5R-5-羟基雷公藤内酯醇的晶型制备与表征

Polymorphism of the 5R-5-hydroxytriptolide

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,其p-XRD、IR、DSC和TG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°和38.26°;红外光谱吸收峰位于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和877.5 cm-1;DSC结合TG分析结果显示LLDT-8在271.2℃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。

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.