药学学报, 2021, 56(2): 577-584
引用本文:
熊婧, 徐德忠, 徐昕怡, 吕扬, 杨世颖, 王嗣岑. 沙库巴曲缬沙坦钠共晶表征方法的建立研究[J]. 药学学报, 2021, 56(2): 577-584.
XIONG Jing, XU De-zhong, XU Xin-yi, L� Yang, YANG Shi-ying, WANG Si-cen. Establishment of a cocrystal characterization method for sacubitril valsartan sodium[J]. Acta Pharmaceutica Sinica, 2021, 56(2): 577-584.

沙库巴曲缬沙坦钠共晶表征方法的建立研究
熊婧1,2, 徐德忠1, 徐昕怡3, 吕扬4, 杨世颖4, 王嗣岑2
1. 中国食品药品检定研究院, 化学药品质量研究与评价重点实验室, 北京 102629;
2. 西安交通大学药学院, 陕西 西安 710061;
3. 国家药典委员会, 北京 100061;
4. 中国医学科学院、北京协和医学院药物研究所药物晶型研究中心, 晶型药物研究北京市重点实验室, 北京 100050
摘要:
沙库巴曲缬沙坦钠是一种离子型共晶药物,通过对其共晶特征建立多种表征方法,全面掌握该药物的晶型状态,为进行有效的质量控制提供基础研究数据。采用粉末X射线衍射(PXRD)、傅里叶变换红外光谱(FTIR)、拉曼光谱(RM)、差示扫描量热(DSC)和固体核磁共振波谱(ssNMR)等多种技术手段,表征沙库巴曲缬沙坦钠原料药及片剂的共晶特征,采用热重分析(TGA)、动态蒸气吸附(DVS)、引湿性试验以及水分测定法等分析方法,对沙库巴曲缬沙坦钠原料药的结晶水、引湿性等进行分析。结果表明,PXRD、FTIR、DSC、ssNMR四种方法能够有效地表征并区分共晶与单体、混合物特征的差异,RM法的区分力较弱,可以作为补充手段对晶型特征进行佐证。结合TGA、DVS、引湿性试验和水分测定结果分析,沙库巴曲缬沙坦钠含有2.5个结晶水,极具引湿性,建议在相对湿度60%以下的环境中贮藏。通过对晶型特征的表征,可探索该药物片剂的质量控制水平和稳定性等工艺信息。本研究为沙库巴曲缬沙坦钠质量标准的建立提供了数据支持。
关键词:    心力衰竭      沙库巴曲缬沙坦钠      共晶      表征      粉末X射线衍射      固体核磁共振波谱      动态蒸气吸附      引湿性     
Establishment of a cocrystal characterization method for sacubitril valsartan sodium
XIONG Jing1,2, XU De-zhong1, XU Xin-yi3, L� Yang4, YANG Shi-ying4, WANG Si-cen2
1. National Institutes for Food and Drug Control, NMPA Key Laboratory for Quality Research and Evaluation of Chemical Drugs, Beijing 102629, China;
2. School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, China;
3. Chinese Pharmacopoeia Commission, Beijing 100061, China;
4. Beijing Key Laboratory of Polymorphic Drugs, Center of Pharmaceutical Polymorphs, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Sacubitril valsartan sodium (LCZ696) is an ionic cocrystal drug. The purpose of this study was to explore the cocrystal features of LC696 by establishing a variety of characterization methods, and thus provide basic research data for effective quality control. The cocrystal characteristics of LCZ696 and its tablets were identified by applying analytical means including powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FTIR), Raman spectra (RM), differential scanning calorimetry (DSC) and solid-state nuclear magnetic resonance spectroscopy (ssNMR). The crystalline water and hygroscopicity of LCZ696 were analyzed by thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), hygroscopicity test and Karl Fischer reaction method. The results show that PXRD, FTIR, DSC and ssNMR can effectively distinguish the features of LCZ696 cocrystal, sacubitril monomer, valsartan monomer, and sacubitril-valsartan (1:1) mixture. RM can be used as a supplementary approach. Combined with the analysis by TGA, DVS, hygroscopicity test and Karl Fischer reaction method results, LCZ696 contains 2.5 crystalline water molecules and is very hygroscopic; we recommend that LCZ696 be stored in an environment with a relative humidity below 60%. By characterizing the crystal features we can establish quality control measure and evaluate the stability of the drug tablets. This study provides data in support for the establishment of the LCZ696 quality standard.
Key words:    heart failure    sacubitril valsartan sodium    cocrystal    characterization    powder X-ray diffraction    solid-state nuclear magnetic resonance spectroscopy    dynamic vapor sorption    hygroscopicity   
收稿日期: 2020-11-25
DOI: 10.16438/j.0513-4870.2020-1811
基金项目: 国家药典委员会药品标准制修订研究课题(2018Y002);化学药品质量研究与评价重点实验室项目.
通讯作者: 杨世颖,Tel:86-29-82656788,E-mail:wangsc@mail.xjtu.edu.cn;王嗣岑,Tel:86-10-63161258,E-mail:ysy@imm.ac.cn
Email: wangsc@mail.xjtu.edu.cn;ysy@imm.ac.cn
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