In Vitro−In Silico Screening for Assessing Variability in Food Effects for Different Solid Forms of a Free Base Drug

Abstract Understanding and predicting food effects for weakly basic, poorly soluble drugs remain a major challenge in oral drug development. Posaconazole (PSZ), a highly lipophilic antifungal agent, exhibits pronounced fasted-fed variability when administered as the free base. In this work, we developed an integrated in vitro-in silico screening strategy to evaluate the impact of physiological variability on the dissolution and predicted absorption of PSZ and its 4-aminobenzoic acid cocrystal form, PSZ-4ABA. Using a two-stage dissolution framework, key gastrointestinal parameters, including pH, bile salt concentration, buffer capacity, gastric residence time, and gastric-to-intestinal volume ratio, were systematically varied within physiologically relevant ranges to assess their influence on drug solubility, supersaturation, and precipitation risk. PSZ-4ABA consistently demonstrated higher apparent solubility and reduced sensitivity to physiological fluctuations compared to the free base, particularly under fasted conditions, where PSZ exhibited greater precipitation risk. Normalized AUC values derived from dissolution profiles revealed that the cocrystal form substantially attenuates variability across fed and fasted states. Physiologically based biopharmaceutics modeling (PBBM), built by incorporating the solubility-pH profile of the free form and cocrystal, further supported these findings. Overall, this study highlights the utility of combining biorelevant dissolution testing with PBBM to identify solid forms with reduced food-effect liability and to anticipate variability arising from gastrointestinal physiology.