Exploring the Supramolecular Interactions and Thermal Stability of Dapsone:Bipyridine Cocrystals by Combining Computational Chemistry with Experimentation

[Image: see text] The application of computational screening methodologies based on H-bond propensity scores, molecular complementarity, molecular electrostatic potentials, and crystal structure prediction has guided the discovery of novel cocrystals of dapsone and bipyridine (DDS:BIPY). The experimental screen, which included mechanochemical and slurry experiments as well as the contact preparation, resulted in four cocrystals, including the previously known DDS:4,4′-BIPY (2:1, CC(44)-B) cocrystal. To understand the factors governing the formation of the DDS:2,2′-BIPY polymorphs (1:1, CC(22)-A and CC(22)-B) and the two DDS:4,4′-BIPY cocrystal stoichiometries (1:1 and 2:1), different experimental conditions (such as the influence of solvent, grinding/stirring time, etc.) were tested and compared with the virtual screening results. The computationally generated (1:1) crystal energy landscapes had the experimental cocrystals as the lowest energy structures, although distinct cocrystal packings were observed for the similar coformers. H-bonding scores and molecular electrostatic potential maps correctly indicated cocrystallization of DDS and the BIPY isomers, with a higher likelihood for 4,4′-BIPY. The molecular conformation influenced the molecular complementarity results, predicting no cocrystallization for 2,2′-BIPY with DDS. The crystal structures of CC(22)-A and CC(44)-A were solved from powder X-ray diffraction data. All four cocrystals were fully characterized by a range of analytical techniques, including powder X-ray diffraction, infrared spectroscopy, hot-stage microscopy, thermogravimetric analysis, and differential scanning calorimetry. The two DDS:2,2′-BIPY polymorphs are enantiotropically related, with form B being the stable polymorph at room temperature (RT) and form A being the higher temperature form. Form B is metastable but kinetically stable at RT. The two DDS:4,4′-BIPY cocrystals are stable at room conditions; however, at higher temperatures, CC(44)-A transforms to CC(44)-B. The cocrystal formation enthalpy order, derived from the lattice energies, was calculated as follows: CC(44)-B > CC(44)-A > CC(22)-A.