Concomitant Polymorphs of the Antihyperlipoproteinemic Bezafibrate

The two polymorphic forms α and β of the active pharmaceutical ingredient 2-[4-[2-(4-chlorobenzamide)ethyl]phenoxy]-2-methylpropanoic acid (bezafibrate) have been reinvestigated and fully characterized by optical microscopy, infrared spectroscopy, differential scanning calorimetry, thermal gravimetric analysis, variable temperature X-ray powder diffraction, and single crystal X-ray diffraction. Form α is obtained from ethanol, whereas form β can be grown from a 2-butanone solution provided that stoichiometric quantities of iso-nicotinamide are present. Without iso-nicotinamide, both forms grow concomitantly from a 2-butanone solution. The two forms are related enantiotropically, with form β converting to form α at 160.7 °C. Form β is the more stable form at room temperature and at temperatures below the transition temperature of 160.7 °C. The two polymorphs arise from conformational differences which result in vastly different hydrogen bonding interactions and subsequent crystal packing in the solid state. The crystal habits of the two forms reflect the different solid-state packing observed by single crystal X-ray diffraction. Computational modelling calculations on the energy of the conformations have been carried out in the solid state and compared to those energy minima calculated in the gas phase.