Multicomponent crystals of nitroimidazole drugs with trithiocyanuric acid: two competing drug–coformer supramolecular motifs

Cocrystal structures formed by trithiocyanuric acid (TTCA) and selected nitroimidazole derivatives, dimetridazole (DMZ·TTCA, C 5 H 7 N 3 O 2 ·C 3 H 3 N 3 S 3 ), tinidazole (TNZ·TTCA·MeOH, C 8 H 13 N 3 O 4 S·C 3 H 3 N 3 S 3 ·CH 3 OH), ornidazole (ONZ·TTCA·MeOH, C 7 H 10 ClN 3 O 3 ·C 3 H 3 N 3 S 3 ·CH 3 OH, and ONZ·TTCA·H 2 O, C 7 H 10 ClN 3 O 3 ·C 3 H 3 N 3 S 3 ·H 2 O) and ronidazole (RNZ·TTCA and 2RNZ·2TTCA, both C 6 H 8 N 4 O 4 ·C 3 H 3 N 3 S 3 ) were investigated to identify recurring drug–coformer aggregation patterns and factors determining supramolecular architecture. Structural analysis showed that TTCA adopts two principal supramolecular motifs: the hydrogen-bonded R 2 2 (8) dimer and linear chain assemblies. Two dominant drug–coformer binding schemes were identified. The first involves N—H...N hydrogen bonding in the para position relative to the TTCA dimer, leading to four-molecule assemblies, which are accompanied by heteronuclear hydrogen bonding in the ortho position. The second motif is associated with TTCA linear chains, where drug molecules are linked through N—H...N interactions and further stabilized by direct intermolecular or solvent-mediated hydrogen bonding. The polymorphic structure 2RNZ·2TTCA combines both supramolecular strategies within a single-crystal architecture. Hirshfeld surface analysis and intermolecular energy calculations confirmed the importance of hydrogen-bond competition in determining the crystal packing and supramolecular organization in TTCA-based cocrystals.