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 distinguished from the standard form (form I) by X-ray diffractometry, differential scanning calorimetry, infrared spectroscopy, microscopy, solution calorimetry, and solid-state nuclear magnetic resonance. The formation of form II was dependent on the crystallizing solvent, being the predominant form isolated from methanol. Recrystallization from other alcoholic 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 transition of form II to form I occurring between 200 and 225 degreesC. Visual examination by hot stage microscopy in this temperature range revealed a dramatic solid-state transition. Single-crystal X-ray analysis was performed on form II which was found to crystallize in the triclinic space group P1 with a = 10.736(2) A, b = 16.921(4) A, c = 17.041(4) A, alpha = 100.76(1) degrees, beta = 95.27(1) degrees, gamma = 97.53(1) degrees, Z = 8, and dcal = 1.33 g/cm3. 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 in pairs through intermolecular hydrogen bonding. Differences were observed in the packing arrangement of the dimers in the polymorphs. The small heat of transition calculated from solution calorimetry (1.5 kJ mol-1) was sufficient to effect a crystallographic rearrangement of the dimers.
Singh
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Pharmaceutical Technology, Department of Pharmacy, and Chemistry and Chemical Technology, University of Bradford, West Yorkshire, BD7 1DP, UK.
Marshall
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Shields
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York
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D002152:Calorimetry, Differential Scanning; D002707:Chlordiazepoxide / Q000737:chemistry*; D003460:Crystallization; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D017550:Spectroscopy, Fourier Transform Infrared; D013696:Temperature; D013818:Thermogravimetry; D014961:X-Ray Diffraction
D002707:Chlordiazepoxide