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

Abstract

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.

Discovery of new cocrystals beyond serendipity: lessons learned from successes and failures

“…135 The difference between the bulk and interfacial pH microenvironment generated by mass transfer limitations, together with the promotion of heterogeneous nucleation on the cocrystal surface, accounts for the presence of PS-SMPT. 136,137 Xuan and co-worker elucidated the phase transformation behavior of various curcumin cocrystals during dissolution at the molecular level. The solution-state stability of curcumin cocrystals was found to be affected by both the composition of dissolution medium and the cocrystal intrinsic thermodynamic stability.…”

“…The dissolution–supersaturation–precipitation (DSP) profile is also intriguingly shaped by the cocrystal concentration. Mendis and Lakerveld have recently developed a predictive dynamic model for the concentration-dependent DSP behavior of dissolving cocrystals in vitro when considering both surface and bulk precipitation, 136 which showed that the cocrystal concentration should only be moderately high to sustain a high supersaturation. For instance, five concentrations (15, 20, 30, 40, and 50 mg in 50 mL of the dissolution medium) of the carbamazepine–succinic acid cocrystal were tested in dissolution experiments.…”