刘瑞丽 杨亚玺 陈东英. 5R-5-羟基雷公藤内酯醇的晶型制备与表征J. 药学学报, 2011,46(11): 1357-1360.
引用本文: 刘瑞丽 杨亚玺 陈东英. 5R-5-羟基雷公藤内酯醇的晶型制备与表征J. 药学学报, 2011,46(11): 1357-1360.
LIU Rui-Li, Yang-E-Xi, Chen-Dong-Yang. Polymorphism of the 5R-5-hydroxytriptolideJ. 药学学报, 2011,46(11): 1357-1360.
Citation: LIU Rui-Li, Yang-E-Xi, Chen-Dong-Yang. Polymorphism of the 5R-5-hydroxytriptolideJ. 药学学报, 2011,46(11): 1357-1360.

5R-5-羟基雷公藤内酯醇的晶型制备与表征

Polymorphism of the 5R-5-hydroxytriptolide

  • 摘要:

    本文对用于治疗类风湿性关节炎的候选新药5R-5-羟基雷公藤内酯醇 (LLDT-8) 进行了晶型研究。采用蒸发结晶和溶析结晶法对LLDT-8进行了晶型制备筛选, 并采用粉末X射线衍射 (p-XRD)、差示扫描量热分析 (DSC)、热重分析 (TG)、红外光谱 (IR) 以及单晶X射线衍射分析技术对制备得到的LLDT-8样品进行了晶型表征。结果表明上述制备方法得到的LLDT-8晶体样品, p-XRDIRDSCTG图谱均一致, 其中粉末X射线衍射八强峰位于7.58°8.14°8.66°15.46°16.46°29.54°31.16° 38.26°; 红外光谱吸收峰位于3 471.32 962.22 887.01 762.61 677.81 432.91 365.41 247.71 080.01 031.7877.5 cm−1; DSC结合TG分析结果显示LLDT-8271.2 左右发生分解。单晶X射线衍射分析表明LLDT-8晶体属单斜晶系, 空间群为P2 (1); 晶胞参数a = 11.460 1 (11), b = 6.320 5 (6), c = 13.028 1 (12), α = 90.00, β = 115.557 (2), γ = 90.00; 分子间形成氢键。进一步通过不同极性溶剂中的匀浆实验进行晶相的稳定性实验, 其粉末X射线衍射图谱未发生变化, 说明其晶型未发生转变, 表明现有晶型具有较好的稳定性, 有利于保证临床疗效的一致性。

     

    Abstract:

    5R-5-hydroxytriptolide (LLDT-8) is a new drug candidate which is in clinical trial treating rheumatoid arthritis.  Polymorph screening of the compound was carried out in this study.  Polymorph of LLDT-8 was prepared by evaporative crystallization and antisolvent crystallization methods and was characterized by powder X-ray diffraction (p-XRD), infrared spectrometry (IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TG).  It was found that p-XRD patterns, DSC curves, TG curves and IR spectra of the LLDT-8 samples prepared by the above recrystallization methods were all consistent.  The 2θ of main peaks in the p-XRD patterns appeared at 7.58°, 8.14°, 8.66°, 15.46°, 16.46°, 29.54°, 31.16° and 38.26°, while the infrared absorption peaks appeared at 3 471.3, 2 962.2, 2 887.0, 1 762.6, 1 677.8, 1 432.9, 1 365.4, 1 247.7, 1 080.0, 1 031.7 and 877.5 cm−1.  LLDT-8 was decomposed at 271.2 based on the determination from DSC and TG.  It was showed in single crystal X-ray diffraction study that LLDT-8 crystal was monoclinic with the space group being P2 (1).  The cell parameters were found to be: a = 11.460 1 (11), b = 6.320 5 (6), c = 13.028 1 (12), α = 90.00, β = 115.557 (2) and γ = 90.00.  The crystal was a hydrogen-bonded dimmer.  The slurry experiments, which were further conducted in solvents with different polarities, confirmed the stability of solid state of LLDT-8 based on the p-XRD determination.  The polymorph of LLDT-8 made assurance of its efficacy consistence during its clinical trials.

     

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