Part of the Special Issue: Facets of Polymorphism in Crystals Conformational Polymorphism in Oxybuprocaine Hydrochloride

The structural and thermodynamic features of three polymorphic forms of the local anesthetic drug oxybuprocaine hydrochloride (OBPHC) were characterized by hot-stage microscopy, differential scanning calorimetry (DSC), pycnometry, Fourier transform infrared spectroscopy (FTIR), FT-Raman and solid-state NMR (SSNMR) spectroscopy as well as X-ray powder and single-crystal diffractometry. Mod II° crystallizes in the space group P21/n, is present in commercial products, and is the thermodynamically stable form at room temperature. Mod II° shows an endothermic transformation to mod I (mp 160 °C) at about 135 °C, indicating an enantiotropic relationship between these forms. Mod I (space group I2/a) shows a high kinetic stability and does not transform back to the more stable mod II° below the thermodynamic transition temperature (∼90 °C) on storage but does so in a solution-mediated process. Cooling mod I below -30 °C results in mod III (P21/a). This transition (Ttrs: -33 °C) is highly reversible, proving the enantiotropic relationship between mod III and mod I. OBPHC is a classic example of conformational polymorphism demonstrating the interplay of molecular interaction forces and conformational flexibility. Two basic types of conformers can be found in the different polymorphs. Only one U-type conformer is present in the asymmetric unit of mod I, whereas in mod III two U-type conformers and in mod II° a type Uand an unusually bent type I conformer can be found. Computational modeling of the isolated molecule suggests that the I-type conformer is more stable than the U-type conformers.