Introduction

Regulatory agencies have encouraged the use of mechanistic absorption (MAM) and physiologically-based pharmacokinetic (PBPK) modeling to reduce both costs and time to market for new and generic drug products. The models require parameterization, and as such, many physicochemical parameters must be determined as a part of the development process. For low solubility weak bases that have high solubility in gastric and low solubility in intestinal fluids, precipitation is an important aspect that needs to be evaluated. Previous simple in vitro transfer experiments have been shown to overestimate precipitation in vivo. The benefit of the biphasic test is the absorptive phase that lowers supersaturation in a manner similar to in vivo and may provide more accurate precipitation estimates. In this work, we present a biphasic in vitro dissolution test coupled to an in silico model using classical nucleation theory that allows for the extraction of precipitation parameters of itraconazole (ITZ). The goal was to test whether or not the absorptive in vitro assay provides precipitation parameters that are more relevant in vivo and can be used in the GastroPlus™ MAM to predict the pharmacokinetics (PK) of ITZ.

Controlled Release Society (CRS) Annual Meeting and Exposition, July 22-24, 2018, New York, New York

By James Mullin, Ke X. Szeto, Viera Lukacova, Michael B. Bolger