A Review On Biopharmaceutical Classification System
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18-12-2010, 10:46 AM

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A Review On Biopharmaceutical Classification System

. Introduction
The oral route of drug administration is the most important method for administering drugs for systemic effects. The development of dosage forms especially for the prolonged release purpose has been a challenge to formulation scientists, because of many independent factors governing the absorption of the drug from the gastrointestinal tract and competitive objectives, that is, any action taken to improve one objective or set of objectives may cause another objective or set of objectives to degrade. For example, modifying the solubility of the drug substance to prolong its release in the gastrointestinal tract may cause a reduction in the overall payload of formulation. A trial and error method of formulation does not allow the formulator to know how close a particular formulation is to the optimum solution, and finding the correct compromise is not straightforward and simple. Hence a fast screen is needed, to enable them to formulate intelligently. For this purpose the drug substances are categorized into four classes based on their solubility parameter and permeability to bio-membranes, and such a classification system is called as a Biopharmaceutical Classification System (BCS)(1).
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 in-vitro 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 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[2].
Biopharmaceutical Classification System (BCS) system allows restricting the prediction using the parameters solubility and intestinal permeability. 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 on these two properties. The solubility classification is based on a United States Pharmacopoeia (USP) aperture. The intestinal permeability classification is based on a comparison to the intravenous injection. All those factors are highly important, since 85% of the most sold drugs in the USA and Europe are orally administered. Ultimate aim of the drug discovery scientist in pharmacokinetic optimization is to tailor the molecules so that they show the features of BCS class I without compromising on pharmacodynamics[3].
The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from immediate release (IR) solid oral dosage forms: dissolution, solubility, and intestinal permeability4. The biopharmaceutical classification system was developed primarily in the context of immediate release (IR) solid oral dosage forms. 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. At first, biowaivers were only applied to Scale‐Up and Postapproval Changes (SUPAC), but later the biowaiver principle was extended to the approval of new generic drug products. As a result, unnecessary human experiments can be avoided and the costs of developing generic products can be significantly lowered. According to the FDA guidance for the industry ‘Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms based on a biopharmaceutics classification system’ (August 2000), a biowaiver can currently be requested only for solid, orally administered immediate‐release products (85% release in 30 min), containing drugs with a high solubility over the pH range from 1 to 7.5 (highest dose in 250ml media) and a high permeability (fraction absorbed 90%). In addition, only excipients which do not affect the rate or extent of absorption may be used. Further restrictions are that drugs with a narrow therapeutic range and drug products designed to be absorbed in the oral cavity may not be considered for biowaivers. A drug’s solubility classification in the BCS is a function of the intended human dose.

Some important definitions[5]
a. Absorption Number (A): It is the ratio of permeability (P) and the gut radius ® times the residence time (T) in the small intestine, which can be written as the ratio of residence time and absorptive time (t).

b. Permeability: It is the ratio of rate of drug transport in receiver compartment (dM/dt) to the product of area of the membrane (A) and apical chamber drug concentration ©.

c. Dissolution Number (D): It is the ratio of the mean residence time (T) to the dissolution time (t), which includes solubility, diffusivity, density and the initial particle radius.

d. Bioavailability: The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

e. Bioequivalence: The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

f. Biowaiver: A biowaiver is an exemption granted by the US FDA 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 dose form meets the requirements for an
"immediate" release dose form.

g. Comparator Product : Product containing similar amounts of the same excipients as the test product, sameness of the manufacturing method and quality of the test product. The difference in drug content or potency between the test and comparator products should be less than 5%.

h. Very rapidly dissolving product: At least 85 % of the labelled amount is released within 15 minutes or less from the test and the comparator product. In this case profile comparison is not

i. Rapidly dissolving product:At least 85 % of the labelled amount is released within 30 minutes or less from the test and the comparator product. Profiles are superimposable or profile comparison test and the comparator product.

2. Biopharmaceutical Classification System
The BCS was first devised in 1995, by Amidon et al. and since then it has become a benchmark in the regulation of bioequivalence of oral drug products. The BCS serves as a guiding tool for formulation scientists, for recommending a strategy to improve the efficiency of drug development by proper selection of dosage form and bioequivalence tests, to recommend a class of immediate release (IR) solid dosage forms, for which bioequivalence may be assessed based on in-vitro dissolution tests, and to lay the effect of excipients(s) on drug permeability. The BCS guidance takes into account three major factors, dissolution, solubility, and intestinal permeability, which govern the rate and extent of drug absorption from immediate release solid dosage forms. The concept of BCS provides a better understanding of the relationship between drug release from the product and the absorption process. In this respect, the rate-limiting step is of primary relevance. The bioavailability will be affected only by the in vivo performance of the dosage form, if dissolution/drug release is rate limiting for the dosage form. In contrast, as long as the permeation through bio-membranes is a rate-limiting process, bioavailability and bioequivalence are not so dependent upon the drug release behavior of the dosage form. Each class of the BCS is having its designated rate-limiting step and the possible tactics for its modification that enable the formulator to select and optimize a dosage form for the drug substance belonging to a particular class of BCS. The BCS has also been included in various guidance documents of regulatory importance (2).
The BCS is a scientific framework for classifying a drug substance based on its aqueous solubility and intestinal permeability [1]. When combined with the in vitro dissolution characteristics of the drug product, the BCS takes into account three major factors: solubility, intestinal permeability, and dissolution rate, all of which govern the rate and extent of oral drug absorption from IR solid oral-dosage forms [2, 3].
Based on these 3 parameters the drug substances can be classified as belonging to one of four classes:
Class 1: High solubility and high permeability
Class 2: Low solubility and high permeability
Class 3: High solubility and low permeability
Class 4: Low solubility and low permeability (4, 5).

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