Biopharmaceutical Classification Of Drugs

Biopharmaceutical Classification System:

The biopharmaceutical classification system was developed primarily in the context of immediate release (IR) solid oral dosage forms. It is the scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability (2). It is a drug development tool that allows estimation of the contributions of three major factors, dissolution, solubility and intestinal permeability that affect oral drug absorption from immediate release solid oral dosage forms. The interest in this classification system is largely because of its application in early drug development and then in the management of product change through its life cycle. It was first introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage Forms: Scale Up And Post Approval Changes (3).

Classification:

According to BCS, drug substances are classified as (Figure 3):

Class I : High Solubility – High Permeability

Class II : Low Solubility – High Permeability

Class III: High Solubility – Low Permeability

Class IV: Low Solubility – Low Permeability

Combined with the dissolution, the BCS takes into account the three major factors governing bioavailability viz. dissolution, solubility and permeability.

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, defined as the ratio of the mean residence time to mean absorption time.
Dissolution number, defined as the ratio of mean residence time to mean dissolution time.
Dose number, defined as the mass divided by the product of uptake volume (250 ml) and solubility of drug (4).

Class I drugs 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 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, 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 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.

Applications of BCS in oral drug delivery technology (5):

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.

The major challenge in development of drug delivery system for class I drugs is to achieve a target release profile associated with a particular pharmcokinetic and/or pharmacodynamic profile. Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug.

The systems that are developed for class II drugs are based on micronisation, lyophilization, addition of surfactants, formulation as emulsions and microemulsions systems, use of complexing agents like cyclodextrins.

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 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.

Conclusion:

The in vivo performance of the drug depends upon its solubility and permeability. The biopharmaceutical classification system is the guiding tool for the prediction of in vivo performance of the drug substance and development of drug delivery system to suit that performance. The knowledge of the biopharmaceutical class of the drug substance is also essential for biowaivers thereby reducing the cost both in terms of money and time.

References:

1. Draft Guidance for Industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms containing certain Active Moieties/ Active Ingredients based on a Biopharmaceutic Classification System, February 1999, CDER/FDA.

2. Amidon G.L., Lennernas H., Shah V.P., Crison J.R.A., A Theoretical Basis For a Biopharmaceutic Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability. Pharm. Res. 12: 413-420 (1995).

3. Guidance for Industry, Immediate Release Solid Oral Dosage Forms: Scale Up and Post Approval Changes, November 1995, CDER/FDA.

4. Medicamento Generico from website http://www.anvisa.go/.

5. Devane J., Oral drug delivery technology: addressing the solubility/ permeability paradigm, Pharm. Technol. 68-74, November 1998.