The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development
Section snippets
INTRODUCTION
The introduction of the biopharmaceutics classification system (BCS) in the 1990s made a significant impact on the development of immediate release (IR) oral dosage forms, enabling the use of in vitro data rather than in vivo human studies for establishing the bioequivalence of low risk (BCS class I) compounds.1., 2.
The BCS also provides a framework to consider key factors (dose, solubility, permeability and dissolution rate) that may influence in vivo performance. The significance of these
THEORETICAL/BACKGROUND
Modelling oral absorption has been the focus of several key papers in the last decade.
One simple concept, widely used in the early stages of drug development, is that of maximum absorbable dose (MAD). Several versions of MAD exist, using different assumptions and means of estimating permeability. In one version proposed by Curatolo11 the derivation uses an absorption rate constant (KA), whilst another by Sun et al.12 uses an estimate of the effective human jejunal permeability (Peff).
METHOD: DEVISING THE MODIFIED CLASSIFICATION SYSTEM
The modified classification aimed to incorporate the following concepts:
- (1).
An estimate of human fasted intestinal solubility (e.g. by using FaSSIF) as the primary measure of in vivo solubility useful for the prediction of the extent of human absorption.
- (2).
A solubility limited absorbable dose (SLAD) concept, based on the idea that for class II drugs at least, permeability and solubility are compensatory.
- (3).
Dissolution rate, expressed as a target drug particle size rather than dose/solubility ratio,
RESULTS-SELECTED EXAMPLE DRUGS
The DCS categorisation of selected drugs is shown in Figure 2. The classification of the selected drugs is shown in Table 2.
DISCUSSION
The BCS is used in the pharmaceutical industry for developability assessment, and is attractive due to its conceptual simplicity. However, based on the evidence presented, the DCS is a convenient way of classifying compounds in a way that is more meaningful in determining human in vivo behaviour and sensitivities. In addition, although other more complex models such as the commercial software Gastro- Plus and PK-Sim may also useful in assessing drug developability issues, their optimal use
CONCLUSION
Based on the examples shown, a revised version of the BCS for assessing developability of drugs for oral immediate release delivery is a useful way of categorising compounds in a simple manner to identify whether dose/solubility ratio, dissolution rate and/or permeability are likely to limit oral absorption of a drug. The introduction of a target particle size via rearrangement of the dissolution number equation provides additional useful information on potential dissolution rate sensitivity.
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