1. Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31
JCPR 2011; 5 (1): 28-31
© 2010 Medipoeia
Role of Biopharmaceutical Classification System In
Received: 03-09-2011
Revised: 04-09-2011 Drug Development Program
Accepted: 6-09-2011
Vikash Dash* and Asha Kesari
ABSTRACT
Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product
development. The tenets of biopharmaceutics, solubility and permeability, are of pivotal
Vikash Dash* and Asha Kesari importance in new drug discovery and lead optimization due to the dependence of drug absorption
Department of Pharmaceutics and pharmacokinetics. Biopharmaceutical classification system (BCS) is based on solubility tests;
Kanak Manjari Institute of for various drugs they correlate with their bioavailability in human body. It is widely used in
Pharmaceutical Sciences, Chhend,
Rourkela: 769015, Orissa,
design and development of innovation drugs, new dosage forms (permeability amplifiers), in
India clinical pharmacology (drug-drug, drug-food interaction) and also by regulation agencies of
several countries as the scientific approach, for testing of waiver on bioavailability. The present
review considers the concept of biopharmaceutical classification system and its role in drug
development program. It gives a brief idea on the future application of BCS in drug entity.
Keywords: Bioavailability, biopharmaceutical classification system, solubility, permeability, drug
development.
1. INTRODUCTION
The Biopharmaceutical classification system (BCS) is a useful tool for decision making in the
discovery and early development of new drug (Ku M. S., 2008).During the drug development process,
the importance is given to its bioavailability and bioequivalence which determines the internal drug
absorption provided by U. S. Food & Drug Administration(Waterbeemd H. V. and Testa B., 2009).
BCS is based on scientific framework describing three rate limiting steps in oral absorption. The three
necessary steps for a drug to be absorbed are (1) release of drug from dosage forms; (2) maintenance of
dissolved state through Gastro-intestinal (G.I) tract; (3) permeation through G.I. membrane into hepatic
circulation. The BCS became a benchmark in the regulation of bioequivalence of oral drug products
(Meyer M.C et al, 1992) and it was first devised in 1995, (Amidon et al, 1995) . Since its inception in
1995, the BCS has become an increasingly important tool for regulation of drug products worldwide
(FDA Guidelines, 1997). Until now, application of BCS has been partially hindered by the lack of a
freely available and accurate database summarising solubility and permeability characteristics of drug
substances. Thus the knowledge of BCS help the formulation scientist to develop a dosage form based
on mechanistic rather than empirical approaches (FDA Guidelines, 2000). The aim of this review is to
present the status of BCS and discuss its future application in pharmaceutical drug development.
CONCEPT BEHIND BCS
Correspondence:
Mr. Vikash Dash The in-vivo performance of orally administered drugs depends upon their solubility and
Department of Pharmaceutics tissue permeability characteristics. The release rate or solubility of the drug substance will not be a
Kanak Manjari Institute of governing parameter if the absorption of the drug is permeation rate limited and in such cases the in-
Pharmaceutical Sciences, Chhend,
Rourkela: 769015, Orissa, India vitro dissolution study can be used to demonstrate the bioavailability (BA) or bioequivalence (BE) of
E-mail:-vikdash@gmail.com, the drug product through in vitro - in vivo correlation (IVIVC). On the other hand if absorption of the
ashakeshri@yahoo.co.in drug is dissolution rate limited that means the drug in the gastrointestinal fluid passes freely through the
Mob: 09178140373, 09437502189 bio-membranes at a rate higher than it dissolves or is released from the dosage form. The specifically

2. Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31
designed in-vivo study will be required in such a case, to access the  Absorption number (An), defined as the ratio of the mean
absorption rate, and hence its bioavailability and to demonstrate the residence time to mean absorption time.
bioequivalence ultimately. Such a drug substance is a good  Dissolution number (Dn), defined as the ratio of mean
residence time to mean dissolution time.
candidate for controlled delivery provided they qualify in terms of
 Dose number (D0), defined as the mass divided by the product
their pharmacokinetics and pharmacodynamics for controlled of uptake volume (250 ml) and solubility of drug
release development. Also if a drug itself is having low solubility
and a slow dissolution rate, the release will automatically get Extension to BCS: (BCS Containing Six Classes)
slower and the dosage form need not have an inbuilt release
Bergstrom et al. in 2003 devised a modified
retardation mechanism, rather the absorption will now be governed
Biopharmaceutical Classification System, in which they
by the gastric emptying rate. Therefore, the dosage form must be
categorized the drugs into six classes based on the solubility and
able to restrain within the absorption window for a sufficient time
permeability. The solubility was classified as "high" or "low" and
so that absorption can take place. In such case, a hydrodynamically
the permeability was allotted as "low", "intermediate," or "high".
balanced (floating) system or a mucoadhesive dosage form will
This new classification was developed based on the calculated
serve the purpose. Hence the BCS can work as a guiding tool for
surface area descriptors on the one hand and solubility and
the development of various oral drug delivery technologies
permeability on the other. Surface areas related to the nonpolar part
(Johnson S.R.and Zheng Weifan, 2006).
of the molecule resulted in good predictions of permeability. It was
tentatively concluded that these models would be useful for early
CLASSIFICATION OF BCS indication with regard to the absorption profiles of the compound
According to BCS, drug substances are classified as (Figure 1): during the early stages of drug discovery so that the necessary
modifications can be made to optimize the pharmacokinetic
Class I drugs parameters (Bergstrom C. A et al, 2003).
These exhibit a high absorption number and a high dissolution CLASS BOUNDARIES USED IN BCS
number. The rate limiting step is drug dissolution and if dissolution
is very rapid then gastric emptying rate becomes the rate  A drug substance is considered HIGHLY SOLUBLE when
determining step. e.g. Metoprolol, Diltiazem, Verapamil, the highest dose strength is soluble in ≤250 ml water over a pH
Propranolol. range of 1 to 7.5.
Class II drugs  A drug substance is considered HIGHLY PERMEABLE
when the extent of absorption in humans is determined to be ≥
These drugs have a high absorption number but a low dissolution 90% of an administered dose, based on mass-balance or in
number. In vivo drug dissolution is then a rate limiting step for comparison to an intravenous reference dose.
absorption except at a very high dose number. The absorption for  A drug product is considered to be RAPIDLY DISSOLVING
class II drugs is usually slower than class II and occurs over a when ≥ 85% of the labelled amount of drug substance dissolves
longer period of time. In vitro- In vivo correlation (IVIVC) is within 30 minutes using USP apparatus I or II in a volume of ≤
usually excepted for class I and class II drugs. e.g. Phenytoin, 900 ml buffer solutions.
Danazol, Ketoconazole, Mefenamic acid, Nifedinpine.
For Class III drugs APPLICATION OF BCS
Here permeability is rate limiting step for drug absorption. These BCS is widely used in design and development of
drugs exhibit a high variation in the rate and extent of drug innovation drugs, new dosage forms (Permeability amplifiers), in
absorption. Since the dissolution is rapid, the variation is clinical pharmacology (drug-drug, drug-food interaction) and also
attributable to alteration of physiology and membrane permeability by regulation agencies of several countries as the scientific
rather than the dosage form factors. e.g. Cimetidine, Acyclovir, approach, for testing of waivers on bioavailability. Given below
Neomycin B, Captopril. the application of BCS in different fields:
Class IV drugs 1. Application of BCS in Oral Drug Delivery Technology
These drugs exhibit a lot of problems for effective oral Once the solubility and permeability characteristics of the
administration. Fortunately, extreme examples of class IV drug are known it becomes an easy task for the research scientist to
compounds are the exception rather than the rule and are rarely decide upon which drug delivery technology to follow or develop.
developed and reach the market. Nevertheless a number of class IV Class-I Drugs
drugs do exist e.g. Taxol.
This classification is associated with drug dissolution and The major challenge in development of drug delivery system for
absorption model, which identifies the key parameters controlling class I drugs is to achieve a target release profile associated with a
drug absorption as a set of dimensionless numbers viz. particular pharmacokinetic and/or pharmacodynamics profile.

3. Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31
Formulation approaches include both control of release rate and i. Selecting a route of experimentation.
certain physicochemical properties of drugs like pH-solubility ii. Clinical development.
profile of drug. iii.Improvement of Bioadhesive system if the drug is
absorbed from the selective area of the intestine.
Class-II Drugs
According to Lipinski et al. (1997), ‘a rule of 5’ is widely adopted
The systems that are developed for class II drugs are based on for screening of compounds that are likely to have poor absorption
micronisation, lyophilization, and addition of surfactants, profiles. According to this rule the poor absorption or permeation
formulation as emulsions and microemulsions systems and use of is more likely when: (Lipinski et al., 1997)
complexing agents like cyclodextrins.
• There are more than five H-bond donors (expressed as a
Class-III Drugs sum of hydroxyl and N-H linkage).
Class III drugs require the technologies that address to fundamental • The molecular weight of the drug moiety is more than 500
limitations of absolute or regional permeability. Peptides and • The log P is over %
proteins constitute the part of class III and the technologies
• There are more than 10 H-bond acceptors
handling such materials are on rise now days.
Compounds that are substrates for the biological transporters are an
Class-IV Drugs exception to the rule.
Class IV drugs present a major challenge for development of drug FUTURE PROSPECT OF BCS
delivery system and the route of choice for administering such
The future application of the BCS is most likely
drugs is parenteral with the formulation containing solubility
increasingly important when the present framework gains
enhancers.
increased recognition, which will probably be the case if the BCS
2. Application of BCS in New Drug Application (NDA) and borders for certain class II and III drugs are extended. The future
Abbreviated New Drug Application (ANDA) revision of the BCS guidelines by the regulatory agencies in
communication with academic and industrial scientists is exciting
The principles of the BCS classification system can be
and will hopefully result in an increased applicability in drug
applied to NDA and ANDA approvals as well as to scale-up and
development. Finally, we emphasize the great use of the BCS as a
post approval changes in drug manufacturing. A waiver of In-vivo
simple tool in early drug development to determine the rate-
Bioavailability and Bioequivalence studies based on the BCS
limiting step in the oral absorption process, which has facilitated
classification can therefore save pharmaceutical companies a
the information between different experts involved in the overall
significant amount of development time and reduce development
drug development process. This increased awareness of a proper
costs
biopharmaceutical characterization of new drugs may in the future
(http://www.fda.gov/AboutFDA/CentersOffices/cder/ucm128219.h
result in drug molecules with a sufficiently high permeability,
tm).
solubility and dissolution rate, and that will automatically increase
3. Application of BCS in optimization of new chemical entity the importance of the BCS as a regulatory tool over time
The pharmacokinetic idea of new chemical entity which is (Lennernäs H. et al, 2005).
already synthesized or identified and has therapeutic value but still CONCLUSION
under investigation for formulation development and final approval
Poor solubility and poor permeability account for many
can be provided by BCS. The BCS provide an opportunity to the
pharmacokinetic failures and about thirty percent of drug
synthetic chemist to manipulate in the chemical structure in the
molecules are rejected due to pharmacokinetic failures. When poor
chemical entity in order to optimize the physicochemical properties
pharmaceutical properties are discovered in development, the cost
of lead molecule for desired delivery and targeting through High
of bringing a potent, but poorly absorbable molecule to the product
Throughput Pharmaceutics (HTP).( Jorgensen W. L. et al, 2002
stage by formulation can become very high. Fast and reliable in
and Lobel L. M. et al, 2003)
vitro prediction strategies are needed to filter out problematic
4. Application of BCS for pharmacological screening molecules at the earliest stage of discovery. This communication
Pharmaceutical drug discovery and delivery groups are will consider recent developments in physiochemical profiles used
to identify molecules with physical properties related to good oral
using Human Drug Absorption (HDA) studies for understanding
absorption. FDA's biopharmaceutical classification system (BCS)
the biopharmaceutical properties of early drug candidates.
is an attempt to rationalize the critical components related to oral
HDA provides significant guidance to a pharmaceitcal formulation absorption and utilization of these principles for selection of a
scientist in:- suitable technology to serve the interests of the early stages of drug
discovery.

4. Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31
Figure-1: Biopharmaceutical Classification System of Drugs
Class II Class I
Low solubility High solubility
High permeability High permeability
e.g. Phenytoin, Danazol e.g. Metoprolol, Diltiazem
Permeability
Class IV Class III
Low solubility High solubility
Low permeability Low permeability
e.g. Taxol e.g. cimetidine, neomycin
Solubility
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