Single-step synthesis of multicomponent cocrystals and salts: the role of laboratory seeding

Abstract

The synthesis of multicomponent cocrystals and salts (MCCS) is an active and contemporary theme in the crystal engineering of pharmaceutical crystal forms. The self-assembly process of multiple molecular components to an ordered and organized crystalline structure becomes increasingly difficult and complex as more than two molecules are present, e.g., ternary, quaternary, and higher-order cocrystals (HOC). One of the most frequent synthetic pathways to promote the self-assembly is mechanochemistry, assisted by a small amount of solvent added. Herein we report a comparative study of two mechanochemical routes on a series of ternary drug systems, halogen bonded ternary cocrystals and quaternary molecular cocrystals: (1) the sequential addition of components in different orders, referred to as the M1 method. The nth component is added to the pre-formed adduct of n − 1 remaining components. (2) The addition of all the components (n) in a single step, referred to as the M2 method. In both methods solvent drop grinding (SDG) or liquid-assisted grinding (LAG) manual operation were used. An excellent match of the experimental PXRD pattern from M1 and M2 procedures with that of the calculated PXRD pattern calculated from single-crystal X-ray diffraction (SC-XRD) data was noted for a majority of the systems tested. The role of crystal seeds/nuclei in forming the multicomponent crystalline products was established under optimal conditions in a single-step synthetic protocol. Concurring positive results on quaternary systems validate the applicability of this method to HOCs. When in a few cases complete transformation to the ternary or quaternary phase was not observed after manual grinding, in such systems ball-mill grinding (BMG) proved to complete the cocrystallization. A simple, efficient and scalable grinding method for MCCS is reported which can be extended to higher-order multicomponent cocrystals.