Slurry in Deep Eutectic Solvents: A Green and Efficient Cocrystal Synthesis Approach via Solvate Formation

Cocrystallization has emerged as a promising strategy to obtain new solid forms of a given compound with tailored properties. In this study, a green and efficient slurry method was proposed for cocrystal synthesis using deep eutectic solvents (DESs), a new generation of green solvents, as both the solvent and reactant (i.e., cocrystal coformer). The method was subjected to cocrystal screening of carbamazepine in a series of choline chloride (ChCl) DESs and compared with the slurry method in organic solvents. The results indicate that as the cocrystal formation by a slurry method in DESs is similar to the solvate formation in organic solvents, it can overcome the issues of traditional cocrystallization in organic solvents, such as individual crystallization caused by solubility differences and the formation of unwanted solvates, thereby improving the screening efficiency of cocrystals. Further, a DES of ChCl and urea was used for cocrystal screening for 30 compounds, and all 30 cocrystals with urea were successfully synthesized after the reaction temperature and water contents of DES were adjusted, further confirming the applicability of the slurry method to various compounds. Finally, the artificial bee colony algorithm, one method of artificial intelligence, was adopted to search for low-energy stable structures of the cocrystal precursors in ChCl-urea DESs. Such given structures combined with the hydrogen bond analysis by the Atoms in Molecules theory indicated that the strong interactions between the drug and ChCl could restrain its cocrystal formation with urea. In conclusion, the slurry method based on DESs proposed in this study can overcome the obstacles of the slurry method in organic solvents, which is a green, efficient, and promising alternative method for cocrystal synthesis.