Development of In Vivo Predictive pH-Gradient Biphasic Dissolution Test for Weakly Basic Drugs: Optimization by Orthogonal Design

The aim of this study was to develop a method for set up and optimization of a pH-gradient biphasic dissolution model by orthogonal test design in light of the correlation with published in vivo data of ketoconazole (KTZ). A pH-gradient biphasic dissolution test was designed with a sequential pH-gradient in the aqueous phase to simulate stomach, duodenum, jejunum, and ileum, and the organic phase was added in simulated small intestine conditions. The model was optimized by orthogonal test design with three factors and three levels and correlating with the published pharmacokinetic data of pure drug. The optimized dissolution conditions were 30 rpm, 100 mL of an organic volume, and pH 5.5, 6.5, and 6.8 in the pH-gradient aqueous phase in USP apparatus 2. Under these conditions, KTZ dissolution displayed a good linear relationship with in vivo absorption (R2 = 0.85). This study indicates that this methodology is feasible to develop an in vivo predictive dissolution test.