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Article(id=1240372081951560565, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1240372078617096528, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2024.01.13, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1676217600000, receivedDateStr=2023-02-13, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773657349336, onlineDateStr=2026-03-16, pubDate=1706630400000, pubDateStr=2024-01-31, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773657349336, onlineIssueDateStr=2026-03-16, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773657349336, creator=13701087609, updateTime=1773657349336, 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=126, endPage=133, ext={EN=ArticleExt(id=1240372082207413114, articleId=1240372081951560565, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Determination of related substances in telmisartan by HPLC, columnId=1239256892686520399, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Safety Monitorin, runingTitle=null, highlight=null, articleAbstract=
Objective:

To establish an HPLC method for the determination of the related substances in telmisartan.

Methods:

Waters Symmetry Shield RP8 (150 mm×4.6 mm, 3.5 μm) column was adopted. The mobile phase A was 0.1% phosphoric acid solution (pH was adjusted to 3.0 with triethylamine), and the mobile phase B was acetonitrile. The gradient elution was performed. The flow rate, column temperature and wavelength were 0.8 mL·min-1, 25 ℃ and 230 nm, respectively.

Results:

The resolutions between the peaks of telmisartan and nine known impurities were greater than 1.5. The limits of quantitation of all impurities were less than 40 ng·mL-1, and the limits of detection of all impurities were less than 10 ng·mL-1. The standard curves of telmisartan and its impurities were linear within the range 30-600 ng·mL-1, and the correlation coefficients were all greater than 0.999 5. The average recovery rates of impurities Ⅰ-Ⅸ were 93.8%, 99.8%, 97.5%, 99.2%, 99.8%, 98.3%, 98.4%, 99.2% and 99.7%, respectively, and the RSDs of 9 results were all less than 2.0%. Changing the flow rate, column temperature, wavelength, mobile phase ratio and pH did not affect the detection results of the related substances. The results of maximum single impurity were 0.02% in three batches of telmisartan, and the results of total impurities were less than 0.10%.

Conclusion:

The method is highly specific, sensitive, precise and accurate, and can be used for the determination of related substances of telmisartan.

, correspAuthors=Bin-feng ZHAO, 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=Chun WANG, Su-zhen ZHANG, Hong-zhu TAO, Ya PENG, Bin-feng ZHAO), CN=ArticleExt(id=1240372086489797632, articleId=1240372081951560565, tenantId=1146029695717560320, journalId=1205117023404326918, language=CN, title=HPLC法测定替米沙坦中的有关物质, columnId=1206272758036623764, journalTitle=药物分析杂志, columnName=安全监测, runingTitle=null, highlight=null, articleAbstract=
目的：

建立高效液相色谱法测定替米沙坦原料药中的有关物质。

方法：

采用Waters Symmetry Shield RP8(150 mm×4.6 mm，3.5 μm)色谱柱，以0.1%磷酸溶液(用三乙胺调pH至3.0)-乙腈为流动相，梯度洗脱，流速0.8 mL·min-1，柱温25 ℃，检测波长230 nm。

结果：

替米沙坦与9种已知杂质色谱峰之间的分离度均>1.5，定量限均<40 ng·mL-1，检测限均<10 ng·mL-1。替米沙坦及各杂质质量浓度在30~600 ng·mL-1范围内线性关系良好(r>0.999 5)。杂质Ⅰ~杂质Ⅸ的平均回收率分别为93.8%、99.8%、97.5%、99.2%、99.8%、98.3%、98.4%、99.2%、99.7%，RSD均<2.0%。改变流速、柱温、波长、流动相比例及pH后，对有关物质的检测结果无影响。3批替米沙坦中最大单杂含量均为0.02%，杂质总量<0.10%。

结论：

经方法学验证，本方法专属性强，灵敏、精密，准确度高，可用于替米沙坦原料药有关物质的测定。

, correspAuthors=赵斌锋, authorNote=null, correspAuthorsNote=
*Tel：(0575)82738381；E-mail：
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Tel： (0575)82738397；E-mail：

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Research progress on synthesis of telmisartan[J]. Guangzhou Chem Ind，2022，50(18)：32, articleTitle=Research progress on synthesis of telmisartan, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1240376121343136409, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, xref=null, ext=[AuthorCompanyExt(id=1240376121351525018, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, companyId=1240376121343136409, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Zhejiang Kinglyuan Pharmaceutical Co, Ltd, Shaoxing 312369, China), AuthorCompanyExt(id=1240376121359913627, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, companyId=1240376121343136409, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=浙江金立源药业有限公司，绍兴 312369)])], figs=[ArticleFig(id=1240376124560167794, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=EN, label=Fig.1, caption=The synthetic route of telmisartan, figureFileSmall=Knif/FoE7jtAwUUYKSCvMA==, figureFileBig=GPgtUlmiT1F33HYQRpPdlg==, tableContent=null), ArticleFig(id=1240376124660831094, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=CN, label=图1, caption=替米沙坦合成路线, figureFileSmall=Knif/FoE7jtAwUUYKSCvMA==, figureFileBig=GPgtUlmiT1F33HYQRpPdlg==, tableContent=null), ArticleFig(id=1240376124765688704, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=EN, label=Fig.2, caption=Chromatogram of specificity test and forced degradation test, figureFileSmall=j3A+idQ8z+VXd7f/AbvdXg==, figureFileBig=IphVFp+pgx9kheHSRAFUsg==, tableContent=null), ArticleFig(id=1240376124836991879, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=CN, label=图2, caption=专属性试验和强制降解试验色谱图

A.未破坏溶液(undestroyed solution) B.酸破坏溶液(destroyed solution by acid) C.碱破坏溶液(destroyed solution by alkali) D.氧化破坏溶液(destroyed solution by oxidation) E.强光破坏溶液(destroyed solution by strong light) F.高温破坏溶液(destroyed solution by heat) G.混合溶液，1~12分别为杂质Ⅷ、杂质Ⅴ、杂质Ⅶ、杂质Ⅳ、替米沙坦、杂质Ⅵ、杂质Ⅸ、杂质Ⅰ、杂质Ⅲ、杂质Ⅱ、4’-溴甲基联苯-2-羧酸甲酯和4’-二溴甲基联苯-2-羧酸甲酯(mixed solution，1-12 were impurity Ⅷ，impurity Ⅴ，impurity Ⅶ，impurity Ⅳ，telmisartan、impurity Ⅵ，impurity Ⅸ，impurity Ⅰ，impurity Ⅲ，impurity Ⅲ，methyl 4’-bromomethyl biphenyl-2-carboxylate and methyl 4’-(dibromomethyl)-2-biphenylcarboxylate，respectively) H.空白溶剂(blank solvent)

, figureFileSmall=j3A+idQ8z+VXd7f/AbvdXg==, figureFileBig=IphVFp+pgx9kheHSRAFUsg==, tableContent=null), ArticleFig(id=1240376124950238091, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=EN, label=Tab.1, caption=

Information on the related substances of telmisartan

, figureFileSmall=null, figureFileBig=null, tableContent=
杂质名称(impurity name)化学结构(structure)
杂质Ⅰ(impurity Ⅰ)
杂质Ⅱ(impurity Ⅱ)
杂质Ⅲ(impurity Ⅲ)
杂质Ⅳ(impurity Ⅳ)
杂质Ⅴ(impurity Ⅴ)
杂质Ⅵ(impurity Ⅵ)
杂质Ⅶ(impurity Ⅶ)
杂质Ⅷ(impurity Ⅷ)
杂质Ⅸ(impurity Ⅸ)
), ArticleFig(id=1240376125025735568, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=CN, label=表1, caption=

替米沙坦有关物质信息

, figureFileSmall=null, figureFileBig=null, tableContent=
杂质名称(impurity name)化学结构(structure)
杂质Ⅰ(impurity Ⅰ)
杂质Ⅱ(impurity Ⅱ)
杂质Ⅲ(impurity Ⅲ)
杂质Ⅳ(impurity Ⅳ)
杂质Ⅴ(impurity Ⅴ)
杂质Ⅵ(impurity Ⅵ)
杂质Ⅶ(impurity Ⅶ)
杂质Ⅷ(impurity Ⅷ)
杂质Ⅸ(impurity Ⅸ)
), ArticleFig(id=1240376125130593175, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=EN, label=Tab.2, caption=

The gradient elution program

, figureFileSmall=null, figureFileBig=null, tableContent=
时间
(time)/min		流动相比例（ratio of mobile phase）/%
流动相A
(mobile phase A)		流动相B
(mobile phase B)
08020
38020
305050
402080
502080
50.18020
608020
), ArticleFig(id=1240376125210284957, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=CN, label=表2, caption=

梯度洗脱程序

, figureFileSmall=null, figureFileBig=null, tableContent=
时间
(time)/min		流动相比例（ratio of mobile phase）/%
流动相A
(mobile phase A)		流动相B
(mobile phase B)
08020
38020
305050
402080
502080
50.18020
608020
), ArticleFig(id=1240376125294171043, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=EN, label=Tab.3, caption=

Results of forced degradation tests

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		相对保留时间
(relative retention time)		有关物质含量(content of related substance)/%
未破坏
(undestroyed)		酸破坏
(destroyed by acid)B		碱破坏
(destroyed by alkali)		氧化破坏
(destroyed by oxidation)		强光破坏
(destroyed by strong light)		高温破坏
(destroyed by heat)
杂质Ⅷ(impurity Ⅷ)0.170.0070.0060.0060.0060.010.007
杂质Ⅴ(impurity Ⅴ)0.71NDNDNDNDNDND
杂质Ⅶ(impurity Ⅶ)0.93NDNDNDNDNDND
杂质Ⅳ(impurity Ⅳ)0.960.0050.0050.0050.0050.0070.005
替米沙坦(telmisartan)1.099.9399.6599.9299.6799.7199.93
降解杂质(degraded impurity)1.05NDNDND0.090.20ND
杂质Ⅵ(impurity Ⅵ)1.11NDNDNDNDNDND
杂质Ⅸ (impurity Ⅸ)1.14ND0.280.0120.064NDND
杂质Ⅰ(impurity Ⅰ)1.270.0070.0070.0070.0080.0080.007
杂质Ⅲ(impurity Ⅲ)1.36NDNDNDNDNDND
杂质Ⅱ(impurity Ⅱ)1.420.0050.0070.0050.0060.0050.006
杂质总量(total impurities)/0.070.350.080.330.290.07
主峰纯度(peak purity)/999.44999.39999.40998.58999.53999.41
主成分含量(content of major compound)/100.1103.699.5100.498.198.9
), ArticleFig(id=1240376125403222953, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=CN, label=表3, caption=

强制降解试验结果

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		相对保留时间
(relative retention time)		有关物质含量(content of related substance)/%
未破坏
(undestroyed)		酸破坏
(destroyed by acid)B		碱破坏
(destroyed by alkali)		氧化破坏
(destroyed by oxidation)		强光破坏
(destroyed by strong light)		高温破坏
(destroyed by heat)
杂质Ⅷ(impurity Ⅷ)0.170.0070.0060.0060.0060.010.007
杂质Ⅴ(impurity Ⅴ)0.71NDNDNDNDNDND
杂质Ⅶ(impurity Ⅶ)0.93NDNDNDNDNDND
杂质Ⅳ(impurity Ⅳ)0.960.0050.0050.0050.0050.0070.005
替米沙坦(telmisartan)1.099.9399.6599.9299.6799.7199.93
降解杂质(degraded impurity)1.05NDNDND0.090.20ND
杂质Ⅵ(impurity Ⅵ)1.11NDNDNDNDNDND
杂质Ⅸ (impurity Ⅸ)1.14ND0.280.0120.064NDND
杂质Ⅰ(impurity Ⅰ)1.270.0070.0070.0070.0080.0080.007
杂质Ⅲ(impurity Ⅲ)1.36NDNDNDNDNDND
杂质Ⅱ(impurity Ⅱ)1.420.0050.0070.0050.0060.0050.006
杂质总量(total impurities)/0.070.350.080.330.290.07
主峰纯度(peak purity)/999.44999.39999.40998.58999.53999.41
主成分含量(content of major compound)/100.1103.699.5100.498.198.9
), ArticleFig(id=1240376125495497645, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=EN, label=Tab.4, caption=

Results of linearity tests

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		线性范围
(linear range)/(ng·mL-1)		回归方程
(regression equation)		r相对响应因子
(relative response factor)
杂质Ⅰ(impurity Ⅰ)29.04~580.90Y=5.412×10-2X+5.033×10-20.999 91.19
杂质Ⅱ(impurity Ⅱ)29.51~590.20Y=5.788×10-2X+0.747 20.999 91.11
杂质Ⅲ(impurity Ⅲ)29.04~580.83Y=6.238×10-2X+0.402 90.999 91.03
杂质Ⅳ(impurity Ⅳ)29.35~587.09Y=6.197×10-2X+1.135×10-20.999 91.04
杂质Ⅴ(impurity Ⅴ)29.70~593.95Y=6.132×10-2X-2.144×10-20.999 91.05
杂质Ⅵ(impurity Ⅵ)29.44~588.79Y=7.007×10-2X+3.866×10-20.999 90.92
杂质Ⅶ(impurity Ⅶ)28.77~575.45Y=6.227×10-2X+2.712×10-20.999 91.03
杂质Ⅷ(impurity Ⅷ)27.61~552.23Y=7.652×10-2X+0.270 80.999 70.84
杂质Ⅸ(impurity Ⅸ)29.68~593.64Y=6.072×10-2X+7.412×10-20.999 91.06
替米沙坦(telmisartan)29.78~595.60Y=6.418×10-2X+1.4830.999 71.00
), ArticleFig(id=1240376125608743859, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=CN, label=表4, caption=

线性试验结果

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		线性范围
(linear range)/(ng·mL-1)		回归方程
(regression equation)		r相对响应因子
(relative response factor)
杂质Ⅰ(impurity Ⅰ)29.04~580.90Y=5.412×10-2X+5.033×10-20.999 91.19
杂质Ⅱ(impurity Ⅱ)29.51~590.20Y=5.788×10-2X+0.747 20.999 91.11
杂质Ⅲ(impurity Ⅲ)29.04~580.83Y=6.238×10-2X+0.402 90.999 91.03
杂质Ⅳ(impurity Ⅳ)29.35~587.09Y=6.197×10-2X+1.135×10-20.999 91.04
杂质Ⅴ(impurity Ⅴ)29.70~593.95Y=6.132×10-2X-2.144×10-20.999 91.05
杂质Ⅵ(impurity Ⅵ)29.44~588.79Y=7.007×10-2X+3.866×10-20.999 90.92
杂质Ⅶ(impurity Ⅶ)28.77~575.45Y=6.227×10-2X+2.712×10-20.999 91.03
杂质Ⅷ(impurity Ⅷ)27.61~552.23Y=7.652×10-2X+0.270 80.999 70.84
杂质Ⅸ(impurity Ⅸ)29.68~593.64Y=6.072×10-2X+7.412×10-20.999 91.06
替米沙坦(telmisartan)29.78~595.60Y=6.418×10-2X+1.4830.999 71.00
), ArticleFig(id=1240376125705212854, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=EN, label=Tab.5, caption=

The recovery of impurities

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		平均回收率(average recovery)/%(n=3)RSD/%
80%回收率溶液
(80% recovery solution)		100%回收率溶液
(100% recovery solution)		120%回收率溶液
(120% recovery solution)
杂质Ⅰ(impurity Ⅰ)94.194.393.11.0
杂质Ⅱ(impurity Ⅱ)99.5100.299.60.45
杂质Ⅲ(impurity Ⅲ)96.797.597.80.69
杂质Ⅳ(impurity Ⅳ)99.099.499.30.30
杂质Ⅴ(impurity Ⅴ)98.8100.2100.41.0
杂质Ⅵ(impurity Ⅵ)97.698.598.90.72
杂质Ⅶ(impurity Ⅶ)98.098.698.60.49
杂质Ⅷ(impurity Ⅷ)99.6100.397.61.6
杂质Ⅸ(impurity Ⅸ)100.8100.897.51.7
), ArticleFig(id=1240376125814264764, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=CN, label=表5, caption=

杂质回收率

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		平均回收率(average recovery)/%(n=3)RSD/%
80%回收率溶液
(80% recovery solution)		100%回收率溶液
(100% recovery solution)		120%回收率溶液
(120% recovery solution)
杂质Ⅰ(impurity Ⅰ)94.194.393.11.0
杂质Ⅱ(impurity Ⅱ)99.5100.299.60.45
杂质Ⅲ(impurity Ⅲ)96.797.597.80.69
杂质Ⅳ(impurity Ⅳ)99.099.499.30.30
杂质Ⅴ(impurity Ⅴ)98.8100.2100.41.0
杂质Ⅵ(impurity Ⅵ)97.698.598.90.72
杂质Ⅶ(impurity Ⅶ)98.098.698.60.49
杂质Ⅷ(impurity Ⅷ)99.6100.397.61.6
杂质Ⅸ(impurity Ⅸ)100.8100.897.51.7
), ArticleFig(id=1240376125931705282, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=EN, label=Tab.6, caption=

Results of sample tests

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		有关物质含量
(content of related substance)/%
lot No. 20201101lot No. 20201102lot No. 20201103
杂质Ⅰ(impurity Ⅰ)0.01NDND
杂质Ⅱ(impurity Ⅱ)0.0070.006ND
杂质Ⅲ(impurity Ⅲ)NDNDND
杂质Ⅳ(impurity Ⅳ)0.0040.0050.003
杂质Ⅴ(impurity Ⅴ)NDNDND
杂质Ⅵ(impurity Ⅵ)NDNDND
杂质Ⅶ(impurity Ⅶ)NDNDND
杂质Ⅷ(impurity Ⅷ)0.0040.0040.005
杂质Ⅸ(impurity Ⅸ)NDNDND
其他单杂(other individual impurity)0.020.020.02
杂质总和(total impurities)0.060.040.03
), ArticleFig(id=1240376126019785670, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372081951560565, language=CN, label=表6, caption=

样品测定结果

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		有关物质含量
(content of related substance)/%
lot No. 20201101lot No. 20201102lot No. 20201103
杂质Ⅰ(impurity Ⅰ)0.01NDND
杂质Ⅱ(impurity Ⅱ)0.0070.006ND
杂质Ⅲ(impurity Ⅲ)NDNDND
杂质Ⅳ(impurity Ⅳ)0.0040.0050.003
杂质Ⅴ(impurity Ⅴ)NDNDND
杂质Ⅵ(impurity Ⅵ)NDNDND
杂质Ⅶ(impurity Ⅶ)NDNDND
杂质Ⅷ(impurity Ⅷ)0.0040.0040.005
杂质Ⅸ(impurity Ⅸ)NDNDND
其他单杂(other individual impurity)0.020.020.02
杂质总和(total impurities)0.060.040.03
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HPLC法测定替米沙坦中的有关物质
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王春 , 张素珍 , 陶鸿珠 , 彭亚 , 赵斌锋 *
药物分析杂志 | 安全监测 2024,44(1): 126-133
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药物分析杂志 | 安全监测 2024, 44(1): 126-133
HPLC法测定替米沙坦中的有关物质
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王春 , 张素珍, 陶鸿珠, 彭亚, 赵斌锋*
作者信息
  • 浙江金立源药业有限公司，绍兴 312369

    • Tel： (0575)82738397；E-mail：

通讯作者:

*Tel：(0575)82738381；E-mail：
Determination of related substances in telmisartan by HPLC
Chun WANG , Su-zhen ZHANG, Hong-zhu TAO, Ya PENG, Bin-feng ZHAO*
Affiliations
  • Zhejiang Kinglyuan Pharmaceutical Co, Ltd, Shaoxing 312369, China
出版时间: 2024-01-31 doi: 10.16155/j.0254-1793.2024.01.13
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摘要
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目的：

建立高效液相色谱法测定替米沙坦原料药中的有关物质。

方法：

采用Waters Symmetry Shield RP8(150 mm×4.6 mm，3.5 μm)色谱柱，以0.1%磷酸溶液(用三乙胺调pH至3.0)-乙腈为流动相，梯度洗脱，流速0.8 mL·min-1，柱温25 ℃，检测波长230 nm。

结果：

替米沙坦与9种已知杂质色谱峰之间的分离度均>1.5，定量限均<40 ng·mL-1，检测限均<10 ng·mL-1。替米沙坦及各杂质质量浓度在30~600 ng·mL-1范围内线性关系良好(r>0.999 5)。杂质Ⅰ~杂质Ⅸ的平均回收率分别为93.8%、99.8%、97.5%、99.2%、99.8%、98.3%、98.4%、99.2%、99.7%，RSD均<2.0%。改变流速、柱温、波长、流动相比例及pH后，对有关物质的检测结果无影响。3批替米沙坦中最大单杂含量均为0.02%，杂质总量<0.10%。

结论：

经方法学验证，本方法专属性强，灵敏、精密，准确度高，可用于替米沙坦原料药有关物质的测定。

替米沙坦  /  原料药  /  有关物质  /  药典标准  /  质量控制  /  高效液相色谱法  /  梯度洗脱
Objective:

To establish an HPLC method for the determination of the related substances in telmisartan.

Methods:

Waters Symmetry Shield RP8 (150 mm×4.6 mm, 3.5 μm) column was adopted. The mobile phase A was 0.1% phosphoric acid solution (pH was adjusted to 3.0 with triethylamine), and the mobile phase B was acetonitrile. The gradient elution was performed. The flow rate, column temperature and wavelength were 0.8 mL·min-1, 25 ℃ and 230 nm, respectively.

Results:

The resolutions between the peaks of telmisartan and nine known impurities were greater than 1.5. The limits of quantitation of all impurities were less than 40 ng·mL-1, and the limits of detection of all impurities were less than 10 ng·mL-1. The standard curves of telmisartan and its impurities were linear within the range 30-600 ng·mL-1, and the correlation coefficients were all greater than 0.999 5. The average recovery rates of impurities Ⅰ-Ⅸ were 93.8%, 99.8%, 97.5%, 99.2%, 99.8%, 98.3%, 98.4%, 99.2% and 99.7%, respectively, and the RSDs of 9 results were all less than 2.0%. Changing the flow rate, column temperature, wavelength, mobile phase ratio and pH did not affect the detection results of the related substances. The results of maximum single impurity were 0.02% in three batches of telmisartan, and the results of total impurities were less than 0.10%.

Conclusion:

The method is highly specific, sensitive, precise and accurate, and can be used for the determination of related substances of telmisartan.

telmisartan  /  active pharmaceutical ingredient  /  related substances  /  pharmacopoeia standard  /  quality control  /  HPLC  /  gradient elution
王春, 张素珍, 陶鸿珠, 彭亚, 赵斌锋. HPLC法测定替米沙坦中的有关物质. 药物分析杂志, 2024 , 44 (1) : 126 -133 . DOI: 10.16155/j.0254-1793.2024.01.13
Chun WANG, Su-zhen ZHANG, Hong-zhu TAO, Ya PENG, Bin-feng ZHAO. Determination of related substances in telmisartan by HPLC[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (1) : 126 -133 . DOI: 10.16155/j.0254-1793.2024.01.13
正文
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替米沙坦是一种强效、持久的非肽类血管紧张素Ⅱ受体(AT1型)拮抗剂，用于成年人原发性高血压的治疗以及降低心血管风险[1-2]，其结构区别于厄贝沙坦、坎地沙坦酯、奥美沙坦酯等其他沙坦类药物[3-4]，未有四氮唑环结构，避免了在制备过程中产生亚硝胺类杂质的风险[5-6]，故近年来替米沙坦的市场份额也在逐年增加。
目前，国内外药典标准均收载了替米沙坦，但有关物质检测方法各异，迄今为止均未有较大的修订，已不能满足更高的检测需求。例如，《中华人民共和国药典》(ChP 2020)[7]中的梯度洗脱不能将已知杂质全部有效分离，系统适用性要求不合理等；欧洲药典(EP 10.0)[8]和美国药典(USP 43)[9]不适用其他合成路线的替米沙坦有关物质检查，方法中的流动相和梯度洗脱容易引起基线波动等。本文替米沙坦的合成采用图1的路线，主要杂质信息见表1，均为工艺杂质。杂质Ⅰ、Ⅱ、Ⅲ、Ⅶ(EP 10.0替米沙坦杂质E)均是由起始原料B中杂质与起始原料A反应产生，杂质Ⅳ(EP 10.0替米沙坦杂质B)是副反应产物，杂质Ⅴ(EP 10.0替米沙坦杂质F)和杂质Ⅵ(EP 10.0替米沙坦杂质G)均是由起始原料A中杂质与起始原料B反应产生，杂质Ⅷ(EP 10.0替米沙坦杂质A)是起始原料B，杂质Ⅸ(EP 10.0替米沙坦杂质Ⅰ)是中间体。为了满足实际的检测需求，本研究建立了HPLC法测定替米沙坦中的有关物质，该法专属性强，灵敏度和准确度高，可有效、准确地检测本文替米沙坦中的杂质。
1 仪器与试药
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1.1 仪器
安捷伦公司Agilent 1260型高效液相色谱仪(配备DAD、VWD检测器)；梅特勒-托利多公司XS205DU型十万分之一电子天平；上海仪电科学仪器股份有限公司PHS-3C 型pH计。
1.2 试药
替米沙坦(批号20201101、20201102、20201103)，浙江金立源药业有限公司。对照品替米沙坦(批号100629-201803，含量99.9%)，中国食品药品检定研究院；杂质Ⅰ(批号20191201，含量96.1%)、杂质Ⅱ(批号20191202，含量97.9%)、杂质Ⅲ(批号20191201，含量96.6%)、杂质Ⅳ(批号20191201，含量97.8%)、杂质Ⅴ(批号20191101，含量98.0%)、杂质Ⅵ(批号20191101，含量97.5%)、杂质Ⅶ(批号20191201，含量95.2%)、杂质Ⅷ(批号20190901，含量91.6%)、杂质Ⅸ(批号20191201，含量99.4%)、4’-二溴甲基联苯-2-羧酸甲酯(批号20181201，含量95.9%)，浙江金立源药业有限公司；4’-溴甲基联苯-2-羧酸甲酯(批号E1731062，含量98.0%)，阿拉丁试剂公司。乙腈为色谱纯，购自上海星可高纯溶剂有限公司；水为纯化水；磷酸、三乙胺均为分析纯。
2 方法与结果
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2.1 色谱条件
采用Waters SymmetryShield RP8(150 mm×4.6 mm，3.5 μm)色谱柱，以0.1%磷酸溶液(用三乙胺调pH至3.0)-乙腈为流动相，按表2程序进行梯度洗脱，流速0.8 mL·min-1，柱温25 ℃，检测波长230 nm，进样体积10 μL。
2.2 溶液配制
2.2.1 供试品溶液
取本品300 mg，置100 mL量瓶中，加甲醇约80 mL与1 mol·L-1氢氧化钠溶液100 μL使溶解，用甲醇稀释至刻度，摇匀，得供试品储备液。精密量取储备液2 mL，置20 mL量瓶中，用甲醇稀释至刻度，摇匀，即得。
2.2.2 对照溶液
精密量取供试品溶液1 mL，置50 mL量瓶中，用甲醇稀释至刻度，摇匀，再精密量取1 mL，用甲醇稀释至20 mL，摇匀，即得。
2.2.3 对照品储备溶液
取杂质Ⅰ的对照品30 mg，精密称定，置100 mL量瓶中，加甲醇溶解并稀释至刻度，摇匀，精密量取2 mL，置20 mL量瓶中，用甲醇稀释至刻度，摇匀，即得杂质Ⅰ对照品储备溶液。同法制备杂质Ⅱ、Ⅲ、Ⅳ、Ⅴ、Ⅵ、Ⅶ、Ⅷ、Ⅸ的对照品储备溶液。取替米沙坦的对照品30 mg，精密称定，置100 mL量瓶中，加甲醇约80 mL与1 mol·L-1 氢氧化钠溶液100 μL使溶解，用甲醇稀释至刻度，摇匀，精密量取2 mL，置20 mL量瓶中，用甲醇稀释至刻度，摇匀，即得替米沙坦对照品储备溶液。
2.2.4 混合溶液
取本品30 mg，置100 mL量瓶中，加甲醇约80 mL和1 mol·L-1 氢氧化钠溶液100 μL使溶解，再精密加入各杂质对照品储备溶液1 mL，并用甲醇稀释至刻度，摇匀，即得。
2.3 专属性试验
分别精密量取供试品溶液、混合溶液各10 μL，注入液相色谱仪，记录色谱图(见图2)。各峰间的分离度均>1.5。
2.4 强制降解试验
(A)未破坏溶液：精密量取供试品储备液2 mL，用甲醇稀释至20 mL，摇匀，即得；(B)强酸破坏溶液：精密量取供试品储备液2 mL，置20 mL量瓶中，加1 mol·L-1盐酸溶液2 mL，避光放置24 h后用1 mol·L-1氢氧化钠溶液中和，再用甲醇稀释至刻度，摇匀，即得；(C)强碱破坏溶液：精密量取供试品储备液2 mL，置20 mL量瓶中，加1 mol·L-1氢氧化钠溶液2 mL，避光放置24 h后用1 mol·L-1盐酸溶液中和，再用甲醇稀释至刻度，摇匀，即得；(D)氧化破坏：精密量取供试品储备液2 mL，置20 mL量瓶中，加3%过氧化氢溶液2 mL，避光放置24 h后用甲醇稀释至刻度，摇匀，即得；(E)强光破坏溶液：精密量取供试品储备液5 mL，置透明玻璃皿中，置照度6 000 lx、近紫外能量1.3 W·m-2的光照仪中放置48 h，将该溶液和用甲醇润洗皿的润洗液置50 mL量瓶中，再用甲醇稀释至刻度，摇匀，即得；(F)高温破坏溶液：取本品适量，置称量瓶中，半敞口在130 ℃烘箱中放置8 h，取出冷却至室温后精密称取30 mg，置100 mL量瓶中，加甲醇约80 mL与1 mol·L-1氢氧化钠溶液100 μL使溶解，用甲醇稀释至刻度，摇匀，即得。精密量取上述溶液各10 μL，按“2.1”项下色谱条件进样分析。试验结果见表3。
替米沙坦在酸条件下未产生新的未知杂质，杂质Ⅸ含量增大的原因是替米沙坦在酸性条件下与溶液中的甲醇发生酯化反应，并非自身降解产生，而在实际生产、贮存、运输、检测等过程中，替米沙坦同时接触酸和醇类试剂的可能性微乎其微；替米沙坦在碱和高温条件下有着优越的稳定性，为制剂的制备工艺提供了科学依据；替米沙坦在氧化和强光条件下有着不同程度的破坏，最大的降解杂质峰保留时间相同，可能为同一种物质，与主峰的分离度符合要求。各破坏溶液主成分峰纯度均>998，按外标法计算主成分含量，结果均>98.0%，说明破坏后物料质量守恒，未产生与主峰重叠的降解杂质。
2.5 检测限和定量限试验
精密量取杂质Ⅷ对照品储备溶液2.4 mL、替米沙坦和其他杂质对照品储备溶液各1.5 mL，用甲醇逐级稀释至2×104 mL体积，摇匀，注入液相色谱仪，记录色谱图，各化合物信噪比为10，替米沙坦、杂质Ⅰ、杂质Ⅱ、杂质Ⅲ、杂质Ⅳ、杂质Ⅴ、杂质Ⅵ、杂质Ⅶ、杂质Ⅷ、杂质Ⅸ定量限分别为22.75、21.55、22.13、21.90、22.38、22.20、22.08、21.54、33.12、22.72 ng·mL-1；精密量取稀释后的定量限溶液3 mL，用甲醇稀释10 mL，摇匀，注入液相色谱仪，记录色谱图，各化合物信噪比为3，替米沙坦、杂质Ⅰ、杂质Ⅱ、杂质Ⅲ、杂质Ⅳ、杂质Ⅴ、杂质Ⅵ、杂质Ⅶ、杂质Ⅷ、杂质Ⅸ检测限分别为6.83、6.47、6.64、6.57、6.71、6.66、6.62、6.46、9.94、6.82 ng·mL-1。结果表明，本方法测定替米沙坦及各杂质的灵敏度高，能满足检测需求。
2.6 线性关系考察
精密量取对照品储备溶液各5 mL，置同一100 mL量瓶中，用甲醇稀释至刻度，摇匀，作为线性储备溶液。分别精密量取线性储备溶液4.0、3.4、2.4、2.0、1.6、1.0 mL，分别置6个10 mL量瓶中，用甲醇稀释至刻度，摇匀，即得相对浓度200%、170%、120%、100%、80%、50%的线性溶液。精密量取100%线性溶液1 mL，用甲醇稀释至10 mL，摇匀，即得相对浓度10%的线性溶液。精密量取上述线性溶液各10 μL，按“2.1”项下色谱条件进样测定，采用最小二乘法以进样浓度对峰面积进行线性回归，相对校正因子采用斜率比值法计算。试验结果见表4，各杂质约在定量限至2倍限度范围内线性关系良好，相关系数r均>0.999，各杂质相对响应因子均在1.0±0.2范围内。
2.7 准确度试验
精密量取杂质对照品储备溶液各5 mL，置同一50 mL量瓶中，用甲醇稀释至刻度，摇匀，作为杂质混合储备溶液。精密量取1 mL，用甲醇稀释至10 mL，摇匀，即得杂质对照品溶液。精密量取供试品储备溶液10份，各1 mL，分别置10 mL量瓶中，其中1份为本底溶液，另外9份平均分成3组，每组分别精密加入杂质混合储备溶液0.8、1.0、1.2 mL，用甲醇稀释至刻度，摇匀，即得相对浓度80%、100%、120%的回收率溶液。精密量取上述溶液各10 μL，按“2.1”项下色谱条件进样测定，采用外标法计算各杂质的加样回收率。试验结果见表5，结果表明本法测定杂质的准确度高。
2.8 精密度试验
2.8.1 重复性
取同批次(20201101)替米沙坦适量，按“2.2.1”项下方法配制6份供试品溶液，按“2.1”项下色谱条件进样测定，按面积归一化法计算杂质含量。结果杂质Ⅰ、Ⅱ、Ⅳ的平均含量分别为0.007%、0.008%、0.004%，RSD依次为5.5%、5.5%、2.7%；6份溶液中杂质Ⅲ、Ⅴ、Ⅵ、Ⅶ、Ⅷ、Ⅸ均未检出；其他最大杂质平均为0.03%，杂质总和平均为0.07%，RSD依次为2.0%、2.6%。结果表明，本方法重复性良好。
2.8.2 中间精密度
由另一实验人员在不同日期配制6份供试品溶液，注入另一高效液相色谱仪（Agilent 1260型，VWD检测器）中，记录色谱图。结果杂质Ⅰ、Ⅱ、Ⅳ的平均含量分别为0.008%、0.007%、0.004%，RSD依次为5.0%、4.5%、5.7%；6份溶液中杂质Ⅲ、Ⅴ、Ⅵ、Ⅶ、Ⅷ、Ⅸ均未检出；其他最大杂质平均为0.03%，杂质总和平均为0.07%，RSD依次为2.3%、1.2%。与重复性试验测得的6组数据合并后，12份杂质Ⅰ、Ⅱ、Ⅳ以及其他最大杂质和总杂含量结果的RSD依次为11%、8.8%、6.4%、2.2%、1.9%，说明该方法中间精密度良好。
2.9 溶液稳定性试验
制得供试品溶液后立即在“2.1”项色谱条件下进样测定，按0 h计，供试品溶液再在室温下放置1、2、4、8、12、16、20 h后再次注入液相色谱仪，考察杂质峰面积的变化。结果最大单一杂质平均含量为0.03%，平均峰面积为5.594，RSD分别为1.6%、2.1%；杂质总量平均为0.08%，杂质峰面积和的平均值为15.49，RSD分别为1.3%、2.1%，结果说明替米沙坦及其杂质在溶液中稳定性良好。
2.10 耐用性试验
取“2.7”项下相对浓度100%的回收率溶液作为耐用性供试溶液，考察不同流速(0.75、0.8、0.85 mL·min-1)、不同柱温(24、25、26 ℃)、不同波长(229、230、231 nm)、不同初始流动相比例(81∶19、80∶20、79∶21)及不同流动相pH(2.95、3.0、3.05)对杂质测定结果的影响。结果表明，不同色谱条件下各杂质含量一致，各峰间的分离度均>1.5，本方法耐用性良好。
2.11 样品测定
取杂质对照品溶液、对照溶液、3批供试品溶液各10 μL，分别按“2.1”项下色谱条件进样测定，采用外标法计算已知杂质含量，采用主成分自身对照法计算未知杂质含量，结果见表6。
3 讨论
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3.1 与药典方法的比较
ChP 2020[7]、EP 10.0[8]或USP 43[9]中替米沙坦有关物质检测方法均不能有效分离本品中所有的已知杂质，3种方法与本方法有着明显的差异，除检测波长一致外，其他如溶液浓度、色谱柱、流动相、流速、杂质限度等均不一致。本方法中供试品溶液质量浓度为0.3 mg·mL-1，进样体积为10 μL，在保证杂质有效检出的前提下使主成分在色谱柱中不过载，而ChP 2020中的供试品溶液质量浓度为0.5 mg·mL-1，进样体积为20 μL，主成分在色谱柱中已达过载状态，导致主峰较宽，容易包裹杂质峰。本方法选用的色谱柱为Waters Symmetry Shield RP8(150 mm×4.6 mm，3.5 μm)，该色谱柱的填料异于普通填料，是在靠近硅胶表面内嵌极性基团，减少了填料表面硅醇基活性，从而减少分析物与硅醇基的相互作用，在pH 2~8范围内使峰形与分离度显著改善；其他药典方法选用的色谱柱填料均为十八烷基硅烷键合硅胶，在分离度和峰拖尾方面不及本法选用的色谱柱，如ChP 2020[7]方法中规定替米沙坦峰拖尾因子不大于2.0，USP 43[9]方法中规定替米沙坦峰拖尾因子应在0.9~1.5，而在耐用性试验下采用本方法所测替米沙坦峰拖尾因子在0.94~1.06。EP 10.0[8]和USP 43[9]色谱条件基本一致，流动相中含有离子对试剂——戊烷磺酸钠，配制不便，运行时可能会出现基线波动，不利于检测，而本方法中流动相基本不含缓冲盐，配制简便，溶剂峰不干扰主峰及各杂质峰的测定。根据实际控制要求，规定本品中单个杂质不得过0.10%，杂质总量不得过0.3%，限度相较于各药典中的杂质限度更严格。
3.2 流动相pH的选择
流动相pH是色谱条件中的关键参数。EP 10.0[8]和USP 43[9]方法中的流动相pH均为3.0，ChP 2020[7]方法中的流动相pH为5.0。经考察发现流动相pH的大小对替米沙坦峰有着较为明显的影响，当pH不小于3.10时，杂质Ⅳ峰与替米沙坦峰间的分离度约>5.0，但替米沙坦峰发生前延，拖尾因子<0.9；当pH不大于2.90时，杂质Ⅳ峰与替米沙坦峰间的分离度<1.5，替米沙坦峰发生拖尾，拖尾因子>1.1。本方法中流动相pH为3.0，替米沙坦峰拖尾因子约为1.0，与杂质Ⅳ峰间的分离度约为3.0，为了有效检测本品中的有关物质，在系统适用性要求中规定替米沙坦峰拖尾因子应为0.9~1.1，与杂质Ⅳ峰间的分离度应>2.0。
3.3 潜在的杂质分析
本品合成路线中的起始原料A即是ChP 2020[7]中的替米沙坦杂质Ⅰ，该原料中主要杂质为4’-二溴甲基联苯-2-羧酸甲酯(起始原料A杂质Ⅰ)，其化学结构中均含卤代烷烃的警示结构[10]，其中起始原料A经查询Ames试验结果呈阳性[11]。参考ICH M7[12]中的方法4和文献[13]中的方法可推算杂质的清除因子，结果残留至本品中的量远低于安全限度。为了更加具体证明清除效果，进行了杂质清除试验，在中间体中添加远超实际水平的起始原料A(约1.5%)和其杂质Ⅰ(1.0%)，并在实验室规模下按照本品工艺连续制备6批替米沙坦，结果6批产品中均未检出，与推算的清除效果一致。在制备本品最后一步反应中，体系中共投入了3次液碱，每一次的强碱都能轻易破坏卤烷烃结构[14]，在此又简单模拟了工艺过程，在杂质溶液中加入1 mol·L-1氢氧化钠溶液，并置75 ℃水浴锅中，结果在1 h内，起始原料A和其杂质Ⅰ均完全被破坏，变成了极性相对较大且容易去除的无警示结构物质。起始原料A及其杂质Ⅰ在本品中的痕量检测采用的是UPLC-MS/MS法[15]，结果在本公司生产的替米沙坦粗品及成品中均未检出，说明清除效果好，工艺中第1次投入的液碱即可完全破坏起始原料A和其杂质Ⅰ杂质，保障替米沙坦质量可控性和安全性。
4 结论
收起
替米沙坦的国内外合成路线基本相似[16]，不同的可能是起始原料A结构，如4’-溴甲基联苯-2-羧酸叔丁酯也可作为合成替米沙坦的起始原料，该物质与起始原料A性质相似，在替米沙坦中检出的可能性也较低，故本方法也适用于该路线生产的替米沙坦有关物质检查。相比于各药典方法，本方法在基线波动、分离效果、峰拖尾方面更优，且灵敏度高、精密度好、准确度高，弥补了药典方法的不足之处，降低了杂质控制风险。
文献
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doi: 10.16155/j.0254-1793.2024.01.13
  • 接收时间：2023-02-13
  • 首发时间：2026-03-16
  • 出版时间：2024-01-31
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  • 收稿日期：2023-02-13
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    浙江金立源药业有限公司，绍兴 312369

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2种不同金属材料的力学参数
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species		 占总种数比例
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total species (%)		 属
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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
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