Abstract
In situ monitoring in cocrystallization processes is of great significance in controlling the quality of crystalline active pharmaceutical ingredients. In this work, a mechanism for cocrystallization through solution-mediated phase transformation is revealed whereby ethenzamide (EA) and saccharin (SAC) were selected to study the cocrystallization process in water as well as kinetics by in situ Raman spectroscopy. It is observed that the formation of cocrystal nucleus required a long time, yet the growth time was short. Therefore, we concluded that this solution-mediated phase transformation process is mainly controlled by the nucleation rate. Furthermore, kinetic parameters of the transformation process at different temperatures obtained by using the Johnson–Mehl–Avrami equation indicated that high temperature would increases the nucleation and growth rate K and decrease the induction time. The influence of different operating factors on the transformation process was also studied to better understand the process. Meanwhile, in situ Raman spectroscopy was proved as an effective approach for exploring the mechanism of cocrystallization.
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