Hydrogen-bonding functionalities of selected azole drugs in multicomponent crystals with trithiocyanuric acid

Five new multicomponent crystalline forms of trithiocyanuric acid with azole active pharmaceutical ingredients (APIs) are described. The azole APIs include imidazole-derived econazole and luliconazole, as well as 1,2,4-triazole-derived isavuconazole, voriconazole and posaconazole, and the crystalline forms reported are econazolium trithiocyanurate, C₁₈H₁₆Cl₃N₂O⁺·C₃H₂N₃S₃⁻, luliconazole-trithiocyanuric acid (1/1), C₁₄H₉Cl₂N₃S₂·C₃H₃N₃S₃, isavuconazole-trithiocyanuric acid (1/1), C₂₂H₁₇F₂N₅OS·C₃H₃N₃S₃, voriconazole-trithiocyanuric acid-water (1/2/3), C₁₆H₁₄F₃N₅O·2C₃H₃N₃S₃·3H₂O, and posaconazole-trithiocyanuric acid (1/1), C₃₇H₄₂F₂N₈O₄·C₃H₃N₃S₃. The crystal architectures are analyzed in the context of the supramolecular assemblies they generate. Robust acid-base pairs, governed by N-H...N hydrogen bonds, are combined into well-defined four-molecule assemblies through N-H...S hydrogen bonds, which form the characteristic ring R²₂(8) synthon between two TTCA molecules. Additional N-H...O or N-H...S interactions, involving the remaining azole functionalities, propagate these four-molecule units into extended chain motifs, columns or layered architectures. To elucidate the nature of these key interactions, a QTAIM analysis was performed and pairwise interaction energies were evaluated to clarify the stability and energetics of the resulting assemblies. The influence of chiral azole molecules, their specific hydrogen-bond functionalities and the solvation conditions on the formation of the supramolecular motifs is also discussed.