An In Vitro Model for Cocrystal Dissolution with Simultaneous Surface and Bulk Precipitation

Cocrystals can be promising means of overcoming the poor aqueous solubility of many drugs. However, precipitation of the stable drug at the cocrystal surface or in the bulk medium is often provoked during cocrystal dissolution due to high drug supersaturation, which prevents sustaining high drug concentrations for enhanced bioavailability. There is a need for predictive in vitro models that can accurately describe this cocrystal dissolution–supersaturation–precipitation (DSP) process to aid drug development and formulation design. Consideration of surface precipitation is often essential for such models given the strong impact of surface precipitation on the drug concentration during cocrystal dissolution. However, DSP models that can explicitly account for the effect of surface precipitation are currently lacking. This work presents a population balance-based model to describe in vitro cocrystal DSP behavior, which accounts for cocrystal dissolution, surface precipitation, and bulk precipitation. Dissolution experiments with carbamazepine–succinic acid cocrystals are conducted for model development and validation. The developed model captures all of the principal experimental trends and predicts the dose-dependent DSP behavior outside the regression data set with reasonable accuracy. The results show that surface precipitation is an essential component of the model. Finally, the new model is integrated with numerical optimization to illustrate how it can be used to identify an optimal dose, particle size, and amount of predissolved coformer.