Attempting to grow a ternary cocrystal from solution often results in two of the components forming a binary cocrystal, while leaving the third component still dissolved in solution. In practice, merely changing the solvent or ratios of the components to favor the ternary cocrystal is frequently an ineffective strategy. The purpose of this research was to determine if ternary cocrystals and their competing binary cocrystals could be synthesized in the absence of solvent. Four ternary cocrystals that had been recently designed and synthesized, each containing a carboxyphenol as a ditopic hydrogen-bond donor and two types of acceptor compounds (an amidine and a pyridine), were selected. Initially the four known ternary cocrystals and their competing binary cocrystals were grown from solution, confirming their stoichiometry through solution pNMR and establishing a fingerprint of each cocrystal by infrared spectroscopy. Attempts were made to regenerate the ternary cocrystals and competing binary cocrystals through one or more of the following non-solution methods: a) neat grinding b) liquid-assisted grinding or c) melting. Two of the four known ternary cocrystals were solvates and consequently their synthesis could only be attempted through liquid assisted grinding. Synthesis of the other two ternary cocrystals was attempted using all the three non-solution methods. Product identity was determined by comparison of the infrared spectra to that of previously identified crystal phases, and all ternary non-solution experiments yielded products whose infrared spectra matched those of the ternary cocrystals obtained from solution. Six known binary cocrystals were regenerated by non-solution methods. Surprisingly, the binary non-solution experiments yielded eleven products whose infrared spectra differed significantly from all previously observed binary phases.

Removing the solubility barrier in ternary cocrystal formation

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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