SOLID-STATE CHARACTERIZATION OF CHLORDIAZEPOXIDE POLYMORPHS

A novel crystal form (form II) of the benzodiazepine chlordiazepoxide is reported. The new polymorphic phase was characterized and distingui shed from the standard form (form I) by X-ray diffractometry, differen tial scanning calorimetry, infrared spectroscopy, microscopy, solution calorimetry, and solid-state nuclear magnetic resonance. The formatio n of form II was dependent on the crystallizing solvent, being the pre dominant form isolated from methanol. Recrystallization from other alc oholic solutions (ethanol, propanol, and butanol) and toluene yielded form I. Differential scanning calorimetry and powder X-ray diffraction indicated that the two forms were enantiotropically related with a tr ansition of form II to form I occurring between 200 and 225 degrees C. Visual examination by hot stage microscopy in this temperature range revealed a dramatic solid-state transition. Single-crystal X-ray analy sis was performed on form II which was found to crystallize in the tri clinic space group P (I) over bar with a = 10.736(2) Angstrom, b = 16. 921(4) Angstrom, c = 17.041(4) Angstrom, alpha = 100.76(1)degrees, bet a = 95.27(1)degrees, gamma = 97.53(1)degrees, Z = 8, and d(cal) = 1.33 g/cm(3). When compared with the published crystal structure of form I , the cell symmetry, volume, and density were similar. Both structures consisted of four crystallographically independent molecules linked i n pairs through intermolecular hydrogen bonding. Differences were obse rved in the packing arrangement of the dimers in the polymorphs. The s mall heat of transition calculated from solution calorimetry (1.5 kJ m ol(-1)) was sufficient to effect a crystallographic rearrangement of t he dimers.