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

Abstract

The synthesis of multi-component 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 multi-component 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 scaleable grinding method for MCCS is reported which can be extended to higher order multi-component cocrystals.