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Article(id=1241314574880797666, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1241314565582025478, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2024-0195, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1711296000000, receivedDateStr=2024-03-25, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773882057161, onlineDateStr=2026-03-19, pubDate=1738252800000, pubDateStr=2025-01-31, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773882057161, onlineIssueDateStr=2026-03-19, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773882057161, creator=13701087609, updateTime=1773882057161, updator=13701087609, issue=Issue{id=1241314565582025478, tenantId=1146029695717560320, journalId=1205117023404326918, year='2025', volume='45', issue='1', pageStart='1', pageEnd='180', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773882054943, creator=13701087609, updateTime=1773882204745, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1241315193960059168, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1241314565582025478, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1241315193964253473, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1241314565582025478, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=135, endPage=145, ext={EN=ArticleExt(id=1241314575228924922, articleId=1241314574880797666, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Structural identification of the related substances in progesterone sustained-release vaginal gel by LC-Q TOF MS, columnId=1206272757852074373, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Safety Monitoring, runingTitle=null, highlight=null, articleAbstract=
Objective:

To identify the related substances of progesterone sustained-release vaginal gel by liquid chromatography mass spectrometry (LC-MS).

Methods:

The separation was carried out on YMC-Triart C18 (150 mm×4.6 mm，3 μm) column by gradient elution using acetonitrile and water as the mobile phases. The accurate mass and elemental composition of the parent ions and their product ions of related substances were determined by electrospray-ionization quadrupole time-of-flight high resolution mass spectrometry (ESI Q TOF MS) at collision energies of 5-45 eV. The structures of the related substances were identified by spectral analysis.

Results:

Under the established analytical condition, progesterone and its related substances were adequately separated, and 18 major related substances were detected and identified by hyphenated techniques in progesterone sustained-release vaginal gel and their stressed samples. Among them, 7 were the impurities listed in the EP or previous reported, and the others were unknown related substances identified for the first time in this paper. The established LC-MS technique was effective for the separation and identification of the related substances of progesterone sustained-release vaginal gel.

Conclusion:

Progesterone is unstable under acid, alkaline, and high-temperature stress conditions, and prone to produce oxidation degradants. The research results can provide a reference for the quality control of progesterone sustained-release vaginal gel.

, correspAuthors=Tai-jun HANG, 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=Jun-ju HAO, Li CHEN, Man-ru NING, Yu-ting LU, Min SONG, Tai-jun HANG), CN=ArticleExt(id=1241314578886357152, articleId=1241314574880797666, tenantId=1146029695717560320, journalId=1205117023404326918, language=CN, title=黄体酮阴道缓释凝胶有关物质的色谱-质谱结构鉴定, columnId=1206272758036623764, journalTitle=药物分析杂志, columnName=安全监测, runingTitle=null, highlight=null, articleAbstract=
目的：

采用色谱-质谱联用技术鉴定黄体酮阴道缓释凝胶中的有关物质。

方法：

采用YMC-Triart C18（150 mm×4.6 mm，3 μm）色谱柱，以乙腈-水为流动相梯度洗脱，对黄体酮阴道缓释凝胶有关物质进行分离，电喷雾正离子化-四极杆-飞行时间串联质谱（ESI Q TOF MS）在5~45 eV碰撞能下高分辨测定各有关物质母离子及其子离子的准确质量和元素组成，并解析鉴定有关物质的结构。

结果：

在所建立的分析条件下，黄体酮及其有关物质分离良好，检测并鉴定出黄体酮阴道缓释凝胶及其强制降解试验样品中18个主要有关物质，其中7个为EP或已知杂质，而其他均为本研究首次鉴定出的未知有关物质。色谱-质谱联用技术能有效地分离鉴定黄体酮阴道缓释凝胶中的有关物质。

结论：

黄体酮在酸、碱、高温干法强制降解条件下不稳定，且易形成氧化降解产物，研究结果可为黄体酮阴道缓释凝胶质量控制提供参考依据。

, correspAuthors=杭太俊, authorNote=null, correspAuthorsNote=
*　Tel：（025）83271090；E-mail：
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Tel：（025）83271090；E-mail：

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Tel：（025）83271090；E-mail：

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Tel：（025）83271090；E-mail：

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a.对照溶液（reference solution）　b. 酸破坏溶液（acidic solution）　c. 碱破坏溶液（alkaline solution）　d. 氧化破坏溶液（oxidation solution）　e. 高温湿法破坏溶液（wet heat solution）　f. 高温干法破坏溶液（dry heat solution）　g. 光照湿法破坏溶液（wet photolytic solution）　h. 光照干法破坏溶液（dry photolytic solution）　i. 供试品溶液（test sample solution）　j. 241 nm混合对照品溶液（mixture solution of references at 241 nm）　k. 286 nm混合对照品溶液（mixture solution of references at 286 nm）

, figureFileSmall=4jtad1nqlU3hHTGfk51Mmg==, figureFileBig=PGriBYaDiXmHzegdHSmTgA==, tableContent=null), ArticleFig(id=1241324067177943805, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=EN, label=Fig. 2, caption=Chemical structures of progesterone and its related substances 1-18, figureFileSmall=df78PRDsgIiMfLqsCR6+Bg==, figureFileBig=dBL3zCHU5lVZGOJ1Ae6m9g==, tableContent=null), ArticleFig(id=1241324067303772930, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=CN, label=图2, caption=黄体酮及其有关物质1~18的化学结构, figureFileSmall=df78PRDsgIiMfLqsCR6+Bg==, figureFileBig=dBL3zCHU5lVZGOJ1Ae6m9g==, tableContent=null), ArticleFig(id=1241324067417019144, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=EN, label=Fig. 3, caption=MS/MS spectra of progesterone and its related substance [M+H]+ ions, figureFileSmall=pX1hyJEew3AdqjqzVFS+wg==, figureFileBig=EHk4IqkezcWF0UQ6AEdSBg==, tableContent=null), ArticleFig(id=1241324067534459662, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=CN, label=图3, caption=黄体酮及其有关物质[M+H]+离子的MS/MS谱图, figureFileSmall=pX1hyJEew3AdqjqzVFS+wg==, figureFileBig=EHk4IqkezcWF0UQ6AEdSBg==, tableContent=null), ArticleFig(id=1241324067706426134, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=EN, label=Fig. 4, caption=Progesterone [M+H]+ ion MS/MS fragmentation pathways, figureFileSmall=LrpCmWCkEi6Oc/DEOC5I7Q==, figureFileBig=iGxpbnFJos5ubxd22p6JCQ==, tableContent=null), ArticleFig(id=1241324067811283738, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=CN, label=图4, caption=黄体酮[M+H]+离子的质谱裂解途径, figureFileSmall=LrpCmWCkEi6Oc/DEOC5I7Q==, figureFileBig=iGxpbnFJos5ubxd22p6JCQ==, tableContent=null), ArticleFig(id=1241324067890975518, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=EN, label=Fig. 5, caption=DAD spectra of related substances 2, 8, 11 and 16, figureFileSmall=lbIvQznW9ccqnouobpwI+A==, figureFileBig=RcxM1Fe3OW/8LldzqeYD4g==, tableContent=null), ArticleFig(id=1241324067983250208, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=CN, label=图5, caption=有关物质2、8、11和16的DAD谱图, figureFileSmall=lbIvQznW9ccqnouobpwI+A==, figureFileBig=RcxM1Fe3OW/8LldzqeYD4g==, tableContent=null), ArticleFig(id=1241324068092302115, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=EN, label=Fig. 6, caption=Related substances 2 and 8[M+H]+ ion MS/MS fragmentation pathways, figureFileSmall=amPoXWeObVoSiZbeHP7mLg==, figureFileBig=g8ISMSpDTb/lRRLCGUxfNg==, tableContent=null), ArticleFig(id=1241324068180382502, tenantId=1146029695717560320, journalId=1205117023404326918, 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figureFileBig=w0wfNh+mAOD9rhEHVafsPA==, tableContent=null), ArticleFig(id=1241324068956328775, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=EN, label=Tab. 1, caption=

Mass balance of progesterone sustained-release vaginal gel and its stressed test solutions

, figureFileSmall=null, figureFileBig=null, tableContent=
破坏条件（stress condition） C/（mg·mL-1）主峰面积
（areaAPI）		（areatotal）
总峰面积		areatotal/C物料平衡比例
（mass balance ratio）
未破坏（none）5.184211.245 2211.489 940.80/
高温干法破坏（dry heat）5.022194.268 8208.596 741.541.02
高温湿法破坏（wet heat）5.378220.095 7229.135 842.611.04
光照湿法破坏（wet photolytic）5.546239.901 7241.187 643.491.07
光照干法破坏（dry photolytic）5.444211.380 4216.878 639.840.98
氧化破坏（oxidation）5.470248.408 3251.299 945.941.13
碱破坏（alkaline）4.977244.586 2224.847 545.181.11
酸破坏（acidic）5.557247.661 2248.220 844.671.09
), ArticleFig(id=1241324069073769292, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=CN, label=表1, caption=

黄体酮阴道缓释凝胶供试品溶液及其强制降解试验溶液物料守恒结果

, figureFileSmall=null, figureFileBig=null, tableContent=
破坏条件（stress condition） C/（mg·mL-1）主峰面积
（areaAPI）		（areatotal）
总峰面积		areatotal/C物料平衡比例
（mass balance ratio）
未破坏（none）5.184211.245 2211.489 940.80/
高温干法破坏（dry heat）5.022194.268 8208.596 741.541.02
高温湿法破坏（wet heat）5.378220.095 7229.135 842.611.04
光照湿法破坏（wet photolytic）5.546239.901 7241.187 643.491.07
光照干法破坏（dry photolytic）5.444211.380 4216.878 639.840.98
氧化破坏（oxidation）5.470248.408 3251.299 945.941.13
碱破坏（alkaline）4.977244.586 2224.847 545.181.11
酸破坏（acidic）5.557247.661 2248.220 844.671.09
), ArticleFig(id=1241324069149266768, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=EN, label=Tab. 2, caption=

Related substances identified in progesterone sustained-release vaginal gel by LC-Q TOF MS

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
（code No.）		（parent ion）m/z
母离子		 tR/min含量
（content）/%		（ion formula）
离子式		Dif碎片离子
（product ions）m/z		来源
（origin）
API315.231 917.26/C21H33O2+1.21297.221 7，279.211 1，255.211 1，239.179 5，213.163 9，173.132 2，159.116 6，147.116 7，133.100 9，123.080 2，109.064 4，97.064 4，79.053 6API
1（CRID-6α）331.227 04.300.19C21H31O3+0.85313.216 4，295.206 0，277.195 5，271.206 0，255.174 6，253.195 3，237.164 0，211.148 1，197.132 6，175.111 6，157.100 8，147.116 5，133.100 8Dr
2329.211 14.600.07C21H29O2+1.64311.199 9，293.189 7，269.189 3，253.157 9，241.157 9Dr
3347.221 84.710.07C21H31O4+0.35315.195 5，297.185 0，287.200 4，229.158 6，123.079 8，109.064 1，97.064 1，79.053 5Dr
4347.221 75.180.06C21H31O4+0.46287.200 8，229.158 5，123.079 6，109.064 1，97.064 0，79.053 4Dr
5（CRID-6β）331.227 25.510.15C21H31O3+1.39313.217 6，295.209 0，277.194 7，271.211 6，255.177 5，253.197 9，237.167 1，211.154 1，197.135 8，175.115 9，157.104 0，147.117 7，133.103 1Dr
6347.221 75.600.07C21H31O4+0.23313.215 9，269.189 8，163.111 3，145.100 5，131.085 2，123.080 0，109.064 2，97.064 1Dr
7347.221 75.870.11C21H31O4+0.20330.219 5，313.216 1，297.184 8，279.173 7，269.189 6，261.184 7，243.174 2，227.142 7，201.163 7，145.100 7，123.079 8，109.064 1，97.064 1Dr
8329.211 06.140.14C21H29O3+1.49311.200 8，269.289 9，189.090 6，173.095 5，159.116 3，133.100 5Dr
9347.221 76.640.05C21H31O4+0.58330.219 1，215.195 2，297.185 0，269.191 2，145.100 4，123.079 4，109.064 1，97.064 1Dr
10287.204 17.670.14C20H31O+1.81269.189 6，251.179 0，229.258 1，211.147 9，185.131 8，173，131 9，159.116 3，145.100 7，123.079 6，109.064 1，97.064 0，79.053 4Dr
11（CRID-6Keto）329.211 18.380.57C21H29O3+0.18311.200 8，293.190 6，269190 5，253.158 8，251.179 7，209.132 6，173.096 0，159.116 5，145.101 0，133.101 0Dr
12347.221 78.590.08C21H31O4+0.61287.200 4，269，189 5，123，119 3，109.064 2，97.064 1Dr
13（EP-B）317.247 710.700.05C21H33O2+0.60299.237 2，281.226 8，273.221 5，255.210 9，241.195 9，177.127 3，159.116 6，147.116 5，133.100 9，123.080 2，109.064 4，97.064 3，79.053 6Pr
14389.269 712.191.19C24H37O4+2.72315.231 1，297.221 0，201.163 1，189.163 0，117.053 9，109.064 0，97.063 9Dr
15389.269 712.450.28C24H37O4+2.62315.231 4，297.220 9，201.163 2，189.163 2，117.053 9，109.064 0，97.064 0Dr
16（EP-H）313.216 214.230.22C21H29O2+0.83295.206 1，255.174 5，211.148 0，175.111 6，159.116 6，147.080 1，133.100 9Pr/Dr
17（EP-C）317.247 716.310.06C21H31O2+0.66299.237 2，281.226 7，273.221 4，255.211 0，241.195 9，177.127 2，159.116 6，147.116 5，133.100 8，123.080 1，109.064 4，97.064 3，79.053 6Dr
18（EP-M）315.232 018.456.15C21H31O2+0.41297.224 9，279.214 1，255.213 3，239.182 2，213.166 2，173.134 3，159.118 4，147.118 3，133.102 5，123.081 7，109.065 8Dr
), ArticleFig(id=1241324069233152851, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1241314574880797666, language=CN, label=表2, caption=

黄体酮阴道缓释凝胶有关物质的LC-Q TOF MS鉴定结果

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
（code No.）		（parent ion）m/z
母离子		 tR/min含量
（content）/%		（ion formula）
离子式		Dif碎片离子
（product ions）m/z		来源
（origin）
API315.231 917.26/C21H33O2+1.21297.221 7，279.211 1，255.211 1，239.179 5，213.163 9，173.132 2，159.116 6，147.116 7，133.100 9，123.080 2，109.064 4，97.064 4，79.053 6API
1（CRID-6α）331.227 04.300.19C21H31O3+0.85313.216 4，295.206 0，277.195 5，271.206 0，255.174 6，253.195 3，237.164 0，211.148 1，197.132 6，175.111 6，157.100 8，147.116 5，133.100 8Dr
2329.211 14.600.07C21H29O2+1.64311.199 9，293.189 7，269.189 3，253.157 9，241.157 9Dr
3347.221 84.710.07C21H31O4+0.35315.195 5，297.185 0，287.200 4，229.158 6，123.079 8，109.064 1，97.064 1，79.053 5Dr
4347.221 75.180.06C21H31O4+0.46287.200 8，229.158 5，123.079 6，109.064 1，97.064 0，79.053 4Dr
5（CRID-6β）331.227 25.510.15C21H31O3+1.39313.217 6，295.209 0，277.194 7，271.211 6，255.177 5，253.197 9，237.167 1，211.154 1，197.135 8，175.115 9，157.104 0，147.117 7，133.103 1Dr
6347.221 75.600.07C21H31O4+0.23313.215 9，269.189 8，163.111 3，145.100 5，131.085 2，123.080 0，109.064 2，97.064 1Dr
7347.221 75.870.11C21H31O4+0.20330.219 5，313.216 1，297.184 8，279.173 7，269.189 6，261.184 7，243.174 2，227.142 7，201.163 7，145.100 7，123.079 8，109.064 1，97.064 1Dr
8329.211 06.140.14C21H29O3+1.49311.200 8，269.289 9，189.090 6，173.095 5，159.116 3，133.100 5Dr
9347.221 76.640.05C21H31O4+0.58330.219 1，215.195 2，297.185 0，269.191 2，145.100 4，123.079 4，109.064 1，97.064 1Dr
10287.204 17.670.14C20H31O+1.81269.189 6，251.179 0，229.258 1，211.147 9，185.131 8，173，131 9，159.116 3，145.100 7，123.079 6，109.064 1，97.064 0，79.053 4Dr
11（CRID-6Keto）329.211 18.380.57C21H29O3+0.18311.200 8，293.190 6，269190 5，253.158 8，251.179 7，209.132 6，173.096 0，159.116 5，145.101 0，133.101 0Dr
12347.221 78.590.08C21H31O4+0.61287.200 4，269，189 5，123，119 3，109.064 2，97.064 1Dr
13（EP-B）317.247 710.700.05C21H33O2+0.60299.237 2，281.226 8，273.221 5，255.210 9，241.195 9，177.127 3，159.116 6，147.116 5，133.100 9，123.080 2，109.064 4，97.064 3，79.053 6Pr
14389.269 712.191.19C24H37O4+2.72315.231 1，297.221 0，201.163 1，189.163 0，117.053 9，109.064 0，97.063 9Dr
15389.269 712.450.28C24H37O4+2.62315.231 4，297.220 9，201.163 2，189.163 2，117.053 9，109.064 0，97.064 0Dr
16（EP-H）313.216 214.230.22C21H29O2+0.83295.206 1，255.174 5，211.148 0，175.111 6，159.116 6，147.080 1，133.100 9Pr/Dr
17（EP-C）317.247 716.310.06C21H31O2+0.66299.237 2，281.226 7，273.221 4，255.211 0，241.195 9，177.127 2，159.116 6，147.116 5，133.100 8，123.080 1，109.064 4，97.064 3，79.053 6Dr
18（EP-M）315.232 018.456.15C21H31O2+0.41297.224 9，279.214 1，255.213 3，239.182 2，213.166 2，173.134 3，159.118 4，147.118 3，133.102 5，123.081 7，109.065 8Dr
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黄体酮阴道缓释凝胶有关物质的色谱-质谱结构鉴定
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郝俊菊 , 陈立 , 宁曼如 , 陆宇婷 , 宋敏 , 杭太俊 *
药物分析杂志 | 安全监测 2025,45(1): 135-145
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药物分析杂志 | 安全监测 2025, 45(1): 135-145
黄体酮阴道缓释凝胶有关物质的色谱-质谱结构鉴定
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郝俊菊 , 陈立, 宁曼如, 陆宇婷, 宋敏, 杭太俊*
作者信息
  • 中国药科大学药物分析系，南京210009

    • Tel：（025）83271090；E-mail：

通讯作者:

*　Tel：（025）83271090；E-mail：
Structural identification of the related substances in progesterone sustained-release vaginal gel by LC-Q TOF MS
Jun-ju HAO , Li CHEN, Man-ru NING, Yu-ting LU, Min SONG, Tai-jun HANG*
Affiliations
  • Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
出版时间: 2025-01-31 doi: 10.16155/j.0254-1793.2024-0195
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摘要
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目的：

采用色谱-质谱联用技术鉴定黄体酮阴道缓释凝胶中的有关物质。

方法：

采用YMC-Triart C18（150 mm×4.6 mm，3 μm）色谱柱，以乙腈-水为流动相梯度洗脱，对黄体酮阴道缓释凝胶有关物质进行分离，电喷雾正离子化-四极杆-飞行时间串联质谱（ESI Q TOF MS）在5~45 eV碰撞能下高分辨测定各有关物质母离子及其子离子的准确质量和元素组成，并解析鉴定有关物质的结构。

结果：

在所建立的分析条件下，黄体酮及其有关物质分离良好，检测并鉴定出黄体酮阴道缓释凝胶及其强制降解试验样品中18个主要有关物质，其中7个为EP或已知杂质，而其他均为本研究首次鉴定出的未知有关物质。色谱-质谱联用技术能有效地分离鉴定黄体酮阴道缓释凝胶中的有关物质。

结论：

黄体酮在酸、碱、高温干法强制降解条件下不稳定，且易形成氧化降解产物，研究结果可为黄体酮阴道缓释凝胶质量控制提供参考依据。

黄体酮阴道缓释凝胶  /  甾体  /  强制降解  /  有关物质  /  结构鉴定  /  色谱-质谱联用
Objective:

To identify the related substances of progesterone sustained-release vaginal gel by liquid chromatography mass spectrometry (LC-MS).

Methods:

The separation was carried out on YMC-Triart C18 (150 mm×4.6 mm，3 μm) column by gradient elution using acetonitrile and water as the mobile phases. The accurate mass and elemental composition of the parent ions and their product ions of related substances were determined by electrospray-ionization quadrupole time-of-flight high resolution mass spectrometry (ESI Q TOF MS) at collision energies of 5-45 eV. The structures of the related substances were identified by spectral analysis.

Results:

Under the established analytical condition, progesterone and its related substances were adequately separated, and 18 major related substances were detected and identified by hyphenated techniques in progesterone sustained-release vaginal gel and their stressed samples. Among them, 7 were the impurities listed in the EP or previous reported, and the others were unknown related substances identified for the first time in this paper. The established LC-MS technique was effective for the separation and identification of the related substances of progesterone sustained-release vaginal gel.

Conclusion:

Progesterone is unstable under acid, alkaline, and high-temperature stress conditions, and prone to produce oxidation degradants. The research results can provide a reference for the quality control of progesterone sustained-release vaginal gel.

progesterone sustained-release vaginal gel  /  steroid  /  stressed degradation  /  related substances  /  structural identification  /  LC-MS
郝俊菊, 陈立, 宁曼如, 陆宇婷, 宋敏, 杭太俊. 黄体酮阴道缓释凝胶有关物质的色谱-质谱结构鉴定. 药物分析杂志, 2025 , 45 (1) : 135 -145 . DOI: 10.16155/j.0254-1793.2024-0195
Jun-ju HAO, Li CHEN, Man-ru NING, Yu-ting LU, Min SONG, Tai-jun HANG. Structural identification of the related substances in progesterone sustained-release vaginal gel by LC-Q TOF MS[J]. Chinese Journal of Pharmaceutical Analysis, 2025 , 45 (1) : 135 -145 . DOI: 10.16155/j.0254-1793.2024-0195
正文
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黄体酮（孕甾-4-烯-3，20-二酮）是天然的孕激素，在临床上主要用于治疗先兆性流产、黄体功能不全以及胚胎移植后的辅助生育等[1-5]。黄体酮属于BCS Ⅳ类药物（低溶解度、低渗透性），目前，临床主要有口服、肌肉注射以及阴道3种给药方式。相比口服与肌注，阴道给予黄体酮，由于独特的“子宫首过效应”，可使药物有效富集于子宫部位，使其生物利用度显著提高[6]。
虽然《中华人民共和国药典》和EP中均收载了黄体酮原料药及其注射剂的质量标准[7-8]，进口药物注册标准（CRID）中收载了其阴道缓释凝胶的质量标准，但是尚未见黄体酮杂质谱的系统研究报道[9-10]。
本文通过强制降解试验并利用LC-Q TOF MS分析方法，实现黄体酮与有关物质的良好分离，并测定了黄体酮有关物质的准确相对分子质量及分子式，结合MS/MS的子离子特征、合成工艺路线与反应机理分析[11-12]，经综合解析鉴定了各有关物质的结构，可为黄体酮的质量控制提供参考依据。
1　仪器与试药
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1.1　仪器
岛津LCMS-9030液-质联用仪，Lab-Solutions数据处理系统（岛津公司）；XS105DU十万分之一电子分析天平（METTLER TOLEDO公司）；KH-250DB型数控超声波清洗器（昆山禾创超声仪器有限公司）；TGL-16K型冷冻离心机（湖南湘仪实验室仪器开发有限公司）。
1.2　试药
黄体酮阴道缓释凝胶（API含量8%，中国药科大学自研，批号20230928-1）；黄体酮对照品（含量 99.6%，中国食品药品检定研究院，批号100027-201810）；市售杂质对照品：6α-羟孕酮（批号15565）、6β-羟孕酮（批号13010）、杂质A（孕甾-4，14-二烯-3，20-二酮，批号12681）、杂质B[（20S）-羟基黄体酮，批号15568]、杂质D[（20S）-3-氧代孕甾-4-烯-20-乙酸酯，批号15504]、杂质J（孕甾-1，4-二烯-3，20-二酮，批号15505）、杂质K[孕甾-4，9（11）-二烯-3，20-二酮，批号19181]、杂质G（21-环己基-孕甾-4-烯-3，20-二酮，批号15569）、杂质M[（17α）-孕甾-4-烯-3，20-二酮，批号15571]、杂质L[（17β）-3-氧代孕甾-4，20-二烯-21-醛，批号15570]均购自中国深圳QCS公司，6Keto-黄体酮（批号0308-RD-0108）、杂质C[（20R）-羟基黄体酮，批号0809-RC-0057]、杂质E[（20R）-3-氧代孕甾-4-烯-20-乙酸酯，批号0809-RC-0059]、杂质H（孕甾-4，6-二烯-3，20-二酮，批号158-12-20）、杂质I[（20RS）-3-氧代孕甾-4-烯-21-醛，批号0820-RC-0001]均购自中国广州CATO公司，HPLC纯度均>92%。
盐酸、氢氧化钠和过氧化氢（AR级，南京化学试剂有限公司）；乙腈、甲醇（HPLC级，Merck公司）；碘化钠（HPLC 级，萨恩化学技术有限公司）；去离子水（市售娃哈哈纯净水）。
2　方法
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2.1　溶液的配制
2.1.1　供试品溶液
取本品适量（约相当于黄体酮4 mg），精密称定，置于10 mL具塞试管中，加80%乙腈约3 mL，超声使溶解，用80%乙腈稀释至刻度，摇匀，12 000 r·min-1离心10 min，取上清液，即得。
2.1.2　对照溶液
精密量取供试品溶液适量，用80%乙腈定量稀释制成每1 mL中约含黄体酮0.4 µg的溶液，即得。
2.1.3　对照品溶液
取各杂质的对照品适量，分别精密称定，置同一10 mL量瓶中，加80%乙腈溶解并定量稀释成每1 mL中含各杂质均约为100 µg的储备溶液。取黄体酮对照品适量，精密称定，置50 mL量瓶中，精密添加上述储备溶液1 mL，加80%乙腈溶解并定量稀释成每1 mL中含各杂质均约为2 µg、黄体酮为400 µg的溶液，即得。
2.1.4　强制降解试验溶液
取本品适量（约相当于黄体酮4 mg），精密称定，加甲醇5 mL后加2 mol·L-1盐酸溶液2 mL并于室温放置3.5 d；或加甲醇5 mL后加1 mol·L-1氢氧化钠溶液1 mL并于室温放置12 h；或加80%乙腈5 mL后加10%过氧化氢溶液1 mL并于室温放置14 d；或于105 ℃烘箱中放置3 d；或于4 500 lx光照放置14 d；或加80%乙腈5 mL后于105 ℃放置14 d；或加80%乙腈5 mL后于4 500 lx光照放置14 d。分别处理后放冷（酸碱处理溶液先中和），均以80%乙腈（酸碱处理溶液用甲醇）溶解并稀释至10 mL，12 000 r·min-1离心10 min，取上清液，即得各强制降解试验溶液。同法配制空白溶液。
2.2　色谱-质谱条件
2.2.1　色谱方法
采用YMC-Triart C18（150 mm×4.6 mm，3 μm）色谱柱，以50%乙腈（A）-80%乙腈（B）为流动相，梯度洗脱（A-B）：0 min（100：0）→20 min（100：0）→27 min（0：100）→45 min（0：100）→50 min（100：0）→55 min（100：0），流速1.0 mL·min-1，柱温30 ℃，检测波长241、286 nm，进样量10 μL。
2.2.2　质谱条件
电喷雾正离子化，高分辨Q TOF MS检测，碘化钠溶液（400 μg·mL-1）准确质量校正。喷雾电压4.0 kV，雾化氮气流量3 L·min-1，加热气流量10 L·min-1，干燥气流量10 L·min-1，氩气（CID）能量5~45 eV，质量数扫描范围m/z 50~1 000。
3　结果
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3.1　有关物质检查
取供试品溶液、对照溶液、混合对照品溶液和强制降解试验溶液，按“2.2.1”项色谱条件进样检测，黄体酮阴道缓释凝胶及其强制降解试验溶液的HPLCUV检测结果见图1。采用0.1%自身稀释对照法计算各有关物质的含量[杂质16（杂质H）采用对照品外标法]，按保留时间由小到大顺序对主要有关物质进行识别和编号。
强制降解试验的结果表明（表1），本品在强酸、强碱和高温干法下均不稳定，全部降解条件下共分离并检出18个有关物质，研究建立的有关物质检查条件对于不同强制降解样品有关物质的检测均物料平衡。其中酸破坏形成5个降解杂质（1、5、8、11、18），碱破坏形成4个降解杂质（5、7、11、18），氧化破坏形成6个主要降解杂质（3、4、6、7、9、12），高温湿法破坏形成5个主要降解杂质（1、5、10、11、12），高温干法破坏形成7个主要降解杂质（1、5、7、11、14、15、18），光照湿法破坏形成1个主要降解杂质（2）。与未破坏供试品溶液（仅检测到已知杂质13、16和17，含量均为0.1%）比较，确定有关物质2~4、6~10、12、14、15为强制降解新增杂质。
3.2　有关物质的结构鉴定
采用高分辨Q TOF MS检测各有关物质的母离子及子离子的准确质量和元素组成，以及其二级质谱特征碎片，由LabSolutions Insight Explore软件预测得到母离子和碎片离子的元素组成。并通过与黄体酮及其已知杂质的质谱特征的对比分析，鉴定各主要有关物质的结构。结果见图2、图3和表2。
3.3　已知有关物质的确证
通过液相色谱定位及质谱定性，并与市售对照品对比鉴定各已知有关物质的结构。结果表明，有关物质1、5、11、13、16、17、18分别与已知杂质6α-羟孕酮、6β-羟孕酮、6Keto-黄体酮、EP-B、EP-H、EP-C和EP-M的结构相应。
对黄体酮和各已知有关物质的一级质谱母离子准确质荷比、二级质谱特征碎片离子和裂解途径分析，以黄体酮为例（图4），发现黄体酮及已知有关物质MS/MS裂解规律如下：
① 黄体酮、EP-B、EP-C和EP-M，化学结构上A环和B环母核完全一致，产生m/z 79、97、109、123、133、147、159碎片离子。
② 黄体酮、EP-M结构上3位和20位各有1个羰基；EP-B、EP-C结构的3位上有1个羰基，20位上有1个羟基。均生成质量数少18和36的特征碎片离子，说明分子连续脱了2个分子的H2O。
③ 黄体酮和EP-M、6α-羟孕酮、6β-羟孕酮、6Keto-黄体酮20位上均有羰基，且2个γ位上均有H原子，分子易发生McLafferty重排。
④ 黄体酮及其有关物质母核中均含环状α，β-不饱和酮结构，易在裂解中失去乙烯酮（CH2=C=O）。
⑤ 黄体酮及其有关物质甾体母核易发生环断裂，环断裂位点取决于环上的取代基。
根据黄体酮及已知有关物质的这些结构特征，并结合已有报道文献分析，可以辅助其未知有关物质结构的分析鉴定[13-14]。
3.4　未知有关物质的确证
对于各未知有关物质，根据其HPLC保留行为、DAD图谱和黄体酮已知有关物质的差异，结合合成和制剂工艺路线分析，可鉴定结构。
有关物质2是光照湿法降解产物，有关物质8是酸碱降解产物。测得有关物质2和8[M+H]+的准确质量分别为329.211 9、329.211 6，均与离子式[C21H29O3]+相应，与黄体酮相比少2个H，多1个O。其中有关物质2根据DAD光谱（图5）显示其与有关物质16具有趋同性，说明结构上有双键与4位双键形成共轭结构，由α，β-不饱和羰基化合物的紫外吸收光谱规律可知，有关物质2结构上为环外双烯（同环二烯的最佳紫外吸收波长应大于300 nm）；有关物质2出峰时间约4.5 min，保留较弱，说明其结构上有羟基使其极性增大，且碎片离子中m/z 241.157 9（C17H21O+）说明羟基在15位；综上推断有关物质2为黄体酮被氧化生成的降解产物：6-烯-15-羟基黄体酮。其MS/MS主要碎片离子m/z 311.199 9（C21H27O2+）、m/z 269.189 3（C19H25O+）分别与[M+H]+中性丢失H2O、H2O和乙烯酮（CH2=C=O）相对应，碎片离子m/z 293.189 7（C21H25O+）、m/z 253.157 9（C18H21O+）、m/z 241.157 9（C17H21O+）分别与m/z 311.199 9中性丢失H2O、丙酮、McLafferty重排后丢失甲基乙烯酮（CH3COCH=CH2）。
有关物质8无m/z 97、109、123碎片离子，推断A环和B环上存在取代基；与有关物质11相比，有关物质8的最佳紫外吸收蓝移（图5），推断其不是有关物质11的差向异构体；且有关物质8出峰时间晚于有关物质5，推断其结构上比黄体酮多1个羰基结构；综上推断有关物质8为黄体酮7位被氧化生成的降解产物：7-羰基-黄体酮。有关物质8的裂解规律与黄体酮一致，主要为环断裂和中性丢失H2O（图6）。
有关物质3、4、6、7、9、12均是氧化降解产生的杂质。测得其[M+H]+的准确质量分别为347.222 7、347.222 5、247.222 1、347.223 3、347.226 7、347.222 2，均与离子式[C21H31O4]+相应，为同分异构体，与黄体酮元素组成相比多了2个O。所以，在黄体酮结构中，存在多个易被氧化降解的位点，潜在多种氧化产物结构，结合文献中提到容易氧化的位点分别为C-5位、C-6位、C-11位以及C-20位[15]和二级质谱区别确证氧化位点。其中有关物质3、4、6、7、9、12均有m/z 97.05、m/z 109.06、m/z 123.08碎片离子，说明A环和B环结构与黄体酮一致，其6位和7位无取代基，有关物质3、4、6、7、9、12结构见图2，以有关物质3和4为代表进行详细解析。
有关物质3和4的MS/MS都有碎片离子C19H27O2+（m/z 287.20）、C16H21O+（m/z 229.16），说明结构中11位为羟基取代。其中有关物质3有碎片离子C20H27O3+（m/z 315.195 5）与[M+H]+相比质量数少了32，根据中性丢失规律，该过程为中性丢失甲醇（CH3OH）或者同时丢失甲基自由基和羟基自由基。结合出峰时间推断有关物质3是黄体酮结构中孕甾体结构上12位和21位被氧化成羟基取代的降解杂质：12，21-二羟基黄体酮。其碎片离子C20H27O3+（m/z 315.195 5）、C20H25O2+（m/z 297.185 0）分别与[M+H]+中性丢失CH3OH、进一步中性丢失H2O相对应。
有关物质4与有关物质3相比，无碎片离子C20H27O3+（m/z 315.195 5）、C20H25O2+（m/z 297.185 0），说明17位支链不同。有关物质4特征碎片离子为C16H21O+（m/z 229.158 5），说明16位有羟基取代，C16H21O+（m/z 229.158 5）与[M+H]+中性丢失H2O、发生2次McLafferty重排并丢失乙烯酮相应。所以，推断有关物质4是黄体酮孕甾体结构上11位和16位被氧化成羟基取代的降解杂质：11，16-二羟基黄体酮。它们的二级质谱裂解过程见图7。
有关物质10是高温干法产生的降解杂质，同时也是高温湿法产生的降解杂质，说明该有关物质易在高温条件下产生。测得有关物质10[M+H]+的准确质量为287.199 9，与离子[C19H27O2]+相应，与黄体酮相比少了2个C和2个H；其保留相对较弱（7.7 min出峰）极性略大，推测被羟基化降解。主要碎片离子为C8H11O+（m/z 123.079 6）、C7H9O+（m/z 109.064 1）、C6H9O+（m/z 97.0640）、C6H7+（m/z 79.0534），表明其A环和B环结构与黄体酮一致。所以，推断有关物质10是黄体酮结构11位被羟基取代、17位乙酰基消除而生的降解杂质：11-羟基-15-烯-17-去乙酰基-黄体酮（图8）。
有关物质14和15是高温干法降解易产生的降解杂质。测得其[M+H]+的准确质量分别为389.268 4、389.268 3，均与离子[C24H37O4]+相对应，与黄体酮相比多了3个C、6个H、2个O。二者裂解碎片一致，保留时间相近，推测二者为20位酮羰基与甘油缩合形成不同醚结构的杂质。MS/MS碎片离子中均有C7H9O+（m/z 109.06）、C6H7+（m/z 79.05），说明A环和B环结构与黄体酮一致。主要碎片离子C21H31O2+（m/z 315.231 1）、C5H9O3+（m/z 117.053 9）分别与[M+H]+醚键断裂、17位支链断裂相对应。碎片离子C19H23O+（m/z 297.221 0）、C15H21+（m/z 201.163 1）、C14H21+（m/z 189.163 0）分别与m/z 315.231 1中性丢失H2O、进一步发生2次McLafferty重排并中性丢失乙炔和羰基、或进一步在B环（9位，5位）相应。所以，推断有关物质14和15是黄体酮20上羰基与辅料中甘油发生亲核反应的降解杂质[16]（图9）。
4　讨论
收起
在本研究建立的LC-Q TOF MS的分析方法下，黄体酮与各有关物质获得有效分离，共检测出18个杂质，其中有关物质13、16、17、18分别与EP中B、H、C、M一致；有关物质1、5、11分别与CRID中6α-羟孕酮、6β-羟孕酮、6Keto-黄体酮一致；其余11个有关物质（2、3、4、6、7、8、9、10、12、14、15）均为本文首次研究鉴定。
试验结果表明，黄体酮结构上存在多个氧化位点，易在各个条件下发生氧化反应。其中，高温、酸降解条件下易在6位上氧化形成有关物质1、5、11，碱降解条件下易在6位氧化形成5、11；氧化降解条件下，易发生氧化生成有关物质3、4、6、7、9，且辅料中山梨酸易断裂形成乙酸参与黄体酮降解，发生酯化反应生成有关物质12；在光照湿法降解条件下，易发生氧化反应生成有关物质2；在酸降解条件下，易发生氧化反应生成有关物质8；在高温干法降解条件下，易发生氧化反应生成有关物质10；在工艺过程中易发生氧化反应产生有关物质13、16、17，其中有关物质16在碱、高温干法、光照干法降解条件有较为明显增加。在高温干法降解条件下，黄体酮与辅料中的甘油发生亲核反应、脱水反应生成有关物质14和15。在酸、碱、高温干法降解条件下，黄体酮结构易在17位发生异构化生成有关物质18。
综上所述，黄体酮在酸、碱、高温干法条件下不稳定，且易发生氧化反应，因此需要注意避酸、避碱、常温密封储存。同时，应注意控制关键制备工艺，并建立相关指标为质量把关[17]。
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doi: 10.16155/j.0254-1793.2024-0195
  • 接收时间：2024-03-25
  • 首发时间：2026-03-19
  • 出版时间：2025-01-31
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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
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