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Article(id=1239231274909487456, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239231265254207730, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2023-0774, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1701705600000, receivedDateStr=2023-12-05, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773385359742, onlineDateStr=2026-03-13, pubDate=1725033600000, pubDateStr=2024-08-31, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773385359742, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773385359742, creator=13701087609, updateTime=1773385359742, updator=13701087609, issue=Issue{id=1239231265254207730, tenantId=1146029695717560320, journalId=1205117023404326918, year='2024', volume='44', issue='8', pageStart='1285', pageEnd='1462', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=0, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773385357440, creator=13701087609, updateTime=1773385579800, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239232197937393856, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239231265254207730, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239232197937393857, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239231265254207730, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1379, endPage=1386, ext={EN=ArticleExt(id=1239231275215671668, articleId=1239231274909487456, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=HPLC determination of related substances in olaparib raw materials, columnId=1206272757852074373, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Safety Monitoring, runingTitle=null, highlight=null, articleAbstract=
Objective:

To establish an HPLC method for the determination of related substances in olaparib raw materials.

Methods:

By using YMC-Pack pro C18 AS(150 mm×4.6 mm，3 μm) column，0.05 mol·L-1 potassium dihydrogen phosphate (pH 3.0 adjusted with dilute phosphoric acid)-methanol-acetonitrile (90:5:5) was as mobile phase A and methanol-acetonitrile-water (45:45:10) was as mobile phase B，in gradient elution，with flow rate of 0.8 mL·min-1. The column temperature was 30 ℃，the detection wavelength was 210 nm，and the injection volume was 10 μL.

Results:

The solvent blank did not interfere with the determination of relevant substances in the test solution，the known impurities Ⅰ-Ⅶ and unknown impurities in the system suitability solution were well separated in the chromatographic system. Olaparib had a good linear relationship with its peak area in the concentration range of 0.083-333.133 μg·mL-1. The concentrations of impurities Ⅰ-Ⅶ were 0.05-3.0 μg·mL-1，there were good linear relationships with their peak area，and their r were 0.999 7 or above. The average recoveries of impurities Ⅰ-Ⅶ were all above 92.0%，and RSDs were less than 4.0%.

Conclusion:

The HPLC method for the detection of the related substances of olaparib raw materials has strong specificity，high sensitivity，high accuracy and good precision，which can meet the requirements for the detection of related substances of olaparib raw materials.

, correspAuthors=Chuan HU, Hong-ming LI, 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=Yan ZOU, Hai-long WU, Li DENG, Chuan HU, Hong-ming LI), CN=ArticleExt(id=1239231279082820109, articleId=1239231274909487456, tenantId=1146029695717560320, journalId=1205117023404326918, language=CN, title=HPLC法检查奥拉帕利原料中有关物质, 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检测奥拉帕利原料中的有关物质。

方法：

采用YMC-Pack pro C18 AS（150 mm×4.6 mm，3 μm）色谱柱，以0.05 mol·L-1的磷酸二氢钾（用稀磷酸调pH至3.0）-甲醇-乙腈（90:5:5）为流动相A，甲醇-乙腈-水（45:45:10）为流动相B，进行梯度洗脱，流速0.8 mL·min-1，柱温30 ℃，检测波长210 nm，进样量10 μL。

结果：

空白溶剂不干扰供试品溶液有关物质测定，系统适用性溶液中已知杂质Ⅰ~Ⅶ及未知杂质在该色谱系统中分离完好；奥拉帕利质量浓度在0.033~411.623 μg·mL-1，杂质Ⅰ~Ⅶ质量浓度均在0.05~3.0 μg·mL-1与其峰面积呈较好的线性关系，其r均在0.999以上；杂质Ⅰ~Ⅶ平均回收率均大于92.0%（RSD均小于4.0%）。

结论：

HPLC法检查奥拉帕利原料有关物质方法专属性强，灵敏度高，准确度高，精密度好，可满足奥拉帕利原料有关物质检测需求。

, correspAuthors=胡川, 李宏名, authorNote=null, correspAuthorsNote=
* 胡川　Tel：18908023052；E-mail：
李宏名　Tel：18581541913；E-mail：
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Tel：15196627806；E-mail：

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Tel：15196627806；E-mail：

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Vol Ⅳ[S]. 2020：480, articleTitle=null, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1239231279292535324, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, xref=1., ext=[AuthorCompanyExt(id=1239231279296729629, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, companyId=1239231279292535324, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.Sinopharm Chuankang Pharmaceutical Co.，Ltd.，Chengdu 611731，China), AuthorCompanyExt(id=1239231279305118238, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, companyId=1239231279292535324, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.国药集团川抗制药有限公司，成都 611731)]), AuthorCompany(id=1239231279389004322, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, xref=2., ext=[AuthorCompanyExt(id=1239231279397392931, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, companyId=1239231279389004322, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.Chengdu Kanghong Pharmaceutical Group Co.，Ltd.，Chengdu 610000，China), AuthorCompanyExt(id=1239231279401587236, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, companyId=1239231279389004322, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.成都康弘药业集团股份有限公司，成都 610000)])], figs=[ArticleFig(id=1239231283679777446, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=EN, label=Fig.1, caption=Chemical structure of olaparib, figureFileSmall=zqknL8qhj2bcVABLBXIU+Q==, figureFileBig=FuL7CYsQN6cyKKn6zieXaQ==, tableContent=null), ArticleFig(id=1239231283780440746, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=CN, label=图1　, caption=奥拉帕利的化学结构, figureFileSmall=zqknL8qhj2bcVABLBXIU+Q==, figureFileBig=FuL7CYsQN6cyKKn6zieXaQ==, tableContent=null), ArticleFig(id=1239231283998544563, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=EN, label=Fig.2, caption=Chromatogram of system applicability, figureFileSmall=ruQ/kKWy1pGRnYzpUw0jRQ==, figureFileBig=J7W84ne9WvLKuold21ndtQ==, tableContent=null), ArticleFig(id=1239231284095013557, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=CN, label=图2　, caption=系统适用性溶液色谱图, figureFileSmall=ruQ/kKWy1pGRnYzpUw0jRQ==, figureFileBig=J7W84ne9WvLKuold21ndtQ==, tableContent=null), ArticleFig(id=1239231284199871157, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=EN, label=Fig.3, caption=Schematic diagram of olaparib acid-base degradation, figureFileSmall=wnnhMeAMY5gUpxdamI2KNA==, figureFileBig=NMz9DRN9yzzUE2p6mvEKkg==, tableContent=null), ArticleFig(id=1239231284321505979, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=CN, label=图3　, caption=奥拉帕利酸碱降解示意图, figureFileSmall=wnnhMeAMY5gUpxdamI2KNA==, figureFileBig=NMz9DRN9yzzUE2p6mvEKkg==, tableContent=null), ArticleFig(id=1239231284581552827, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=EN, label=Tab.1, caption=

Chemical structure and source of impurities Ⅰ-Ⅶ

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
（compound）		结构
（structure）		来源
（source）
杂质Ⅰ（impurityⅠ）工艺杂质（process impurities）
杂质Ⅱ（impurityⅡ）工艺杂质（process impurities）
杂质Ⅲ（impurity Ⅲ）中间体、降解产物（intermediate，degradation products）
杂质Ⅳ（impurity Ⅳ）工艺杂质（process impurities）
杂质Ⅴ（impurityⅤ）起始原料、降解产物（starting materials，degradation products）
杂质Ⅵ（impurity Ⅵ）工艺杂质（process impurities）
杂质Ⅶ（impurity Ⅶ）工艺杂质（process impurities）
), ArticleFig(id=1239231284682216129, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=CN, label=表1, caption=

已知杂质结构及来源

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
（compound）		结构
（structure）		来源
（source）
杂质Ⅰ（impurityⅠ）工艺杂质（process impurities）
杂质Ⅱ（impurityⅡ）工艺杂质（process impurities）
杂质Ⅲ（impurity Ⅲ）中间体、降解产物（intermediate，degradation products）
杂质Ⅳ（impurity Ⅳ）工艺杂质（process impurities）
杂质Ⅴ（impurityⅤ）起始原料、降解产物（starting materials，degradation products）
杂质Ⅵ（impurity Ⅵ）工艺杂质（process impurities）
杂质Ⅶ（impurity Ⅶ）工艺杂质（process impurities）
), ArticleFig(id=1239231284787073729, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=EN, label=Tab.2, caption=

Results of linear relationship

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
（compound）		线性范围
（linear range）/（μg·mL-1）		回归方程
（regressive equation）		r相对校正因子
（relative correction factor）		LOD/（μg·mL-1）LOQ/（μg·mL-1）
杂质Ⅰ（impurity Ⅰ）0.061~3.028Y=149.8X-0.4321.0000.620.020.05
杂质Ⅱ（impurity Ⅱ）0.062~3.104Y=51.10X+0.1560.999 91.890.020.06
杂质Ⅲ（impurity Ⅲ）0.060~3.008Y=102.0X-0.2651.0000.970.020.06
杂质Ⅳ（impurity Ⅳ）0.059~2.929Y=86.87X-0.3651.0001.100.020.06
杂质Ⅴ（impurity Ⅴ）0.059~2.953Y=107.7X-0.1221.0000.890.020.03
杂质Ⅵ（impurity Ⅵ）0.061~3.044Y=113.3X-0.4421.0000.850.020.05
奥拉帕利（olaparib）0.033~411.623Y=92.31X+354.50.999 41.000.020.04
杂质Ⅶ（impurity Ⅶ）0.058~2.880Y=96.21X-0.8341.0000.920.020.05
), ArticleFig(id=1239231284896125637, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=CN, label=表2, caption=

各杂质线性关系考察结果

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
（compound）		线性范围
（linear range）/（μg·mL-1）		回归方程
（regressive equation）		r相对校正因子
（relative correction factor）		LOD/（μg·mL-1）LOQ/（μg·mL-1）
杂质Ⅰ（impurity Ⅰ）0.061~3.028Y=149.8X-0.4321.0000.620.020.05
杂质Ⅱ（impurity Ⅱ）0.062~3.104Y=51.10X+0.1560.999 91.890.020.06
杂质Ⅲ（impurity Ⅲ）0.060~3.008Y=102.0X-0.2651.0000.970.020.06
杂质Ⅳ（impurity Ⅳ）0.059~2.929Y=86.87X-0.3651.0001.100.020.06
杂质Ⅴ（impurity Ⅴ）0.059~2.953Y=107.7X-0.1221.0000.890.020.03
杂质Ⅵ（impurity Ⅵ）0.061~3.044Y=113.3X-0.4421.0000.850.020.05
奥拉帕利（olaparib）0.033~411.623Y=92.31X+354.50.999 41.000.020.04
杂质Ⅶ（impurity Ⅶ）0.058~2.880Y=96.21X-0.8341.0000.920.020.05
), ArticleFig(id=1239231285021954761, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=EN, label=Tab.3, caption=

Recovery results

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		加入量
(added)/μg		测定量
(measured)/μg		回收率
(recovery)/%		平均回收率
(average recovery)/%		RSD/%
杂质Ⅰ(impurity Ⅰ)1.497 61.434 595.894.90.78
1.497 61.415 194.5
1.497 61.419 894.8
2.995 22.832 494.6
2.995 22.805 393.7
2.995 22.837 294.7
5.990 45.761 996.2
5.990 45.676 694.8
5.990 45.676 694.8
杂质Ⅱ(impurity Ⅱ)1.538 01.446 894.193.11.1
1.538 01.436 193.4
1.538 01.439 793.6
3.076 02.891 394.0
3.076 02.828 692.0
3.076 02.858 892.9
6.152 05.810 394.4
6.152 05.641 291.7
6.152 05.641 291.7
杂质Ⅲ(impurity Ⅲ)1.509 71.435 295.195.11.2
1.509 71.432 994.9
1.509 71.464 397.0
3.019 42.891 695.8
3.019 42.829 893.7
3.019 42.891 795.8
6.038 85.792 395.9
6.038 85.663 893.8
6.038 85.663 893.8
杂质Ⅳ(impurity Ⅳ)1.462 11.378 194.397.62.2
1.462 11.466 3100.3
1.462 11.408 796.3
2.924 22.898 799.1
2.924 22.916 199.7
2.924 22.906 899.4
5.848 45.725 097.9
5.848 45.605 695.8
5.848 45.605 695.8
杂质Ⅴ(impurityⅤ)1.489 41.376 692.495.22.8
1.489 41.442 596.9
1.489 41.341 690.1
2.978 82.907 197.6
2.978 82.918 698.0
2.978 82.874 996.5
5.957 65.752 496.6
5.957 65.631 894.5
5.957 65.631 794.5
杂质Ⅵ(impurity Ⅵ)1.515 61.360 089.792.33.5
1.515 61.334 488.0
1.515 61.384 791.4
3.031 22.997 299.0
3.031 22.771 391.4
3.031 22.738 890.4
6.062 45.679 393.7
6.062 45.731 294.5
6.062 45.635 293.0
杂质Ⅶ(impurity Ⅶ)1.446 71.362 794.296.12.8
1.446 71.352 493.5
1.446 71.321 391.3
2.893 42.823 197.6
2.893 42.824 497.6
2.893 42.770 395.7
5.786 85.788 5100.0
5.786 85.648 897.6
5.786 85.646 897.6
), ArticleFig(id=1239231285160366798, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=CN, label=表3, caption=

回收率试验结果

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		加入量
(added)/μg		测定量
(measured)/μg		回收率
(recovery)/%		平均回收率
(average recovery)/%		RSD/%
杂质Ⅰ(impurity Ⅰ)1.497 61.434 595.894.90.78
1.497 61.415 194.5
1.497 61.419 894.8
2.995 22.832 494.6
2.995 22.805 393.7
2.995 22.837 294.7
5.990 45.761 996.2
5.990 45.676 694.8
5.990 45.676 694.8
杂质Ⅱ(impurity Ⅱ)1.538 01.446 894.193.11.1
1.538 01.436 193.4
1.538 01.439 793.6
3.076 02.891 394.0
3.076 02.828 692.0
3.076 02.858 892.9
6.152 05.810 394.4
6.152 05.641 291.7
6.152 05.641 291.7
杂质Ⅲ(impurity Ⅲ)1.509 71.435 295.195.11.2
1.509 71.432 994.9
1.509 71.464 397.0
3.019 42.891 695.8
3.019 42.829 893.7
3.019 42.891 795.8
6.038 85.792 395.9
6.038 85.663 893.8
6.038 85.663 893.8
杂质Ⅳ(impurity Ⅳ)1.462 11.378 194.397.62.2
1.462 11.466 3100.3
1.462 11.408 796.3
2.924 22.898 799.1
2.924 22.916 199.7
2.924 22.906 899.4
5.848 45.725 097.9
5.848 45.605 695.8
5.848 45.605 695.8
杂质Ⅴ(impurityⅤ)1.489 41.376 692.495.22.8
1.489 41.442 596.9
1.489 41.341 690.1
2.978 82.907 197.6
2.978 82.918 698.0
2.978 82.874 996.5
5.957 65.752 496.6
5.957 65.631 894.5
5.957 65.631 794.5
杂质Ⅵ(impurity Ⅵ)1.515 61.360 089.792.33.5
1.515 61.334 488.0
1.515 61.384 791.4
3.031 22.997 299.0
3.031 22.771 391.4
3.031 22.738 890.4
6.062 45.679 393.7
6.062 45.731 294.5
6.062 45.635 293.0
杂质Ⅶ(impurity Ⅶ)1.446 71.362 794.296.12.8
1.446 71.352 493.5
1.446 71.321 391.3
2.893 42.823 197.6
2.893 42.824 497.6
2.893 42.770 395.7
5.786 85.788 5100.0
5.786 85.648 897.6
5.786 85.646 897.6
), ArticleFig(id=1239231285252641488, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=EN, label=Tab.4, caption=

Results of three batches of raw material drug samples

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
（compound）		含量（content）/%
批号（lot No.）211101批号（lot No.）211102批号（lot No.）211103
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）0.04%0.03%0.04%
杂质Ⅶ（impurity Ⅶ）0.10%0.09%0.09%
其他单个杂质（any other impurity）///
总杂质（total impurities）0.14%0.12%0.13%
), ArticleFig(id=1239231285336527569, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239231274909487456, language=CN, label=表4, caption=

3批原料药样品测定结果（n=3）

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
（compound）		含量（content）/%
批号（lot No.）211101批号（lot No.）211102批号（lot No.）211103
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）0.04%0.03%0.04%
杂质Ⅶ（impurity Ⅶ）0.10%0.09%0.09%
其他单个杂质（any other impurity）///
总杂质（total impurities）0.14%0.12%0.13%
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HPLC法检查奥拉帕利原料中有关物质
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邹艳 1 , 吴海龙 1 , 邓丽 1 , 胡川 2, * , 李宏名 1, *
药物分析杂志 | 安全监测 2024,44(8): 1379-1386
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药物分析杂志 | 安全监测 2024, 44(8): 1379-1386
HPLC法检查奥拉帕利原料中有关物质
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邹艳1 , 吴海龙1, 邓丽1, 胡川2, * , 李宏名1, *
作者信息
  • 1.国药集团川抗制药有限公司，成都 611731
  • 2.成都康弘药业集团股份有限公司，成都 610000

    • Tel：15196627806；E-mail：

通讯作者:

* 胡川　Tel：18908023052；E-mail：
李宏名　Tel：18581541913；E-mail：
HPLC determination of related substances in olaparib raw materials
Yan ZOU1 , Hai-long WU1, Li DENG1, Chuan HU2, * , Hong-ming LI1, *
Affiliations
  • 1.Sinopharm Chuankang Pharmaceutical Co.，Ltd.，Chengdu 611731，China
  • 2.Chengdu Kanghong Pharmaceutical Group Co.，Ltd.，Chengdu 610000，China
出版时间: 2024-08-31 doi: 10.16155/j.0254-1793.2023-0774
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摘要
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目的：

建立高效液相色谱法检测奥拉帕利原料中的有关物质。

方法：

采用YMC-Pack pro C18 AS（150 mm×4.6 mm，3 μm）色谱柱，以0.05 mol·L-1的磷酸二氢钾（用稀磷酸调pH至3.0）-甲醇-乙腈（90:5:5）为流动相A，甲醇-乙腈-水（45:45:10）为流动相B，进行梯度洗脱，流速0.8 mL·min-1，柱温30 ℃，检测波长210 nm，进样量10 μL。

结果：

空白溶剂不干扰供试品溶液有关物质测定，系统适用性溶液中已知杂质Ⅰ~Ⅶ及未知杂质在该色谱系统中分离完好；奥拉帕利质量浓度在0.033~411.623 μg·mL-1，杂质Ⅰ~Ⅶ质量浓度均在0.05~3.0 μg·mL-1与其峰面积呈较好的线性关系，其r均在0.999以上；杂质Ⅰ~Ⅶ平均回收率均大于92.0%（RSD均小于4.0%）。

结论：

HPLC法检查奥拉帕利原料有关物质方法专属性强，灵敏度高，准确度高，精密度好，可满足奥拉帕利原料有关物质检测需求。

奥拉帕利  /  聚腺苷二磷酸核糖聚合酶（PARP）抑制剂  /  有关物质  /  方法研究  /  质量控制  /  高效液相色谱
Objective:

To establish an HPLC method for the determination of related substances in olaparib raw materials.

Methods:

By using YMC-Pack pro C18 AS(150 mm×4.6 mm，3 μm) column，0.05 mol·L-1 potassium dihydrogen phosphate (pH 3.0 adjusted with dilute phosphoric acid)-methanol-acetonitrile (90:5:5) was as mobile phase A and methanol-acetonitrile-water (45:45:10) was as mobile phase B，in gradient elution，with flow rate of 0.8 mL·min-1. The column temperature was 30 ℃，the detection wavelength was 210 nm，and the injection volume was 10 μL.

Results:

The solvent blank did not interfere with the determination of relevant substances in the test solution，the known impurities Ⅰ-Ⅶ and unknown impurities in the system suitability solution were well separated in the chromatographic system. Olaparib had a good linear relationship with its peak area in the concentration range of 0.083-333.133 μg·mL-1. The concentrations of impurities Ⅰ-Ⅶ were 0.05-3.0 μg·mL-1，there were good linear relationships with their peak area，and their r were 0.999 7 or above. The average recoveries of impurities Ⅰ-Ⅶ were all above 92.0%，and RSDs were less than 4.0%.

Conclusion:

The HPLC method for the detection of the related substances of olaparib raw materials has strong specificity，high sensitivity，high accuracy and good precision，which can meet the requirements for the detection of related substances of olaparib raw materials.

olaparib  /  PARP inhibitor  /  related substances  /  method study  /  quality control  /  high performance liquid chromatography（HPLC）
邹艳, 吴海龙, 邓丽, 胡川, 李宏名. HPLC法检查奥拉帕利原料中有关物质. 药物分析杂志, 2024 , 44 (8) : 1379 -1386 . DOI: 10.16155/j.0254-1793.2023-0774
Yan ZOU, Hai-long WU, Li DENG, Chuan HU, Hong-ming LI. HPLC determination of related substances in olaparib raw materials[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (8) : 1379 -1386 . DOI: 10.16155/j.0254-1793.2023-0774
正文
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奥拉帕利（olaparib，AZD2281），商品名为利普卓（lynpara），化学名为4-(3-{[4-(环丙基羰基)哌嗪-1-基]羰基}4-氟苯基)甲基]酞嗪-1(2H)-酮，化学结构见图1，是阿斯利康公司开发上市的全球首款口服小分子聚腺苷二磷酸核糖聚合酶(PARP)抑制剂[1-3]，2014年后逐渐在欧洲、美国、日本、英国和中国等多个地区上市。该药疗效显著，对BRCA突变的晚期上皮性卵巢癌、输卵管癌、原发性腹膜癌、转移性去势抵抗性前列腺癌等多种癌症具有靶向治疗作用[4-8]，安全性好，不良反应轻微[9-11]。且有研究表明奥拉帕利对内毒素致急性肺损伤有保护作用[12]。
各国药典中均未收载原料质量标准，有关物质研究情况少有文献报道[13]。本研究基于合成工艺及降解途径[14]，采用HPLC法拟在原料中研究控制如下杂质（见表1），经有关物质方法筛选，按照出峰时间顺序将这7个杂质命名为杂质Ⅰ~Ⅶ，并根据分析方法验证指导原则[15]，对方法进行了详细的验证，建立了专属性强，灵敏度高，准确度高，精密度好的有关物质检测方法，适合于对奥拉帕利原料有关物质进行质控。
1　仪器与试药
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1.1　仪器
Agilent 1260高效液相色谱仪（Agilent公司，包括四元梯度泵、自动进样器、柱温箱、二极管阵列检测器、ChemStation工作站）；XSE205DU型电子天平（Mettler Toledo公司，d=0.01 mg）；FE20型酸度计（Mettler Toledo公司）；HK-UP-UV-40超纯水仪（成都浩康科技有限公司）。
1.2　试药
甲醇和乙腈（色谱纯，国药集团化学试剂有限公司）；磷酸二氢钾（分析纯，国药集团化学试剂有限公司）；磷酸（分析纯，成都市科隆化学品有限公司）。
杂质Ⅰ（批号200427，纯度100.0%）、杂质Ⅱ（批号200826，纯度100.0%）由上海达瑞精细化学品有限公司提供；杂质Ⅲ（批号210216，纯度99.65%）、杂质Ⅳ（批号210122，纯度96.75%）、杂质Ⅴ（批号210112，纯度98.1%）、杂质Ⅵ（批号210123，纯度99.33%）、杂质Ⅶ（批号210116，纯度96.05%）、奥拉帕利对照品（批号210622，纯度99.86%）均为自制，纯度测定方法为HPLC。
2　方法与结果
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2.1　色谱条件
采用YMC-Pack pro C18 AS（150 mm×4.6 mm，3 μm或相似性能）色谱柱，以0.05 mol·L-1的磷酸二氢钾（用稀磷酸调pH至3.0）-甲醇-乙腈（90:5:5）为流动相A，甲醇-乙腈-水（45:45:10）为流动相B，梯度洗脱（0~25 min，95%A→80%A；25~62 min，80%A→30%A；62~63 min，30%A→95%A；63~70min，95%A），流速0.8 mL·min-1，柱温30 ℃，检测波长210 nm，进样体积10 μL。
2.2　溶液的配制
2.2.1　供试品溶液
取奥拉帕利原料约10 mg，精密称定，置50 mL量瓶中，加80%甲醇溶解并稀释制成每1 mL中约含0.2 mg的溶液，摇匀，即得。
2.2.2　对照溶液
精密量取供试品溶液1 mL，置100 mL量瓶中，用80%甲醇稀释至刻度，摇匀，制成每1 mL中约含2 μg的溶液，即得。
2.2.3　混合杂质储备液
取杂质Ⅰ、杂质Ⅱ、杂质Ⅲ、杂质Ⅳ、杂质Ⅵ的对照品适量，精密称定，置同一量瓶中，加80%甲醇溶解并稀释制成每1 mL中约含0.15 mg的混合杂质储备液。
2.2.4　杂质Ⅴ储备液
取杂质Ⅴ对照品约7.5 mg，精密称定，置50 mL量瓶中，加DMSO 1 mL溶解后，用80%甲醇稀释至刻度，摇匀，即得。
2.2.5　杂质Ⅶ储备液
取杂质Ⅶ对照品约7.5 mg，精密称定，置50 mL量瓶中，加DMSO 1 mL溶解后，用80%甲醇稀释至刻度，摇匀，即得。
2.2.6　系统适用性溶液
取奥拉帕利对照品约10 mg，精密称定，置50 mL量瓶中，精密加入混合杂质储备液、杂质Ⅴ和杂质Ⅶ储备液各0.1 mL，用80%甲醇溶解并稀释至刻度，摇匀，制成每1 mL中约含奥拉帕利0.2 mg和各杂质约0.3 μg的系统适用性溶液。
2.2.7　回收率测定用供试品储备液
精密称取奥拉帕利对照品约50 mg，置25 mL量瓶中，加80%甲醇溶解并稀释至刻度，摇匀，制成每1 mL中约含奥拉帕利2 mg的溶液，即得。
2.2.8　回收率测定用混合杂质对照品储备液
分别取混合杂质储备液、杂质Ⅴ储备液、杂质Ⅶ储备液各1 mL，置50 mL量瓶中，加80%甲醇稀释至刻度，摇匀，即得。
2.2.9　回收率混合杂质对照品溶液
精密量取“2.2.8”项下回收率测定用混合杂质对照品储备液2 mL，置50 mL量瓶中，加80%甲醇稀释至刻度，摇匀，制成每1 mL中约含各杂质0.12 μg的溶液，即得。
2.3　专属性试验
精密称取奥拉帕利原料约10 mg，置50 mL量瓶中，分别进行强酸降解（5 mol·L-1盐酸溶液2 mL，60 ℃放置1 h）、强碱降解（5 mol·L-1氢氧化钠溶液2.5 mL，60 ℃放置20 min）、氧化降解（30%双氧水2 mL，室温放置50 h）、高温降解（105 ℃高温放置30 h）、光照降解（加80%甲醇溶解并定容，溶液分成2份，1份置于4 500 lx光照箱中放置24 h，另1份置于遮光袋中后在4 500 lx光照箱中放置24 h作为遮光对照溶液），酸碱降解进行中和，得到各降解样品。各降解样品（除光照降解外）加80%甲醇溶解并稀释至刻度，摇匀，即得降解后的各供试品溶液。
取“2.2.1”项下供试品溶液、“2.2.6”项下系统适用性溶液和上述各降解供试品溶液，按“2.1”项下色谱条件进样分析，记录色谱图。结果（图2）显示系统适用性溶液中已知杂质Ⅰ~Ⅶ及未知杂质在该色谱系统中分离完好，空白溶剂不干扰供试品溶液有关物质检测。强降解试验结果表明，本品对光和高温很稳定，但在强酸、强碱降解后，杂峰总量和杂峰个数增加，主要产生已知杂质Ⅲ和Ⅴ，强氧化条件下生产少许杂质Ⅵ，未知杂质未出现，各降解条件下主峰与杂质分离良好。表明所建立的方法专属性良好。
2.4　方法学验证
2.4.1　线性关系考察
分别称取杂质Ⅰ~Ⅶ的对照品各适量，精密称定，加80%甲醇溶解并稀释至刻度，制成含量均约为150 μg·mL-1的相应单一成分储备液；精密称取奥拉帕利对照品约20 mg，置50 mL量瓶中，分别加入各储备液1 mL，加80%甲醇稀释至刻度，作为杂质混合储备液，并加80%甲醇逐级稀释。以质量浓度（μg·mL-1）为横坐标，峰面积为纵坐标，进行线性回归，各杂质与奥拉帕利线性范围满足测定要求，结果见表2。
其中，K为线性回归方程斜率。
根据校正因子试验，标准中拟定杂质计算采用加校正因子的自身对照法。
加校正因子的自身对照法：各已知杂质峰面积乘以校正因子不得大于对照溶液主峰面积的0.15倍（0.15%），其他单个杂质峰面积不得大于对照溶液峰面积的0.1倍（0.1%）；各杂质峰面积的和不得大于对照溶液主峰面积的0.5倍（0.5%）。
2.4.2　检测限与定量限
取“2.4.1”项下杂质混合储备液用80%甲醇逐级稀释，并精密吸取10 μL进样分析，以信噪比S/N约为10的浓度作为定量限（LOQ），以信噪比S/N约为3的浓度作为检测限（LOD），计算各成分的LOD和LOQ，结果见表2。
2.4.3　回收率试验
精密量取“2.2.7”项回收率供试品储备液1 mL，置10 mL量瓶中，分别精密加入“2.2.8”项回收率测定用混合杂质对照品储备液0.5、1.0和2.0 mL各3份，加80%甲醇稀释至刻度，摇匀，制成50%、100%和200%（低、中、高）3个浓度水平的供试溶液。按“2.1”项下色谱条件进行分析，计算回收率。结果见表3。
2.4.4　重复性试验
按“2.4.3”项下回收率试验中100%杂质水平供试溶液制备方法，平行制备6份供试品溶液，按“2.1”项下的色谱条件进行分析，记录色谱图，按外标法计算供试品中各杂质的含量。结果杂质Ⅰ~Ⅶ的含量平均值为0.13%、0.13%、0.13%、0.13%、0.13%、0.17%、0.23%，RSD（n=6）均小于3%，表明方法的重复性较好。
2.4.5　中间精密度试验
按“2.4.4”项下重复试验中供试溶液配制方法，平行制备6份供试溶液，分别考察不同时间、不同实验仪器、不同色谱柱、不同分析实验人员对精密度的影响。结果杂质Ⅰ~Ⅶ含量的RSD（n=12）均小于4.0%，结果表明方法的中间精密度较好。
2.4.6　溶液稳定性试验
按“2.4.3”项下回收率试验中100%杂质水平供试品溶液制备方法配制供试品溶液，室温放置，分别于0、4、8、12、24、36、48、72、96 h进样测定，按面积归一化统计杂质检出量。结果供试品溶液室温放置96 h后各杂质含量和0 h相比没有差异，RSD均小于5%，显示供试品溶液在室温96 h内稳定性良好。
2.4.7　耐用性试验
按“2.2”项下方法配制供试品溶液，分别考察流动相pH微小变化（±0.2）、流动相有机比例微小变化（甲醇乙腈各1.0%变化比例）、缓冲盐浓度微小变化（±0.02 mol·L-1）、柱温微小变化（±5 ℃）、流速微小变化（±0.2 mL·min-1）、波长微小变化（±2 nm）及不同批号色谱柱对杂质含量检验结果的影响。结果表明色谱条件微小变化对样品测定没有影响，各杂质的RSD小于15%，杂质个数无变化，主杂峰分离度符合要求，方法耐用性良好。
2.5　样品检测
取奥拉帕利原料3批，按“2.2”项下方法制备供试品溶液，按“2.1”项下色谱条件进样检测，记录样品中各杂质的峰面积并计算各杂质成分含量，结果见表4。
3　讨论
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3.1　杂质限度的初步考虑
本品制剂为片剂，每日2次，每次300 mg，因此制剂最大日剂量为600 mg，按照ICH指导原则Q3A(R2)，原料药最大日剂量小于2 g·d-1时，报告限为0.05%，鉴定限为0.1%，质控限为0.15%。因此，拟定杂质Ⅰ~Ⅶ均不得过0.15%，其他单个杂质不得过0.1%，总杂质不得过1.0%，并在此基础上进行方法验证。
3.2　检测波长的选择
本实验在确定检测波长时，用DAD检测器对奥拉帕利及拟研究的7个杂质对照品溶液进行了紫外扫描，发现杂质Ⅴ最大吸收波长在205 nm处，奥拉帕利及其他各杂质均在210 nm左右有最大吸收，因此，根据各杂质的光谱图，最终确认210 nm为有关物质检测波长。
3.3　色谱柱的考察
前期方法筛选时色谱柱CAPCELL PAK C18（150 mm×4.6 mm，3 μm）不能对主峰后的杂质有效分离，因此，推荐本品有关物质检测采用品牌为YMC-C18（150 mm×4.6 mm，3 μm）的色谱柱。
3.4　降解杂质
在奥拉帕利分子中，有2个未成环的酰胺键（见图3），在酸性或碱性条件下，均容易降解，理论分析降解产物为杂质Ⅲ和杂质Ⅴ。强降解试验结果显示，奥拉帕利在高温、光照、氧化条件下相对稳定，在酸性条件和碱性条件下不稳定，主要降解杂质为杂质Ⅲ和杂质Ⅴ，与理论分析一致。
4　结论
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本次研究基于合成工艺过程及降解途径，开发了HPLC法检测奥拉帕利原料中有关物质的分析方法，并对方法进行了详细的验证。通过方法学验证，表明该方法的专属性强，灵敏度高，准确度高，精密度好，可有效地分离奥拉帕利原料中各工艺杂质和降解杂质，满足有关物质的检测需求。且HPLC法通用性高，所用试剂常见且易获得，可用于奥拉帕利原料的质量控制。
文献
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2024年第44卷第8期
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doi: 10.16155/j.0254-1793.2023-0774
  • 接收时间：2023-12-05
  • 首发时间：2026-03-13
  • 出版时间：2024-08-31
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  • 收稿日期：2023-12-05
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    1.国药集团川抗制药有限公司，成都 611731
    2.成都康弘药业集团股份有限公司，成都 610000

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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
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