Droplet-Confined Spherical Crystallization of Cyclandelate and Cyclandelate−Tenoxicam in Water and the Mechanism Study

Abstract Spherical particles, considered as high-value-added products, have attracted wide attention in various areas, such as pharmaceuticals, foods, and energetic materials. Conventional spherical crystallization techniques usually rely on the utilization of multicomponent solvents and complex operations. In this study, a droplet-confined spherical crystallization method is proposed in water for cyclandelate and cyclandelate−tenoxicam based on thermal-induced liquid−liquid phase separation (LLPS). Single-component and multicomponent drug spheres were successfully prepared without the use of organic solvents. At a crystallization temperature of 5 °C, the angle of repose decreased by about 46% for cyclandelate spheres prepared at 300 rpm and by 43% for cyclandelate−tenoxicam spheres prepared at 600 rpm when compared with the raw materials. The size distribution of the spherical particles can be effectively regulated by the droplet size distribution, which is controlled by the stirring rates. Simulation studies for LLPS show that the difference in molecular polarity and weak intermolecular interactions between the drug molecules and water contributes to phase separation, whereas the similar molecular polarity and stronger intermolecular interactions between cyclandelate and tenoxicam favor their association and the formation of multi-component droplets.