Prediction of solubility and permeability class membership: provisional BCS classification of the world's top oral drugs

Abstract

The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. Since its introduction in 1995, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development, and regulation, and extensive validation/discussion/extension of the BCS is continuously published in the literature. The BCS has been effectively implanted by drug regulatory agencies around the world in setting bioavailability/bioequivalence standards for immediate-release (IR) oral drug product approval. In this review, we describe the BCS scientific framework and impact on regulatory practice of oral drug products and review the provisional BCS classification of the top drugs on the global market. The Biopharmaceutical Drug Disposition Classification System and its association with the BCS are discussed as well. One notable finding of the provisional BCS classification is that the clinical performance of the majority of approved IR oral drug products essential for human health can be assured with an in vitro dissolution test, rather than empirical in vivo human studies.

Fig. 1

The Biopharmaceutics Classification System as defined by Amidon et al. (5). The BCS classifies drugs by their solubility and permeability properties in order to stand for the most fundamental view of the drug intestinal absorption process following oral administration

Fig. 2

Provisional BCS classification of the 123 oral drugs in immediate-release solid dosage forms on the WHO Essential Medicines List, based on dose number (D ₀) for the solubility criterion and Log P/CLogP correlations for the permeability classification (25)

Fig. 3

Provisional BCS classification of oral drugs in IR solid dosage forms on the top 200 US, GB, ES, and JP drugs lists using dose number (D ₀) for the solubility criterion and CLogP for the permeability classification (26)

Fig. 4

Comparison of the provisional classification of 164 drugs according to the BDDCS and the BCS. BDDCS classification was carried out using 50% as the cutoff for extensive metabolism and the BCS using metoprolol as the reference permeability drug (26)

Fig. 5

The provisional BCS classification service as offered by Therapeutic Systems Research Laboratory (TSRL Inc., Ann Arbor, MI) website