Stoichiometric Diversity of Caffeine and 4-Hydroxybenzoic Acid Cocrystals in Batchelor Vortex Flow

In this study, we explored the influence of fluid flow on the stoichiometric diversity in cocrystal formation. The cocrystallization of caffeine (CAF) with 4-hydroxybenzoic acid (4-HBA) was carried out using rotating disk (RD) and mixing tank (MT) crystallizers, which generated distinct flow regimes: Batchelor vortex and turbulent eddy flows, respectively. The outcomes revealed the formation of hitherto unknown (1:3) cocrystals, alongside the known (2:1) and (1:2) cocrystals. Notably, the fluid motion was found to significantly affect the nucleation of cocrystals with stoichiometric diversity, with stable (1:3) cocrystal nucleation being more effective in the Batchelor vortex flow due to improved molecular alignment. The phase transformation of cocrystals was also subject to the influence of fluid dynamics. In the Batchelor vortex flow, (2:1) and (1:2) cocrystals transitioned directly to (1:3) cocrystals, whereas in the turbulent eddy flow, (2:1) first converted to (1:2) cocrystals before reaching the (1:3) cocrystals. Kinetic factors related to nucleation and phase transformation led to the temporary formation of either metastable (2:1) and (1:2) cocrystals or stable (1:3) cocrystals, depending on the fluid motion pattern. However, aligning with thermodynamic principles, only the stable (1:3) cocrystal was the ultimate product at the end of the process. This research underscores the significance of fluid flow patterns in controlling the stoichiometry of cocrystals, with important implications for pharmaceutical development and material science applications.