Operation Design of Co-Crystallization Using Homogeneity Evaluation Including “Single Component Excess” Index

Abstract

In controlling the quality of crystalline particles, the comprehensive uniformity of the distribution of characteristics, such as particle size and crystal shape, is essential. Improvement of comprehensive uniformity is also required for multicomponent crystals, such as cocrystals. Because cocrystals are composed of two or more pure components, undesirable crystals may precipitate. Therefore, it is necessary to consider comprehensive uniformity, including component characteristics. We proposed the "single component excess (s.c.e.)" index as the absolute di erence between the concentrations of each pure component. In this paper, an operation method under high-productivity conditions for improving the quality of cocrystals has been proposed by evaluating the changes in s.c.e. and uniformity in distribution of particle size and crystal shape using homogeneity. CBZ-SAC (1 : 1) cocrystal Form I was obtained by integrating the two driving forces generated by the reaction crystallization and anti-solvent crystallization methods. The homogeneity was initially high when using the driving force of the reaction crystallization method and further increased under the driving force of the anti-solvent crystallization method. Considering these results, both homogeneity and productivity were improved by the sequential generation of the two driving forces. Thus, it was possible to design a method that achieves quality and productivity in co-crystallization using homogeneity, including the s.c.e.