zero-order kinetics i.e. yields a linear plot
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4

34
To obtain good in vitro-in vivo dissolution rate correlation, the in
vitro dissolution must always be carried under sink conditions.
This can be achieved in one or more of the following ways:
1. Bathing the dissolving solid in fresh solvent from time to time.
2. Increasing the volume of dissolution fluid.
3. Removing the dissolved drug by partitioning it from the aqueous
phase of the dissolution fluid into an organic phase placed either
above or below the dissolution fluid—for example, hexane or
chloroform.
4. Adding a water miscible solvent such as alcohol to the
dissolution fluid, or
5. By adding selected adsorbents to remove the dissolved drug.

The in vitro sink conditions are so maintained that Cb is always less

than 10% of Cs.
35
The Noyes-Whitney’s equation assumes that the surface area of
the dissolving solid remains constant during dissolution, which
is practically not possible for dissolving particles. Hence,
dissolution methods that involve use  of constant surface area
discs are employed to determine the rate of dissolution.
To account for the particle size decrease and change in surface
area accompanying dissolution, Hixson and Crowell’s cubic
root law of dissolution is used:
Wo1/3 – W1/3 = Kt                            (4)
where,
Wo = original mass of the drug
W = mass of the drug remaining to dissolve at time t
K= dissolution rate constant

36
 Danckwert’s Model (Penetration or Surface Renewal
Theory)
Danckwert did not approve of the existence of a stagnant layer and
suggested that turbulence in the dissolution medium exists at the
solid/liquid interface.

As a result, the agitated fluid consisting of macroscopic mass of eddies or

packets reach the solid/liquid interface in a random fashion due to eddy
currents, absorb the solute by diffusion and carry it to the bulk of the
solution. Such solute containing packets are continuously replaced with
new packets of fresh solvent due to which the drug concentration at the
solid/liquid interface never reaches Cs and has a lower limiting value of Ci.
 
Since the solvent packets are exposed to new solid surface each time, the
theory is called as surface renewal theory.

37
• The Danckwert’s model is expressed by equation:
V dc/dt = dm/dt = A (Cs-Cb) √ƳD
where,
m = mass of solid dissolved, and
γ = rate of surface renewal (or the interfacial tension).

• Fig. 5. Danckwert’s model for drug dissolution 38

Interfacial Barrier Model (Double Barrier or Limited
Solvation Theory)
The diffusion layer model and the Danckwert’s model were based on two
assumptions:
1. The rate-determining step that controls dissolution is the mass transport.
2. Solid-solution equilibrium is achieved at the solid/liquid interface.
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 the crystal will have a different interfacial barrier. Such a concept
is given by the following equation:

G = Ki (Cs-Cb)
where,
G = dissolution rate per unit area, and
Ki = effective interfacial transport constant.
In this theory, the diffusivity D may not be independent of saturation concentration
Cs. The interfacial barrier model can be extended to both diffusion layer model
and the Danckwert’s model 39
2. Particle Size and Effective Surface Area of the Drug
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 1, 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.
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3. Polymorphism and Amorphism
Depending upon 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.
Polymorphs are of two types:
1. Enantiotropic polymorph is the one which can be reversibly
changed into another form by altering the temperature or
pressure e.g. sulphur, and
2. Monotropic polymorph is the one which is unstable at
all temperatures and pressures e.g. glyceryl stearates.

41
• The polymorphs differ from each other with respect to their
physical properties such as solubility, melting point, density,
hardness and compression characteristics.
• They can be prepared by crystallizing the drug from different
solvents under diverse conditions.
• The existence of the polymorphs can be determined by using
techniques such as optical crystallography, X-ray diffraction,
differential scanning calorimetry, etc.
•  Chloramphenicol palmitate, cortisone acetate and phenobarbital
are other examples where the amorphous forms exhibit higher
water solubility. Thus, the order for dissolution of different solid
forms of drugs is —
Amorphous > Metastable > Stable.

42
 4. Hydrates/Solvates (Pseudopolymorphism)
• 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 pseudopolymorphs. This phenomenon is called
as pseudopolymorphism. 
• 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. 43
 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.
[H+]d = hydrogen ion concentration of the diffusion layer, and
[H+]b = hydrogen ion concentration of the bulk of the solution, then,
for salts of weak acids, [H+]d < [H+]b
for salts of weak bases, [H+]d > [H+]b
• 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.

44
Fig.6. Dissolution and absorption of an acidic drug administered in a
salt form

The selection of appropriate salt form for better dissolution rate is also
important. It has been shown that the choline and the isopropanolamine
salts of theophylline dissolve 3 to 4 times more rapidly than the
ethylene-diamine salt and show better bioavailability.

45
6. Drug pKa and Lipophilicity and GI pH—pH Partition Hypothesis

• The pH partition theory (Brodie et al) explains in simple terms,

the process of drug absorption from the GIT and its
distribution across all biological membranes. The theory
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:
1. The dissociation constant (pKa) of the drug.
2. The lipid solubility of the unionised drug (a function of
drug Ko/w).
3. The pH at the absorption site.

46
• Since most drugs are weak electrolytes (weak acids or weak
bases), their degree of ionisation depends upon the pH of the
biological fluid.
• If the pH on either side on the membrane is different, then the
compartment whose pH favours greater ionisation of the drug
will contain greater amount of drug, and only the unionised or
undissociated fraction of drug, if sufficiently lipid soluble, can
permeate the membrane passively until the concentration of
unionised drug on either side of the membrane becomes equal
i.e. until equilibrium is attained.
• The above statement of the hypothesis was based on
the assumptions that:
1. The GIT is a simple lipoidal barrier to the transport of drug.
2. Larger the fraction of unionised drug, faster the absorption.
3. Greater the lipophilicity (Ko/w) of the unionised drug, better the
absorption.
47
 7. Drug pKa and Gastrointestinal pH
• The amount of drug that exists in unionised form is a
function of dissociation constant (pKa) of the drug and
pH of the fluid at the absorption site.
• 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 ionised at this
pH can be determined by Henderson-
Hasselbach equations. 48
For weak acids
pH= pka + log ionised drug (1)
unionised drug

For weak base

pH = pka + log unionised drug (2)
ionised drug
When the concentration of ionised and unionised drug becomes
equal, the second term of equations 1 and 2 reduces to zero
(since log 1 = zero), and thus pH = pKa. The pKa is a
characteristic of the drug.

49
 Limitations of pH-Partition Hypothesis
The pH-partition hypothesis over-simplified the otherwise
complicated process of drug absorption and therefore has its own
limitations. Some of the deviations from the theory are:
1. Presence of virtual membrane pH
2. Absorption of ionised drug
3. Influence of GI surface area and residence time of drug
4. Presence of aqueous unstirred diffusion layer

50
1) Presence of Virtual Membrane pH
• The pH-partition hypothesis suggested that only the unionised
drug at a given GI lumen pH is absorbed. An S-shaped curve,
called as the pH-absorption curve denoting the dissociation of
drug, is obtained when pH is plotted versus rate of drug
absorption (Fig. 7).

Fig. 7. pH-absorption curve for acidic and basic drugs. Dotted

lines indicate curves predicted by pH-partition hypothesis and
bold lines indicate the practical curves.
51
• However, differences in the extent of absorption of
salicylic acid has been observed at a given GI pH
than that predicted by pH-partition hypothesis.
• The experimental pH-absorption curves are less
steep and shift to the left (lower pH values) for a
basic drug and to the right (higher pH values) for an
acidic drug.
• This led to the suggestion that a virtual pH, also
called as the microclimate pH, different from the
luminal pH exists at the membrane surface. This
virtual membrane pH actually determines the
extent of drug ionisation and thus, drug absorption.
52
 2. Absorption of Ionised Drugs:
•  An important assumption of the theory was that 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. However, the
pH-absorption curve shift suggested that ionised forms of some
drugs also get absorbed to a considerable extent.
• If such drugs have a large lipophilic group in their structure,
despite their ionisation, they will be absorbed passively—for
example, morphinan derivatives. Other mechanisms are also
involved in the absorption of ionised drugs such as active
transport, ion-pair transport and convective flow.
53
3. Influence of GI Surface Area and Residence Time of Drug:
•  According to the pH-partition theory, acidic drugs are best
absorbed from stomach (acidic pH) and basic drugs from
intestine (alkaline pH) in which conditions they are unionised to
a large extent.
• This could be true under conditions where the surface area of
stomach and intestine are same. It could also mean that once an
acidic drug reaches the intestine, the remaining fraction will be
poorly absorbed and that unless a basic drug reaches the
intestine and gets absorbed considerably, it may not be able to
attain its therapeutic level.
• But, irrespective of the GI pH and the degree of ionisation, both
acidic and basic drugs are more rapidly absorbed from the
intestine, primarily because of its large surface area and
secondly, because of long residence time of the drug in the
intestine.
54
 4. Presence of Aqueous Unstirred Diffusion Layer:
•  The pH-shift in the absorption of acidic and basic drugs, as
discussed earlier, also accounts for the fact that the bulk of
the luminal fluid is not in direct contact with the membrane
but a barrier called as aqueous unstirred diffusion layer is
interposed between them.
• In the original pH-partition theory, the rate-limiting step in the
absorption of drugs was the partitioning in the lipid barrier.
• With the incorporation of unstirred aqueous diffusion layer, a
drug must diffuse first through this aqueous barrier and then
through the lipoidal barrier. Thus, drugs having large partition
coefficient can rapidly penetrate the lipid membrane but
diffusion through unstirred water layer is the rate-limiting step
in their absorption. This applies in particular to high molecular
weight fatty acids and bile acids.
55
 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, 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.

56
DOSAGE FORM (PHARMACO-TECHNICAL)
FACTORS
1. Disintegration Time:
• Disintegration time (DT) is of particular importance in case of
solid dosage forms like tablets and capsules.
• If a solid dosage form does not conform to the DT, it signifies
bioavailability problems because the subsequent process of
dissolution will be much slower and absorption may be
insufficient. Coated tablets, especially sugar coated ones have
long DT.
• Rapid disintegration is thus important in the therapeutic
success of a solid dosage form.

57
• 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.
• 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.

58
2) Manufacturing/Processing Variables
• Drug dissolution is the single most important factor in the
absorption of drugs such as tablets and capsules.
• Several manufacturing processes influence drug dissolution
from solid dosage forms. Processes of such importance in the
manufacture of tablets are:
1. Method of granulation, and
2. Compression force.
• The processing factor of importance in the manufacture of
capsules that can influence its dissolution is the intensity of
packing of capsule contents.

59
• 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 limitations of this
method include—
(i) Formation of crystal bridge by the presence of liquid,
(ii) The liquid may act as a medium for affecting chemical
reactions such as hydrolysis, and
(iii) The drying step may harm the thermolabile drugs.

60
• Compression Force: The compression force employed in
tabletting process influence density, porosity, hardness,
disintegration time and dissolution of tablets. The curve
obtained by plotting compression force versus rate of
dissolution can take one of the 4 possible shapes shown in Fig.

Fig :  Influence of compression force on dissolution rate of tablets

61
• 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, and in many cases,
promotes tighter bonding between the particles, all of which
result in slowing of the dissolution rate of tablets (curve A).
• On the other hand, higher compression forces cause
deformation, crushing or fracture of drug particles into smaller
ones or convert a spherical granule into a disc shaped particle
with a large increase in the effective surface area. This results in
an increase in the dissolution rate of the tablet (curve B).
• A combination of both the curves A and B is also possible as
shown in curves C and D. In short, the influence of compression
force on the dissolution rate is difficult to predict and a thorough
study on each formulation should be made to ensure better
dissolution and bioavailability.
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Intensity of Packing of Capsule Contents: Like the
compression force for tablets, packing density in case of
capsule dosage form can either inhibit or promote
dissolution.
• Diffusion of GI fluids into the tightly filled capsules creates
a high pressure within the capsule resulting in rapid
bursting and dissolution of contents.
• Opposite is also possible. It has been shown that capsules
with finer particles and intense packing have poor drug
release and dissolution rate due to a decrease in pore size
of the compact and poor penetrability by the GI fluids.

63
 3) Pharmaceutical Ingredients/Excipients (Formulation factors)

• 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.
• Despite their inertness and utility in the dosage form,
excipients can influence absorption of drugs. The more the
number of excipients in a dosage form, the more complex it is
and greater the potential for absorption and bioavailability
problems.
• 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.
64
4) Nature and Type of Dosage Form
• Apart from the proper selection of drug, clinical success
often depends to a great extent on the proper selection of
dosage form of that drug.
• For a given drug, a 2 to 5 fold or perhaps more difference
could be observed in 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.
• The relative rate at which a drug from a dosage form is
presented to the body depends upon the complexity of
dosage form.
65
• The more complex a dosage form, greater the number of rate-
limiting steps and greater the potential for bioavailability
problems.
• As a general rule, the bioavailability of a drug from various
dosage forms decreases in the following order:
• Solutions > Emulsions > Suspensions > Capsules > Tablets >
Coated Tablets > Enteric Coated Tablets > Sustained Release
Products.
• Thus, absorption of a drug from solution is fastest with least
potential for bioavailability problems whereas absorption
from a sustained release product is slowest with greatest
bioavailability risk.

66
• Fig. 2.26. Course of events that occur following oral administration of
various dosage forms 67
5) 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.
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• In case of solid dosage forms, especially tablets,
disintegration and dissolution rates are greatly affected due
to aging and storage conditions.
• An increase in these parameters of tablets has been
attributed to excipients that harden on storage (e.g. PVP,
acacia, etc.) while the decrease is mainly due to
softening/crumbling of the binder during storage (e.g. CMC).
• Changes that occur during the shelf-life of a dosage form are
affected mainly by large variations in temperature and
humidity.
• In one of the studies conducted on prednisone tablets
containing lactose as the filler, high temperature and high
humidity resulted in harder tablets that disintegrated and
dissolved slowly.

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B) PATIENT RELATED FACTORS AFFECTING
DRUG ABSORPTION
1. Age
• In infants, the gastric pH is high and intestinal
surface and blood flow to the GIT is low resulting in
altered absorption pattern in 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 small intestine.

70
 2. Gastric Emptying

• Apart from dissolution of a drug and its permeation through the

biomembrane, the passage from stomach to the small intestine,
called as gastric emptying, can also be a rate-limiting step in
drug absorption because the major site of drug absorption is
intestine. Thus, generally speaking, rapid gastric emptying
increases bioavailability of a drug.
• For better dissolution and absorption, the gastric emptying can
be promoted by taking the drug on empty stomach. 

71
Rapid gastric emptying is advisable where:
1. A rapid onset of action is desired e.g.
sedatives.
2. Dissolution of drug occurs in the intestine e.g.
enteric-coated dosage forms.
3. The drugs are not stable in the gastric fluids
e.g. penicillin G and erythromycin.
4. The drug is best absorbed from the distal part
of the small intestine e.g. vitamin B12

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3. Intestinal Transit
• Since small intestine is the major site for absorption of most
drugs, long intestinal transit time is desirable for complete drug
absorption.
• The residence time depends upon the intestinal motility or
contractions.
• The mixing movement of the intestine that occurs due to
peristaltic contractions promote drug absorption, firstly,
by increasing the drug-intestinal membrane contact, and
secondly, by enhancing drug dissolution especially of poorly
soluble drugs, through induced agitation.
• However, as the contents move down the intestine into the
colon, its viscosity gradually increases due to absorption of
water and electrolytes which limits the design of sustained
release products of drugs having short biological half-lives.
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Transit Time for Contents from Different
Regions of Intestine

74
4. Gastrointestinal pH

• A tremendous 107 fold difference in the hydrogen ion

concentration is observed between the gastric and colon
fluids. The GI pH generally increases gradually as one move
down the stomach to the colon and rectum.
• The disintegration of some dosage forms is pH sensitive. With
enteric-coated formulations, the coat dissolves only in the
intestine followed by disintegration of the tablet.  
•  A pH that favours formation of salt of the drug enhances the
dissolution of that drug. Since drug dissolution is one of the
important rate-determining steps in drug absorption, GI pH is
of great significance in the oral bioavailability of drugs.
• GI pH also influences the chemical stability of drugs.
The acidic stomach pH is known to affect degradation of
penicillin G and erythromycin.
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5. Disease States

• Several disease states can influence the rate

and extent of drug absorption. The 3 major
classes of disease states that can influence the
bioavailability of a drug are:
a) Gastrointestinal diseases,
b) Cardiovascular diseases, and
c) Hepatic diseases.

76
 a) Gastrointestinal diseases

i. Altered GI motility
ii. Gastrointestinal diseases and infections
Abnormalities associated with celiac disease include increased
gastric emptying rate and GI permeability, altered intestinal
drug metabolism, steatorrhea (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.
iii. Gastrointestinal surgery
Gastrectomy can result in drug dumping in the intestine,
osmotic diarrhoea and reduced intestinal transit time. Intestinal
surgery also influences drug absorption for predictable reasons.

77
b. 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.

c. 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.
78
6. Blood Flow to the GIT
• The GIT is extensively supplied by blood capillary network and
the lymphatic system. The absorbed drug can thus be taken up
by the blood or the lymph, 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.
• Blood flow is also important for actively absorbed drugs since
oxygen and energy is required for transportation.

79
7. Gastrointestinal Contents

Food-drug interactions: Presence of food may either delay,

reduce, increase or may not affect drug absorption.
• Food-drug interactions may be due to the influence of
food on physiologic functions (alterations in the GI
emptying rate, GI fluid secretions, pH, blood flow and
absorptive processes) and/or a consequence of
physicochemical interaction with the drug (alteration in
drug dissolution profile, complexation and adsorption).
• As a general rule, 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.
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Fluid volume: 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.

81
Interaction of drug with normal GI constituents: The GIT
contains a number of normal constituents such as
mucin, bile salts and enzymes which influence drug
absorption.
• Mucin, a protective mucopolysaccharide that lines the
GI mucosa, interacts with streptomycin and certain
quaternary ammonium compounds and retards their
absorption. 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.

82
8. Presystemic Metabolism/First-Pass Effects
• 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).
2. Destabilisation or destruction of drug.
3. First-pass/presystemic metabolism

Fig 9:Processes that reduce the availability of orally

administered drugs
83
 DDA regulation for BA/BE
• 2.9.1 An applicant is required to submit reports on
bioavailability and bioequivalence study. The methods
and approaches to conduct such studies may be
followed as per WHO guidelines or equivalent (US FDA
guidance, EU guidance).
• 2.9.2 Bioavailability and BE study is not required for
drug products intended to use as IVinjection.
• 2.9.3 An applicant can request BCS biowaiver for orally
administered solid dosage forms(detailed guidelines
on BCS –based biowaiver and BE study may be refered
to WHO Technical Series 937 Annex 7)
84
2.9.4 Conditions requiring BE study report are:
a) Locally applied, systemically acting products
b) Non-oral immediate release forms with systemic action
c) Modified release products; e.g.; sustained release tablet
d) Transdermal products
e) Narrow therapeutic drugs, drugs with low bioavailability,
non linear kinetics, poor dissolution profile, variable
bioavailability/bioequivalence, modified release dosage form
having blood steady state concentration such as sodium
valproate, valproic acid, carbamazepine, antibiotics etc,
f) Oral products intended to be absorbed in the oral cavity
g) In-vivo BA/BE profile or in-vitro dissolution profile should be
compared with Innovator/leading/comparator brand of the
product.
85
• https://www.pharmacy180.com/article/factors-influencing-dr
ug-absorption-and-bioavailability-2451/
• Bramankar D.M. and Jaiswal B. Sunil, Biopharmaceutics and
Pharmacokinetics, A Treatise, Absorption of Drugs, 26-77.
• https://pharmainfonepal.com/wpcontent/uploads/
2020/12/Medicine-registration-guidance-2073.pdf

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