Possible Failures in Co-crystal Search

Co-crystallization experiments may fail for a number of reasons. First of all, the discovery of a co-crystal under equilibrium conditions is excluded when no thermodynamically stable co-crystal exists, that is, when no co-crystal phase is present in the binary phase diagram. Under these circumstances, a co-crystal will not appear in the ternary system either, no matter which solvent or other crystallization parameters are chosen. 

The formation of a co-crystal may also be compromised by the competition with solvate formation of any of the species under consideration, that is, A, B, or AB. Depending on the concentrations of the components involved, the 

Competition of co-crystal formation with solvate formation, (a) of component A and (b) of the co-crystal AB. The dashed lines indicate the situation without solvate formation. 

Strategies to lower the risk of solvate formation include an increase in temperature (the desolvated state is typieally favored by entropy) and a decrease in the solvent activity. The latter ean be achieved by lowering the solvent concentration by using the highest possible concentration of the non-solvate-forming component and employing solvent mixtures. 

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