Prolific Solid-Form Landscape of Probucol: Crystallization from Solutions

In this work, the solid-form landscape of probucol is investigated by crystallization from solutions in various solvents (methanol, ethanol, acetonitrile, and dichloromethane), under different experimental conditions. A total of four polymorphs were obtained from ethanol, changing the experimental conditions (FI to FIV), which were characterized by thermal analysis, infrared spectroscopy, and powder and single-crystal X-ray diffraction. Form I is the stable polymorph at least for T ≥ −15 °C. FIII and FIV, identified in this work for the first time, could only be obtained after long induction times (weeks or months) at subambient conditions. A comparison of the crystal structures of the polymorphs shows that the molecular flexibility and hindrance of the hydroxyl groups are relevant in the diversity of solid forms of probucol. FI (and FIV), FII, and FIII are conformational polymorphs: bent conformations (central chain dihedral angles) for FI, FIII, and FIV and a straighter conformation in FII, which has a high degree of void volume. Three solvates were obtained by crystallizations from methanol, acetonitrile, and dichloromethane, with low induction times, which are more stable than FI. These solvates (crystal structures solved in this work) are almost isostructural to FII, with the solvent molecules located in FII voids.