The extensive solid-form landscape of sulfathiazole: geometrical similarity and interaction energies

Abstract

A set of 96 crystal structures containing sulfathiazole (SLFZ) is presented, comprising 52 new crystal structures and 39 structures retrieved from the Cambridge Structural Database. The set comprises five polymorphs, 59 co-crystals, 29 salts and three other structures, providing one of the most extensive solid-form landscapes established for a single active pharmaceutical ingredient. The crystal structures are energy-minimised using DFT-D calculations to yield a standardised set. Geometrical comparisons are made using the programs CrystalCMP, COMPACK and XPac, and the results are combined and compared. Consistent conclusions are drawn on full 3-D isostructurality within the set, identifying a group of 18 isostructural co-crystals, and 11 further isostructural groups of salts or co-crystals comprising two or three structures. Aside from the fully isostructural groups, common 2-D supramolecular constructs (SCs) are restricted to groups of only two or three structures and there are no 2-D SCs that are observed especially frequently. Transferable 1-D SCs are more common, and examples are identified based on hydrogen-bonded and non-hydrogen bonded interactions between SLFZ molecules. Closely-related 1-D SCs comprising translated SLFZ molecules linked by hydrogen bonds are found in one polymorph and almost half of the multi-component set. A comparison of the five SLFZ polymorphs and the 91 multi-component crystal structures identifies several pairwise interactions between SLFZ molecules that are present in one of the polymorphs and at least one multi-component structure. A centrosymmetric R²₂(8) N–H⋯N hydrogen-bonded pair occurs in one polymorph and approximately 80% of the co-crystals. Intermolecular interaction energies, calculated using the PIXEL method, show that this R²₂(8) dimer is by far the most stabilising pairwise interaction in any structure. In general, however, there is no straightforward correlation between intermolecular interaction energies of the pairwise motifs in the polymorphs and their frequency of occurrence in the multi-component set. The extensive SLFZ set provides a challenge for systematic geometrical comparison of crystal structures, and some observations are made on the methodology and consistency of the applied programs.