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

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 P(e)-limit (> or = 14-times higher rate constant limit for dissolution than for permeation), and is stricter for drugs with a long half-life (t(1/2)). Available human in-vivo, in-vitro, and in-silico P(e)-methods cannot classify P(e) 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 P(e) drug products. It has not been possible to find a highly permeable product with a Dose number (D(o)) < 385 (< 2400 in the fed state) that is clearly incompletely absorbed, and near complete uptake has been shown for a drug product with a D(o) 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 30 min and 3 h, respectively); the limit for high P(e) is increased (to >P(e) of metoprolol); accurate P(e)-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 t(1/2) 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.