Application of a continuous intrinsic dissolution–permeation system for relative bioavailability estimation of polymorphic drugs

Abstract

A new continuous dissolution–permeation system, consisting of an intrinsic dissolution apparatus and an Ussing chamber, was developed for screening and identification of high-bioavailability polymorphisms at pre-formulation stages. Three different solid forms of two model drugs (agomelatine and carbamazepine) were used to confirm the system’s predictive ability. Ranks for cumulative permeation of the three solids were: Form III>Form I>Form II for agomelatine, and Form III>Form I>the dihydrate form for carbamazepine. Regression analysis of these parameters and published pharmacokinetics confirmed linear IVIVCs (most correlation coefficients >0.9). To confirm dissolution–absorption relationships, permeability coefficients were calculated. Relatively constant values among various polymorphisms for each drug supported a linear dependency between polymorphism-increased dissolution and polymorphism-enhanced permeation. A combined analysis of intrinsic dissolution rates and permeability coefficients revealed that both drugs are of the BCS II class and have dissolution-limited absorption. In conclusion, our new system was valuable not only for high-bioavailability polymorphism screening, but also for drug classification within the BCS system.