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Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31

JCPR 2011; 5 (1): 28-31 2010 Medipoeia Received: 03-09-2011 Revised: 04-09-2011 Accepted: 6-09-2011

Role of Biopharmaceutical Classification System In Drug Development Program


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 importance in new drug discovery and lead optimization due to the dependence of drug absorption and pharmacokinetics. Biopharmaceutical classification system (BCS) is based on solubility tests; for various drugs they correlate with their bioavailability in human body. It is widely used in design and development of innovation drugs, new dosage forms (permeability amplifiers), in 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.

Vikash Dash* and Asha Kesari Department of Pharmaceutics Kanak Manjari Institute of Pharmaceutical Sciences, Chhend, Rourkela: 769015, Orissa, India

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 Department of Pharmaceutics Kanak Manjari Institute of Pharmaceutical Sciences, Chhend, Rourkela: 769015, Orissa, India E-mail:-vikdash@gmail.com, ashakeshri@yahoo.co.in Mob: 09178140373, 09437502189

The in-vivo performance of orally administered drugs depends upon their solubility and tissue permeability characteristics. The release rate or solubility of the drug substance will not be a governing parameter if the absorption of the drug is permeation rate limited and in such cases the invitro dissolution study can be used to demonstrate the bioavailability (BA) or bioequivalence (BE) of the drug product through in vitro - in vivo correlation (IVIVC). On the other hand if absorption of the drug is dissolution rate limited that means the drug in the gastrointestinal fluid passes freely through the bio-membranes at a rate higher than it dissolves or is released from the dosage form. The specifically

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 rate, and hence its bioavailability and to demonstrate the bioequivalence ultimately. Such a drug substance is a good candidate for controlled delivery provided they qualify in terms of their pharmacokinetics and pharmacodynamics for controlled release development. Also if a drug itself is having low solubility and a slow dissolution rate, the release will automatically get slower and the dosage form need not have an inbuilt release retardation mechanism, rather the absorption will now be governed by the gastric emptying rate. Therefore, the dosage form must be able to restrain within the absorption window for a sufficient time so that absorption can take place. In such case, a hydrodynamically balanced (floating) system or a mucoadhesive dosage form will serve the purpose. Hence the BCS can work as a guiding tool for the development of various oral drug delivery technologies (Johnson S.R.and Zheng Weifan, 2006). CLASSIFICATION OF BCS According to BCS, drug substances are classified as (Figure 1): Class I drugs These exhibit a high absorption number and a high dissolution number. The rate limiting step is drug dissolution and if dissolution is very rapid then gastric emptying rate becomes the rate determining step. e.g. Metoprolol, Diltiazem, Verapamil, Propranolol. Class II drugs These drugs 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 class II and occurs over a longer period of time. In vitro- In vivo correlation (IVIVC) is usually excepted for class I and class II drugs. e.g. Phenytoin, Danazol, Ketoconazole, Mefenamic acid, Nifedinpine. For Class III drugs Here permeability is rate limiting step for drug absorption. 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 the dosage form factors. e.g. Cimetidine, Acyclovir, Neomycin B, Captopril. Class IV drugs These drugs exhibit a lot of problems for effective oral administration. Fortunately, extreme examples of class IV compounds are the exception rather than the rule and are rarely developed and reach the market. Nevertheless a number of class IV drugs do exist e.g. Taxol. This classification is associated with drug dissolution and absorption model, which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz.

Absorption number (An), defined as the ratio of the mean residence time to mean absorption time. Dissolution number (Dn), defined as the ratio of mean residence time to mean dissolution time. Dose number (D0), defined as the mass divided by the product of uptake volume (250 ml) and solubility of drug Extension to BCS: (BCS Containing Six Classes) Bergstrom et al. in 2003 devised a modified Biopharmaceutical Classification System, in which they categorized the drugs into six classes based on the solubility and permeability. The solubility was classified as "high" or "low" and the permeability was allotted as "low", "intermediate," or "high". This new classification was developed based on the calculated surface area descriptors on the one hand and solubility and permeability on the other. Surface areas related to the nonpolar part of the molecule resulted in good predictions of permeability. It was tentatively concluded that these models would be useful for early indication with regard to the absorption profiles of the compound during the early stages of drug discovery so that the necessary modifications can be made to optimize the pharmacokinetic parameters (Bergstrom C. A et al, 2003). CLASS BOUNDARIES USED IN BCS A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in 250 ml water over a pH range of 1 to 7.5. A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose. A drug product is considered to be RAPIDLY DISSOLVING when 85% of the labelled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of 900 ml buffer solutions. APPLICATION OF BCS BCS is widely used in design and development of innovation drugs, new dosage forms (Permeability amplifiers), in clinical pharmacology (drug-drug, drug-food interaction) and also by regulation agencies of several countries as the scientific approach, for testing of waivers on bioavailability. Given below the application of BCS in different fields: 1. Application of BCS in Oral Drug Delivery Technology Once the solubility and permeability characteristics of the drug are known it becomes an easy task for the research scientist to decide upon which drug delivery technology to follow or develop. Class-I Drugs The major challenge in development of drug delivery system for class I drugs is to achieve a target release profile associated with a particular pharmacokinetic and/or pharmacodynamics profile.

Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug. Class-II Drugs The systems that are developed for class II drugs are based on micronisation, lyophilization, and addition of surfactants, formulation as emulsions and microemulsions systems and use of complexing agents like cyclodextrins. Class-III Drugs 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. Class-IV Drugs Class IV drugs present a major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral with the formulation containing solubility enhancers. 2. Application of BCS in New Drug Application (NDA) and Abbreviated New Drug Application (ANDA) The principles of the BCS classification system can be applied to NDA and ANDA approvals as well as to scale-up and post approval changes in drug manufacturing. A waiver of In-vivo Bioavailability and Bioequivalence studies based on the BCS classification can therefore save pharmaceutical companies a significant amount of development time and reduce development costs (http://www.fda.gov/AboutFDA/CentersOffices/cder/ucm128219.h tm). 3. Application of BCS in optimization of new chemical entity The pharmacokinetic idea of new chemical entity which is already synthesized or identified and has therapeutic value but still under investigation for formulation development and final approval can be provided by BCS. The BCS provide an opportunity to the synthetic chemist to manipulate in the chemical structure in the chemical entity in order to optimize the physicochemical properties of lead molecule for desired delivery and targeting through High Throughput Pharmaceutics (HTP).( Jorgensen W. L. et al, 2002 and Lobel L. M. et al, 2003) 4. Application of BCS for pharmacological screening Pharmaceutical drug discovery and delivery groups are using Human Drug Absorption (HDA) studies for understanding the biopharmaceutical properties of early drug candidates. HDA provides significant guidance to a pharmaceitcal formulation scientist in:-

i. Selecting a route of experimentation. ii. Clinical development. iii.Improvement of Bioadhesive system if the drug is absorbed from the selective area of the intestine. According to Lipinski et al. (1997), a rule of 5 is widely adopted for screening of compounds that are likely to have poor absorption profiles. According to this rule the poor absorption or permeation is more likely when: (Lipinski et al., 1997)

There are more than five H-bond donors (expressed as a


sum of hydroxyl and N-H linkage).

The molecular weight of the drug moiety is more than 500 The log P is over % There are more than 10 H-bond acceptors
Compounds that are substrates for the biological transporters are an exception to the rule. FUTURE PROSPECT OF BCS The future application of the BCS is most likely increasingly important when the present framework gains increased recognition, which will probably be the case if the BCS borders for certain class II and III drugs are extended. The future revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting and will hopefully result in an increased applicability in drug development. Finally, we emphasize the great use of the BCS as a simple tool in early drug development to determine the ratelimiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. 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 (Lennerns H. et al, 2005). CONCLUSION Poor solubility and poor permeability account for many pharmacokinetic failures and about thirty percent of drug molecules are rejected due to pharmacokinetic failures. When poor pharmaceutical properties are discovered in development, the cost of bringing a potent, but poorly absorbable molecule to the product stage by formulation can become very high. Fast and reliable in vitro prediction strategies are needed to filter out problematic molecules at the earliest stage of discovery. This communication will consider recent developments in physiochemical profiles used to identify molecules with physical properties related to good oral absorption. FDA's biopharmaceutical classification system (BCS) is an attempt to rationalize the critical components related to oral absorption and utilization of these principles for selection of a suitable technology to serve the interests of the early stages of drug discovery.

Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31

Figure-1: Biopharmaceutical Classification System of Drugs

Class II
Low solubility High permeability e.g. Phenytoin, Danazol Permeability

Class I
High solubility High permeability e.g. Metoprolol, Diltiazem

Class IV
Low solubility Low permeability e.g. Taxol

Class III
High solubility Low permeability e.g. cimetidine, neomycin

Solubility
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