Shape and Polarity in Co-crystal Formation: Database Analysis and Experimental Validation

Abstract

Supramolecular synthons provide the most important and successful approach to the rational design of co-crystals. Yet, the relatively low success rate of co-crystal screening experiments demonstrates that the availability of appropriate synthons is only one of many factors that influence co-crystallisation. The aim of our work was to identify other factors and to use them in developing design strategies that are complementary to supramolecular synthons. Co-crystal structures were extracted from the Cambridge Structural Database and molecular descriptors were calculated for each molecule in this data set. Statistical analysis of the resulting database revealed that co-crystals are usually formed by molecules that have similar shapes and polarities. Observed distributions of the corresponding descriptors were used to derive criteria for likely co-crystal formation. Screening experiments on more than 200 compound pairs were analysed to test the usefulness of these criteria. The results show that performing only the experiments that match the criteria can significantly increase the success rate of screening. The relative influence of supramolecular synthons and shape similarity was investigated by screening experiments in which both the shapes of the molecules and the strength of the supramolecular heterosynthons were varied systematically. Co-crystals were obtained reliably if both strong synthons and similar molecular shapes favoured their formation. Molecules of dissimilar shapes co-crystallised only when extremely strong synthons could be formed. Mismatch between expected co-crystallisation behaviour and experimental results for four steroids led to the recognition of a new specific interaction between the steroid α-face and the π-electron density of aromatic co-formers.