BCS fundamentals. Objectives of and factors affecting BCS Classes of BCS and examples of drugs Biowaver Criteria Limitations of BCS Extensions to BCS

1. BIOPHARMACEUTICAL
CLASSIFICATION SYSTEM
(BCS)
Presented By:-
Vaishnavi A. Bhosale
M.S. Pharmaceutics ( 1st Semester)
NIPER Hyderabad
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2. CONTENTS:
• Introduction
• Objectives of BCS
• Factors affecting BCS Classification
• Classes of BCS
• Applications
• Bio wavers
• Limitations of BCS
• Extensions to BCS
• Conclusion
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3. INTRODUCTION
• BCS is a scientific framework for classifying drugs based on
their AQUEOUS SOLUBILITY, INTESTINAL
PERMEABILITY and DISSOLUTION RATE
• The fundamental basis established by Dr. Gordon Amidon
• First introduced into the regulatory decision making process
in the guidance document on Immediate Release Solid Oral
Dosage forms for Scale up and Post Approval changes.
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What is the need for
classification based on
biopharmaceutics of drug ?
It is important
in determining
Bioavailability

4. • The principle of the BCS is that if two drug products yield the same
concentration profile along the GIT , they will yield the same plasma
profile after oral administration. This can be summarized by the
following:
where, J is the Flux across the gut wall
Pw is the the permeability of the gut wall to the drug
Cw is the concentration profile at the gut wall
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J = Pw Cw

5. OBJECTIVES OF BCS:-
• To identify the challenges of formulation Design.
• To guide decisions w.r.t. IVIVC.
• To improve the efficiency of drug development and identifying
expendable clinical bioequivalence tests.
• To explain when a waiver for in vivo bioavailability and
bioequivalence may be requested.
• To assist in QC in SUPAC.
• To recommend a class of immediate-release (IR) solid oral dosage
forms for which bioequivalence may be assessed based on in vitro
dissolution tests.
• To recommend methods for classification according to dosage form
dissolution along with the solubility-permeability characteristics of
the drug product.
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6. FACTORS AFFECTING BCS :-
• The Biopharmaceutical Classification System has been
developed to provide a scientific approach to follow for
prediction of in vivo pharmacokinetics of oral immediate
release (IR) drug product by classifying drug based on:-
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1. SOLUBILITY
3. DISSOLUTION
RATE
2. PERMEABILITY

7. 1. SOLUBILITY
• The maximum amount of solute dissolved in a given solvent under
standard conditions of temperature, pressure and pH.
• Solubility is the ability of the drug to be solution after dissolution
• A drug substance is classified as ‘HIGHLY SOLUBLE’ if the highest
single therapeutic dose is completely soluble in 250 ml or less of
aqueous media over the pH range of 1.0 – 7.5 at 37 ± 1°C
• Methods for determination of solubility
1. Miniaturized shake-flask method
2. Semi-automated Potentiometric acid/base titrations
3. A computational screening model
4. Miniature device
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8. 2. PERMEABILITY
• Permeability of the drug to pass the biological membrane.
• Permeability is indirectly based on the extent of absorption of a drug substance .
• Drug substance is considered to be ‘HIGHLY PERMEABLE’, when the extent
of absorption in human determined to be 90% or more of administered drug or
compare to in vivo reference dose.
• Determination of permeability
A. HUMAN PHARMACOKINETIC STUDIES
• Mass balance studies
• Absolute bioavailability studies
B. INTESTINAL PERFUSION METHODS
 In vivo or in situ intestinal perfusion in a suitable animal model.
 In vitro permeability methods using excised intestinal tissues
 In vitro permeation studies across a monolayer of cultured epithelial cells . e.g.
Caco-2 cells or TC-7 cells
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9. 3. DISSOLUTION
• It is process in which solid substance solubilises in given solvent i.e.
mass transfer from solid surface to liquid phase.
• Using USP apparatus I at 100 rpm or USP apparatus II at 50 rpm .
• Dissolution Media [900 ml],
1. 0.1 N HCl or simulated gastric fluid (pH 1.2)
without enzyme.
2. pH 4.5 buffer & pH 6.8 buffer.
3. Simulated intestinal fluid without enzyme
 Compare dissolution profiles of test and reference products using a
similarity factor (f2).
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10. 10
Sr.
No.
Dimensionless
Parameter
Ratio of Ideally
should be
Indicative
of
1. Absorption
Number
(An)
Mean Residence
time in G.I.T./
Mean
absorption time
An > 1 G.I.
Permeability
to drug
substance
2. Dissolution
Number
(Dn)
Mean Residence
Time / Mean
Dissolution
Time
Dn > 1 Drug Release
from the
formulation
3. Dose Number
(Do)
(Highest dose/
Volume) /
Solubility
Do < 1 Solubility of
the drug
substance
This classification is associated with drug dissolution and
absorption model, which identifies the key parameters controlling
drug absorption as a set of dimensionless numbers.

11. CLASSES OF BCS
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CLASS I
High Solubility
High Permeability
35 % ( in market)
25 % ( NCE)
CLASS III
High Solubility
Low Permeability
25 % (in market)
5 % ( NCE)
CLASS II
Low Solubility
High Permeability
30% (in market)
70% (NCE)
CLASS IV
Low Solubility
Low Permeability
10% (in market)
20% ( NCE)

12. CLASS I DRUGS
• The drugs of this class exhibit high absorption number
and high dissolution number.
• For those class 1 drugs formulated as IR products,
dissolution rate generally exceeds gastric emptying.
• Behave like an oral solution in-vivo.
• The rate-limiting step is gastric emptying.
• These compounds are well absorbed.
• Absorption rate is usually higher than the excretion rate.
• E.g. Amiloride, Metaprolol, paracetamol etc
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13. CLASS II DRUGS
• The drugs of this class have a high absorption number but a
low dissolution number.
• In vivo drug dissolution is then a rate-limiting step for
absorption except at a very high dose number.
• The absorption for Class II drugs is usually slower than for
Class I and occurs over a longer period of time.
• The bioavailability of these products is limited by their
solvation rates.
• Hence, a correlation between the in vivo bioavailability and
the in vitro solvation can be found.
• E.g. Ritonavir, Tamoxifen, Glibenclamide, etc
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14. SUBCLASSES OF CLASS II
• Basis- significant impact of pKa on the solubility and
dissolution of drugs.
• BCS Class II drug product dissolution in vitro as well as in
vivo is highly dependent on acidic or basic nature of drug.
• Hence, the class II drugs are sub classified as:
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CLASS II a
Weakly acidic
drugs
pKa ≤ 5
CLASS II b
Weakly basic
drugs
pKa ≥ 6
CLASS II c
Neutral Drugs

15. SUB CLASSES OF CLASS II
• Class II a Drugs
• Drugs are insoluble at gastric pH & soluble at intestinal pH
• At intestinal pH (~6.5), the dissolution would increase upto 100 times
• Hence, dissolution rate would be faster than gastric emptying rate
• Thus, these drugs reflect gastric emptying and luminal pH differences.
• Examples- ibuprofen and ketoprofen
CLASS II b DRUGS
• Exhibit high solubility and dissolution rates at acidic pH in stomach
• May precipitate in intestinal pH
• Examples- carvedilol and ketoconazole
CLASS II c DRUGS
• Solubility is not affected by in vivo pH change
• Example- fenofibrate and danazole
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16. CLASS III DRUGS
• Drug permeability is the rate-limiting step for drug absorption, but
the drug is solvated very quickly.
• These drugs exhibit a high variation in the rate and extent of drug
absorption.
• Since the dissolution is rapid, the variation is attributable to
alteration of physiology and membrane permeability rather than
dosage form factors.
• E.g. Lisinopril, Atenolol, Cimetidine, etc
• CLASS IV DRUGS
• The drugs of this class are problematic for effective oral
administration.
• These compounds have poor bioavailability.
• They are usually not well absorbed through the intestinal
mucosa, and a high variability is expected.
• E.g. Taxol, Griseofulvin, etc
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17. APPLICATIONS
• Application in early drug development and then in
the management of product change through its life
cycle
• Aids fundamental understanding of the
biopharmaceutical and physical properties of the drug
• Aids discriminatory dissolution method development
• Can help guide the development of in-vitro/in-vivo
correlations
• Can be used to obtain a biowaiver
• Development of poorly soluble drugs
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18. Applications of BCS in Oral Drug Delivery
system
CLASS I DRUGS.
• Achieve a target release profile associated with a particular pharmacokinetic and/or
pharmacodynamic profile.
• Formulation approaches include both control of release rate and certain
physicochemical properties of drugs like pH-solubility profile of drug
• Pregabalin is a BCS Class 1 compound (highly permeable and highly soluble).
Pregabalin is an amino acid and its lowest aqueous solubility occurs at its
isoelectric point (at pH 7.4). It is considered high solubility as the amount of
water needed (<10 mL) to dissolve the highest dose strength (300 mg) at pH 7.4
is less than the 250 mL criteria. Pregabalin meets the BCS criteria for a highly
permeable compound as greater than 90% of the dose is excreted unchanged
in the urine
CLASS II DRUGS
• Micronisation
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19. • Addition of surfactants
• Solid dispersions
• Salt Formation
• Formulation as emulsions and microemulsions systems
• Use of complexing agents like cyclodextrins
• Solid dispersions of ezetimibe were prepared by melt extrusion
method using Kollidon VA64 as carrier. Solid dispersions have
exhibited very high solubility in pH 4.5 acetate buffer than the other
buffer media. The ezetimibe drug content in all the dispersions were
found to be in the range of 99.6 to 99.76 %.
CLASS III DRUGS
• Require the technologies that address to fundamental limitations of
absolute or regional permeability.
• Peptides and proteins constitute the part of class III and the technologies
handling such materials are on rise now days
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20. The different formulation strategies for enhancement of oral bioavailability of
BCS class III drugs over here is categorized into (a) formulations imparting
lipophilic character to drug and (b) formulations that increase gastric retention
time of drug.
Double emulsion
Niosomes
CLASS IV DRUGS
• Major challenge for development of drug delivery system and the route of
choice for administering such drugs is parenteral (solubility enhancers.)
• Hydrochlorothiazide (HCTZ)7 which is a well categorized
• Thiazide diuretic, considered as the first-line of treatment for hypertension and
listed as an essential medicine in WHO list. Although, it’s an essential
medication but due to its low bioavailability (65%) low permeability9 and
extensive hepatic metabolism, it loses its therapeutic efficacy. Hence, to evade
all these limitations an up graded delivery mechanisms are required which can
be attained by designing the polymer based nanoparticle drug delivery system.
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21. 21

22. BIOWAVER
• A BIOWAIVER is an exemption from conducting human bioequivalence
studies when the active ingredient(s) meet certain solubility and
permeability criteria in vitro and when the dissolution profile of the dosage
form meets the requirements for an "immediate" release dosage form.
• PREREQUISITES FOR BIO WAVER ( ICH M9 guideline)
• Rapid and similar dissolution.
• High solubility & High permeability.
• Wide therapeutic window.
• Excipients used in dosage form used previously in approved IR
solid dosage forms.
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23. REQUEST FOR BIOWAVER
Data Supporting Rapid and
Similar Dissolution
Data supporting High
Permeability
Data supporting High
Solubility
Dissolution data obtained with
12 individual units of the test
and reference products at each
specified testing interval for
each individual dosage unit. A
graphic representation of the
mean dissolution profiles for
the test and reference products
in the three media.
· Data supporting similarity
in dissolution profiles between
the test and reference products
in each of the three media,
using the f2 metric.
For direct permeability
methods, information
supporting method suitability
with a description of the study
method, criteria for selection of
human subjects, animals, or
epithelial cell line, drug
concentrations, description of
the analytical method, method
to calculate extent of
absorption or permeability, and
information on efflux potential
(if appropriate).
Description of test methods
(analytical method, buffer
composition).
· Information on chemical
structure, molecular weight,
nature of drug substance,
dissociation constants.
· Test results summarized
in a table with solution pH,
drug solubility, volume to
dissolve highest dose strength.
· Graphical representation
of mean pH-solubility profile
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24. 24
ACCEPTANCE REJECTION
• Immediate release, solid orally
administered dosage forms or suspensions
designed to deliver drug to the systemic
circulation
• Where the drug substances exhibit high
solubility and, either high permeability
(BCS Class I) or low permeability (BCS
Class III)
• When the drug substances in test and
reference products are identical even if
they contain different salts provided that
both belong to BCS Class I (high
solubility and high permeability).
• Drug products having a narrow
therapeutic index
• When the test product contains a
different ester, ether, isomer, mixture of
isomers, complex or derivative of a drug
substance from that of the reference
product, since these differences may lead
to different bio availabilities .
•Drug products with buccal or sublingual
absorption
ELIGIBILITY CRITERIA FOR BIOWAVER

25. EXCIPIENTS INCLUDED
• Ideally, the composition of the test product should mimic
that of the reference product.
• However, where excipient differences exist, they should
be assessed for their potential to affect in vivo absorption.
• This should include consideration of the drug substance
properties as well as excipient effects.
• To be eligible for a BCS-based biowaiver, the sponsor
should justify why the proposed excipient differences will
not affect the absorption profile of the drug substance
under consideration, i.e., rate and extent of absorption,
using a mechanistic and risk-based approach.
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26. LIMITATIONS OF BCS
• Effects of Food, Absorptive transporters, Efflux transporters &
Routes of elimination(renal/biliary) are important determinants of
BA for immediate release oral dosage forms, which are not
considered in BCS.
• Limitations of BCS as a Predictor of Drug Disposition
• Permeability (90% absorption) is difficult to determine, and
difficult to convince the regulatory agency .
• There is little predictability for BCS classification drugs beyond
Class 1 primarily due to the difficulty of
• determining and proving 90% absorption, many drugs are
misclassified (e.g. HIV protease inhibitors as Class 4 compounds).
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27. EXTENSIONS TO BCS
1. Six class BCS:
• The drugs are classified into six classes.
• The solubility was classified as “low” or “high”
permeability was allotted as “low” “intermediate” or
“high”.
2. Quantitative BCS (QBCS):
• Quantitative BCS (QBCS) was developed using the dose:
solubility ratio as core parameter for classification.
• States that solubility is a static equilibrium parameter and
cannot describe the dynamic character of the dissolution
process for the entire dose administered.
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28. 3. Pulmonary BCS
• The BCS is limited to the gastrointestinal tract.
• The pulmonary BCS (PBCS) consider the specific biology of
the lung as well as particle deposition, aerosol physics, and
the subsequent processes of drug absorption and solubility
4. BDDCS CLASSIFICATION
• BDDCS (Biopharmaceutical Drug Disposition and
Classification System) divides compounds into four classes
based on their permeability and solubility.
• This classification system is useful in predicting effects of
efflux and uptake transporters on oral absorption as well as
on post absorption systemic levels following oral and
intravenous dosing.
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29. BDDCS
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30. CONCLUSION
• BCS aims to provide a regulatory tool for replacing certain
BE studies by accurate in vitro dissolution tests.
• This increased awareness of a proper biopharmaceutical
characterization of new drugs may in the future result in drug
molecules with a sufficiently high permeability, solubility
and dissolution rate and that will automatically increase the
importance of the BCS as a regulatory tool over time
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31. REFERENCES
• Brahmankar, D. M and Jaiswal, Sunil. B (2009). Biopharmaceutics and Pharmacokinetics – A
Treatise. 2nd edition. Vallabh Prakashan, Page no. 27-29 and 332 - 335.
• Leon shargel, Susanna wu-pong, Andrew B.C.Yu , Applied Biopharmaceutics &
Pharmacokinetics, 5th edition 2005, published by the Mc Graw hills companies, page no.
431-436 & 482-484.
• Wagh M.P, Patel J.S., 2010, International Journal of Pharmacy and Pharmaceutical Sciences,
Vol 2, Page 12-19
• SV Deshmane, PP Chinchole, RM Gaurkhede, MA Channawar, AV Chandewar. The
Biopharmaceutics Classification System: A Review. Research J. Pharm. and Tech. 2(1): Jan.-
Mar. 2009; Page 8-11
• General Notes on Biopharmaceutics Classification System (BCS)- based Biowaiver
Applications by WHO
• ICH M9 Guideline.
• Ghadi R, Dand N. BCS class IV drugs: Highly notorious candidates for formulation
development. J Control Release. 2017 Feb 28;248:71-95
• Ashis kumar mehatha, vidyadhara Suryadevara*, sasidhar R lankapalli , abhijit M deshmukh,
laxmana p sambath , 2014, turk j pharm sci, formulation and optimization of ezetimibe
containing solid dispersions using kollidon VA64, 113-126
• Pregabalin zentiva assessment report (EMEA)
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