An Efficient and Organic Solvent-Free Slurry Method for Cocrystal Synthesis: Using Betaine Deep Eutectic Solvents as Dual-Functional Solvents and Reactants

The cocrystal strategy has been widely applied in the development of solid chemicals due to its potential to achieve tailored properties. However, traditional cocrystallization heavily relies on organic solvents, posing environmental and health risks and limited efficiency due to unwanted solvate formation and individual crystallization events. Our group has recently proposed a novel and efficient slurry method for cocrystal synthesis using deep eutectic solvents (DESs), a new generation of green and sustainable solvents, as both solvents and reactants (i.e., cocrystal coformers). To enrich the variety of DESs and systematically explore the impact factors on cocrystal formation, a series of betaine (BET) DESs were synthesized and subjected to cocrystal screening herein. The findings reveal that the slurry method in DESs exhibits higher efficiency than the conventional slurry in organic solvents. In the DESs of BET-urea-H2O, all compounds produced binary cocrystals with urea or BET, or ternary cocrystals with urea and BET, except for a few highly soluble systems. However, target cocrystals (cocrystals with urea herein) can be obtained by modulating the water content or ratio of DESs to manipulate the intermolecular interactions within the DESs. Finally, the Artificial Bee Colony algorithm and the theory of Atoms in Molecules were employed to investigate a possible cocrystal formation mechanism in DESs. Overall, the slurry method in DESs effectively overcomes the challenges of traditional cocrystallization in organic solvents, providing a green, sustainable, and efficient approach to cocrystal synthesis.