Bioavailability and bioequivalence study

Bioavailability and
Bioequivalence study
Dr. V. S. Kashikar
Asso. Prof., Head, Dept. of Pharmaceutics
PES Modern College of Pharmacy (For
Ladies), Moshi.
1

Biopharmaceutics Classification System
 BCS is a scientific framework for classifying drug
substances based on their aqueous solubility and
intestinal permeability.
 It is a drug development tool that allows estimation of
solubility, dissolution and intestinal permeability affect
that oral drug absorption.
 Key parameters are characterized in BCS classification
are :
1. Absorption number (An)
2. Dissociation number (Dn)
3. Dose number (Do)
2

 Absorption No. (An) :- It is the ratio of Residence time
(Tres) to Mean absorbance time (Tabs)
An ˃ 1 → indicate Complete absorption
 Dissolution No. (Dn) :- The time required for drug
dissolution which is the ratio of intestinal residence time
to the dissolution time.
Higher the Dn → Higher fraction dose absorbed.
 Dose No. (Do):- It is the ratio of dose concentration to
drug solubility.
Do ≤ 1→ higher solubility.
Do ˃ 1→ low solubility.
3

Class Boundaries
 HIGHLY SOLUBLE:- The highest dose strength should be soluble in <
250 ml water over a pH range of 1 to 7.5.
Acc. To BCS the highest dose strength volume in 250 ml, where the D/S
ratio <250 refer to highly soluble But it s not true for pediatric patient
 HIGHLY PERMEABLE:- When the extent of absorption in humans is
determined to be > 90% of an administered dose.
Based on mass balance or compared with an iv route.
 RAPIDLY DISSOLVING :- When > 85% of the labeled amount of drug
substance dissolves within 30 minutes using USP apparatus I or II in a
volume of < 900 ml buffer solutions
This study is important for biological and in vivo-in vitro
correalation.(IVIVC).
4

Biowaiver
 The term Biowaiver is applied to a regulatory drug approval process
when the drug dossier (application) is approved based on the evidence
of equivalence other than through in vivo equivalence testing.
 In 1995 the American Department of Health & Human Service US
Food & Drug Administration (HHS-FDA) instigated the
Biopharmaceutics Classification System (BCS), with the aim of
granting so-called biowaivers for SUPACs.
 BCS provides biowaivers for Class I, II, III drugs with some
specification.
 As the BCS is only applicable to APIs which are absorbed from the
small intestine.
6

 A Biowaiver means that in vivo bioavailability
and/or bioequivalence studies may be waived
(i.e. not considered necessary for product approval).
Bioavailability :- It means the rate and extent to which
the active drug substance is absorbed from a
pharmaceutical dosage form and becomes available at
the site of action.
Bioequivalence :-It refers to the drug substance in two or
more identical dosage forms, reaches in systemic
circulation at the same rate and to the same relative
extent.
7

Biowaiver for Bioequivalence study
 If two product, containing the same , have the same
concentration time profile at the intestinal membrane
surface then they will have the same rate and extent of
the absorption.
8
Generic Product Innovator Product / Std
recommended by USFDA
Ex. Paracetamol Tablet 650
mg
DOLO-650 mg
API - Paracetamol API - Paracetamol
Tablet (oral) Tablet (oral)
Bioavailability 80 % Bioavailability 80 %

Need & Objective for BE studies
 If a new product is intended to be a substitute
for an approved medicinal product as a
pharmaceutical equivalent or alternative, the
equivalence with this product should be shown
or justified.
 In order to ensure clinical performance of such
drug products, bioequivalence studies should be
performed.
9

10
Different Approaches
for establishing BE
Standard: in
vivo BE study
Clinical Study In vitro study

In vitro BE studies
 In vitro studies, i.e. dissolution studies can be used
instead of in vivo bioequivalence under certain
circumstances, called as biowaiver .
 For waiver of in vivo, bioequivalence test and reference
product should exhibit similar dissolution profile under
the dissolution test condition defined for rapidly
dissolving product.
 Two dissolution profile may be considered similar.
When both test and the reference products dissolve 85 %
or more of the labeled amount in less than 15 minutes in
all three dissolution media (at acidic i.e 01.N HCL, at
pH 4.5 buffer and at 6.8 buffer ). A profile comparison
is unnecessary.
11

Techniques For Improving Bioavailability
 One approach to improve the systemic availability of the
drug is to deliver it by alternative routes of
administration such as parenteral, nasal, vaginal, rectal
or transdermal. However, improvement of the oral
bioavailability of the drug is the most realistic approach,
as it is the most preferred and convenient route of
administration.
 The techniques to improve oral bioavailability of the
drugs are described as follows:
12

Enhancement Of Drug Solubility Or
Dissolution Rate
1. Micronization
2. Nanonization
3. Supercritical Fluid Re-crystalization
4. Spray Freezing into Liquid (SFL)
5. Evaporative Precipitation into Aqueous Solution
(EPSA)
6. Use of Surfactants
7. Use of Salt Forms
8. Use of Precipitation Inhibitors
9. Alteration of pH of the Drug Microenvironment
10. Use of Amorphous, Anhydrates, Solvates and
Metastable polymorphs
13

11. Solvent Deposition
12. Precipitation
13. Selective Absorption on Insoluble Carriers
14. Solid Solutions
15. Eutetic Mixtures
16. Solid Dispersions
17. Molecular Encapsulation with Cyclodextrins
14

 Micronization :-
The process involves reducing the size of the solid
particles to 1 to 10 microns commonly by spray drying
or by use of air attrition methods. This process is also
called as mico-milling.
 Nanonisation :-
It is a process of the dry powder is converted to
nanocrystals of sizes 200-600 nm . Eg. Amphotericin B.
i. Pearl milling
ii. Homogenisation in water
iii. Homogenisation in non-aqueous media.
15

 Spray Freezing into Liquid (SFL) :-
This technique involves an aqueous, organic, aqueous-
organic cosolvent solution, aqueous organic emulsion
and suspension containing drug and pharmaceutical
excipients (CO2, helium, propane, ethane).
The frozen particles are then lyophilized to obtain dry
and free-flowing micronized powders.
SFL powder containing amorphous nanostructured
aggregates with high surface area and excellent
wettability.
16

 Solvent Deposition :-
In this method, the poorly aqueous soluble drug such as
nifedipine is dissolved in an organic solvent like alcohol
and deposited on an inert, hydrophilic, solid matrix such
as starch or MCC by evaporation of solvent.
17

 Solid Dispersions :
 These are generally prepared by Solvent or co-
precipitation method whereby both the guest solute and
the solid carrier solvent are dissolved in a common
volatile liquid solvent such as alcohol.
 The liquid solvent is removed by evaporation under
reduced pressure or by freeze drying which results in
amorphous precipitation of guest in a crystalline carrier.
 These method is suitable for thermolabile substances.
18

Enhancement Of Drug Permeability
Across Biomembrane
1. Lipid technology :
With an increase in the number of emerging
hydrophobic drugs, several lipid –based formulations
have been designed to improve their bioavailability.
2. Ion pairing :
The ion pairing approach involves co-administration of a
hydrophilic or polar with a suitable lipophilic
counterion, which consequently improves the
partitioning of the resultant ion-pair into the intestinal
membrane.
These technique use to improve the oral BA of ionisable
drugs. Eg ; Atenolol
19

3. Penetration Enhancers :
Compound which facilitate the transport of drugs across
the biomembrane are called penetration / permeation
enhancer or promoters.
This method is used mainly in cases of hydrophilic
drugs which are expected to have difficulty in
penetrating the lipid structure of the biomembrane.
Eg. of Penetration enhancers :-
Citric acid, SLS, EDTA, Salicylates and fatty acids such
as oleic acid linoleic acid arachidonic acid.
20

Enhancement of Drug Stability
1. Enteric coating :
Enteric-coated systems utilize polymeric coatings that
are insoluble in the gastric media and therefore, prevent
or retard drug release in the stomach. Such systems
release the drug in the alkaline media in intestine.
Eg. Erythromycin, penicilin v, benzimidazole,
omeprazol can be improved by enteric coating.
2. Complexation :
It can be used to increase the stability of drug in GI
media. Generally Beta- cyclodextrins are potential
carriers for increasing the oral bioavailability of
caffeiene, sodium salicylate, sodium benzoate.
21

3. Use of Metabolic inhibiters :
Co-administration of drug (with low BA) and its
metabolism, which can selectively inhibit any of the
contributing processes, would result in increased
fractional absorption and hence increases bioavailability.
22

Significance of Biowaiver
 It can save both time and money—if the immediate -
release, orally administered drug meets specific criteria,
the FDA will grant a waiver for expensive and time-
consuming bioequivalence studies.
 Valuable tool for formulation scientist for selection of
design of formulated drug substance.
 When integrated with other information provide a
tremendous tool for efficient drug development.
 Reduces cost and time of approving Scale- up and post
approval challenges.
 Applicable in both pre-clinical and clinical drug
development process.
23

Reference
1. Shekhawat P, Pokharkar V, Understanding peroral
absorption: regulatory aspects and contemporary approaches
to tackling solubility and permeability hurdles, Review
Article, Acta Pharmaceutica Sinica B, 2017, Volume 7, Page
no. 260-280.
2. Dahan A, Miller J, Amidon G , Prediction of Solubility and
Permeability Class Membership: Provisional BCS
Classification of the World’s Top Oral Drugs , Review
Article , American Association of Pharmaceutical Scientists,
2009 , Volume 11, Page no.740 - 746.
3. Chavda H, Patel C, Anand I, Biopharmaceutics
Classification System, Review Article , Sys Rev Pharm,
2010, Volume 1, Page no. 62-69.
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4. Valsami G, Macheras P, Computational-Regulatory Developments
in the Prediction of Oral Drug Absorption, Review Article , Wiley
VCH Verlag GmbH & Co. KGaA, Weinheim , 2011, Page no. 112-
121.
5. Murakami T, Absorption sites of orally administered drugs in the
small intestine, Review Article, Informa UK Limited, trading as
Taylor & Francis Group, 2017
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