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.