Biopharmaceutical Classification Of Drugs

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Dr Abhijit V Gothoskar

Oral route of drug administration is, still the route of choice for the formulators. The in vivo performance of orally administered drug depends upon its solubility and tissue permeability characteristics.

Based on these characteristics drug substances are divided into four classes and the classification system is called as Biopharmaceutical Classification System. This article focuses on the methods of determination of solubility and permeability of drug substance and its subsequent use in classification of drug in one of the four classes. The biopharmaceutical classification system acts as a guiding tool for development of various oral drug delivery technologies.

Introduction:

The oral route of drug administration is the route of choice for the formulators and continues to dominate the area of drug delivery technologies. However, though popular, this route is not free from limitations of absorption and bioavailability in the milieu of gastrointestinal tract. These limitations are even more prominent with the advent of protein and peptide drugs and the compounds emerging as a result of combinatorial chemistry and the technique of high throughput screening.

Whenever a dosage form is administered orally, the events that follow are depicted in Figure1. The drug in the dosage form is released and dissolves in the surrounding gastrointestinal fluid to form a solution. This process is solubility limited. Once the drug is in the solution form, it passes across the membranes of the cells lining the Gastro-Intestinal tract. This process is permeability limited. Then onwards the drug is absorbed into systemic circulation. In short, the oral absorption and hence bioavailability of drug is determined by the extent of drug solubility and permeability.

Determination of solubility:

The solubility of a substance is the amount of substance that has passed into solution when equilibrium is attained between the solution and excess, i.e. undissolved substance, at a given temperature and pressure.

A drug substance is considered highly soluble when the highest dose strength is soluble in 250 ml or les of aqueous medium over the pH range of 1-7.5 (1). The volume estimate of 250 ml is derived form the typical volume of water consumed during the oral administration of dosage form, which is about a glassful, or 8 ounces of water. This boundary value is a refection of the minimum fluid volume anticipated in stomach the time of drug administration. The pH solubility profile of the drug substance is determined at 37 ± 10C in aqueous medium with pH in the range of 1-7.5. A sufficient number of pH conditions should be evaluated to accurately define the pH-solubility profile. The number of pH conditions for a solubility determination depends upon ionization characteristics of the test drug substance. A minimum of three replicate determinations of solubility in each pH condition should be carried out. Standard buffer solutions described in pharmacopoeias are considered appropriate for use in solubility studies. If these are not suitable for physical or chemical reasons, other buffer solutions can also be used provided the pH of these solutions are verified. Methods other than shake flask method are also used with justification to support the ability of such methods to predict equilibrium solubility of test drug substance. e. g. acid or base titration methods. The concentration of drug substance in selected buffers or pH conditions should be determined using a validated solubility-indicating assay that can distinguish between the drug substance from its degradation products. If degradation of drug is observed as a function of buffer composition and/or pH, it should be taken into consideration.

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Determination of permeability:


Fundamental to understanding of the nature of gastrointestinal permeability limitations are methods and techniques to both screen and grade these characteristics. Figure 2 summarizes these techniques with their complexities.

These methods range from simple oil/water (O/W) partition coefficient to absolute bioavailability studies.

The methods that are routinely used for determination of permeability include:

a. Human studies

Mass balance studies
Absolute bioavailability studies
Intestinal perfusion methods

b. In vivo or in situ intestinal perfusion in a suitable animal model

c. In vitro permeability methods using excised intestinal tissues

d. Monolayers of suitable epithelial cells e.g. Caco-2 cells or TC-7 cells

In mass balance studies, unlabelled, stable isotopes or radiolabelled drug substances are used to determine the extent of drug absorption. However this method gives highly variable estimates and hence other methods are sought for.

In absolute bioavailability studies, oral bioavailability is determined and compared against the intra venous bioavailability as reference.

Intestinal perfusion models and in vitro methods are recommended for passively transported drugs. The observed low permeability of some drug substances in human could be attributed to the efflux of drug by various membrane transporters like p-glycoprotein. This leads to misinterpretation of the permeability of drug substance.

An interesting alternative to intestinal tissue models is the use of well-established in vitro systems based on the human adenocarcinoma cell line Caco-2. These cells serve as a model of small intestinal tissue. The differentiated cells exhibit the microvilli typical of the small intestinal mucosa and the integral membrane proteins of the brush-border enzymes. In addition, they also form the fluid-filled domes typical of a permeable epithelium. Recent investigations of Caco-2 cell lines have indicated their ability to transport ions, sugars and peptides. The directed transport of bile acids and vitamin B12 across Caco-2 cell lines has also been observed. These properties have established the Caco-2 cell line as a reliable in vitro model of the small intestine.

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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.

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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.

About Authors

A. V. Gothoskar1 , S. M. Khangaonkar2

1 Area Technical Manager, MR Technologies, Colorcon Asia Pvt Ltd.,Verna Industrial Estate, Verna, Goa, India.
2 Post graduate student NDMVP Samaj’s College of Pharmacy, Nashik, Maharashtra .

Dr Abhijit V Gothoskar
Dr Abhijit V Gothoskar has completed his graduation, post-graduation and doctorate from Pune University, India. He is the gold medalist at graduate and post graduate levels for his outstanding performance. His research areas include Oral Controlled Drug Delivery Systems and applications of polymers in the field of pharmaceuticals. He has worked as a Senior Lecturer in Pharmaceutics in Maharashtra Institute of Pharmacy, Pune for five years and is currently working as Modified Release Area Technical Manager at Colorcon Asia Pvt Ltd. His current job responsibilities include generation of applications data, development of platform technologies for OCRS and trouble shooting.

Contact information:

Phone: +91-832-2883434 Fax: +91-832-2883440 e-mail: abhijit_gothoskar@yahoo.com

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