Structural and Computational Insights into Cocrystal Interactions: A Case on Cocrystals of Antipyrine and Aminophenazone

This study aimed to gain insight into cocrystal interactions through solid-state characterization and theoretical computation. We formulated four novel cocrystalline phases of antipyrine (AN) and aminophenazone (AM) with coformer fumaric acid (FA) and saccharin (SA), respectively. The cocrystals were prepared by solvent-assisted grinding and slow evaporation. Solid-state characterization was conducted through differential scanning calorimetry, powder X-ray diffraction, and single-crystal X-ray diffraction. Crystal structure analysis showed that AN and SA created a 1:1 cocrystal. However, the proton transfer reaction caused AM and SA to produce a 1:1 salt through charge-assisted strong hydrogen-bonding interactions between the quaternary ammonium cationic group and the carbonyl group. As expected, the presence of two carboxyl groups with the same property in FA indicated that AN and AM formed 2:1 cocrystals with FA. Density functional calculations indicated that H bond interactions in cocrystals mainly involved pairwise interactions in the global maxima and minima sites on molecular electrostatic potential surfaces, but this rule did not apply to the salt. In addition, the H-bond interaction was further explained by using the highest occupied molecular orbital, lowest unoccupied molecular orbital, Hirshfeld surface, and mutual penetration distances of the van der Waals surface.