Cooling Crystallization of Sulfamethazine-Acetylsalicylic Acid Cocrystal: Estimating Nucleation Kinetics and Real-Time Phase Identification

Cooling cocrystallization of 1:1 sulfamethazine-acetylsalicylic acid (SMZ-ASA) cocrystal from acetonitrile is investigated based on the ternary phase diagrams (TPDs) established at 5, 15, 25, and 35 °C. Nucleation kinetics of the cocrystal and pure coformers analyzed using classical nucleation theory (CNT) revealed that the nucleation rate of the cocrystal is significantly lower, approximately 1/111 times that of pure ASA and 1/21 times that of SMZ at similar supersaturations. Cooling cocrystallization was scaled up from 20 mL to 2 L, transitioning from a magnetically stirred to an overhead-stirred system. This scale-up facilitated the study of nucleation and the successful production of cocrystals in larger volumes. Cooling in the stable cocrystal region in the TPD produced pure cocrystals. Cooling crystallization in the SMZ + cocrystal region near the SMZ invariant point in TPD led to the formation of pure cocrystal instead of SMZ-cocrystal mixture due to the influence of nucleation kinetics. Conversely, in the ASA + cocrystal region near the ASA invariant point, a mixed solid phase was obtained. In-situ Raman spectroscopy revealed that pure ASA nucleated first, followed by cocrystal formation approximately 30 min later.