Exploring the Crystal Structure Landscape of Sulfasalazine through Various Multicomponent Crystals

Abstract

Sulfasalazine is used as an anti-inflammatory drug to treat large intestine diseases and atrophic arthritis. In the solid state, two tautomers are known: an amide tautomer (triclinic polymorph) and an imide tautomer (monoclinic polymorph). Crystallization of six new multicomponent solids of sulfasalazine with three cocrystal formers and three salt formers has been achieved by slurry, liquid-assisted grinding and slow evaporation methods. All of the solid forms are characterized by X-ray diffraction techniques, thermal analysis, and Fourier transform infrared spectroscopy. The crystal structural analysis reveals that two sulfasalazine molecules or anions arrange in a head-to-head fashion involving their pyridyl, amide, and sulfonyl groups in an R 2 2(7):R 2 2(8):R 2 2(7) motif. This is the key structural unit appearing in both sulfasalazine imide polymorph and all six multicomponent crystals. In addition, sulfasalazine exists in the amide form in all unsolvated multicomponent crystals obtained in this work and adopts the imide tautomer in the solvated cocrystals and salt. Hirshfeld surface analysis and the associated two-dimensional (2D) fingerprint plots demonstrate that sulfasalazine has significant hydrogen bond donor capability when cocrystallized and is a significant hydrogen bond acceptor in the salts. The frontier molecular orbital analysis indicates that sulfasalazine cocrystals are chemically more stable than the salts.

Weak but Vital: The Role of Solvents in Crystal Packing and Coassembly for the Formation of Multicomponent Salt Solvates of Clozapine with Oxalic Acid

“…The thermal stability of paliperidone · nicotinic acid · 2H 2 O · 2MeOH was improved by about 40 K compared to pure paliperidone, while the solubility and dissolution rate of paliperidone had also been significantly enhanced in a simulated human environment via the paliperidone salt solvate form (883.78 times solubility in pure water while 166.57 times in pH = 6.8). Huang et al found a salt solvate sulfasalazine·imidazole·MeCN, but they only analyzed the structure, which crystallized with one sulfasalazine – anion, one imidazole + cation, and one acetonitrile molecule in the asymmetric unit. Jiao et al synthesized four drug–drug salt solvates of piroxicam (PX), tenoxicam (TNX), lornoxicam (LNX), and meloxicam (MLX) with norfloxacin (NF) and ciprofloxacin (CIP), i.e., MLX•CIP•ACN, PX•NF•2MeOH, LNX•NF•H 2 O•0.3MeOH, and TNX•CIP•2MeOH, with approximately 3.0, 1.4, 1.6, and 1.1 times solubility higher than the original pure components, respectively.…”