Predicting in vivo absorption behavior of oral modified release dosage forms containing pH-dependent poorly soluble drugs using a novel pH-adjusted biphasic in vitro dissolution test.

The focus of in vitro dissolution testing during early development of modified release (MR) formulations is to provide predictive estimates of drug release in respect to in vivo performance of a drug product. However, there are enormous challenges in MR drug development to establish proper dissolution conditions for a predictive test. To overcome limitations of dissolution testing at constant pH, a modified USP apparatus 2 was developed, combining biphasic dissolution with a pH-gradient in the aqueous dissolution medium. Quasi sink conditions in the aqueous phase were introduced by the removal of dissolved active via distribution to an organic phase. Results from in vitro drug-release studies and in vivo absorption studies of four MR formulations made by different technologies comprising the pH-dependent poorly soluble drugs, dipyridamole and the investigational drug BIMT 17, indicated that dissolution testing using the biphasic approach enabled an improved forecast of the in vivo behavior and bioavailability of modified release formulations compared to conventional dissolution testing at pH 1, pH 5.5, or pH 6.8. It can be concluded that the novel pH-adjusted dissolution test might be a useful tool in early drug development to develop, select, and optimize MR prototypes of Biopharmaceutical Classification System (BCS) II compounds. 2010 Elsevier B.V. All rights reserved.