The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development

doi:10.1002/jps.22217

Journal of Pharmaceutical Sciences

Volume 99, Issue 12, December 2010, Pages 4940-4954

https://doi.org/10.1002/jps.22217 Get rights and content

ABSTRACT:

A revised classification system for oral drugs was developed using the biopharmaceutics classification system (BCS) as a starting point. The revised system is designed to have a greater focus on drug developability. Intestinal solubility, the compensatory nature of solubility and permeability in the small intestine and an estimate of the particle size needed to overcome dissolution rate limited absorption were all considered in the revised system. The system was then validated by comparison with literature on the in vivo performance of a number of test compounds. Observations on the test compounds were consistent with the revised classification, termed the developability classification system (DCS), showing it to be of greater value in predicting what factors are critical to in vivo performance than the widely used BCS.

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 (P_eff). $MAD = S \times K A \times V \times$

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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The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development

ABSTRACT:

Section snippets

INTRODUCTION

THEORETICAL/BACKGROUND

METHOD: DEVISING THE MODIFIED CLASSIFICATION SYSTEM

RESULTS-SELECTED EXAMPLE DRUGS

DISCUSSION

CONCLUSION

J Pharm Sci

Eur J Pharm Sci

Pharm Sci Techol Today

Adv Drug Deliv Rev

Eur J Pharm Biopharm

Adv Drug Deliv Rev

J Drug Deliv Sci Techol

Adv Drug Deliv Rev

Drug Discov Today

Eur J Med Chem

J Pharm Sci

Eur J Med Chem

Adv Drug Deliv Rev

J Mol Graph Model

Int J Pharm

J Pharm Sci

J Pharm Sci

Lancet

Adv Drug Deliv Rev

Eur J Pharm Sci

J Invest Dermatol

Eur J Pharm Sci

J Pharm Sci

J Pharm Sci

Int J Pharm

Int J Pharm

J Pharm Sci

Int J Pharm

Int J Pharm

J Pharm Sci

J Pharm Sci

J Pharm Sci

A theoretical basis for a biopharmaceutic drug classification system: The correlation of in vitro drug product dissolution and in vivo bioavailability

Pharm Res

Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine

Pharm Res

Biopharmaceutics classification system: The scientific basis for biowaiver extensions

Pharm Res

The “high solubility” definition of the current FDA guidance on biopharmaceutical classification system may be too strict for acidic drugs

Pharm Res

Proposal to waive in vivo bioequivalence requirements for the WHO Model List of Essential Medicines immediate release, solid oral dosage forms

Predicting drug disposition via application of BCS: Transport/absorption/elimination interplay and development of a Biopharmaceutics Drug Disposition Classification System

Pharm Res

In vitro testing of drug absorption for drug developability assessment

Cur Opin Drug Discov Dev

Jejunal permeability in humans in vivo and rats in situ: Investigation of molecular size selectivity and solvent drag

Acta Physiol Scand

A mechanistic approach to understanding the factors affecting drug absorption: A review of fundamentals

J Clin Pharmacol

An integrated model for determining causes of poor oral drug absorption

Pharm Res

A physiological model for the estimation of the fraction dose absorbed in humans

J Med Chem

Dissolution testing as a prognostic tool for oral drug absorption: Immediate release dosage forms

Pharm Res

Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs

Pharm Res

Dissolution media simulating conditions in the proximal human gastrointestinal tract: An update

Pharm Res

The BCS: Where do we go from here?

Pharm Tech

Dissolution media simulating the intralumenal composition of the small intestine: Physiological issues and practical aspects

J Pharm Pharmacol