Insights into the Solid-State Landscape of Iguratimod, a Disease-Modifying Antirheumatic Drug

This work significantly expands the understanding of the solid-form landscape of iguratimod, a nonsteroidal anti-inflammatory disease-modifying antirheumatic drug (DMARD) used to treat rheumatoid arthritis, with promising potential for other therapeutic applications. Comprehensive solid-form screening by melt cooling, grinding, and crystallization from solutions, complemented by mechanochemical exploration of cocrystals and coamorphous phases, revealed rich solid-form diversity. Nicotinamide, sulfasalazine, and folic acid were selected as pharmaceutically relevant coformers, while picolinamide, isonicotinamide, and benzamide were employed to provide molecular-level insight into the recognition phenomena. Three polymorphs (I, II, and III, the latter reported for the first time) were identified, and conditions for their preparation were established. Crystallization from solutions predominantly yielded form II, and two new solvates, with methanol and acetonitrile, were discovered. Equimolar cocrystals of iguratimod with benzamide, picolinamide, and nicotinamide were obtained, with the nicotinamide cocrystal being the first structurally resolved iguratimod cocrystal reported to date. In contrast, attempts to form a cocrystal with isonicotinamide failed, underscoring the specificity of molecular recognition in this system. Neat grinding produced amorphous iguratimod and multicomponent amorphous phases with nicotinamide, sulfasalazine, and folic acid, showing enhanced kinetic stability over that of the pure amorphous drug. This highlights multicomponent amorphous phases as promising routes to stabilize amorphous drugs.