Solid state characterization of E2101, a novel antispastic drug.
E2101, a novel antispastic drug, was found to exist in at least two polymorphs that were confirmed by X-ray powder diffraction (XRD). These two species are designated forms I and II. The physicochemical and thermodynamic properties of these polymorphs were characterized by variable temperature XRD, thermal analysis, hygroscopicity measurements, and dissolution studies. The transition temperature was also estimated from the solubilities determined at various temperatures. The E2101 polymorphs were anhydrous and adsorbed little moisture under high humidity conditions. The melting onsets and heats of fusion for form I were 148.1 +/- 0.2 degrees C and 38.2 +/- 1.0 kJ/mol, respectively, and for form II were 139.8 +/- 0.4 degrees C and 35.2 +/- 0.5 kJ/mol, respectively. The intrinsic dissolution rate of form II in JP 2 medium was 1.5-fold faster than that of form I, corresponding to the rank order of the aqueous solubility and the enthalpy of fusion. Accordingly, form I was thought to be thermodynamically more stable than form II and thus suitable for further development. According to the thermal analysis and variable temperature XRD results, the recrystallization of form I occurred at approximately 145 degrees C after form II melted, however, no crystal transition behavior was observed below the lower melting point. The DSC thermograms at various heating rates and van't Hoff plots from the solubility studies indicated that the polymorphic pair would be monotropic.
Kushida
Ikuo
I
Eisai Company, Ltd., Analytical Research Laboratories, 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan. i-kushida@hhc.eisai.co.jp
Ashizawa
Kazuhide
K
D000081:Acetamides / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D006813:Humidity; D007700:Kinetics; D009125:Muscle Relaxants, Central / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D012995:Solubility; D012997:Solvents; D013816:Thermodynamics; D014961:X-Ray Diffraction
D000081:Acetamides; C469845:E 2101; D009125:Muscle Relaxants, Central; D010880:Piperidines; D012997:Solvents