Solid State Characterizations and Analysis of Stability in Azelnidipine Polymorphs

被引:11
作者
Li, Dong [2 ]
Wang, Min [1 ]
Yang, Caiqin [1 ]
Wang, Jing [1 ]
Ren, Guodong [2 ]
机构
[1] Hebei Med Univ, Sch Pharmaceut Sci, Shijiazhuang 050017, Peoples R China
[2] Hebei Univ, Coll Life Sci, Baoding 071002, Peoples R China
关键词
azelnidipine; polymorph; solid state NMR; THz spectrum; solubility; thermodynamics; DRUG; TRANSFORMATION; SPECTROSCOPY; CRYSTALS;
D O I
10.1248/cpb.c12-00245
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Azelnidipine, a new dihydropyridine calcium ion antagonist, was protected by patent in Japan. In present study, identifications of the crystal phases, including two polymorphic and a pseudopolymorphic crystal forms of azelnidipine, were attempted using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), IR-, Raman-, THz-, and ss-NMR-spectroscopy. PXRD identified three different crystal forms, while, spectroscopy analysis provided the information of crystal structure involving intermolecular interactions. The transition thermodynamics of the azelnidipine polymorphs were extensively investigated by solubility method. The solubility of the two polymorphs of alpha and beta in 50% ethanol at 25, 31, 37, 42, and 49 degrees C was investigated; the values obtained were used to calculate the thermodynamic parameters of the transition reaction. The temperature of polymorphic phase transition in 50% ethanol was 50.78 degrees C, and the values of Delta G(alpha,beta)(0), Delta H-alpha,beta(0), and Delta S-alpha,beta(0) at 25 degrees C were -1.18 kJ.mol(-1), -14.81 kJ.mol(-1), and -45.73 J.mol(-1).K-1, respectively. Form beta was proved to be thermodynamic stable form at room temperature and enantiotropically related with form alpha. The kinetics of the solid-state decomposition, studied using DSC analysis, showed that the activation energies of decomposition of the polymorphs alpha and beta at high temperatures were 148.67 and 151.93 kJ.mol(-1).
引用
收藏
页码:995 / 1002
页数:8
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