Exploring the Solid-State Landscape of Atropisomers in (±)-Lesinurad: Insights into Crystallographic Analysis, Transformation Behavior, and Dissolution Performance

Axial chirality is a unique form of chirality characterized by restricted rotation around a covalent bond due to steric or electronic hindrances, a phenomenon known as atropisomerism. The separation of (+)- and (−)-lesinurad from the racemic mixture suggests a potential advantage of (+)-lesinurad in treating hyperuricemia and gout due to its enhanced therapeutic efficacy. Although the crystalline structure profoundly affects a compound’s physicochemical properties, the crystallographic landscapes of (+)- and (−)-lesinurad have yet to be explored. This study delves into the solid-state features of these atropisomers, identifying several novel polymorphic forms: two anhydrous polymorphs (forms A and B) and five solvates (SACE-H2O, SETH, SNPA, SIPA, SMTBE) for (+)-lesinurad and one solvate for (−)-lesinurad, all characterized extensively. For the first time, the crystal structures of six solvates and form II of racemic lesinurad are elucidated using single-crystal diffraction, revealing that SACE-H2O, SETH, SNPA, and SIPA are isostructural. Notably, form II of racemic lesinurad undergoes a reversible single-crystal to single-crystal transformation at around 94 °C, transitioning between two polymorphs: a room-temperature variant (form II) and a high-temperature variant (form II-HT). Furthermore, we examined the equilibrium solubility and dissolution behavior of forms II, A, and B in a pH 6.8 aqueous solution, discovering enhanced solubility and dissolution rates for forms A and B compared with form II of racemic lesinurad.