Evaluation and suggested improvements of the Biopharmaceutics Classification System (BCS)

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Abstract
This review has evaluated the Biopharmaceutics Classification System (BCS) and improvements have been proposed. The BCS has a very strict solubility/dissolution limit, a generous Pe-limit (≥ 14-times higher rate constant limit for dissolution than for permeation), and is stricter for drugs with a long half-life (t1/2). Available human in-vivo, in-vitro, and in-silico Pe-methods cannot classify Pe for moderately to highly permeable substances sufficiently well, and in-vitro data often underpredict the in-vivo dissolution potential and rate. Good in-vivo dissolution and absorption can be expected for most high Pe drug products. It has not been possible to find a highly permeable product with a Dose number (Do) < 385 (< 2400 in the fed state) that is clearly incompletely absorbed, and near complete uptake has been shown for a drug product with a Do of 660000. The potential implication of these findings is that many true BCS Class I drug products are incorrectly classified. This could be a reason for the limited use of this system. On this basis, it has been suggested that: the limit for high for solubility/dissolution is decreased (to >40 and >95% dissolved within 30min and 3 h, respectively); the limit for high Pe is increased (to >Pe of metoprolol); accurate Pe-models or in-vivo fraction absorbed data are used; solubility/dissolution tests are performed using real or validated simulated gastrointestinal fluids; in-vitro/in-vivo dissolution relationships are established; the t½ is considered; and the rate-limiting step for in-vivo absorption is determined. A major change could be to reduce the BCS into two classes: permeation-rate (Class I) or dissolution-rate (Class II) limited absorption. It is believed that this could give a better balance and increase the number of biowaivers.

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