Objectives of Bioavailability studies :

During primary stages of development of

suitable dosage forms of new drug entity .

Determination of influence of excipients ,

patient related factors & possible interaction
with other drugs on the efficiency of
absorption .

Development of new formulations of existing

drugs .
Significance of Bioavailability
Drugs having low therapeutic index, e.g. cardiac
glycosides, quinidine, phenytoin etc
Narrow margin of safety ( e.g. antiarrythmics,
antidiabetics, adrenal steroids, theophylline )

Drugs whose peak levels are required for the

effect e.g. phenytoin, phenobarbitone,
primidone, sodium valporate, anti-
hypertensives,antidiabetics and antibiotics.

Drugsthat are absorbed by an active

transport,e.g. amino acid analogues. Purine
analogues etc.
Drugs which are disintegrated in the
alimentary canal and liver,
e.g.chiorpromazine etc. or those which
under go firstthat
Formulations passgive
metabolism.
sustained release
of drug.
Any new formulation has to be tested for
its bioavailability profile.
Drugs with steep dose response
relationship i.e. drugs obeying zero order
kinetics / mixed order elimination kinetics
( e.g. warfarin , phenytoin, digoxin,
 Bioavailable fraction (F)
Itrefers to the fraction of administered
dose that enters the systemic circulation.

Bioavailable dose
F=
------------------------------
Administered dose
 Absolute Bioavailability
Def : (F)
“When the systemic availability of a drug
administered
orally is determined in comparison to its
intravenous administration ,is called as
Absolute Bioavailability”

Dose (iv) x AUC (oral)

% Absorption = ------------------------------- X
100
Dose (oral) x AUC (iv)
Relative Bioavailability ( Fr )
Def :
“ When the systemic availability of the drug after
oral administration is compared with that of oral
standard of same drug ( such as aqueous or non
aqueous solution or a suspension ) is referred as
Relative Bioavailability”
e.g. comparison between cap. Amox and susp.
Amox
Measurement of Bioavailability
1 ) Plasma level-time studies:
Two dosage forms that exhibit super
imposable plasma level-time profiles
should result in identical
therapeutic response.

[AUC]oral x [D] iv
F = ------------------------------
[AUC]iv x [ D ]oral
Based on the plasma concentration-time curve, the following
measurements are important for bioavailability studies.

MINIMUM EFFECTIVE PLASMA CONCENTRATION-The minimum

plasma concentration of the drug required to achieve a given
pharmacological or therapeutic response. This value varies
from drug to drug and from individual to individual as well as
with the type and severity of the disease.

MAXIMUM SAFE CONCENTRATION-The plasma concentration

of the drug beyond which adverse effects are likely to
happen.
THERAPEUTIC RANGE-The range of plasma drug concentration in which
the desired response is achieved yet avoiding adverse effect. The aim
is clinical practice is to maintain plasma drug concentration within the
therapeutic range.

ONSET OF ACTION-On set of action is the time required to achieve the

minimum effective plasma concentration following administration of
drug formulation.

DURATION OF ACTION-Duration of action of the therapeutic effect of the

drug is defined as the time period during which the plasma
concentration of the drug exceeds the minimum effective level.

INTENSITY OF ACTION-In general, the difference between the peak

plasma concentration and the minimum effective plasma concentration
provides a relative measure of the intensity of the therapeutic response
of the drug.
 Important
parameters
- peak

plasma
Cmax concentrati
on

t
- time taken to reach peak
concentration
max
- it indicates rate of
absorption

 AUC - Area Under the plasma

level time Curve
On the other hand, if the two curves represent blood concentrations
following equal doses of two different formulations of the same
cardiac glycoside
An example can explain how difference in bioavailability of a given drug
from different formulations marketed by various firm, can result in a
patient being either over, under or correctly medicated.

Product D is more desirable form of a dosage form specially for

drugs with narrow safety margin and relatively shorter half life.
In multiple dose study:
 b) URINARY
This EXCRETION-
method can be based if urinary excretion of unchanged
drug is the main mechanism of elimination of the drug

•Bioavailability can be calculated as follows,

•Bioavailability can be calculated as
F = (Du∞)
f follows,
F = (Du∞)
f
F = Fraction of the dose absorbed
Du∞ = cumulative amount of drug excreted in the urine f =
fraction of unchanged drug excreted in the urine

5x the elimination ½ life = time at which the drug is “completely” (97%)

eliminated from the body
1x ½ life - 50% of the original drug removed 2x ½ life - 75%
3x ½ life - 87.5% 4x ½ life - 93.75% 5x ½ life - 96.875%
a. (dXu / dt)max Maximum urinary excretion rate
:
b : Time for maximum urinary
(tu )
. max
excretion rate
c. Cumulative amount of
Xu : drug excreted in the
 Biological fluids used for
determination of Bioavailability
1. Plasm
a
2. Urine
3. Saliva
4. CSF
5. Bile
B. Pharmacodynamic methods
1)Acute Pharmacological Response :

- Used when pharmacokinetic

methods are difficult , inaccurate &
non reproducible.

- E.g. Change in ECG/EEG readings.

Pupil diameter Disadvantages :
 More variable
 Active metabolite interferes with the

result.
2 ) Therapeutic Response :
- measurement of clinical response to a drug
formulation given to patients suffering from
disease for which it is intended to be used.

Disadvantages :
 Improper quantification of observed

response.
Drug dissolution rate &
Bioavailability :
Correlation between Dissolution testing and
bioavailability

In vivo determination test :

Tool in the development of new dosage form.

In vitro dissolution test :

To ensure batch to batch consistency
Best available tool which can
quantitatively assure about bioavailability.
Drug Dissolution Apparatus
In vitro drug dissolution rate and
bioavailability
Factors to be
considered:
1. Factors relating to dissolution
apparatus
2. Factors relating to dissolution
fluid
3. Process parameters
Types of dissolution apparatus
 Closed
 compartment
Open
 compartment
Official compendial
methods:
1.Rotating basket
2.Rotating paddle
3.Reciprocating cylinder
4.Flow-through cell
5.Paddle over disc
6.Cylinder apparatus
7.Reciprocating disc
Dissolution acceptance criteria
Q is defined as percentage of drug content
dissolved in a given time period.
Objectives of dissolution profile
comparison
Development of bioequivalent drug products.
Demonstrating equivalence after change in
formulation of drug product.
Biowaiver of drug product of lower dose
strength in proportion to higher dose
strength product containing same active
ingredient and excipients.
Method for comparison of
dissolution profile
Based on the determination of difference
factor f1 and similarity factor f2
Factors affecting Bioavailability :
A ) Pharmaceutic factors :
1) Physicochemical properties of drug :
1 Drug solubility & dissolution rate. Particle size & effective
.
2 surface area. Polymorphism & Amorphism.
.
3 Amorphous > metastable > stable
.  Pseudopolymorphism (Hydrates / Solvates ) Anhydrates >
4 hydrates e.g. Theophylline, Ampicillin Organic solvates > non
.  solvates e.g. fludrocortisone
 Salt form of the drug.
5 Weakly acidic drugs – strong basic salt e.g.barbiturates ,
.  sulfonamides. Weakly basic drugs – strong acid salt
 Lipophilicity of the drug . pKa of the drug & pH . Drug
6 stability.
.
7
.
8
.
2) Dosage form characteristics &
Pharmaceutic Ingredients :
1. Disintegration time (tab/cap)
2. Dissolution time.
3. Manufacturing variables.
4. Pharmaceutic ingredients ( excipients /
adjuvants )
5.  Nature & type
Solutions> of dosage
Emulsions> form.
Suspensions> Cap> Tab>
Enteric Coated Tab > Sustained Release

6. Product age & storage

conditions.
B ) Patient related factors :
In Vitro-in vivo correlation
A predictive mathematical
describes
model thethat
relationship between
an in- vitro property of a dosage
form and an in- vivo response.
 Purpose of
IVIVC
The optimization of formulations may require changes in the
composition, manufacturing process, equipment, and
batch sizes.

In order to prove the validity of a new formulation, which

is bioequivalent with a target formulation, a considerable
amount of efforts is required to study bioequivalence
(BE)/ bioavailability (BA).

The main purpose of an IVIVC model - to utilize in vitro

dissolution profiles as a surrogate for in vivo
bioequivalence and to support biowaivers.
40
Basic approaches
By establishing a relationship usually linear,
between the in vitro dissolution and in vivo
bioavailability parameters.
By using data from previous bioavailability
studies to modify the dissolution
methodology.
In vitro-in vivo correlations
Correlations based on the plasma level
data
Correlationsbased on the urinary
excretion data
Correlations
based on the
pharmacological response
IVIVC levels
 Level A:
 Point to point correlation is developed between in vitro
dissolution rate and the in vivo rate of absorption
 Level B:
 Utilises statistical moment analysis and the mean in vitro
dissolution time is compared to either the mean residence
time or the mean in vivo dissolution time
 Level C:
 single point correlation that relates one dissolution time point
to one pharmacokinetic parameter

Multiple level C
S.No In Vitro In Vivo
% Dissolution profile Plasma concentration Time profile
1 % drug dissolved at time Plasma con at time t
2 t Max drug dissolved at t Cmax

3 Time taken for max extent of drug release

Tmax

4 Total amount of drug dissolution AUCt0 , AUC 0 ∞

5 Time for a certain % of drug to dissolve Time for a certain % drug reaches the
circulation

Kinetic Parameter Pharmacokinetic parameter

6 Dissolution rate constant Absorption rate constant

7 Dissolution half life Absorption half life

8 % of drug dissolved at time t % drug absorbed at time

t

Statistical moment analysis

9
MDT (mean Dissolution Time) MRT (mean residence
time)
 BCS
Classifications
According to the BCS, drug
substances are classified as follows:

Class I - High Permeability, High

Solubility
Class II - High Permeability, Low
Solubility
Class III - Low Permeability, High
Solubility
Class IV - Low Permeability, Low
Solubility
BIOEQUIVALENC
 Definition E
:
“ It is a relative term which denotes that the
drug substance in two or more identical dosage
forms , reaches the circulation at the same
relative rate & to same relative extent i.e.
their plasma concentration- time profiles will be
identical without significant statistical
differences.”
Pharmaceutical equivalence :
“Drug products are considered to be pharmaceutical
equivalents if they contain the same active ingredients
and are identical in strength or concentration, dosage
form, and route of administration.”

Therapeutic equivalence :
“ It indicates that two or more drug products that
contain the same therapeutically active ingredient,
elicit identical pharmacological
effects & can control the disease to the same extent”

Clinical equivalence:
“ when the same drug from two or more dosage forms
gives identical in vivo effects as measured by a
pharmacological response or by control of a symptom or
a disease.”