首页 期刊 论文 学科刊群 资讯 加盟 关于
EN
image
Article(id=1240372084933718441, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1240372078617096528, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2024.01.10, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1677340800000, receivedDateStr=2023-02-26, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773657350047, onlineDateStr=2026-03-16, pubDate=1706630400000, pubDateStr=2024-01-31, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773657350047, onlineIssueDateStr=2026-03-16, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773657350047, creator=13701087609, updateTime=1773657350047, updator=13701087609, issue=Issue{id=1240372078617096528, tenantId=1146029695717560320, journalId=1205117023404326918, year='2024', volume='44', issue='1', pageStart='1', pageEnd='184', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773657348540, creator=13701087609, updateTime=1773657513974, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240372772564685717, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1240372078617096528, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240372772564685718, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1240372078617096528, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=101, endPage=108, ext={EN=ArticleExt(id=1240372086640800216, articleId=1240372084933718441, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Detection of trace genotoxic impurities in rivaroxaban by HPLC-MS/MS*, columnId=1239256892686520399, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Safety Monitorin, runingTitle=null, highlight=null, articleAbstract=
Objective:

To establish an HPLC-MS/MS method for the determination of the genotoxic impurities (S)-5-chloro-N-(3-chloro-2-hydroxypropyl) thiophene-2-amide and 4-(3-oxy-4-morpholine) nitrobenzene in rivaroxaban. The factors affecting impurities separation and the response of mass spectrometry were systematically investigated.

Methods:

A ZORBAX SB-C18 column(150 mm×2.1 mm, 3.5 μm) was used with 10 mmol·L-1 ammonium formate solution-methanol as mobile phase at flow rate of 0.4 mL·min-1. And MRM detection by electrospray positive ionization was used.

Results:

(S)-5-chloro-N-(3-chloro-2-hydroxypropyl) thiophene-2-amide and 4-(3-oxy-4-morpholine) nitrobenzene had good linear relationships in the range of 0.008-3.4 ng·mL-1 and 0.2-3.4 ng·mL-1, respectively. The average recoveries(n=9) were 97.9% and 98.9%, RSD were 0.94% and 0.68% respectively. The limits of quantitation were 0.008 ng·mL-1 and 0.2 ng·mL-1 respectively. The results of genotoxic impurity residue determination in 15 batches of rivaroxaban samples were far below the limit value.

Conclusion:

The method is sensitive and specific, and can effectively detect trace genotoxic impurities in rivaroxaban.

, correspAuthors=Jian WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Ping LI, Feng-mei ZHANG, Ping ZHOU, Yue-feng CAO, Jian WANG), CN=ArticleExt(id=1240372088226247227, articleId=1240372084933718441, tenantId=1146029695717560320, journalId=1205117023404326918, language=CN, title=HPLC-MS/MS法检测利伐沙班中痕量基因毒性杂质*, columnId=1206272758036623764, journalTitle=药物分析杂志, columnName=安全监测, runingTitle=null, highlight=null, articleAbstract=
目的：

建立HPLC-MS/MS法检测利伐沙班中基因毒性杂质(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯的方法，系统考察影响杂质分离和质谱响应的因素。

方法：

采用ZORBAX SB-C18(150 mm×2.1 mm，3.5 μm)色谱柱，以10 mmol·L-1甲酸铵溶液-甲醇为流动相，梯度洗脱，流速0.4 mL·min-1；电喷雾正离子化MRM检测。

结果：

(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯质量浓度分别在0.008~3.4 ng·mL-1和0.2~3.4 ng·mL-1范围内线性关系良好，平均回收率(n=9)分别为97.9%和98.9%，RSD分别为0.94%和0.68%；定量限分别为0.008 ng·mL-1和0.2 ng·mL-1；15批利伐沙班样品中基因毒性杂质残留量检测结果均远低于限度值。

结论：

该方法灵敏度高，专属性强，可有效检测和控制利伐沙班中痕量基因毒性杂质的含量。

, correspAuthors=王建, authorNote=null, correspAuthorsNote=
**Tel：(0571)87180358；E-mail：
, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=UtjRv2phYAw7BUoMiVpYbg==, magXml=Fkhp1gPcZO2ch2k7uPYRpA==, pdfUrl=null, pdf=IlSrq4vpDd8LgEW0Zs2iKA==, pdfFileSize=3226815, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=awpnB8rCFiuffgK9z+VZzw==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=868v0qqeFIY/vwhS2eWzCg==, mapNumber=null, authorCompany=null, fund=null, authors=

Tel： (0571)87180358；E-mail：

, authorsList=李萍, 张凤妹, 周萍, 曹粤锋, 王建)}, authors=[Author(id=1240376120793682562, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=1223686298@qq.com, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1240376120953066122, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, authorId=1240376120793682562, language=EN, stringName=Ping LI, firstName=Ping, middleName=null, lastName=LI, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, 2, address=1.Zhejiang University of Technology, Hangzhou 310014, China
2.Zhejiang Institute for Food and Drug Control, Key Laboratory for Core Technology of Generic Drug Evaluation National Medical Product Administration & Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou 310051, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1240376121091478159, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, authorId=1240376120793682562, language=CN, stringName=李萍, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, 2, address=1.浙江工业大学，杭州 310014
2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051, bio={"content":"

Tel： (0571)87180358；E-mail：

"}, bioImg=null, bioContent=

Tel： (0571)87180358；E-mail：

, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1240376120583967349, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, xref=1., ext=[AuthorCompanyExt(id=1240376120588161654, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120583967349, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.Zhejiang University of Technology, Hangzhou 310014, China), AuthorCompanyExt(id=1240376120596550263, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120583967349, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.浙江工业大学，杭州 310014)]), AuthorCompany(id=1240376120680436349, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, xref=2., ext=[AuthorCompanyExt(id=1240376120688824956, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120680436349, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.Zhejiang Institute for Food and Drug Control, Key Laboratory for Core Technology of Generic Drug Evaluation National Medical Product Administration & Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou 310051, China), AuthorCompanyExt(id=1240376120701407869, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120680436349, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051)])]), Author(id=1240376121196335764, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1240376121305387671, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, authorId=1240376121196335764, language=EN, stringName=Feng-mei ZHANG, firstName=Feng-mei, middleName=null, lastName=ZHANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=2, address=2.Zhejiang Institute for Food and Drug Control, Key Laboratory for Core Technology of Generic Drug Evaluation National Medical Product Administration & Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou 310051, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1240376121385079452, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, authorId=1240376121196335764, language=CN, stringName=张凤妹, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=2, address=2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1240376120680436349, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, xref=2., ext=[AuthorCompanyExt(id=1240376120688824956, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120680436349, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.Zhejiang Institute for Food and Drug Control, Key Laboratory for Core Technology of Generic Drug Evaluation National Medical Product Administration & Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou 310051, China), AuthorCompanyExt(id=1240376120701407869, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120680436349, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051)])]), Author(id=1240376121473159845, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1240376121565434540, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, authorId=1240376121473159845, language=EN, stringName=Ping ZHOU, firstName=Ping, middleName=null, lastName=ZHOU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1.Zhejiang University of Technology, Hangzhou 310014, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1240376121657709236, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, authorId=1240376121473159845, language=CN, stringName=周萍, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1.浙江工业大学，杭州 310014, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1240376120583967349, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, xref=1., ext=[AuthorCompanyExt(id=1240376120588161654, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120583967349, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.Zhejiang University of Technology, Hangzhou 310014, China), AuthorCompanyExt(id=1240376120596550263, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120583967349, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.浙江工业大学，杭州 310014)])]), Author(id=1240376121741595328, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, orderNo=3, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1240376121867424457, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, authorId=1240376121741595328, language=EN, stringName=Yue-feng CAO, firstName=Yue-feng, middleName=null, lastName=CAO, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=2, address=2.Zhejiang Institute for Food and Drug Control, Key Laboratory for Core Technology of Generic Drug Evaluation National Medical Product Administration & Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou 310051, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1240376121951310546, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, authorId=1240376121741595328, language=CN, stringName=曹粤锋, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=2, address=2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1240376120680436349, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, xref=2., ext=[AuthorCompanyExt(id=1240376120688824956, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120680436349, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.Zhejiang Institute for Food and Drug Control, Key Laboratory for Core Technology of Generic Drug Evaluation National Medical Product Administration & Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou 310051, China), AuthorCompanyExt(id=1240376120701407869, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120680436349, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051)])]), Author(id=1240376122035196631, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, orderNo=4, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=wangjianhw2000@aliyun.com, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1240376122156831456, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, authorId=1240376122035196631, language=EN, stringName=Jian WANG, firstName=Jian, middleName=null, lastName=WANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, 2, **, address=1.Zhejiang University of Technology, Hangzhou 310014, China
2.Zhejiang Institute for Food and Drug Control, Key Laboratory for Core Technology of Generic Drug Evaluation National Medical Product Administration & Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou 310051, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1240376122249106152, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, authorId=1240376122035196631, language=CN, stringName=王建, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, 2, **, address=1.浙江工业大学，杭州 310014
2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1240376120583967349, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, xref=1., ext=[AuthorCompanyExt(id=1240376120588161654, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120583967349, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.Zhejiang University of Technology, Hangzhou 310014, China), AuthorCompanyExt(id=1240376120596550263, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120583967349, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.浙江工业大学，杭州 310014)]), AuthorCompany(id=1240376120680436349, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, xref=2., ext=[AuthorCompanyExt(id=1240376120688824956, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120680436349, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.Zhejiang Institute for Food and Drug Control, Key Laboratory for Core Technology of Generic Drug Evaluation National Medical Product Administration & Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou 310051, China), AuthorCompanyExt(id=1240376120701407869, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120680436349, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051)])])], keywords=[Keyword(id=1240376122442044148, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, orderNo=1, keyword=rivaroxaban), Keyword(id=1240376122525930236, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, orderNo=2, keyword=genotoxic impurity), Keyword(id=1240376122630787842, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, orderNo=3, keyword=HPLC-MS/MS), Keyword(id=1240376122710479621, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, orderNo=4, keyword=(S)-5-chloro-N-(3-chloro-2-hydroxypropyl) thiophene-2-amide), Keyword(id=1240376122777588489, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, orderNo=5, keyword=4-(3-oxy-4-morpholine) nitrobenzene), Keyword(id=1240376122861474571, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, orderNo=1, keyword=利伐沙班), Keyword(id=1240376123033441043, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, orderNo=2, keyword=基因毒性杂质), Keyword(id=1240376123184435995, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, orderNo=3, keyword=液相色谱-质谱联用法), Keyword(id=1240376123276710686, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, orderNo=4, keyword=(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺), Keyword(id=1240376123381568293, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, orderNo=5, keyword=4-(3-氧代-4-吗啉基)硝基苯)], refs=[Reference(id=1240376125218673565, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2020, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=王开, journalName=null, refType=null, unstructuredReference=王开. 利伐沙班片的处方和工艺开发[D]. 杭州：浙江大学，2020, articleTitle=利伐沙班片的处方和工艺开发, refAbstract=null), Reference(id=1240376125298365348, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2020, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[1], rfOrder=1, authorNames=WANG K, journalName=null, refType=null, unstructuredReference=WANG K. Formulation and Process Development of Rivaroxaban Tablets[D]. Hangzhou：Zhejiang University，2020, articleTitle=Formulation and Process Development of Rivaroxaban Tablets, refAbstract=null), Reference(id=1240376125407417258, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2022, volume=28, issue=3, pageStart=385, pageEnd=null, url=null, language=null, rfNumber=[2], rfOrder=2, authorNames=白龙, 李洁, journalName=血栓与止血学, refType=null, unstructuredReference=白龙，李洁. 活血通肺汤联合利伐沙班片治疗急性肺动脉栓塞的疗效观察[J]. 血栓与止血学，2022，28(3)：385, articleTitle=活血通肺汤联合利伐沙班片治疗急性肺动脉栓塞的疗效观察, refAbstract=null), Reference(id=1240376125503886254, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2022, volume=28, issue=3, pageStart=385, pageEnd=null, url=null, language=null, rfNumber=[2], rfOrder=3, authorNames=BAI L, LI J, journalName=Chin J Thromb Hemost, refType=null, unstructuredReference=BAI L，LI J. Clinical observation of Huoxue Tongfei decoction combined with rivaroxaban tablets in the treatment of acute pulmonary embolism[J]. Chin J Thromb Hemost，2022，28(3)：385, articleTitle=Clinical observation of Huoxue Tongfei decoction combined with rivaroxaban tablets in the treatment of acute pulmonary embolism, refAbstract=null), Reference(id=1240376125608743862, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2021, volume=6, issue=20, pageStart=156, pageEnd=null, url=null, language=null, rfNumber=[3], rfOrder=4, authorNames=朱道平, journalName=系统医学, refType=null, unstructuredReference=朱道平. 在静脉血栓的治疗中采取利伐沙班片治疗的临床效果分析[J]. 系统医学，2021，6(20)：156, articleTitle=在静脉血栓的治疗中采取利伐沙班片治疗的临床效果分析, refAbstract=null), Reference(id=1240376125709407160, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2021, volume=6, issue=20, pageStart=156, pageEnd=null, url=null, language=null, rfNumber=[3], rfOrder=5, authorNames=ZHU DP, journalName=Syst Med, refType=null, unstructuredReference=ZHU DP. Analysis of the clinical effect of rivaroxaban tablets in the treatment of venous thrombosis[J]. Syst Med，2021，6(20)：156, articleTitle=Analysis of the clinical effect of rivaroxaban tablets in the treatment of venous thrombosis, refAbstract=null), Reference(id=1240376125810070459, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2020, volume=33, issue=10, pageStart=109, pageEnd=null, url=null, language=null, rfNumber=[4], rfOrder=6, authorNames=王欢, 曾莉娜, 姚松, journalName=临床误诊误治, refType=null, unstructuredReference=王欢，曾莉娜，姚松，等. 利伐沙班片在血栓栓塞性疾病中的应用进展[J]. 临床误诊误治，2020，33(10)：109, articleTitle=利伐沙班片在血栓栓塞性疾病中的应用进展, refAbstract=null), Reference(id=1240376125935899587, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2020, volume=33, issue=10, pageStart=109, pageEnd=null, url=null, language=null, rfNumber=[4], rfOrder=7, authorNames=WANG H, ZENG LN, YAO S, journalName=Clin Misdiagn Misther, refType=null, unstructuredReference=WANG H，ZENG LN，YAO S，et al. Application progress of rivaroxaban tablets in thromboembolic diseases[J]. Clin Misdiagn Misther，2020，33(10)：109, articleTitle=Application progress of rivaroxaban tablets in thromboembolic diseases, refAbstract=null), Reference(id=1240376126023979974, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2019, volume=28, issue=23, pageStart=2840, pageEnd=null, url=null, language=null, rfNumber=[5], rfOrder=8, authorNames=汪生, 杭太俊, journalName=中国新药杂志, refType=null, unstructuredReference=汪生，杭太俊. 药物中基因毒性杂质检测策略的研究[J]. 中国新药杂志，2019，28(23)：2840, articleTitle=药物中基因毒性杂质检测策略的研究, refAbstract=null), Reference(id=1240376126124643280, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2019, volume=28, issue=23, pageStart=2840, pageEnd=null, url=null, language=null, rfNumber=[5], rfOrder=9, authorNames=WANG S, HANG TJ, journalName=Chin J New Drugs, refType=null, unstructuredReference=WANG S，HANG TJ. Strategies for determination of genotoxic impurities in pharmaceuticals[J]. Chin J New Drugs，2019，28(23)：2840, articleTitle=Strategies for determination of genotoxic impurities in pharmaceuticals, refAbstract=null), Reference(id=1240376126208529366, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2017, volume=37, issue=1, pageStart=105, pageEnd=null, url=null, language=null, rfNumber=[6], rfOrder=10, authorNames=徐洁, journalName=药物分析杂志, refType=null, unstructuredReference=徐洁. 利伐沙班中苯胺类潜在基因毒性杂质的HPLC法测定[J]. 药物分析杂志，2017，37(1)：105, articleTitle=利伐沙班中苯胺类潜在基因毒性杂质的HPLC法测定, refAbstract=null), Reference(id=1240376126279832538, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2017, volume=37, issue=1, pageStart=105, pageEnd=null, url=null, language=null, rfNumber=[6], rfOrder=11, authorNames=XU J, journalName=Chin J Pharm Anal, refType=null, unstructuredReference=XU J. Determination of aniline potential genotoxic impurity in Rivaroxaban by HPLC[J]. Chin J Pharm Anal，2017，37(1)：105, articleTitle=Determination of aniline potential genotoxic impurity in Rivaroxaban by HPLC, refAbstract=null), Reference(id=1240376126384690142, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2021, volume=41, issue=4, pageStart=714, pageEnd=null, url=null, language=null, rfNumber=[7], rfOrder=12, authorNames=陈轶嘉, 石玲玲, 陈阳, journalName=药物分析杂志, refType=null, unstructuredReference=陈轶嘉，石玲玲，陈阳，等. 无催化剂衍生GC-MS法测定利伐沙班基因毒杂质5-氯-2-酰氯噻吩[J]. 药物分析杂志，2021，41(4)：714, articleTitle=无催化剂衍生GC-MS法测定利伐沙班基因毒杂质5-氯-2-酰氯噻吩, refAbstract=null), Reference(id=1240376126523102181, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2021, volume=41, issue=4, pageStart=714, pageEnd=null, url=null, language=null, rfNumber=[7], rfOrder=13, authorNames=CHEN YJ, SHI LL, CHEN Y, journalName=Chin J Pharm Anal, refType=null, unstructuredReference=CHEN YJ，SHI LL，CHEN Y，et al. Determination of genotoxic 5-chlorothiophene-2-carbonyl chloride in rivaroxaban by GC-MS with catalyst-free derivatization[J]. Chin J Pharm Anal，2021，41(4)：714, articleTitle=Determination of genotoxic 5-chlorothiophene-2-carbonyl chloride in rivaroxaban by GC-MS with catalyst-free derivatization, refAbstract=null), Reference(id=1240376126602793960, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2017, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[8], rfOrder=14, authorNames=冯贵成, journalName=null, refType=null, unstructuredReference=冯贵成. 抗凝血药物利伐沙班合成工艺研究[D]. 杭州：浙江工业大学，2017, articleTitle=抗凝血药物利伐沙班合成工艺研究, refAbstract=null), Reference(id=1240376126699262957, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2017, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[8], rfOrder=15, authorNames=FENG GC, journalName=null, refType=null, unstructuredReference=FENG GC. Study of the Synthesis Process of Antithrombotic Drug Rivaroxaban[D]. Hangzhou：Zhejiang University of Technology，2017, articleTitle=Study of the Synthesis Process of Antithrombotic Drug Rivaroxaban, refAbstract=null), Reference(id=1240376126799926256, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2020, volume=34, issue=3, pageStart=8, pageEnd=null, url=null, language=null, rfNumber=[9], rfOrder=16, authorNames=李果, journalName=天津化工, refType=null, unstructuredReference=李果. 利伐沙班合成工艺研究[J]. 天津化工，2020，34(3)：8, articleTitle=利伐沙班合成工艺研究, refAbstract=null), Reference(id=1240376126879618037, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2020, volume=34, issue=3, pageStart=8, pageEnd=null, url=null, language=null, rfNumber=[9], rfOrder=17, authorNames=LI G, journalName=Tianjin Chem Ind, refType=null, unstructuredReference=LI G. Study on the synthetic technology of Rivaroxaban[J]. Tianjin Chem Ind，2020，34(3)：8, articleTitle=Study on the synthetic technology of Rivaroxaban, refAbstract=null), Reference(id=1240376126984475643, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2019, volume=46, issue=3, pageStart=176, pageEnd=null, url=null, language=null, rfNumber=[10], rfOrder=18, authorNames=王倩倩, 顾铭盼, 沈志超, journalName=广东化工, refType=null, unstructuredReference=王倩倩，顾铭盼，沈志超. HPLC法测定利伐沙班中基因杂质5-氯噻吩-2-甲酰氯[J]. 广东化工，2019，46(3)：176, articleTitle=HPLC法测定利伐沙班中基因杂质5-氯噻吩-2-甲酰氯, refAbstract=null), Reference(id=1240376127110304765, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2019, volume=46, issue=3, pageStart=176, pageEnd=null, url=null, language=null, rfNumber=[10], rfOrder=19, authorNames=WANG QQ, GU MP, SHEN ZC, journalName=Guangdong Chem Ind, refType=null, unstructuredReference=WANG QQ，GU MP，SHEN ZC. Methods for the determination of genotoxic 5-chlorothiophene-2-carbonyl chloride in rivaroxaban using HPLC[J]. Guangdong Chem Ind，2019，46(3)：176, articleTitle=Methods for the determination of genotoxic 5-chlorothiophene-2-carbonyl chloride in rivaroxaban using HPLC, refAbstract=null), Reference(id=1240376127206773760, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2017, volume=1, issue=2, pageStart=180, pageEnd=null, url=null, language=null, rfNumber=[11], rfOrder=20, authorNames=BARSAM SJ, PATEL JP, ROBERTS LN, journalName=Res Pract Thromb Haemost, refType=null, unstructuredReference=BARSAM SJ，PATEL JP，ROBERTS LN，et al. The impact of body weight on rivaroxaban pharmacokinetics[J]. Res Pract Thromb Haemost，2017，1(2)：180, articleTitle=The impact of body weight on rivaroxaban pharmacokinetics, refAbstract=null), Reference(id=1240376127315824642, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2017, volume=37, issue=2, pageStart=265, pageEnd=null, url=null, language=null, rfNumber=[12], rfOrder=21, authorNames=张云峰, 钱建钦, 王建, journalName=药物分析杂志, refType=null, unstructuredReference=张云峰，钱建钦，王建. HPLC-MS/MS法分析氟胞嘧啶中痕量基因毒性杂质N，N-二甲基苯胺[J]. 药物分析杂志，2017，37(2)：265, articleTitle=HPLC-MS/MS法分析氟胞嘧啶中痕量基因毒性杂质N，N-二甲基苯胺, refAbstract=null), Reference(id=1240376127575871495, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2017, volume=37, issue=2, pageStart=265, pageEnd=null, url=null, language=null, rfNumber=[12], rfOrder=22, authorNames=ZHANG YF, QIAN JQ, WANG J, journalName=Chin J Pharm Anal, refType=null, unstructuredReference=ZHANG YF，QIAN JQ，WANG J. Determination of trace level of genotoxic impurity N，N-dimethylaniline in flucytosine by HPLC-MS/MS[J]. Chin J Pharm Anal，2017，37(2)：265, articleTitle=Determination of trace level of genotoxic impurity N，N-dimethylaniline in flucytosine by HPLC-MS/MS, refAbstract=null), Reference(id=1240376127680729099, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2022, volume=39, issue=10, pageStart=1336, pageEnd=null, url=null, language=null, rfNumber=[13], rfOrder=23, authorNames=王建, 周萍, 刘贵君, journalName=中国现代应用药学, refType=null, unstructuredReference=王建，周萍，刘贵君，等. HPLC-MS/MS分析阿哌沙班中基因毒性杂质及基质效应消除研究[J]. 中国现代应用药学，2022，39(10)：1336, articleTitle=HPLC-MS/MS分析阿哌沙班中基因毒性杂质及基质效应消除研究, refAbstract=null), Reference(id=1240376127781392400, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2022, volume=39, issue=10, pageStart=1336, pageEnd=null, url=null, language=null, rfNumber=[13], rfOrder=24, authorNames=WANG J, ZHOU P, LIU GJ, journalName=Chin J Mod Appl Pharm, refType=null, unstructuredReference=WANG J，ZHOU P，LIU GJ，et al. Study on genotoxic impurities and elimination of matrix effect in apixaban by HPLC-MS/MS[J]. Chin J Mod Appl Pharm，2022，39(10)：1336, articleTitle=Study on genotoxic impurities and elimination of matrix effect in apixaban by HPLC-MS/MS, refAbstract=null), Reference(id=1240376127861084179, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=2006, volume=null, issue=null, pageStart=2, pageEnd=null, url=null, language=null, rfNumber=[14], rfOrder=25, authorNames=EMEA, journalName=null, refType=null, unstructuredReference=EMEA. Guideline on the Limits of Genotoxic Impurities[R]. 2006：2, articleTitle=Guideline on the Limits of Genotoxic Impurities, refAbstract=null), Reference(id=1240376127949164564, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, doi=null, pmid=null, pmcid=null, year=1994, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[15], rfOrder=26, authorNames=null, journalName=null, refType=null, unstructuredReference=ICH Q2(R1). Current Step4 Version：Parent Guideline Dated 27 October 1994[S]. 1994, articleTitle=null, refAbstract=null)], funds=[Fund(id=1240376125042512788, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, awardId=202201, language=CN, fundingSource=*浙江省药品监管系统科技计划项目(202201), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1240376120583967349, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, xref=1., ext=[AuthorCompanyExt(id=1240376120588161654, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120583967349, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.Zhejiang University of Technology, Hangzhou 310014, China), AuthorCompanyExt(id=1240376120596550263, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120583967349, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.浙江工业大学，杭州 310014)]), AuthorCompany(id=1240376120680436349, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, xref=2., ext=[AuthorCompanyExt(id=1240376120688824956, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120680436349, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.Zhejiang Institute for Food and Drug Control, Key Laboratory for Core Technology of Generic Drug Evaluation National Medical Product Administration & Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou 310051, China), AuthorCompanyExt(id=1240376120701407869, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, companyId=1240376120680436349, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051)])], figs=[ArticleFig(id=1240376123595477806, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, label=Fig.1, caption=Impurity structures, figureFileSmall=uciDVfg7a4K/+Ee4YmESew==, figureFileBig=RwHAK+fR1iBaopRUtPwAjA==, tableContent=null), ArticleFig(id=1240376123675169589, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, label=图1, caption=杂质结构式

A.(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺[(S)-5-chloro-N-(3-chloro-2-hydroxypropyl)thiophene-2-amide] B.4-(3-氧代-4-吗啉基)硝基苯[4-(3-oxy-4-morpholine)nitrobenzene]

, figureFileSmall=uciDVfg7a4K/+Ee4YmESew==, figureFileBig=RwHAK+fR1iBaopRUtPwAjA==, tableContent=null), ArticleFig(id=1240376123784221498, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, label=Fig.2, caption=Mass spectrograms of (S)-5-chloro-N-(3-chloro-2-hydroxypropyl)thiophene-2-amide reference solution and 4-(3-oxy-4-morpholine)nitrobenzene reference solution, figureFileSmall=+3ioTN2G75hmaryk7nMA8Q==, figureFileBig=ccbjjlAptx2eb2MSlId8vw==, tableContent=null), ArticleFig(id=1240376123880690497, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, label=图2, caption=(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺对照品溶液和4-(3-氧代-4-吗啉基)硝基苯对照品溶液质谱图

A.(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯混合对照品一级MS扫描[primary MS scan for (S)-5-chloro-N-(3-chloro-2-hydroxypropyl)thiophene-2-amide and 4-(3-oxy-4-morpholine)nitrobenzene] B.(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺MS2裂解[(S)-5-chloro-N-(3-chloro-2-hydroxypropyl)thiophene-2-amide MS2 fragmentation] C.4-(3-氧代-4-吗啉基)硝基苯MS2裂解[4-(3-oxy-4-morpholine)nitrobenzene MS2 fragmentation]

, figureFileSmall=+3ioTN2G75hmaryk7nMA8Q==, figureFileBig=ccbjjlAptx2eb2MSlId8vw==, tableContent=null), ArticleFig(id=1240376123968770892, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, label=Fig.3, caption=MS cleavage pathway of impurities, figureFileSmall=G1uuMS6w+ZTSrB8aM1d+Aw==, figureFileBig=uvgBJc+zoe5J7VkYDADcjw==, tableContent=null), ArticleFig(id=1240376124069434194, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, label=图3, caption=杂质可能的质谱裂解途径

A.(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺[(S)-5-chloro-N-(3-chloro-2-hydroxypropyl)thiophene-2-amide] B.4-(3-氧代-4-吗啉基)硝基苯[4-(3-oxy-4-morpholine)nitrobenzene]

, figureFileSmall=G1uuMS6w+ZTSrB8aM1d+Aw==, figureFileBig=uvgBJc+zoe5J7VkYDADcjw==, tableContent=null), ArticleFig(id=1240376124170097499, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, label=Fig.4, caption=HPLC chromatogram of rivaroxaban destruction test, figureFileSmall=m0fnECMD35U2P80T9l3pZw==, figureFileBig=u1f5SimFOyTOQOVx3Lyf1Q==, tableContent=null), ArticleFig(id=1240376124295926628, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, label=图4, caption=利伐沙班破环试验色谱图

A.酸破坏溶液(acid destruction solution) B.碱破坏溶液(alkali destruction solution) C.氧化破坏溶液(oxidative destruction solution) D.高温破坏溶液(high temperature destruction solution) E.强光破坏溶液(strong light destruction solution) F.供试品溶液(test solution) G.混合对照品溶液(mixed reference solution)

, figureFileSmall=m0fnECMD35U2P80T9l3pZw==, figureFileBig=u1f5SimFOyTOQOVx3Lyf1Q==, tableContent=null), ArticleFig(id=1240376124425950056, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, label=Tab.1, caption=

Quantitative and qualitative ion pairs and acquisition voltages

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		离子对
(ion pair) m/z		Q1/VCE/VQ3/V
(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺[(S)-5-chloro-N-
(3-chloro-2-hydroxypropyl) thiophene-2-amide]		253.8→144.9定量(quantify)-25-21-28
253.8→73.1-19-53-15
4-(3-氧代-4-吗啉基)硝基苯[4-(3-oxy-4-morpholine)nitrobenzene]222.8→105.1定量(quantify)-27-28-19
222.8→91.3-17-44-18
), ArticleFig(id=1240376124543390578, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, label=表1, caption=

定量和定性离子对及采集电压

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		离子对
(ion pair) m/z		Q1/VCE/VQ3/V
(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺[(S)-5-chloro-N-
(3-chloro-2-hydroxypropyl) thiophene-2-amide]		253.8→144.9定量(quantify)-25-21-28
253.8→73.1-19-53-15
4-(3-氧代-4-吗啉基)硝基苯[4-(3-oxy-4-morpholine)nitrobenzene]222.8→105.1定量(quantify)-27-28-19
222.8→91.3-17-44-18
), ArticleFig(id=1240376124673414008, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, label=Tab.2, caption=

Recovery rate of results of (S)-5-chloro-N-(3-chloro-2-hydroxypropyl)thiophene-2-amide and 4-(3-oxy-4-morpholine)nitrobenzene

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		实测浓度
(measured concentration)/(ng·mL-1)		理论浓度
(theoretical concentration)/(ng·mL-1)		回收率
(recovery)/%		平均回收率
(average recovery)/%		RSD/%
(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺1.011.0298.697.90.94
[(S)-5-chloro-N-(3-chloro-2-hydroxypropyl)1.001.0298.2
thiophene-2-amide]1.011.0298.4
2.082.04102.0
2.002.0497.9
2.002.0498.0
2.923.0795.4
2.933.0795.6
2.983.0797.0
4-(3-氧代-4-吗啉基)硝基苯0.960.96100.098.90.68
(4-(3-oxy-4-morpholine)nitrobenzene)0.960.9699.6
0.940.9697.8
1.901.9298.7
1.911.9299.5
1.921.92100.0
2.852.8998.7
2.832.8999.0
2.822.8997.6
), ArticleFig(id=1240376124740522877, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, label=表2, caption=

(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯回收率测定结果

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		实测浓度
(measured concentration)/(ng·mL-1)		理论浓度
(theoretical concentration)/(ng·mL-1)		回收率
(recovery)/%		平均回收率
(average recovery)/%		RSD/%
(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺1.011.0298.697.90.94
[(S)-5-chloro-N-(3-chloro-2-hydroxypropyl)1.001.0298.2
thiophene-2-amide]1.011.0298.4
2.082.04102.0
2.002.0497.9
2.002.0498.0
2.923.0795.4
2.933.0795.6
2.983.0797.0
4-(3-氧代-4-吗啉基)硝基苯0.960.96100.098.90.68
(4-(3-oxy-4-morpholine)nitrobenzene)0.960.9699.6
0.940.9697.8
1.901.9298.7
1.911.9299.5
1.921.92100.0
2.852.8998.7
2.832.8999.0
2.822.8997.6
), ArticleFig(id=1240376124811826053, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=EN, label=Tab.3, caption=

Determination of genotoxic impurity residues in rivaroxaban

, figureFileSmall=null, figureFileBig=null, tableContent=
批号
(lot No.)		含量(content)/(μg·g-1)
(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺
[(S)-5-chloro-N-(3-chloro-2-hydroxypropyl) thiophene-2-amide]		4-(3-氧代-4-吗啉基)硝基苯
[4-(3-oxy-4-morpholine) nitrobenzene]
13021001CNDND
D10291-20210101NDND
RIC2101001NDND
RIC2101002NDND
RIC21030010.10ND
A00050NDND
A00051NDND
A00056NDND
14621010201NDND
210306NDND
210307NDND
210308NDND
DK44-20052610.12ND
DK44-2005271NDND
DK44-20052810.08ND
), ArticleFig(id=1240376124912489352, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372084933718441, language=CN, label=表3, caption=

利伐沙班中基因毒性杂质残留量测定结果

, figureFileSmall=null, figureFileBig=null, tableContent=
批号
(lot No.)		含量(content)/(μg·g-1)
(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺
[(S)-5-chloro-N-(3-chloro-2-hydroxypropyl) thiophene-2-amide]		4-(3-氧代-4-吗啉基)硝基苯
[4-(3-oxy-4-morpholine) nitrobenzene]
13021001CNDND
D10291-20210101NDND
RIC2101001NDND
RIC2101002NDND
RIC21030010.10ND
A00050NDND
A00051NDND
A00056NDND
14621010201NDND
210306NDND
210307NDND
210308NDND
DK44-20052610.12ND
DK44-2005271NDND
DK44-20052810.08ND
)], attaches=null, journal=Journal(id=1205114436974182403, delFlag=0, nameCn=药物分析杂志, nameEn=Chinese Journal of Pharmaceutical Analysis, nameHistory1=null, nameHistory2=null, issn=0254-1793, eissn=, cn=11-2224/R, coden=null, periodic=月刊, language=CN, oaType=1, ccby=null, superviseOffice=null, ownerOffice=null, pubOffice=null, editorOffice=null, officeType=null, aims=null, clcCode=null, officeProv=null, officeCity=null, officeAddr=null, officeZip=null, officeEmail=, officePhone=, editDirector=null, officeDirector=null, officeDirectorPhone=null, officeStaffNum=null, officeEmpNum=null, coverPicUrl=E+iq5BU+frOtpo6YF6JpQQ==, journalPrice=null, startedYear=null, abbrevIsoEn=Chinese Journal of Pharmaceutical Analysis, journalRemark=null, publicationField=null, createdTime=1765251271721, updatedTime=1765252167692, createdBy=18614031015, updatedBy=13701087609, firstLetterCn=C, firstLetterEn=C, subjectCode=Life Sciences, subjectName=生命医学, subjectCodeEn=Life Sciences, subjectNameEn=null, picCn=E+iq5BU+frOtpo6YF6JpQQ==, picEn=n/3T/+AptjYTGmmMsE/a0Q==, jcr=null, cjcr=null, exts=[JournalExt(id=1205118195070906572, language=CN, name=药物分析杂志, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1765252167718, updatedTime=1765252167718, createdBy=13701087609, updatedBy=13701087609, submissionGuidelinesUrl=, submissionAuthorUrl=https://ywfxauthor.manuscriptcloud.com/login, submissionEditorUrl=https://ywfxeditor.manuscriptcloud.com/login, submissionReviewUrl=https://ywfxauthor.manuscriptcloud.com/login, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""}), JournalExt(id=1205118195133821133, language=EN, name=Chinese Journal of Pharmaceutical Analysis, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1765252167733, updatedTime=1765252167733, createdBy=13701087609, updatedBy=13701087609, submissionGuidelinesUrl=, submissionAuthorUrl=https://ywfxauthor.manuscriptcloud.com/login, submissionEditorUrl=https://ywfxeditor.manuscriptcloud.com/login, submissionReviewUrl=https://ywfxauthor.manuscriptcloud.com/login, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""})], databaseList=null, tenantJournalId=1205117023404326918, websiteList=[Website(id=1205118568045195478, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1205117023404326918, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/ywfxzz/CN, language=CN, createTime=1765252256642, createBy=18614031015, updateTime=1765252521924, updateBy=18614031015, name=药物分析杂志-中文, tplId=1146099689490845704, title=药物分析杂志, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1205154326156128935, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568045195478, code=articleTextType, value=kx, createTime=1765260782040, updateTime=1765260782040, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154326135157412, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568045195478, code=banner, value=null, createTime=1765260782035, updateTime=1765260782035, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154326172906154, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568045195478, code=grayFlag, value=0, createTime=1765260782044, updateTime=1765260782044, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154326126768803, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568045195478, code=logo, value=https://castjournals.cast.org.cn/joweb/ywfxzz/CN/file/pic?fileId=5+7UKv7ckvsJ8AsWJeRI6g==, createTime=1765260782033, updateTime=1765260782033, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154326181294764, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568045195478, code=minRunFlag, value=0, createTime=1765260782046, updateTime=1765260782046, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154326147740326, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568045195478, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/ywfxzz/CN/file/pic, createTime=1765260782038, updateTime=1765260782038, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154326177100459, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568045195478, code=silenceFlag, value=0, createTime=1765260782045, updateTime=1765260782045, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154326143546021, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568045195478, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_cn_619/, createTime=1765260782037, updateTime=1765260782037, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154326160323240, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568045195478, code=themeColor, value=null, createTime=1765260782041, updateTime=1765260782041, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154326164517545, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568045195478, code=themeStyle, value=null, createTime=1765260782042, updateTime=1765260782042, creator=18614031015, updator=18614031015)]), Website(id=1205118568124887259, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1205117023404326918, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/ywfxzz/EN, language=EN, createTime=1765252256661, createBy=18614031015, updateTime=1765252537379, updateBy=18614031015, name=药物分析杂志-英文, tplId=1146101810881728533, title=Chinese Journal of Pharmaceutical Analysis, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1205154361170174338, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568124887259, code=articleTextType, value=kx, createTime=1765260790388, updateTime=1765260790388, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154361145008511, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568124887259, code=banner, value=null, createTime=1765260790382, updateTime=1765260790382, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154361195340165, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568124887259, code=grayFlag, value=0, createTime=1765260790394, updateTime=1765260790394, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154361132425598, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568124887259, code=logo, value=https://castjournals.cast.org.cn/joweb/ywfxzz/EN/file/pic?fileId=5+7UKv7ckvsJ8AsWJeRI6g==, createTime=1765260790379, updateTime=1765260790379, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154361207923079, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568124887259, code=minRunFlag, value=0, createTime=1765260790397, updateTime=1765260790397, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154361157591425, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568124887259, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/ywfxzz/EN/file/pic, createTime=1765260790385, updateTime=1765260790385, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154361199534470, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568124887259, code=silenceFlag, value=0, createTime=1765260790396, updateTime=1765260790396, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154361149202816, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568124887259, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_en_623/, createTime=1765260790383, updateTime=1765260790383, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154361174368643, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568124887259, code=themeColor, value=null, createTime=1765260790389, updateTime=1765260790389, creator=18614031015, updator=18614031015), WebsiteProps(id=1205154361186951556, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1205118568124887259, code=themeStyle, value=null, createTime=1765260790392, updateTime=1765260790392, creator=18614031015, updator=18614031015)])], journalTitle=药物分析杂志, weixinUrl=null, journalUrl=null, iacademicId=null, status=1, seqNo=null, journalTitleEn=Chinese Journal of Pharmaceutical Analysis, journalPhotoCn=E+iq5BU+frOtpo6YF6JpQQ==, journalPhotoEn=n/3T/+AptjYTGmmMsE/a0Q==, journalFirstLetter=C, journalRecommend=null, journalNew=null, journalCollection=null, jcrJf=null, cjcrJf=null, jcrJfStr=null, cjcrJfStr=null, submissionFirstDecision=null, sciSubjectClassification=null, casSubjectClassification=null, citeScore=null, totalCitationFrequency=null, icpCode=null, psCode=null, advertisingLicenseCode=null, copyrightInformation=null, country=null, option=, provinceCode=null, provinceName=null, collectFlag=false), detailUrlCn=https://castjournals.cast.org.cn/joweb/ywfxzz/CN/10.16155/j.0254-1793.2024.01.10, detailUrlEn=https://castjournals.cast.org.cn/joweb/ywfxzz/EN/10.16155/j.0254-1793.2024.01.10, pdfUrlCn=https://castjournals.cast.org.cn/joweb/ywfxzz/CN/PDF/10.16155/j.0254-1793.2024.01.10, pdfUrlEn=https://castjournals.cast.org.cn/joweb/ywfxzz/EN/PDF/10.16155/j.0254-1793.2024.01.10, aliStartDate=null, aliEndDate=null, collectionFlag=false, citedCount=null, citedUrl=null, reference=null)
收藏切换
HPLC-MS/MS法检测利伐沙班中痕量基因毒性杂质*
收藏切换
PDF下载
李萍 1, 2 , 张凤妹 2 , 周萍 1 , 曹粤锋 2 , 王建 1, 2, **
药物分析杂志 | 安全监测 2024,44(1): 101-108
收起
收藏切换
药物分析杂志 | 安全监测 2024, 44(1): 101-108
HPLC-MS/MS法检测利伐沙班中痕量基因毒性杂质*
全屏
李萍1, 2 , 张凤妹2, 周萍1, 曹粤锋2, 王建1, 2, **
作者信息
  • 1.浙江工业大学，杭州 310014
  • 2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051

    • Tel： (0571)87180358；E-mail：

通讯作者:

**Tel：(0571)87180358；E-mail：
Detection of trace genotoxic impurities in rivaroxaban by HPLC-MS/MS*
Ping LI1, 2 , Feng-mei ZHANG2, Ping ZHOU1, Yue-feng CAO2, Jian WANG1, 2, **
Affiliations
  • 1.Zhejiang University of Technology, Hangzhou 310014, China
  • 2.Zhejiang Institute for Food and Drug Control, Key Laboratory for Core Technology of Generic Drug Evaluation National Medical Product Administration & Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou 310051, China
出版时间: 2024-01-31 doi: 10.16155/j.0254-1793.2024.01.10
文章导航
收藏切换
摘要
收起
目的：

建立HPLC-MS/MS法检测利伐沙班中基因毒性杂质(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯的方法，系统考察影响杂质分离和质谱响应的因素。

方法：

采用ZORBAX SB-C18(150 mm×2.1 mm，3.5 μm)色谱柱，以10 mmol·L-1甲酸铵溶液-甲醇为流动相，梯度洗脱，流速0.4 mL·min-1；电喷雾正离子化MRM检测。

结果：

(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯质量浓度分别在0.008~3.4 ng·mL-1和0.2~3.4 ng·mL-1范围内线性关系良好，平均回收率(n=9)分别为97.9%和98.9%，RSD分别为0.94%和0.68%；定量限分别为0.008 ng·mL-1和0.2 ng·mL-1；15批利伐沙班样品中基因毒性杂质残留量检测结果均远低于限度值。

结论：

该方法灵敏度高，专属性强，可有效检测和控制利伐沙班中痕量基因毒性杂质的含量。

利伐沙班  /  基因毒性杂质  /  液相色谱-质谱联用法  /  (S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺  /  4-(3-氧代-4-吗啉基)硝基苯
Objective:

To establish an HPLC-MS/MS method for the determination of the genotoxic impurities (S)-5-chloro-N-(3-chloro-2-hydroxypropyl) thiophene-2-amide and 4-(3-oxy-4-morpholine) nitrobenzene in rivaroxaban. The factors affecting impurities separation and the response of mass spectrometry were systematically investigated.

Methods:

A ZORBAX SB-C18 column(150 mm×2.1 mm, 3.5 μm) was used with 10 mmol·L-1 ammonium formate solution-methanol as mobile phase at flow rate of 0.4 mL·min-1. And MRM detection by electrospray positive ionization was used.

Results:

(S)-5-chloro-N-(3-chloro-2-hydroxypropyl) thiophene-2-amide and 4-(3-oxy-4-morpholine) nitrobenzene had good linear relationships in the range of 0.008-3.4 ng·mL-1 and 0.2-3.4 ng·mL-1, respectively. The average recoveries(n=9) were 97.9% and 98.9%, RSD were 0.94% and 0.68% respectively. The limits of quantitation were 0.008 ng·mL-1 and 0.2 ng·mL-1 respectively. The results of genotoxic impurity residue determination in 15 batches of rivaroxaban samples were far below the limit value.

Conclusion:

The method is sensitive and specific, and can effectively detect trace genotoxic impurities in rivaroxaban.

rivaroxaban  /  genotoxic impurity  /  HPLC-MS/MS  /  (S)-5-chloro-N-(3-chloro-2-hydroxypropyl) thiophene-2-amide  /  4-(3-oxy-4-morpholine) nitrobenzene
李萍, 张凤妹, 周萍, 曹粤锋, 王建. HPLC-MS/MS法检测利伐沙班中痕量基因毒性杂质*. 药物分析杂志, 2024 , 44 (1) : 101 -108 . DOI: 10.16155/j.0254-1793.2024.01.10
Ping LI, Feng-mei ZHANG, Ping ZHOU, Yue-feng CAO, Jian WANG. Detection of trace genotoxic impurities in rivaroxaban by HPLC-MS/MS*[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (1) : 101 -108 . DOI: 10.16155/j.0254-1793.2024.01.10
正文
收起
利伐沙班为Bayer研制的全球首个新型口服抗凝药[1]，临床上可用于治疗冠状动脉疾病、急性冠心病、经导管主动脉瓣置换术后抗血栓治疗和预防髋膝置换术后静脉血栓形成[2-4]。利伐沙班中基因毒性杂质4-(4-氨基苯基)-3-吗啉酮、5-氯噻吩-2-甲酰氯和5-氯-2-酰氯噻吩的检测已有报道[5-8]，针对工艺相关[9-10]的(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯(图1，虚线部分为基因毒性杂质警示结构)的测定，尚未见报道。本研究结合国家药典委员会利伐沙班原料药标准修订工作，收集了7家生产企业15批样品，根据ICH M7要求建立了LC-MS/MS[11-13]测定上述2种杂质的方法。并基于TTC计算方法，根据欧盟药品管理局(EMEA)、FDA和ICH M7[14-15]指南，以利伐沙班日最大推荐量为20 mg计算，基因毒性杂质的限度为1.5 μg·d-1÷20 mg·d-1=75 μg·g-1，将利伐沙班中2个基因毒性杂质(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯的限度设定为20 μg·g-1进行研究。
1 仪器与试药
收起
1.1 仪器
LC-30AD高效液相色谱仪、LC-MS-8060三重四极杆质谱仪(岛津公司)；XPE百万分之一电子天平(梅特勒-托利多公司)。
1.2 试药
甲醇、乙腈为色谱纯(Merck公司)；水为超纯水(Millipore公司)；甲酸铵为色谱纯(Sigma-Aldrich公司)。
利伐沙班原料药：批号13021001C，由连云港润众制药有限公司提供；批号D10291-20210101，由江苏中邦制药有限公司提供；批号RIC2101001、RIC2101002、RIC2101003，由扬子江药业集团江苏海慈生物药业有限公司提供；批号A00050、A00051、A00056，由上海汇伦江苏药业有限公司提供；批号14621010201，由南京正大天晴制药有限公司提供；批号210306、210307、210308，由江苏嘉逸医药有限公司提供；批号DK44-2005261、DK44-2005271、DK44-2005281，由上虞京新药业股份有限公司提供。
对照品(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺(批号6002-Z6-3655-7-S，含量98.3%)和4-(3-氧代-4-吗啉基)硝基苯(批号FG130139-PWS，含量99.6%)，由上虞京新药业股份有限公司提供。
2 方法与结果
收起
2.1 液相色谱-质谱条件
2.1.1 液相色谱条件
采用ZORBAX SB-C18(150 mm×2.1 mm，3.5 μm)色谱柱，柱温40 ℃，以10 mmol·L-1甲酸铵溶液-甲醇为流动相，线性梯度洗脱(0~1.5 min，10% B；1.5~20 min，10% B→55% B；20~21 min，55% B→10% B；21~30 min，10% B)，流速0.4 mL·min-1，进样量20 μL，紫外检测波长250 nm。
2.1.2 质谱条件
电喷雾正离子化，MRM监测(表1，图2、3)。雾化气流量为3 L·min-1，加热气流量为10 L·min-1，接口电压为4 kV，检测电压为2.0 kV，CID为270 kPa，接口温度为300 ℃，脱溶剂管温度为250 ℃，加热块温度为400 ℃，干燥器流量为10 L·min-1。
2.2 溶液配制
2.2.1 稀释剂
以乙腈-水(40∶60)为稀释剂。
2.2.2 供试品溶液
取样品细粉约10 mg，精密称定，置100 mL量瓶中，加入稀释剂使溶解并稀释至刻度，摇匀，即得。
2.2.3 混合对照品溶液
取(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯的对照品各适量，加入稀释剂使溶解并稀释制成20 ng·mL-1的溶液，即得。
2.2.4 破坏溶液
酸破坏溶液：精密称取利伐沙班原料药(批号DK44-2005261)约10.00 mg置100 mL量瓶中，加入稀释剂约60 mL使溶解，加0.2 mol·L-1盐酸溶液1 mL，60 ℃水浴加热10 min，放冷至室温，加入0.2 mol·L-1氢氧化钠溶液1 mL中和，用稀释剂稀释至刻度，摇匀，即得。碱破坏溶液：精密称取利伐沙班原料药(批号DK44-2005261)约10.00 mg置100 mL量瓶中，加入稀释剂约60 mL使溶解，加0.2 mol·L-1氢氧化钠溶液1 mL，60 ℃水浴加热10 min，放冷至室温，加入0.2 mol·L-1盐酸溶液1 mL中和，用稀释剂稀释至刻度，摇匀，即得。氧化破坏溶液：精密称取利伐沙班原料药(批号DK44-2005261)约10.00 mg置100 mL量瓶中，加入稀释剂约60 mL使溶解，加入3%过氧化氢溶液1 mL，60 ℃水浴加热10 min，放冷至室温，用稀释剂稀释至刻度，摇匀，即得。高温破坏溶液：精密称取利伐沙班原料药(批号DK44-2005261)约10.00 mg置100 mL量瓶中，加入稀释剂约60 mL使溶解，100 ℃水浴加热30 min，放冷至室温，用稀释剂稀释至刻度，摇匀，即得。强光照射破坏溶液：取利伐沙班原料药(批号DK44-2005261)，于强光下(4 500 lx)照射3 d后，精密称取约10.00 mg置100 mL量瓶中，加入稀释剂溶解并稀释至刻度，摇匀，即得。
2.3 方法学验证
2.3.1 方法专属性试验
利伐沙班峰与(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺峰和4-(3-氧代-4-吗啉基)硝基苯峰完全分离，利伐沙班峰对于(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺峰和4-(3-氧代-4-吗啉基)硝基苯峰的检测无干扰。取“2.2.4”项下各破坏溶液、供试品溶液和混合对照品溶液按“2.1.1”项下液相色谱条件分别进样，试验表明，待测的2种基因毒性杂质峰与利伐沙班主峰完全分离，在酸、碱、氧化、高温和强光的加速破坏下并未产生能够干扰2种基因毒性杂质检测的降解产物，见图4。
2.3.2 线性关系考察
精密称取(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺的对照品10.37 mg以及4-(3-氧代-4-吗啉基)硝基苯的对照品9.66 mg，分别置200 mL量瓶中，加入稀释剂使溶解并稀释至刻度，摇匀，得每1 mL中含(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯均约50 μg的混合对照品储备液；取各对照品储备液，逐级稀释，制成含(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺质量浓度分别为3.4、3、2.4、2(限度值)、1、0.008 ng·mL-1的对照品溶液，含4-(3-氧代-4-吗啉基)硝基苯质量浓度分别为3.4、3、2.4、2(限度值)、1、0.2 ng·mL-1的对照品溶液，分别进样分析，以浓度(X)为横坐标，峰面积(Y)为纵坐标，绘制标准曲线并进行线性回归，结果(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯的线性方程分别为
结果表明，(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯质量浓度分别在0.008~3.4 ng·mL-1和0.2~3.4 ng·mL-1范围内，与峰面积呈良好的线性关系。
2.3.3 检测限与定量限测定
取“2.3.2”项下混合对照品储备液适量，用稀释剂稀释制成质量浓度分别为0.1、0.2、0.008、0.000 8 ng·mL-1的混合对照品溶液，进样分析。分别测得(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺的定量限为0.008 ng·mL-1(S/N=10.1)，检测限为0.000 8 ng·mL-1(S/N=3.8)；4-(3-氧代-4-吗啉基)硝基苯的定量限为0.2 ng·mL-1(S/N=11.9)，检测限为0.1 ng·mL-1(S/N=3.8)。检测灵敏度可满足痕量基因毒性杂质的测定要求。
2.3.4 回收率试验
取样品(批号DK44-2005261)约20 mg，分别置200 mL量瓶中，共9份，精密加入限度浓度值50%、100%和150% 3个浓度水平(1、2、3 ng·mL-1)的(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺对照品溶液和4-(3-氧代-4-吗啉基)硝基苯对照品溶液并稀释至刻度，摇匀，即得每个浓度水平3份溶液，进样分析。结果见表2，(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯的平均回收率分别为97.9%、98.9%，RSD分别为0.94%、0.68%。
2.3.5 稳定性试验
取(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺对照品溶液和4-(3-氧代-4-吗啉基)硝基苯对照品溶液，分别在0、4、6、8、12 h进样分析。结果5个时间点峰面积的RSD分别为1.2%、1.6%，说明溶液12 h内稳定。
2.4 样品测定
取利伐沙班15批样品细粉各约10 mg，按“2.2.2”项下方法制备供试品溶液，进样分析。15批利伐沙班样品中基因毒性杂质残留量检测结果，均远低于限度值。结果见表3。
3 讨论
收起
3.1 色谱柱的选择
利伐沙班注册标准中有关物质项下液相色谱流动相A为0.02 mol·L-1磷酸二氢钠缓冲液，流动相B为乙腈，考虑到兼容质谱需要使用挥发性的流动相，将流动相A调整为10 mmol·L-1甲酸铵溶液，按照梯度1(0~1.5 min，5% B；1.5~30 min，5% B→40% B；30~31 min，40% B→70% B；31~35 min，70% B；35~36 min，70% B→5% B；36~45 min，5% B)洗脱，流速1.0 mL·min-1，采用色谱柱1[Boston Green ODS C18(250 mm×4.6 mm，5 μm)]，出峰时间长、基线波动大并且需要分流。因此将色谱柱1调整为兼容质谱的细口径色谱柱2[ZORBAX-SB C18(150 mm×2.1 mm，3.5 μm)]，流速调整为0.4 mL·min-1，其他色谱条件均不变，结果表明(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯的出峰时间均缩短10 min，色谱图基线波动情况得到了明显改善。
但4-(3-氧代-4-吗啉基)硝基苯检测的灵敏度非常低，无法满足作为痕量基因毒性杂质检测的要求，改变色谱柱后4-(3-氧代-4-吗啉基)硝基苯峰依然峰形较差、质谱响应较小，因此需要通过试验不同的洗脱方式、流动相和溶剂，考察对杂质分离和质谱响应的影响，选择出最佳的检测条件，改善杂质峰的峰形、分离，提高质谱响应。
3.2 洗脱方式的选择
考察等度洗脱[10 mmol·L-1甲酸铵溶液-乙腈(60∶40)]与梯度洗脱(按梯度1)，结果发现(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯2个杂质的极性与主成分相差较大，等度洗脱时主峰保留时间合适而杂质出峰过快，4-(3-氧代-4-吗啉基)硝基苯在溶剂峰位置出峰，故选择梯度洗脱。
3.3 流动相种类的选择
考察不同种类的流动相(10 mmol·L-1甲酸铵溶液-乙腈；0.1%甲酸的水溶液-乙腈；10 mmol·L-1甲酸铵溶液-甲醇)按“2.1.1”项下液相色谱条件进行梯度洗脱。
结果显示，当选择0.1%甲酸溶液-乙腈为流动相时质谱基线差并且质谱响应不能达到检测灵敏度的要求；当选择10 mmol·L-1甲酸铵溶液-甲醇时，与10 mmol·L-1甲酸铵溶液-乙腈相比不仅质谱基线平稳以及质谱响应大幅增加，而且2种杂质的出峰时间均提前了约2 min。其中(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺峰的质谱响应增加了1倍，4-(3-氧代-4-吗啉基)硝基苯峰的质谱响应相较于其他2种流动相增加了15倍，大大提高了痕量基因毒性杂质检测的灵敏度。
3.4 溶剂的选择
考察了4种不同的溶剂[乙腈-水(40∶60)、乙腈：水-甲醇(20∶60∶20)、乙腈、甲醇]，结果发现当溶剂使用乙腈-水(40∶60)时质谱响应最高。使用不同的溶剂进行试验均不存在明显的基质效应。
在确定了色谱柱、洗脱方式、流动相和溶剂后，按梯度1的洗脱程序2种基因毒性杂质和利伐沙班均能在20 min内洗脱完全，因此可缩短色谱运行时间，将梯度1洗脱时间由每针45 min缩短至每针30 min，按照梯度2(0~1.5 min，10% B；1.5~20 min，10% B→55% B；20~21 min，55% B→10% B；21~30 min，10% B)进行实验。
4 结论
收起
本文开发了采用HPLC-MS/MS法检测利伐沙班中基因毒性杂质(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯的方法，优选了色谱条件和质谱条件，方法灵敏度高，专属性强，能满足痕量杂质的测定要求。代表性利伐沙班供试品中大都均未检出(S)-5-氯-N-(3-氯-2-羟丙基)噻吩-2-酰胺和4-(3-氧代-4-吗啉基)硝基苯2个基因毒性杂质。
基金
收起
  • *浙江省药品监管系统科技计划项目(202201)
文献
收起
参考文献 引证文献
排序方式：
[1]
王开. 利伐沙班片的处方和工艺开发[D]. 杭州：浙江大学，2020
WANG K. Formulation and Process Development of Rivaroxaban Tablets[D]. Hangzhou：Zhejiang University，2020
[2]
白龙，李洁. 活血通肺汤联合利伐沙班片治疗急性肺动脉栓塞的疗效观察[J]. 血栓与止血学，2022，28(3)：385
BAI L，LI J. Clinical observation of Huoxue Tongfei decoction combined with rivaroxaban tablets in the treatment of acute pulmonary embolism[J]. Chin J Thromb Hemost，2022，28(3)：385
[3]
朱道平. 在静脉血栓的治疗中采取利伐沙班片治疗的临床效果分析[J]. 系统医学，2021，6(20)：156
ZHU DP. Analysis of the clinical effect of rivaroxaban tablets in the treatment of venous thrombosis[J]. Syst Med，2021，6(20)：156
[4]
王欢，曾莉娜，姚松，等. 利伐沙班片在血栓栓塞性疾病中的应用进展[J]. 临床误诊误治，2020，33(10)：109
WANG H，ZENG LN，YAO S，et al. Application progress of rivaroxaban tablets in thromboembolic diseases[J]. Clin Misdiagn Misther，2020，33(10)：109
[5]
汪生，杭太俊. 药物中基因毒性杂质检测策略的研究[J]. 中国新药杂志，2019，28(23)：2840
WANG S，HANG TJ. Strategies for determination of genotoxic impurities in pharmaceuticals[J]. Chin J New Drugs，2019，28(23)：2840
[6]
徐洁. 利伐沙班中苯胺类潜在基因毒性杂质的HPLC法测定[J]. 药物分析杂志，2017，37(1)：105
XU J. Determination of aniline potential genotoxic impurity in Rivaroxaban by HPLC[J]. Chin J Pharm Anal，2017，37(1)：105
[7]
陈轶嘉，石玲玲，陈阳，等. 无催化剂衍生GC-MS法测定利伐沙班基因毒杂质5-氯-2-酰氯噻吩[J]. 药物分析杂志，2021，41(4)：714
CHEN YJ，SHI LL，CHEN Y，et al. Determination of genotoxic 5-chlorothiophene-2-carbonyl chloride in rivaroxaban by GC-MS with catalyst-free derivatization[J]. Chin J Pharm Anal，2021，41(4)：714
[8]
冯贵成. 抗凝血药物利伐沙班合成工艺研究[D]. 杭州：浙江工业大学，2017
FENG GC. Study of the Synthesis Process of Antithrombotic Drug Rivaroxaban[D]. Hangzhou：Zhejiang University of Technology，2017
[9]
李果. 利伐沙班合成工艺研究[J]. 天津化工，2020，34(3)：8
LI G. Study on the synthetic technology of Rivaroxaban[J]. Tianjin Chem Ind，2020，34(3)：8
[10]
王倩倩，顾铭盼，沈志超. HPLC法测定利伐沙班中基因杂质5-氯噻吩-2-甲酰氯[J]. 广东化工，2019，46(3)：176
WANG QQ，GU MP，SHEN ZC. Methods for the determination of genotoxic 5-chlorothiophene-2-carbonyl chloride in rivaroxaban using HPLC[J]. Guangdong Chem Ind，2019，46(3)：176
[11]
BARSAM SJ，PATEL JP，ROBERTS LN，et al. The impact of body weight on rivaroxaban pharmacokinetics[J]. Res Pract Thromb Haemost，2017，1(2)：180
[12]
张云峰，钱建钦，王建. HPLC-MS/MS法分析氟胞嘧啶中痕量基因毒性杂质N，N-二甲基苯胺[J]. 药物分析杂志，2017，37(2)：265
ZHANG YF，QIAN JQ，WANG J. Determination of trace level of genotoxic impurity N，N-dimethylaniline in flucytosine by HPLC-MS/MS[J]. Chin J Pharm Anal，2017，37(2)：265
[13]
王建，周萍，刘贵君，等. HPLC-MS/MS分析阿哌沙班中基因毒性杂质及基质效应消除研究[J]. 中国现代应用药学，2022，39(10)：1336
WANG J，ZHOU P，LIU GJ，et al. Study on genotoxic impurities and elimination of matrix effect in apixaban by HPLC-MS/MS[J]. Chin J Mod Appl Pharm，2022，39(10)：1336
[14]
EMEA. Guideline on the Limits of Genotoxic Impurities[R]. 2006：2
[15]
ICH Q2(R1). Current Step4 Version：Parent Guideline Dated 27 October 1994[S]. 1994
2024年第44卷第1期
PDF下载
68
31
引用本文
BibTeX
文章信息
doi: 10.16155/j.0254-1793.2024.01.10
  • 接收时间：2023-02-26
  • 首发时间：2026-03-16
  • 出版时间：2024-01-31
补充材料
相关文章
文章信息
作者
出版历史
  • 收稿日期：2023-02-26
基金
*浙江省药品监管系统科技计划项目(202201)
作者信息
    1.浙江工业大学，杭州 310014
    2.浙江省食品药品检验研究院 国家药品监督管理局仿制药评价关键技术重点实验室浙江省药品接触材料质量控制研究重点实验室，杭州 310051

通讯作者:

**Tel：(0571)87180358；E-mail：
参考文献
分享链接
https://castjournals.cast.org.cn/joweb/ywfxzz/CN/10.16155/j.0254-1793.2024.01.10
分享至
全文二维码

扫描看全文

引用本文
BibTeX
本文的引用情况
2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
相关链接
论文
最新文章
热读文章
热点专题
内参
蓝皮书
产业发展报告
传播力报告
期刊分级目录
资讯
学术新闻
行业新闻
学术会议
行业会议
关于
关于我们
联系我们
北京市海淀区学院南路86号
100081
010-62199257
qkjq@cast.org.cn

中国科学技术协会版权所有 京ICP 备10216604号-4 海淀分局备案 1101084647
科技导报社主办 中国科协信息中心技术支持