Crystallization is typically highly sensitive to even minor structural differences in target molecules. As a result, obtaining crystals of complex compounds often requires extensive trial-and-error experiments for each target molecule. We recently reported a second-generation crystalline sponge (2G-CS), in which a coordination cage is fixed within a crystal lattice. In the 2G-CS, target molecules are first encapsulated within the cage in solution, followed by salt formation with a symmetry-mismatched polyanion, leading to the formation of single crystals suitable for structure analysis. However, practical implementation still requires case-by-case optimization of crystallization conditions. In this study, we demonstrate that combining the cage with a specific polyanion enables crystallization of a wide range of structurally distinct guest molecules under a single set of standardized conditions. In a test set comprising 39 guest molecules, 31 cases (80%) were successfully crystallized using the same conditions. These examples include polar, medium-sized, and structurally complex molecules, most of which are of pharmaceutical interest. Crystal structures showed that the polyanion induced a predominant packing type for cages and anions in crystals. We suggest that this recurrent packing type may contribute to the ability to obtain crystals under standardized conditions despite variations in guest structures.
He et al. (2026) studied this question.