Conformational Polymorphism in Oxybuprocaine Hydrochloride

Abstract

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 P 2 1 / 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 I 2/ 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 ( P 2 1 / a ). This transition ( T trs: −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 U- and 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.