Abstract

Understanding the impact of dynamic alterations in gastrointestinal fluid properties and intestinal dissolution of poorly soluble drugs, such as lapatinib, is crucial for predicting drug absorption in vivo. The current study employs a micro-dissolution pH shift model to forecast the dynamic dissolution of lapatinib in buffer and bio-relevant media by application of analytical design of experiments. The utilization of a Box-Behnken design has resulted in a robust analytical method. According to an in vitro micro-dissolving pH shift experiment in United States Pharmacopeia buffers, lapatinib displays a typical weak base pH-dependent solubility, with 15% drug release at pH 1.2 and dropping to 2% at pH 6.5 buffers. In contrast, the solubility of the compound was initially measured to be 0.0127 mg/ ml in fasted state-simulated gastric fluid; however, pH alterations by the addition of fasted state-simulated intestinal fluid 6.5 resulted in a significant increase to 0.0291 mg/ml. The in vitro pH-effect risk for dissolution experiment in bio-relevant media is 0.80, suggesting that the existence of salts in fasted state-simulated intestinal fluid results in the formation of a macroaggregate that is accountable for improved solubility of lapatinib. Thus, using a bio-relevant buffer in a pH shift model may improve this in vitro technique’s predictive ability and aid weakly drug advancement in the intestinal environment.

Key words: Analytical QbD, biorelevant dissolution media, pH shift, lapatinib, intestinal absorption