An Efficient and\nOrganic Solvent-Free Slurry Method\nfor Cocrystal Synthesis: Using Betaine Deep Eutectic Solvents as Dual-Functional\nSolvents and Reactants

The cocrystal strategy has been widely applied in the\ndevelopment\nof solid chemicals due to its potential to achieve tailored properties.\nHowever, traditional cocrystallization heavily relies on organic solvents,\nposing environmental and health risks and limited efficiency due to\nunwanted solvate formation and individual crystallization events.\nOur group has recently proposed a novel and efficient slurry method\nfor cocrystal synthesis using deep eutectic solvents (DESs), a new\ngeneration of green and sustainable solvents, as both solvents and\nreactants (i.e., cocrystal coformers). To enrich the variety of DESs\nand systematically explore the impact factors on cocrystal formation,\na series of betaine (BET) DESs were synthesized and subjected to cocrystal\nscreening herein. The findings reveal that the slurry method in DESs\nexhibits higher efficiency than the conventional slurry in organic\nsolvents. In the DESs of BET-urea-H<sub>2</sub>O, all compounds produced\nbinary cocrystals with urea or BET, or ternary cocrystals with urea\nand BET, except for a few highly soluble systems. However, target\ncocrystals (cocrystals with urea herein) can be obtained by modulating\nthe water content or ratio of DESs to manipulate the intermolecular\ninteractions within the DESs. Finally, the Artificial Bee Colony algorithm\nand the theory of Atoms in Molecules were employed to investigate\na possible cocrystal formation mechanism in DESs. Overall, the slurry\nmethod in DESs effectively overcomes the challenges of traditional\ncocrystallization in organic solvents, providing a green, sustainable,\nand efficient approach to cocrystal synthesis.