A Journey through Solvent Space: New Solvates of Probucol

Abstract A systematic expansion of the solid-form landscape of the antihyperlipidemic drug probucol was carried out using a diverse set of solvents spanning a broad physicochemical space, providing insight into the formation of probucol solvated forms. Five new solvates were discovered (with cyclohexane, carbon tetrachloride, tetrahydrofuran, 1,4-dioxan and dimethylsulfoxide), and comprehensively characterized, including their crystal structures, infrared spectra, thermal behaviour and solid-state stability. The results show that solvate formation is governed primarily by solvent molecular size and shape, together with hydrogen-bond acceptor ability. Solvates were obtained with small apolar solvents, and with small hydrogen-bond accepting molecules capable of accessing the sterically hindered hydroxyl groups of probucol and forming stabilizing hydrogen-bonding intermolecular interactions. In contrast, solvate formation was not observed for hydrogen-bond donor solvents or for larger, more flexible solvent molecules. The stability of the solvated forms was assessed under controlled temperature and relative humidity conditions, revealing a common dessolvation pathway (except for the dimethylsulfoxide solvate, which remained stable after 15 days), albeit at different rates, leading to the formation probucol polymorph II. Competitive slurry experiments carried out in selected binary solvent mixtures confirmed that the domains of stability of the solvates are determined by their solubilities in the respective pure solvent.