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Article(id=1201177210121053078, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201177206518145841, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0372, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1679846400000, receivedDateStr=2023-03-27, revisedDate=1685289600000, revisedDateStr=2023-05-29, acceptedDate=null, acceptedDateStr=null, onlineDate=1764312563685, onlineDateStr=2025-11-28, pubDate=1704988800000, pubDateStr=2024-01-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764312563685, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764312563685, creator=13701087609, updateTime=1764312563685, updator=13701087609, issue=Issue{id=1201177206518145841, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='1', pageStart='1', pageEnd='268', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764312562826, creator=13701087609, updateTime=1764312760268, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201178034725417827, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201177206518145841, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201178034725417828, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201177206518145841, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=202, endPage=213, ext={EN=ArticleExt(id=1201177210775364529, articleId=1201177210121053078, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Structural identification of the related substances in phloroglucinol injection by two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

This study aimed to identify the related substances of phloroglucinol injection by two-dimensional liquid chromatography quadrupole time-of-flight mass spectrometry (2D-LC-Q-TOF/MS). The first-dimensional separation was carried out on an HSS T3 (250 mm × 4.6 mm, 5 μm) column by gradient elution using 1.36 g·L-1 potassium dihydrogen phosphate buffer solution (pH adjusted to 3.0 with diluted phosphoric acid) and acetonitrile as the mobile phases. The separated components were then trapped in switch valve tube lines respectively and delivered to the second-dimensional desalting gradient elution which was performed with a BDS C18 (100 mm × 4.6 mm, 2.4 μm) column using 0.1% formic acid and methanol as the mobile phases. After rapid desalting, electrospray-ionization quadrupole time-of-flight high resolution mass spectrometry was used for determining the accurate masses and elemental compositions of the parents and their product ions for both phloroglucinol and its related substance. Structures of the related substances were then figured out by mass spectrometry elucidation, organic reaction mechanism analysis, and/or comparison with reference substances. Under the established analytical conditions, phloroglucinol and its related substances were adequately separated, 17 main related substances were detected and identified in the injection and its stressed samples for the first time. The identification results can provide reference for the quality control of phloroglucinol injection.

, correspAuthors=Tai-jun HANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., 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=Jia-ming LIU, Yu-ting LU, Min SONG, Tai-jun HANG), CN=ArticleExt(id=1201177215938552149, articleId=1201177210121053078, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=间苯三酚注射液有关物质的二维液相色谱-质谱联用鉴定, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

采用二维液相色谱-质谱联用技术鉴定间苯三酚注射液中的有关物质。以HSS T3 (250 mm × 4.6 mm, 5 μm) 为色谱柱, 1.36 g·L-1磷酸二氢钾(稀磷酸调节pH调至3.0)-乙腈为一维流动相进行梯度洗脱, 实现间苯三酚注射液有关物质的分离。各分离成分经多通道切换阀分别被捕集于截留管中, 然后输送到BDS C18 (100 mm × 4.6 mm, 2.4 μm) 色谱柱, 以0.1%甲酸水溶液-甲醇为二维流动相, 进行梯度洗脱实现快速脱盐。电喷雾负离子化-四极杆-飞行时间串联高分辨质谱检测各有关物质母离子及其子离子的准确质量和元素组成, 通过质谱解析、有机反应机制分析, 甚至对照品对照鉴定它们的结构。在所建立的分析条件下, 间苯三酚及其有关物质分离良好, 首次检测并鉴定出间苯三酚注射液及其强制降解实验样品中17个主要有关物质, 鉴定结果可为间苯三酚注射液质量控制提供参考依据。

, correspAuthors=杭太俊, authorNote=null, correspAuthorsNote=
*杭太俊, Tel: 86-25-83271090, E-mail:
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Bioorg Med Chem Lett, 1996, 6: 2279-2280., articleTitle=null, refAbstract=null)], funds=[Fund(id=1201177222129345324, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, awardId=NMPA-KLIPCD-2020-03, language=CN, fundingSource=国家药品监督管理局化学药品杂质谱研究重点实验室开放课题资助项目(NMPA-KLIPCD-2020-03), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1201177216177627502, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, xref=null, ext=[AuthorCompanyExt(id=1201177216181821807, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, companyId=1201177216177627502, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China), AuthorCompanyExt(id=1201177216190210418, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, companyId=1201177216177627502, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国药科大学药物分析系, 江苏 南京 210009)])], figs=[ArticleFig(id=1201177218715181658, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=grUn+7pqlEsshut2/mAabA==, figureFileBig=2jbKG48pu/KCzQw1Jo8lLQ==, tableContent=null), ArticleFig(id=1201177218799067742, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 1, caption= Phloroglucinol and its known related substances listed in EP , figureFileSmall=grUn+7pqlEsshut2/mAabA==, figureFileBig=2jbKG48pu/KCzQw1Jo8lLQ==, tableContent=null), ArticleFig(id=1201177219063308910, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=dxENVakc+nlgWYgL7CWMeA==, figureFileBig=3+LaJxg+ms1HhlveWta4dg==, tableContent=null), ArticleFig(id=1201177219184943737, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 2, caption= Phloroglucinol polymers in nature , figureFileSmall=dxENVakc+nlgWYgL7CWMeA==, figureFileBig=3+LaJxg+ms1HhlveWta4dg==, tableContent=null), ArticleFig(id=1201177219306578561, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=Z3eyIauJM8a0vgihKmmPfQ==, figureFileBig=PCxC003ChVA9CpUei7PLqQ==, tableContent=null), ArticleFig(id=1201177219428213382, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 3, caption= 1D-HPLC chromatograms of phloroglucinol injection and its stressed test solutions. API-a: Phloroglucinol; API-b: Trimethyl phloroglucinol; 1-17: Related substances 1-17; a: Solvent blank; b: 0.1% Self-reference; c: References (related substances EP-A, EP-B, EP-D, EP-E, EP-I, EP-K, EP-L, EP-O, <a href="javascript:;" class="mag_content_a mag_xref_table" onclick="clickTabXref(this,'Table2')" rid="Table2">Table 2</a>); d: Test sample; e: Oxidation; f: Thermal stress; g: Photolysis; h: Acid hydrolysis; i: Alkaline hydrolysis , figureFileSmall=Z3eyIauJM8a0vgihKmmPfQ==, figureFileBig=PCxC003ChVA9CpUei7PLqQ==, tableContent=null), ArticleFig(id=1201177219516293772, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=t5LyHRZiq/wnCeNA/h7KSg==, figureFileBig=rwn2V9+F9YO8BhS0Uer2TQ==, tableContent=null), ArticleFig(id=1201177219616957075, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 4, caption= 2D-HPLC chromatograms of API and its related substances , figureFileSmall=t5LyHRZiq/wnCeNA/h7KSg==, figureFileBig=rwn2V9+F9YO8BhS0Uer2TQ==, tableContent=null), ArticleFig(id=1201177219793117851, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=2+Bz4lyqi1Vk3s7KPKsEzA==, figureFileBig=/3nMKPbX/lNAeOVMBwjrew==, tableContent=null), ArticleFig(id=1201177219910558370, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 5, caption= Chemical structures of the major impurities found in phloroglucinol injection , figureFileSmall=2+Bz4lyqi1Vk3s7KPKsEzA==, figureFileBig=/3nMKPbX/lNAeOVMBwjrew==, tableContent=null), ArticleFig(id=1201177220007027371, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=qSPhIc93YseaPpaL1rwPiQ==, figureFileBig=WkDm5wubcTStWduJOALKcQ==, tableContent=null), ArticleFig(id=1201177220099302065, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 6, caption= MS/MS spectra of the major impurities found in phloroglucinol injection API-a (<i>m</i>/<i>z</i> 125); EP-A (<i>m</i>/<i>z</i> 125); EP-D (<i>m</i>/<i>z</i> 233); EP-E (<i>m</i>/<i>z</i> 125); EP-I (<i>m</i>/<i>z</i> 160); EP-K (<i>m</i>/<i>z</i> 142); EP-O (<i>m</i>/<i>z</i> 176); 1 (<i>m</i>/<i>z</i> 255); 2 (<i>m</i>/<i>z</i> 251); 3 (<i>m</i>/<i>z</i> 237); 4 (<i>m</i>/<i>z</i> 255); 5 (<i>m</i>/<i>z</i> 223); 6 (<i>m</i>/<i>z</i> 253); 7 (<i>m</i>/<i>z</i> 279); 8 (<i>m</i>/<i>z</i> 169); 9 (<i>m</i>/<i>z</i> 247); 10 (<i>m</i>/<i>z</i> 287); 11 (<i>m</i>/<i>z</i> 247); 12 (<i>m</i>/<i>z</i> 247); 13 (<i>m</i>/<i>z</i> 373); 14 (<i>m</i>/<i>z</i> 373); 15 (<i>m</i>/<i>z</i> 373); 16 (<i>m</i>/<i>z</i> 265); 17 (<i>m</i>/<i>z</i> 297) , figureFileSmall=qSPhIc93YseaPpaL1rwPiQ==, figureFileBig=WkDm5wubcTStWduJOALKcQ==, tableContent=null), ArticleFig(id=1201177220187382456, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=uaex00x+sGY8dQCOBGaExw==, figureFileBig=+hwXiK4Xxaa3kfreZ7aLsQ==, tableContent=null), ArticleFig(id=1201177220292240064, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 7, caption= Phloroglucinol and its typical known related substances [M-H]<sup>-</sup> ions MS/MS fragmentation pathways , figureFileSmall=uaex00x+sGY8dQCOBGaExw==, figureFileBig=+hwXiK4Xxaa3kfreZ7aLsQ==, tableContent=null), ArticleFig(id=1201177220392903365, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=XTZ6h1OmmFjqmi5Ujs/cPg==, figureFileBig=SAFOzEhrjv4es+bp5FIu4g==, 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tableContent=null), ArticleFig(id=1201177220850082522, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=S7DBsd5pmhS61pDgrCi6qg==, figureFileBig=Ye7YOc0I6zSVsZT/7E8hnQ==, tableContent=null), ArticleFig(id=1201177220921385692, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 10, caption= Related substance <strong>11</strong> formation mechanism , figureFileSmall=S7DBsd5pmhS61pDgrCi6qg==, figureFileBig=Ye7YOc0I6zSVsZT/7E8hnQ==, tableContent=null), ArticleFig(id=1201177220980105952, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=GuU0qKsZcf0uAtTUoDHYCg==, figureFileBig=LCQkRS0VCAYw5aPOJgBHew==, tableContent=null), ArticleFig(id=1201177221084963557, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 11, caption= Related substance <strong>11</strong> [M-H]<sup>-</sup> ion MS/MS fragmentation pathways , figureFileSmall=GuU0qKsZcf0uAtTUoDHYCg==, figureFileBig=LCQkRS0VCAYw5aPOJgBHew==, tableContent=null), ArticleFig(id=1201177221168849643, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=ujTidEiIGHHONKb4yiKUgw==, figureFileBig=/X1V17q9K7zpuNV3WS1C/w==, tableContent=null), ArticleFig(id=1201177221240152815, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 12, caption= Isomers of phloroglucinol trimer , figureFileSmall=ujTidEiIGHHONKb4yiKUgw==, figureFileBig=/X1V17q9K7zpuNV3WS1C/w==, tableContent=null), ArticleFig(id=1201177221332427511, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=nBP20eMZqUox/ENrfPDFxQ==, figureFileBig=xcWB/ybjs+CNWM5wC2tvfg==, tableContent=null), ArticleFig(id=1201177221437285118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 13, caption= Related substance <strong>15</strong> [M-H]<sup>-</sup> ion MS/MS fragmentation pathways , figureFileSmall=nBP20eMZqUox/ENrfPDFxQ==, figureFileBig=xcWB/ybjs+CNWM5wC2tvfg==, tableContent=null), ArticleFig(id=1201177221558919940, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=raba/cmNERWG1Kxy4KGs6Q==, figureFileBig=/ZEt6f4OZ/+aKYPQYqAK0A==, tableContent=null), ArticleFig(id=1201177221634417419, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Figure 14, caption= Related substance <strong>16</strong> [M-H]<sup>-</sup> ion MS/MS fragmentation pathways , figureFileSmall=raba/cmNERWG1Kxy4KGs6Q==, figureFileBig=/ZEt6f4OZ/+aKYPQYqAK0A==, tableContent=null), ArticleFig(id=1201177221739275025, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
SampleAreaTotal area/CCalibration
API-aTotal
Non-stressed26 267 13927 034 5823.38×1091.00
Acid hydrolysis25 734 19429 768 3843.72×1091.10
Alkaline hydrolysis25 719 54629 326 7203.67×1091.08
Oxidation23 995 58924 844 6753.11×1090.92
Thermal stress25 780 72828 795 3053.60×1091.07
Photolysis25 860 16628 330 2233.54×1091.05
), ArticleFig(id=1201177221823161110, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Table 1, caption=

Mass balance of phloroglucinol injection and its stressed test solutions (8.0×10-3 mg·L-1)

, figureFileSmall=null, figureFileBig=null, tableContent=
SampleAreaTotal area/CCalibration
API-aTotal
Non-stressed26 267 13927 034 5823.38×1091.00
Acid hydrolysis25 734 19429 768 3843.72×1091.10
Alkaline hydrolysis25 719 54629 326 7203.67×1091.08
Oxidation23 995 58924 844 6753.11×1090.92
Thermal stress25 780 72828 795 3053.60×1091.07
Photolysis25 860 16628 330 2233.54×1091.05
), ArticleFig(id=1201177221902852893, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No.Parent ion (m/z)tR/minIon formulaDiff.Product ion (m/z)λmax/nmOrigin
API-a125.022 715.78C6H5O3--13.7657.033 7, 41.002 1266.6API
EP-A125.023 015.02C6H5O3--11.3697.027 9, 79.017 4, 69.033 2, 55.017 6, 41.002 0265.9-
EP-D233.043 927.00C12H9O5--7.08189.053 4, 147.043 3, 123.043 4, 121.064 1, 65.002 0251.7-
EP-E125.022 710.45C6H5O3--13.7679.017 3, 69.033 1, 55.017 7287.3-
EP-I160.955 449.70C6H3OCl2--7.70124.977 7, 89.000 9277.8-
EP-K142.988 642.28C6H4O2Cl--13.50107.012 1, 96.967 9, 79.017 2, 63.022 6282.5-
EP-O176.950 347.09C6H3O2Cl2--7.12140.973 0, 112.978 0292.1-
1255.049 55.88C11H11O7--6.00211.059 5, 167.070 0, 97.027 7260.6Dr
2251.018 010.81C11H7O7--6.89179.033 0, 165.017 5, 137.022 9, 93.033 1265.4Dr
3237.038 312.42C11H9O6--9.11219.026 9, 175.037 8, 151.037 8, 109.027 8271.3Dr
4255.049 113.39C11H11O7--7.57193.049 0, 149.059 5, 125.059 2, 97.068 4, 85.028 2261.8Dr
5223.022 914.14C10H7O6--8.56179.033 5, 137.023 0, 109.027 9, 95.012 4227.5, 337.2Dr
6253.033 021.64C11H9O7--9.41209.043 2, 191.035 0, 167.032 7261.8Dr
7279.012 122.76C12H7O8--9.10235.022 9, 193.012 5, 178.996 9, 151.002 3263.0Dr
8169.013 828.27C7H5O5--2.66151.002 0, 107.012 4, 83.012 5, 65.002 2255.9Pr
9247.022 329.12C12H7O6--10.16219.028 1, 205.012 8, 177.017 7282.0Dr
10287.017 931.53C14H7O7--6.38243.027 6, 199.037 9, 155.048 6268.9Dr
11247.023 232.15C12H7O6--6.52229.011 5, 177.016 9, 151.001 6, 137.022 5, 133.027 6266.6Dr
12247.023 233.93C12H7O6--6.52229.012 0, 203.032 9, 177.017 4, 151.002 1261.8Dr
13373.055 835.34C18H13O9--1.90329.064 0, 285.074 4, 203.032 8, 175.038 3, 125.022 9270.1Dr
14373.053 735.76C18H13O9--7.53329.063 1, 285.073 8, 247.021 9, 203.032 3, 125.022 6259.4Dr
15373.053 836.36C18H13O9--7.26329.063 6, 285.074 2, 203.032 5, 175.038 1, 125.022 8265.4Dr
16265.035 637.18C12H9O7-0.83247.022 1, 221.042 8, 219.027 1, 203.032 3, 169.012 0, 151.001 6292.7Dr
17297.038 348.47C16H9O6--7.27280.034 4, 253.048 1, 227.032 3, 183.009 9272.5Dr
), ArticleFig(id=1201177222011904805, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210121053078, language=CN, label=Table 2, caption=

Related substances characteristics identified in phloroglucinol injection by 2D-LC-Q-TOF/MS. Pr: Process related substance; Dr: Degradation related substance

, figureFileSmall=null, figureFileBig=null, tableContent=
No.Parent ion (m/z)tR/minIon formulaDiff.Product ion (m/z)λmax/nmOrigin
API-a125.022 715.78C6H5O3--13.7657.033 7, 41.002 1266.6API
EP-A125.023 015.02C6H5O3--11.3697.027 9, 79.017 4, 69.033 2, 55.017 6, 41.002 0265.9-
EP-D233.043 927.00C12H9O5--7.08189.053 4, 147.043 3, 123.043 4, 121.064 1, 65.002 0251.7-
EP-E125.022 710.45C6H5O3--13.7679.017 3, 69.033 1, 55.017 7287.3-
EP-I160.955 449.70C6H3OCl2--7.70124.977 7, 89.000 9277.8-
EP-K142.988 642.28C6H4O2Cl--13.50107.012 1, 96.967 9, 79.017 2, 63.022 6282.5-
EP-O176.950 347.09C6H3O2Cl2--7.12140.973 0, 112.978 0292.1-
1255.049 55.88C11H11O7--6.00211.059 5, 167.070 0, 97.027 7260.6Dr
2251.018 010.81C11H7O7--6.89179.033 0, 165.017 5, 137.022 9, 93.033 1265.4Dr
3237.038 312.42C11H9O6--9.11219.026 9, 175.037 8, 151.037 8, 109.027 8271.3Dr
4255.049 113.39C11H11O7--7.57193.049 0, 149.059 5, 125.059 2, 97.068 4, 85.028 2261.8Dr
5223.022 914.14C10H7O6--8.56179.033 5, 137.023 0, 109.027 9, 95.012 4227.5, 337.2Dr
6253.033 021.64C11H9O7--9.41209.043 2, 191.035 0, 167.032 7261.8Dr
7279.012 122.76C12H7O8--9.10235.022 9, 193.012 5, 178.996 9, 151.002 3263.0Dr
8169.013 828.27C7H5O5--2.66151.002 0, 107.012 4, 83.012 5, 65.002 2255.9Pr
9247.022 329.12C12H7O6--10.16219.028 1, 205.012 8, 177.017 7282.0Dr
10287.017 931.53C14H7O7--6.38243.027 6, 199.037 9, 155.048 6268.9Dr
11247.023 232.15C12H7O6--6.52229.011 5, 177.016 9, 151.001 6, 137.022 5, 133.027 6266.6Dr
12247.023 233.93C12H7O6--6.52229.012 0, 203.032 9, 177.017 4, 151.002 1261.8Dr
13373.055 835.34C18H13O9--1.90329.064 0, 285.074 4, 203.032 8, 175.038 3, 125.022 9270.1Dr
14373.053 735.76C18H13O9--7.53329.063 1, 285.073 8, 247.021 9, 203.032 3, 125.022 6259.4Dr
15373.053 836.36C18H13O9--7.26329.063 6, 285.074 2, 203.032 5, 175.038 1, 125.022 8265.4Dr
16265.035 637.18C12H9O7-0.83247.022 1, 221.042 8, 219.027 1, 203.032 3, 169.012 0, 151.001 6292.7Dr
17297.038 348.47C16H9O6--7.27280.034 4, 253.048 1, 227.032 3, 183.009 9272.5Dr
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间苯三酚注射液有关物质的二维液相色谱-质谱联用鉴定
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刘佳明 , 陆宇婷 , 宋敏 , 杭太俊 *
药学学报 | 研究论文 2024,59(1): 202-213
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药学学报 | 研究论文 2024, 59(1): 202-213
间苯三酚注射液有关物质的二维液相色谱-质谱联用鉴定
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刘佳明, 陆宇婷, 宋敏, 杭太俊*
作者信息
  • 中国药科大学药物分析系, 江苏 南京 210009

通讯作者:

*杭太俊, Tel: 86-25-83271090, E-mail:
Structural identification of the related substances in phloroglucinol injection by two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry
Jia-ming LIU, Yu-ting LU, Min SONG, Tai-jun HANG*
Affiliations
  • Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
出版时间: 2024-01-12 doi: 10.16438/j.0513-4870.2023-0372
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摘要
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采用二维液相色谱-质谱联用技术鉴定间苯三酚注射液中的有关物质。以HSS T3 (250 mm × 4.6 mm, 5 μm) 为色谱柱, 1.36 g·L-1磷酸二氢钾(稀磷酸调节pH调至3.0)-乙腈为一维流动相进行梯度洗脱, 实现间苯三酚注射液有关物质的分离。各分离成分经多通道切换阀分别被捕集于截留管中, 然后输送到BDS C18 (100 mm × 4.6 mm, 2.4 μm) 色谱柱, 以0.1%甲酸水溶液-甲醇为二维流动相, 进行梯度洗脱实现快速脱盐。电喷雾负离子化-四极杆-飞行时间串联高分辨质谱检测各有关物质母离子及其子离子的准确质量和元素组成, 通过质谱解析、有机反应机制分析, 甚至对照品对照鉴定它们的结构。在所建立的分析条件下, 间苯三酚及其有关物质分离良好, 首次检测并鉴定出间苯三酚注射液及其强制降解实验样品中17个主要有关物质, 鉴定结果可为间苯三酚注射液质量控制提供参考依据。

间苯三酚注射液  /  有关物质  /  结构鉴定  /  二维液相色谱-质谱联用

This study aimed to identify the related substances of phloroglucinol injection by two-dimensional liquid chromatography quadrupole time-of-flight mass spectrometry (2D-LC-Q-TOF/MS). The first-dimensional separation was carried out on an HSS T3 (250 mm × 4.6 mm, 5 μm) column by gradient elution using 1.36 g·L-1 potassium dihydrogen phosphate buffer solution (pH adjusted to 3.0 with diluted phosphoric acid) and acetonitrile as the mobile phases. The separated components were then trapped in switch valve tube lines respectively and delivered to the second-dimensional desalting gradient elution which was performed with a BDS C18 (100 mm × 4.6 mm, 2.4 μm) column using 0.1% formic acid and methanol as the mobile phases. After rapid desalting, electrospray-ionization quadrupole time-of-flight high resolution mass spectrometry was used for determining the accurate masses and elemental compositions of the parents and their product ions for both phloroglucinol and its related substance. Structures of the related substances were then figured out by mass spectrometry elucidation, organic reaction mechanism analysis, and/or comparison with reference substances. Under the established analytical conditions, phloroglucinol and its related substances were adequately separated, 17 main related substances were detected and identified in the injection and its stressed samples for the first time. The identification results can provide reference for the quality control of phloroglucinol injection.

phloroglucinol injection  /  related substances  /  structural identification  /  2D-LC-Q-TOF/MS
刘佳明, 陆宇婷, 宋敏, 杭太俊. 间苯三酚注射液有关物质的二维液相色谱-质谱联用鉴定. 药学学报, 2024 , 59 (1) : 202 -213 . DOI: 10.16438/j.0513-4870.2023-0372
Jia-ming LIU, Yu-ting LU, Min SONG, Tai-jun HANG. Structural identification of the related substances in phloroglucinol injection by two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry[J]. Acta Pharmaceutica Sinica, 2024 , 59 (1) : 202 -213 . DOI: 10.16438/j.0513-4870.2023-0372
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间苯三酚是一种平滑肌解痉药, 其与间苯三酚三甲醚制成的复方注射液解痉效果更明显、作用迅速, 不良反应极少, 且不具有任何阿托品样反应。间苯三酚注射液在临床上得到了广泛应用[1-4], 已成为痉挛性疼痛治疗的首选药物[5], 并可与多种药物配伍使用[6]。
间苯三酚被欧洲药典(EP)[7]收载(图 1), 关于间苯三酚注射液的质量研究报道较少, 大多数为间苯三酚的含量测定[8-11], 关于间苯三酚有关物质研究仅围绕已知杂质的来源分析和含量测定展开[12-15], 尚未见间苯三酚注射液杂质谱的研究报道。而天然产物研究则报道了几种间苯三酚聚合物结构(图 2), 可为间苯三酚注射液有关物质结构解析提供参考[16]。
二维液相色谱-质谱联用分析技术自动化程度高且灵敏度高, 是药物有关物质鉴定的有效技术[17, 18]。本研究建立了适用于间苯三酚注射液有关物质分析及鉴定的二维液相色谱-质谱联用法, 采用正、负离子扫描相结合的方式确定有关物质的母离子, 并通过2D-LC-Q-TOF/MS测定了间苯三酚注射液有关物质母离子及子离子的准确质量及分子式, 在此基础上结合MS/MS的子离子特征分析、间苯三酚羟基与芳环的烯醇式或酮式互变异构特征(图 1)[19]、苯酚类化合物在紫外辐射及羟基自由基氧化条件下可分解成小分子酸(如马来酸、苹果酸、草酸、丁烯酸等) 的特性[20, 21], 进行综合解析, 分析鉴定了各有关物质的结构及其形成规律, 研究结果可为间苯三酚注射液的质量控制提供参考依据。
材料与方法
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药品与试剂  间苯三酚注射液(Spasfon, 批号: 207524, 规格为4 mL: 间苯三酚40 mg间苯三酚三甲醚0.040 mg), 间苯三酚(中国Aladdin公司, 批号: E2113376), 间苯三酚有关物质EP-B (间苯二酚, EDQM, 批号: P1609010), 间苯三酚有关物质EP-I (2, 6-二氯苯酚, 批号: 2686-004A1), 间苯三酚有关物质EP-L (3, 5-二氯苯胺, 批号: 1-LJC-42-1), 间苯三酚有关物质EP-O (4, 6-二氯间苯二酚, 批号: 1-MWC-84-1), 间苯三酚有关物质EP-K (4-氯间苯二酚, 批号: 9-MWC-68-1), 间苯三酚有关物质EP-E (1, 2, 4-苯三酚, 批号: 4-QL-163-2), 上述对照品均购置于加拿大TRC公司; 间苯三酚有关物质EP-A (邻苯三酚, 批号: W990709), 间苯三酚有关物质EP-D (2, 3′, 4, 5′, 6-五羟基联苯, 批号: 1030661), 上述对照品均购置于英国LGC公司; 2, 4, 6-三羟基苯甲酸(美国Sinco Pharmachem公司, 批号: 19-11-3001)。甲酸、磷酸、磷酸二氢钾(AR级, 南京化学试剂有限公司), 乙腈、甲醇(HPLC级, Merck公司), 去离子水(市售娃哈哈纯净水)。
仪器  岛津2D-LCMS-9030 Q-TOF高分辨质谱仪、Lab⁃Solutions数据处理系统(日本岛津公司); PB-10型pH计、BS 110S型分析天平(德国Sartorius公司)。
供试品溶液  精密量取本品适量, 用一维流动相A定量稀释制成每1 mL中含间苯三酚8 mg, 间苯三酚三甲醚8 μg的溶液。
对照溶液  精密量取供试品溶液适量, 用一维流动相A定量稀释成每1 mL含间苯三酚8 μg的溶液。
对照品溶液  取间苯三酚及其有关物质对照品(EP-A、EP-B、EP-D、EP-E、EP-I、EP-K、EP-L、EP-O) 适量, 分别精密称定, 用一维流动相A-B (90∶10) 溶解并定量稀释制成每1 mL中含各对照品均约为20 μg的混合溶液。
强制降解实验溶液  取间苯三酚注射液4 mL, 于80 ℃烘箱中放置8 h, 放冷后用一维流动相A定量稀释至5 mL, 制成高温降解实验溶液; 取间苯三酚注射液4 mL, 于光照4500 lx放置8 h后用一维流动相A定量稀释至5 mL, 制成光照降解实验溶液; 取间苯三酚注射液4 mL, 加3%过氧化氢溶液(一维流动相A稀释) 800 μL并于60 ℃水浴放置12 h, 放冷后用一维流动相A定量稀释至5 mL制成氧化降解实验溶液; 取间苯三酚注射液4 mL, 加4.0 mol·L-1盐酸400 μL并于60 ℃水浴放置24 h, 经酸碱中和处理后放冷后用一维流动相A定量稀释至5 mL得酸降解实验溶液; 取间苯三酚注射液4 mL, 加1.0 mol·L-1氢氧化钠溶液400 μL并于室温放置30 min, 经酸碱中和处理放冷后用一维流动相A定量稀释至5 mL得碱降解实验溶液。各样品经处理后制成每1 mL中含间苯三酚8 mg, 间苯三酚三甲醚8 μg的溶液。
色谱分析方法
一维液相色谱方法Waters XSelect HSS T3 (250 mm × 4.6 mm, 5 μm) 色谱柱; 流动相A相为1.36 g·L-1磷酸二氢钾溶液(稀磷酸调节pH至3.0), B相为乙腈, 线性梯度洗脱(A∶B): 0 min (100∶0)→15 min (100∶0)→35 min (75∶25)→50 min (20∶80)→55 min (20∶80)→60 min (100∶0)→70 min (100∶0), 流速1.0 mL·min-1, 柱温25 ℃, 检测波长265 nm, 进样量20 μL。
二维液相色谱方法Thermo Hypersil BDS C18 (100 mm × 4.6 mm, 2.4 μm) 色谱柱; 流动相A相为0.1%甲酸溶液, B相为甲醇, 线性梯度洗脱(A∶B): 0 min (100∶0)→3 min (100∶0)→10 min (5∶95)→13 min (5∶95)→13.1 min (100∶0)→18 min (100∶0), 流速0.5 mL·min-1, 柱温25 ℃, 检测波长265 nm。
质谱分析方法  将二维液相色谱与Q-TOF/MS串联, 采用电喷雾正、负离子化检测, TOF/MS质谱测定参数: 雾化器流量3 L·min-1, 干燥气流量10 L·min-1, 加热气流量10 L·min-1, 喷雾电压4.5 kV, 接口温度300 ℃, 离子传输管温度250 ℃, 扫描范围m/z 50~1 000。二级质谱氩气CID碰撞能量5~45 eV。
结果
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1 有关物质检查
建立的二维液相分析法, 适用于间苯三酚注射液有关物质检查和联用质谱鉴定。图 3为间苯三酚注射液及其强制降解实验溶液的HPLC-UV谱图。采用0.1%自身对照法计算有关物质的含量, 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。
强制降解实验表明(表 1), 本品对强碱、强光照射、高温条件均不稳定, 共分离并检出17个主要有关物质。其中, 间苯三酚注射液供试品中检出1个有关物质(图 3d, 有关物质8); 氧化破坏形成1个主要降解产物(图 3e, 有关物质4); 高温破坏形成8个主要降解产物(图 3f, 有关物质2、7、9~13和16); 光照破坏形成7个主要降解产物(图 3g, 有关物质1、3、5~7、9和17); 酸破坏形成1个主要降解产物(图 3h, 有关物质9); 碱破坏形成4个主要降解产物(图 3i, 有关物质9和13~15)。各有关物质在二维除盐洗脱下均获得良好峰形(图 4)。
2 有关物质的结构鉴定
电喷雾离子化条件下间苯三酚既能够正离子化又能够负离子化, 负离子化具有更好的专属性。研究通过电喷雾正、负离子化检测一级质谱, 利用各有关物质母离子的正、负离子准确质量相差2的特性, 确定负离子扫描模式下母离子的准确质量。
根据各有关物质的母离子及子离子的准确质量和元素组成, 以及它们的二级质谱特征碎片裂解规律, 并与间苯三酚和已知有关物质的质谱特征的对比分析, 鉴定各主要有关物质的结构。结果见表 2和图 5、6。
3 已知有关物质的确证
通过对间苯三酚注射液主成分及EP收录已知杂质的正、负离子扫描结果发现: 间苯三酚、EP-A、EP-D和EP-E在正、负离子扫描模式下均有响应, EP-K、EP-O和EP-I仅在负离子扫描模式下有响应, EP-B和EP-L仅在正离子扫描模式下有响应, 间苯三酚三甲醚在正、负离子扫描模式下均无响应。考虑到各未知有关物质也可能出现在某种扫描模式下无响应的情况, 故采用正、负离子扫描模式, 利用正、负离子扫描模式下母离子质量数相差2的特性确定17个未知杂质的母离子, 鉴于各有关物质负离子响应更佳, 故通过负离子条件下已知有关物质的保留时间及质谱裂解规律(图 7) 推断各未知杂质的结构, 总结规律如下。
间苯三酚及已知有关物质化学结构与保留时间规律: ① EP-B在EP-E、EP-A及间苯三酚后出峰, EP-I在EP-K、EP-O后出峰, 均说明母核相同情况下, 羟基数目越多, 极性越大, 出峰时间越早。② EP-D在间苯三酚后出峰, 说明间苯三酚形成聚合物后, 极性减小, 出峰时间延后。
间苯三酚及已知有关物质MS/MS裂解规律: ①间苯三酚、EP-A、EP-E羟基取代位置不同, 负ESI-Q-TOF/MS测得三者的准确质量分别为125.022 7、125.023 0、125.022 7, 均与离子式[C6H5O3]-相应。碎片离子m/z 41.002 1 (C2HO-)、55.017 6 (C3H3O-) 由苯环开裂而来。鉴于苯环上被羟基取代, [M-H]-可接连脱去CO, 生成质量数少28的特征碎片离子m/z 97.027 9 (C5H5O2-) 和69.033 2 (C4H5O-)。m/z 79.017 4 (C5H3O-) 是由[M-H]-脱去一分子CO和一分子H2O产生。②负ESI-Q-TOF/MS测得EP-D的准确质量为233.043 9, 与离子式[C12H9O5]-相应。特征碎片离子m/z 189.053 4 (C11H9O3-) 由[M-H]-经重排脱去一分子CO2产生。③负ESI-Q-TOF/MS测得EP-K、EP-O和EP-I的准确质量分别为142.988 6、176.950 3、160.955 4, 分别与离子式[C6H4ClO2]-、[C6H3Cl2O2]-和[C6H3Cl2O]-相应。上述有关物质的母离子中, 苯环可脱去HCl, 生成质量数少36的特征碎片离子。
间苯三酚及已知有关物质均以苯环为基本结构单元, 特征碎片离子的形成主要通过脱水、脱CO及苯环开裂形成, 在间苯三酚聚合物中若苯环上存在空间位置相近的羟基取代可发生重排脱去一分子CO2。
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、最大吸收波长(表 2) 和质谱特征, 结合反应机制, 可鉴定结构。
有关物质8为间苯三酚注射液工艺杂质, 具有在高温条件下降解的特点, 经过正、负离子扫描后, 确定其[M-H]-的准确离子质量为169.013 8, 与离子式[C7H5O5]-相应, 与间苯三酚元素组成相比多一个C元素和两个O元素。MS/MS主要特征碎片离子(图 8) m/z 125.023 0 (C6H5O3-) 与[M-H]-脱去CO2相应, 推定有关物质8为间苯三酚与工艺过程中引入的二氧化碳进行反应生成的工艺杂质: 2, 4, 6-三羟基苯甲酸, 并经对照品进行确证, 保留时间、DAD图谱及质谱信息均一致。
有关物质1为间苯三酚注射液特征光降解杂质, 且保留较弱, 极性较大, 测得其[M-H]-的准确离子质量为255.048 8, 与离子式[C11H11O7]-相应, 恰好比间苯三酚注射液主成分间苯三酚三甲醚的相对分子质量多88, 其MS/MS主要特征碎片离子m/z 211.059 5 (C10H11O5-) 和167.070 0 (C9H11O3-) 分别与[M-H]-接连脱去CO2相应, 推断有关物质1为间苯三酚三甲醚与注射液中溶有的CO2反应生成的产物, 即间苯三酚三甲醚二羧酸。
有关物质2为间苯三酚注射液高温条件下的特征降解杂质。测得其[M-H]-的准确离子质量为251.018 0, 与离子式[C11H7O7]-相应。其MS/MS主要特征碎片离子m/z 189.019 3 (C10H5O4-)、179.033 0 (C9H7O4-) 与[M-H]-脱去一分子CO2后, 分别脱去一分子H2O和一分子CO相应。m/z 165.017 5 (C8H5O4-) 和137.022 9 (C7H5O3-) 分别与[M-H]-脱去一分子CO2和乙烯酮(CH2=C=O)、进而内酯环开裂脱去一分子CO后重新环合相应。推断在高温环境下间苯三酚苯环上羟基被羧基取代, 与小分子有机酸马来酸发生Michael加成后游离羧基与邻位羟基脱水缩合成稳定的五元环, 产生降解产物有关物质2, 即3-羧甲基-4-羟基-2-氧代-2, 3-二氢苯并呋喃-6-甲酸。
有关物质3为间苯三酚注射液特征光降解杂质。测得它的[M-H]-的准确离子质量为237.038 3, 与离子式[C11H9O6]-相应, 根据元素组成与不饱和度推测为有关物质8与小分子有机酸反应形成的产物。其MS/MS主要特征碎片离子m/z 219.026 9 (C11H7O5-)、175.037 8 (C10H7O3-) 分别与[M-H]-脱去一分子H2O和一分子CO2相应。特征基峰碎片m/z 109.027 8 (C6H5O2-) 与苯环RDA开裂相应。推断有关物质3为有关物质8与一分子丁烯酸发生酯化反应形成的产物, 即(Z)-4-(2-丁烯酰氧基)-2, 6-二羟基苯甲酸。
有关物质4为间苯三酚注射液特征氧化降解杂质。测得它的[M-H]-的准确离子质量为255.049 1, 与离子式[C11H11O7]-相应, 与有关物质3相比多一个O且减少了一个不饱和度。推测有关物质4为间苯三酚在CO2环境下生成有关物质8后, 发生烯醇互变生成活泼的碳负离子, 与一分子丁烯酸发生加成反应形成的降解产物, 即3-(3-甲基丙酸基)-2, 4, 6-三羟基苯甲酸。其MS/MS主要特征碎片离子m/z 211.059 0 (C10H11O5-) 和193.049 0 (C10H9O4-) 分别为[M-H]-脱去一分子CO2、进而脱去一分子H2O相应, 特征基峰碎片m/z 149.059 5 (C9H9O2-) 与[M-H]-脱去两分子CO2和一分子H2O相应。
有关物质5为间苯三酚注射液特征光降解杂质。测定得其[M-H]-的准确离子质量为223.022 9, 与离子式[C10H7O6]-相应, 且最大吸收波长向长波移动。其MS/MS主要特征碎片离子m/z 179.033 5 (C9H7O4-) 和137.023 0 (C7H5O3-) 分别与母离子丢失一分子CO2、进而苯环开裂丢失一分子乙烯酮(CH2=C=O) 相应。推断有关物质5为间苯三酚发生酮式烯醇互变形成环己三酮后, 与间苯三酚光解产物马来酸的活泼双键发生Michael加成, 游离羧基与邻位羟基脱水缩合生成稳定的六元环。有关物质5为5, 7-二羟基-2-氧代苯并二氢吡喃-4-甲酸。
有关物质6为间苯三酚注射液特征光降解杂质。测得它的[M-H]-的准确离子质量为253.033 0, 与离子式[C11H9O7]-相应。其MS/MS主要特征碎片离子(图 9) m/z 209.043 2 (C10H9O5-) 和191.035 0 (C10H7O4-) 分别为[M-H]-脱去一分子CO2、进而脱去一分子H2O形成, 推断有关物质6为间苯三酚被氧化成为1, 2, 3, 5-环己四酮后, 母核发生酮式烯醇互变, 与一分子丁烯酸发生加成反应, 一分子羟基被一分子羧基取代。有关物质6为8-羟基-3-甲基苯并[b]1, 4-二氧六环-2, 6-二羧酸。
有关物质7为间苯三酚注射液特征光降解杂质。测得它的[M-H]-的准确离子质量为279.012 1, 与离子式[C12H7O8]-相应, 猜测为间苯三酚被光解氧化后偶联生成的降解杂质, 其MS/MS主要特征碎片离子m/z 235.022 9 (C11H7O6-) 和193.012 5 (C9H5O5-) 分别与[M-H]-脱去CO2、进一步脱去一分子乙烯酮(CH2=C=O) 相应, m/z 178.996 9 (C8H3O5-) 和151.002 3 (C7H3O4-) 分别与[M-H]-脱去CO2和一分子环丙酮(C3H4O)、进一步脱去CO相应, 推断有关物质7为两分子间苯三酚发生光解氧化后发生羟醛缩合的产物: 二羟化二聚间苯三酚。
有关物质9、11、12经过正、负离子扫描后, 确定其[M-H]-的准确离子质量分别为247.022 3、247.023 2和247.023 2, 均与离子式[C12H7O6]-相应, 结合碳、氧数目, 推测三者均为两分子间苯三酚反应后形成。有关物质9在酸、碱、光照、高温条件下均可产生, 有关物质11、12均为高温条件下的特征杂质。有关物质9的负离子二级质谱图及最大吸收波长(表 2) 与有关物质11、12相差较大, 其MS/MS主要特征碎片离子m/z 219.028 1 (C11H7O5-) 与[M-H]-脱去一分子CO相应, m/z 205.012 8 (C10H5O5-)、177.017 7 (C9H5O4-) 分别与[M-H]-脱去乙烯酮(CH2=C=O)、进一步脱去CO相应。结合参考文献[22]推断有关物质9的反应机制, 起始于间苯三酚的自由基和O2-的形成, 这两种自由基可发生相应的歧化反应, 进而参与间苯三酚二聚体的形成, 生成降解产物1, 3, 6, 8-四羟基二苯并[b, e]1, 4-二氧六环。有关物质11、12的负离子二级质谱图具有高度相似性, 推测有关物质11、12为高温条件下间苯三酚被氧化成为1, 2, 3, 5-环己四酮后与另一分子间苯三酚缩合脱水形成的产物, 以有关物质11为例, 反应机制如图 10所示。由于发生缩合的位点不同从而产生同分异构体, 经由裂解碎片合理推断反应发生位点, 推断有关物质11为顺二酮化-二聚间苯三酚, 有关物质12为反二酮化-二聚间苯三酚。二者相同主要碎片离子m/z 229.011 5 (C12H5O5-) 和219.027 8 (C11H7O5-) 分别与[M-H]-脱去一分子H2O和一分子CO相应, m/z 203.032 9 (C11H7O4-) 与[M-H]-经重排后脱去一分子CO2相应, m/z 177.016 9 (C9H5O4-) 与[M-H]-中性丢失一分子环丙二酮(C3H2O2) 相应, m/z 151.001 6 (C7H3O4-) 与[M-H]-中性丢失一分子乙烯酮(CH2=C=O) 和一分子环丙烯酮(C3H2O) 相应。有关物质11的特征碎片离子(图 11) m/z 137.022 5 (C7H5O3-) 与[M-H]-脱去一分子环丙烯酮(C3H2O) 和两分子CO相应, m/z 133.027 6 (C8H5O2-) 与[M-H]-经重排后脱去一分子CO2、进一步脱去一分子CO和一分子乙烯酮(CH2=C=O) 相应。
有关物质10为间苯三酚注射液特征氧化杂质, 经过正、负离子扫描后, 确定其[M-H]-的准确离子质量为287.017 9, 与离子式[C14H7O7]-相应, 其MS/MS主要碎片离子m/z为243.027 6 (C13H7O5-)、199.037 9 (C12H7O3-)、155.048 6 (C11H7O-), 碎片离子的准确离子质量均相差44, 各主要碎片离子经母离子接连丢失CO2产生。依据有关物质10的不饱和度及元素组成, 推断其为间苯三酚羟基被羧基取代后, 两分子产物发生C-C偶联[23]和歧化反应的产物, 即1, 9-二羟基二苯并[b, d]呋喃-3, 7-二羧酸。
有关物质13、14、15经过正、负离子扫描后测得其[M-H]-的准确离子质量分别为373.055 8、373.053 7和373.053 8, 均与离子式[C18H13O9]-相应, 依据间苯三酚的分子元素组成, 推断有关物质13、14、15为三分子间苯三酚发生化学反应聚合形成。有关物质13在碱、高温破坏条件下均可产生; 有关物质14、15在碱破坏条件下产生。推断间苯三酚三聚体可能存在的异构体如图 12所示, 三者的主要碎片离子大致相同(图 13), MS/MS主要特征碎片离子均为329.064 0 (C17H13O7-)、285.074 4 (C16H13O5-)、247.022 4 (C12H7O6-)、203.032 8 (C11H7O4-)、175.038 3 (C10H7O3-) 与125.022 9 (C6H5O3-), 各碎片离子主要通过分子内重排脱去CO2及苯环开裂形成。结合强制降解破坏条件及保留时间与游离羟基个数的相关性, 推测有关物质13为间苯三酚氧化后通过羟醛缩合、迈克尔加成等反应形成的降解产物α-三聚间苯三酚; 结合参考文献[21]推测有关物质14为三分子间苯三酚自氧化发生C-C偶联生成间-三聚间苯三酚; 有关物质15三间苯三酚醚的形成机制同有关物质9。
有关物质16为间苯三酚注射液特征氧化降解杂质, 经过正、负离子扫描后, 确定其[M-H]-的准确离子质量为265.035 6, 与离子式[C12H9O7]-相应, 结合碳和氧的个数, 与两分子间苯三酚结构式相比少2个H, 多一个O, 结合参考文献[22, 24], 推测有关物质16为间苯三酚发生自氧化生成1, 2, 3, 5-四羟基苯后与一分子间苯三酚发生歧化反应的产物, 即二间苯三酚醚。其MS/MS主要碎片离子(图 14) m/z 221.042 8 (C11H9O5-)、203.032 3 (C11H7O4-) 分别与[M-H]-脱去一分子CO2、进一步脱去一分子H2O相应。
有关物质17为间苯三酚注射液特征光照降解杂质, 经过正、负离子扫描后, 确定其[M-H]-的准确离子质量为297.038 3, 与离子式[C16H9O6]-相应, 根据元素组成及保留时间推断其为两分子间苯三酚经去羟基化后与小分子有机酸形成的内酯化合物。其MS/MS主要碎片离子m/z 280.034 4 (C16H8O5-·) 与母离子[M-H]-脱去羟基自由基相应, m/z 253.048 1 (C15H9O4-) 与[M-H]-内酯环断裂脱去一分子CO2后重新环合相应。m/z 227.032 3 (C13H7O4-) 与[M-H]-内酯环脱去丙烯酸酯单元相应, m/z 183.009 9 (C11H3O3-) 与[M-H]-内酯环脱去丙烯酸酯单元后、开环脱氢、同时脱去一分子乙烯酮(CH2=C=O) 相应。合理推测有关物质17为间苯三酚在光照条件下光解产生的马来酸与两分子苯酚类化合物脱水成酯, 同时发生C-C偶联而形成较为稳定的内酯化合物, 即二聚间苯二酚马来酸酯。
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本研究开发2D-LC-Q-TOF-MS联用分析方法, 适用于间苯三酚注射液有关物质的色谱-质谱联用鉴定。间苯三酚主成分及各杂质均能得到有效的分离, 共检测到17个未经报道过的有关物质。本文采用ESI+-Q-TOF/MS和ESI--Q-TOF/MS分别进行扫描, 确定有关物质的母离子, 解决了在单一扫描模式下难以确定母离子准确质量的问题, 所检出的17个有关物质均为本文首次鉴定。
实验结果表明, 在工艺过程中作为保护气的二氧化碳会与间苯三酚反应生成2, 4, 6-三羟基苯甲酸工艺杂质8。间苯三酚三甲醚在光照条件下易与CO2发生反应生成降解杂质1。与此同时, 苯酚类化合物在高温、氧化及光照条件易开环断裂成小分子有机酸马来酸、丁烯酸等参与间苯三酚的降解, 发生加成反应、酯化反应产生降解杂质2~6和17。在光照、碱、高温破坏条件下, 间苯三酚易发生羟醛缩合生成杂质7、11~13, 在高温、碱破坏条件下, 间苯三酚易发生C-C偶联和歧化反应生成相应聚合物杂质9、10和14~16。间苯三酚注射液在光照、高温、碱性条件下不稳定, 因此应注意避光、避碱, 常温储存。
作者贡献: 刘佳明负责实验操作、有关物质结构鉴定及论文撰写; 陆宇婷和宋敏负责实验指导、参与文章修改; 杭太俊提供文章思路、参与有关物质结构鉴定、负责文章修改及定稿。
利益冲突: 本文不存在任何利益冲突。
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  • 国家药品监督管理局化学药品杂质谱研究重点实验室开放课题资助项目(NMPA-KLIPCD-2020-03)
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doi: 10.16438/j.0513-4870.2023-0372
  • 接收时间：2023-03-27
  • 首发时间：2025-11-28
  • 出版时间：2024-01-12
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  • 收稿日期：2023-03-27
  • 修回日期：2023-05-29
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国家药品监督管理局化学药品杂质谱研究重点实验室开放课题资助项目(NMPA-KLIPCD-2020-03)
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    中国药科大学药物分析系, 江苏 南京 210009

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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