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Article(id=1240372085361537451, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1240372078617096528, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2024.01.09, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1683734400000, receivedDateStr=2023-05-11, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773657350149, onlineDateStr=2026-03-16, pubDate=1706630400000, pubDateStr=2024-01-31, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773657350149, onlineIssueDateStr=2026-03-16, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773657350149, creator=13701087609, updateTime=1773657350149, 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=89, endPage=100, ext={EN=ArticleExt(id=1240372087106367986, articleId=1240372085361537451, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Identification of the related substances in penciclovir cream by two-dimensional LC-MS techniques*, columnId=1239256892686520399, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Safety Monitorin, runingTitle=null, highlight=null, articleAbstract=
Objective:

To identify the structures of the related substances in penciclovir cream by two-dimensional liquid chromatography quadrupole time-of-flight tandem mass spectrometry (2D-LC-Q TOF/MS) technique.

Methods:

The first-dimension separation of the related substances in penciclovir cream and its stressed samples according to ICH were carried out on an ODS (250 mm×4.6 mm, 5 μm) column with gradient elution by 0.15% formic acid 10 mmol·L-1 ammonium formate buffer solution and acetonitrile as mobile phases, and each related substance was enriched separately. The second-dimension gradient elution was performed on a Phenomenex Luna SCX (250 mm×4.6 mm, 5 μm) column with 0.1% formic acid 20 mmol·L-1 ammonium formate buffer solution and acetonitrile as mobile phases for each of the related substances to achieve good separation with the matrix of penciclovir cream. The accurate mass and elemental composition of the parent ions and their product ions of the related substances were determined by positive electrospray-ionization quadrupole time-of-flight high resolution mass spectrometry, and the structures of all the related substances were elucidated.

Results:

Under the established 2D-LC-Q TOF/MS analytical conditions, penciclovir and its related substances were adequately separated, and 21 major related substances were detected and identified in the penciclovir cream and its stressed samples. According to their chromatographic retention behavior, spectral characteristics, mass spectrometry characteristics and their differences from other known related substances of nucleoside drugs and combing with synthesis and formulation process route, their structures can be identified all of which were identified for the first time.

Conclusion:

The results can provide reference for the quality control of penciclovir cream.

, 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=Abbosova Zokirjonovna Diyorakhon, Li-jie WANG, Yu-ting LU, Min SONG, Tai-jun HANG), CN=ArticleExt(id=1240372092550574729, articleId=1240372085361537451, tenantId=1146029695717560320, journalId=1205117023404326918, language=CN, title=喷昔洛韦乳膏有关物质的二维色谱-质谱联用鉴定*, columnId=1206272758036623764, journalTitle=药物分析杂志, columnName=安全监测, runingTitle=null, highlight=null, articleAbstract=
目的：

基于二维高效液相色谱-四极杆-飞行时间串联质谱技术(2D-LC-Q TOF/MS)，鉴定喷昔洛韦乳膏有关物质的结构。

方法：

采用ODS(250 mm×4.6 mm，5 μm)色谱柱，以0.15%甲酸10 mmol·L-1甲酸铵缓冲溶液-乙腈为流动相，进行一维梯度洗脱，对喷昔洛韦乳膏及其依照ICH原则强制降解样品的有关物质进行分离，并分别富集各有关物质；再采用Phenomenex Luna SCX(250 mm×4.6 mm，5 μm)色谱柱，以0.1%甲酸20 mmol·L-1甲酸铵缓冲溶液-乙腈为流动相，进行二维梯度洗脱，实现各有关物质与喷昔洛韦乳膏基质的良好分离。利用电喷雾正离子化-四极杆-飞行时间串联质谱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，并解析鉴定其结构。

结果：

在所建立的2D-LC-Q TOF/MS分析条件下，喷昔洛韦与其有关物质分离良好，检测出喷昔洛韦乳膏及其强制降解样品中21个主要有关物质。根据其色谱保留行为、光谱特征、质谱特征及与其他核苷类药物已知有关物质的差异，结合合成和制剂工艺路线分析，可鉴定出它们的结构，它们均为首次被鉴定出的有关物质。

结论：

研究结果为喷昔洛韦乳膏的质量控制提供了参考依据。

, correspAuthors=杭太俊, authorNote=null, correspAuthorsNote=
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a. 0.1%自身对照(0.1% self-reference) b.样品(test sample) c.高温干法破坏(dry heat stress) d.高温湿法破坏(wet heat stress) e.光照湿法破坏(wet photolytic stress) f.光照干法破坏(dry photolytic stress) g.氧化破坏(oxidation stress) h.碱破坏(alkaline stress) i.酸破坏(acidic stress)

, figureFileSmall=aVkb2wVL82pjFnmHkd+bOg==, figureFileBig=imKDR8lC+1+v/YptgKcxCA==, tableContent=null), ArticleFig(id=1240376126707658862, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=EN, label=Fig.2, caption=MS spectrum of the excipient polyethylene glycol, figureFileSmall=6vAVB1usD5yxY3CYHF6X1w==, figureFileBig=mu+KJq5HNimMBgcXgbjc1A==, tableContent=null), ArticleFig(id=1240376126795739251, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=CN, label=图2, caption=辅料聚乙二醇的一级质谱图, figureFileSmall=6vAVB1usD5yxY3CYHF6X1w==, figureFileBig=mu+KJq5HNimMBgcXgbjc1A==, tableContent=null), ArticleFig(id=1240376126879625337, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=EN, label=Fig.3, caption=The comparison second dimensional liquid chromatograms of penciclovir and its related substances, figureFileSmall=zKGA+Z736JvrNILvpGs0Ow==, figureFileBig=NVlJ9V+bMe5q459dd951cA==, tableContent=null), ArticleFig(id=1240376126980288641, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=CN, label=图3, caption=喷昔洛韦乳膏及其有关物质二维液相色谱比较图

a.ELSD b.UVD

, figureFileSmall=zKGA+Z736JvrNILvpGs0Ow==, figureFileBig=NVlJ9V+bMe5q459dd951cA==, tableContent=null), ArticleFig(id=1240376127114506373, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=EN, label=Fig.4, caption=The overlayed second dimensional liquid chromatograms of penciclovir and its related substances, figureFileSmall=fK2JfVmFvH24Y9a6RNUL0A==, figureFileBig=OcClQcMmefyNW/1CxUw1uQ==, tableContent=null), ArticleFig(id=1240376127206781066, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=CN, label=图4, caption=喷昔洛韦乳膏及其有关物质的二维液相色谱叠加图, figureFileSmall=fK2JfVmFvH24Y9a6RNUL0A==, figureFileBig=OcClQcMmefyNW/1CxUw1uQ==, tableContent=null), ArticleFig(id=1240376127311638672, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=EN, label=Fig.5, caption=MS/MS spectra of penciclovir and its related substances [M+H]+ ions, figureFileSmall=119MAHDCzu1CWt8c3IF0bg==, figureFileBig=Y1eqE0KedUxrIZMa9KMkuQ==, tableContent=null), ArticleFig(id=1240376127441662102, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=CN, label=图5, caption=喷昔洛韦及其有关物质[M+H]+离子的二级质谱图

API(m/z 254) 1(m/z 270) 2(m/z 215) 3(m/z 344) 4 (m/z 344) 5(m/z 312) 6(m/z 286) 7(m/z 270) 8(m/z 284) 9(m/z 300) 10 (m/z 312) 11(m/z 282) 12(m/z 356) 13(m/z 266) 14(m/z 400) 15(m/z 296) 16 (m/z 400) 17(m/z 326) 18(m/z 529) 19(m/z 137) 20(m/z 561) 21(m/z 504) 22 (m/z 519) 23(m/z 151)

, figureFileSmall=119MAHDCzu1CWt8c3IF0bg==, figureFileBig=Y1eqE0KedUxrIZMa9KMkuQ==, tableContent=null), ArticleFig(id=1240376127533936796, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=EN, label=Fig.6, caption=Chemical structures of penciclovir and its related substances 1-23, figureFileSmall=dygkfSKHEv4F4SiJatScFw==, figureFileBig=xpbg9EszA7vih5CP2IwpMw==, tableContent=null), ArticleFig(id=1240376127638794398, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=CN, label=图6, caption=喷昔洛韦及其有关物质1~23的化学结构, figureFileSmall=dygkfSKHEv4F4SiJatScFw==, figureFileBig=xpbg9EszA7vih5CP2IwpMw==, tableContent=null), ArticleFig(id=1240376127718486179, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=EN, label=Fig.7, caption=MS/MS fragmentation pathways of penciclovir，acyclovir and guanine [M+H]+ ions, figureFileSmall=5Zc/KSp6t9gG90PmndAxyA==, figureFileBig=s/e3AZ8oeA6Eqp5AYPkGaA==, tableContent=null), ArticleFig(id=1240376127814955177, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=CN, label=图7, caption=喷昔洛韦、阿昔洛韦及鸟嘌呤[M+H]+离子的二级碎片裂解途径, figureFileSmall=5Zc/KSp6t9gG90PmndAxyA==, figureFileBig=s/e3AZ8oeA6Eqp5AYPkGaA==, tableContent=null), ArticleFig(id=1240376127915618478, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=EN, label=Fig.8, caption=DAD spectra of penciclovir，related substance 1 and related substance 7, figureFileSmall=6/NXv3RQkyebs1p1CAkasA==, figureFileBig=eo1OenPaj65dTQUAEyE5lA==, tableContent=null), ArticleFig(id=1240376127995310261, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=CN, label=图8, caption=喷昔洛韦、有关物质1、有关物质7的DAD图, figureFileSmall=6/NXv3RQkyebs1p1CAkasA==, figureFileBig=eo1OenPaj65dTQUAEyE5lA==, tableContent=null), ArticleFig(id=1240376128129527995, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=EN, label=Tab.1, caption=

Mass balance of penciclovir cream and its stressed test solutions

, figureFileSmall=null, figureFileBig=null, tableContent=
样品
(sample)		C/(mg·mL-1)有关物质峰面积
(areaimpurity)		总峰面积
(areatotal)		areatotal/C物料平衡比例
(mass balance ratio)
未破坏(non-stressed)1.086 4411 64128 701 6952.64×1071.00
高温干法破坏(dry heat stress)1.079 43 567 79730 677 8312.84×1071.08
高温湿法破坏(wet heat stress)1.125 81 850 99129 278 5102.60×1070.98
光照湿法破坏(wet photolytic stress)1.025 8509 84626 677 0342.60×1070.98
光照干法破坏(dry photolytic stress)1.006 0384 13227 346 1562.72×1071.03
氧化破坏(oxidation stress)1.123 4579 84329 188 8802.60×1070.98
碱破坏(alkaline stress)1.077 6853 82127 977 0222.60×1070.98
酸破坏(acidic stress)1.095 81 251 66529 857 7832.72×1071.03
), ArticleFig(id=1240376128196636864, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=CN, label=表1, caption=

喷昔洛韦乳膏有关物质强制降解试验样品物料平衡结果

, figureFileSmall=null, figureFileBig=null, tableContent=
样品
(sample)		C/(mg·mL-1)有关物质峰面积
(areaimpurity)		总峰面积
(areatotal)		areatotal/C物料平衡比例
(mass balance ratio)
未破坏(non-stressed)1.086 4411 64128 701 6952.64×1071.00
高温干法破坏(dry heat stress)1.079 43 567 79730 677 8312.84×1071.08
高温湿法破坏(wet heat stress)1.125 81 850 99129 278 5102.60×1070.98
光照湿法破坏(wet photolytic stress)1.025 8509 84626 677 0342.60×1070.98
光照干法破坏(dry photolytic stress)1.006 0384 13227 346 1562.72×1071.03
氧化破坏(oxidation stress)1.123 4579 84329 188 8802.60×1070.98
碱破坏(alkaline stress)1.077 6853 82127 977 0222.60×1070.98
酸破坏(acidic stress)1.095 81 251 66529 857 7832.72×1071.03
), ArticleFig(id=1240376128255357124, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=EN, label=Tab.2, caption=

Related substances identified in penciclovir cream by LC-Q-TOF/MS

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
(No.) 		母离子
(parent ion)m/z		tR/min离子式
(ion formula)		Dif碎片离子
(product ions) m/z		来源
(origin)
1270.120 65.410C10H16N5O4+3.517227.114 7，197.104 0，185.092 8，168.052 5，130.087 3，113.045 8，85.064 9Dr
2215.114 48.696C8H15N4O3+2.417197.102 1，113.046 0，85.065 1，67.055 7Dr
3344.158 210.501C13H21N5O6+4.969326.146 7，308.138 5，296.1376，242.089 6，224.078 5，206.065 6，194.067 6，178.074 5Dr
4344.155 911.892C13H21N5O6+-1.685326.145 4，296.135 5，242.089 6，224.088 5，194.069 1，178.073 8Dr
5312.131 613.288C12H18N5O5+4.389294.122 3，266.127 0，254.125 9，210.062 9，192.052 5，164.057 2，152.057 7，135.030 7，85.0634Dr
6286.115 813.421C10H15N5O5+4.054223.107 5，206.104 6，165.065 2，152.057 5Dr
API254.125 915.119C10H16N5O3+4.525152.057 3，135.030 5，110.035 1，85.064 8，67.054 0API
7270.119 618.116C10H16N5O4+-0.111252.110 4，234.099 4，206.103 4，180.052 4，168.052 2，152.057 2，85.065 3Dr
8284.134 020.038C11H18N5O4+-4.575266.125 7，254.124 8，164.057 6，152.057 5，103.076 4，85.066 0Dr/Pr
9300.131 621.031C11H18N5O5+4.331282.123 5，266.129 3，238.104 6，164.055 4Dr
10312.130 321.661C12H18N5O5+-0.064294.116 8，266.121 3，210.063 2，192.052 4，164.057 0，115.055 5，85.066 1Dr
11282.120 622.520C11H16N5O4+3.226218.101 8，152.057 4，135.030 9，110.036 2Dr
12356.156 824.035C14H22N5O6+0.814310.152 1，254.089 7，236.078 6，208.083 7，190.075 0，103.075 8，85.064 6Dr
13266.124 825.822C11H16N5O3+0.263236.115 6，206.104 7，164.057 3，152.057 2，135.030 5，115.075 4，83.049 1Dr
14400.182 626.984C16H26N5O7+-0.050382.176 6，280.141 8，224.080 0，206.068 8，178.073 1，135.031 3Dr
15296.136 527.349C12H18N5O4+3.917254.129 7，204，095 9，152.057 2，135.030 0，110.033 9Pr
16400.182 427.904C16H26N5O7+-0.775382.175 2，298.114 8，280.142 4，224.081 1，206.058 6，178.0732Dr
17326.147 328.294C13H20N5O5+4.170308.135 8，280.141 2，224.078 8，206.067 9，178.072 8，85，063 5Dr
18529.229 230.054C22H29N10O6+4.894511.221 0，427.158 4，325.093 0，164.055 4Dr
19137.024 231.390C7H5O3--1.38793.034 3Exp-Dr
20561.253 931.939C23H33N10O7+1.996459.186 7，325.163 0，308.136 8，280.140 2，254.125 5，236.115 1，178.071 5，152.057 9Dr
21504.269 632.148C21H38N5O9+3.589442.232 0，310.152 3，266.125 5，248.114 5，166.072 4，83.048 6Dr
22519.242 832.887C21H31N10O6+1.021266.127 6，254.125 0，164.062 2，152.057 3Dr/Pr
23151.040 243.988C8H7O3-0.794136.016 2，92.026 3Exp
), ArticleFig(id=1240376128368603339, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372085361537451, language=CN, label=表2, caption=

喷昔洛韦乳膏有关物质的LC-Q-TOF/MS鉴定结果

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
(No.) 		母离子
(parent ion)m/z		tR/min离子式
(ion formula)		Dif碎片离子
(product ions) m/z		来源
(origin)
1270.120 65.410C10H16N5O4+3.517227.114 7，197.104 0，185.092 8，168.052 5，130.087 3，113.045 8，85.064 9Dr
2215.114 48.696C8H15N4O3+2.417197.102 1，113.046 0，85.065 1，67.055 7Dr
3344.158 210.501C13H21N5O6+4.969326.146 7，308.138 5，296.1376，242.089 6，224.078 5，206.065 6，194.067 6，178.074 5Dr
4344.155 911.892C13H21N5O6+-1.685326.145 4，296.135 5，242.089 6，224.088 5，194.069 1，178.073 8Dr
5312.131 613.288C12H18N5O5+4.389294.122 3，266.127 0，254.125 9，210.062 9，192.052 5，164.057 2，152.057 7，135.030 7，85.0634Dr
6286.115 813.421C10H15N5O5+4.054223.107 5，206.104 6，165.065 2，152.057 5Dr
API254.125 915.119C10H16N5O3+4.525152.057 3，135.030 5，110.035 1，85.064 8，67.054 0API
7270.119 618.116C10H16N5O4+-0.111252.110 4，234.099 4，206.103 4，180.052 4，168.052 2，152.057 2，85.065 3Dr
8284.134 020.038C11H18N5O4+-4.575266.125 7，254.124 8，164.057 6，152.057 5，103.076 4，85.066 0Dr/Pr
9300.131 621.031C11H18N5O5+4.331282.123 5，266.129 3，238.104 6，164.055 4Dr
10312.130 321.661C12H18N5O5+-0.064294.116 8，266.121 3，210.063 2，192.052 4，164.057 0，115.055 5，85.066 1Dr
11282.120 622.520C11H16N5O4+3.226218.101 8，152.057 4，135.030 9，110.036 2Dr
12356.156 824.035C14H22N5O6+0.814310.152 1，254.089 7，236.078 6，208.083 7，190.075 0，103.075 8，85.064 6Dr
13266.124 825.822C11H16N5O3+0.263236.115 6，206.104 7，164.057 3，152.057 2，135.030 5，115.075 4，83.049 1Dr
14400.182 626.984C16H26N5O7+-0.050382.176 6，280.141 8，224.080 0，206.068 8，178.073 1，135.031 3Dr
15296.136 527.349C12H18N5O4+3.917254.129 7，204，095 9，152.057 2，135.030 0，110.033 9Pr
16400.182 427.904C16H26N5O7+-0.775382.175 2，298.114 8，280.142 4，224.081 1，206.058 6，178.0732Dr
17326.147 328.294C13H20N5O5+4.170308.135 8，280.141 2，224.078 8，206.067 9，178.072 8，85，063 5Dr
18529.229 230.054C22H29N10O6+4.894511.221 0，427.158 4，325.093 0，164.055 4Dr
19137.024 231.390C7H5O3--1.38793.034 3Exp-Dr
20561.253 931.939C23H33N10O7+1.996459.186 7，325.163 0，308.136 8，280.140 2，254.125 5，236.115 1，178.071 5，152.057 9Dr
21504.269 632.148C21H38N5O9+3.589442.232 0，310.152 3，266.125 5，248.114 5，166.072 4，83.048 6Dr
22519.242 832.887C21H31N10O6+1.021266.127 6，254.125 0，164.062 2，152.057 3Dr/Pr
23151.040 243.988C8H7O3-0.794136.016 2，92.026 3Exp
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喷昔洛韦乳膏有关物质的二维色谱-质谱联用鉴定*
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Abbosova Zokirjonovna Diyorakhon , 王李杰 , 陆宇婷 , 宋敏 , 杭太俊 **
药物分析杂志 | 安全监测 2024,44(1): 89-100
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药物分析杂志 | 安全监测 2024, 44(1): 89-100
喷昔洛韦乳膏有关物质的二维色谱-质谱联用鉴定*
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Abbosova Zokirjonovna Diyorakhon , 王李杰, 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：
Identification of the related substances in penciclovir cream by two-dimensional LC-MS techniques*
Abbosova Zokirjonovna Diyorakhon , Li-jie WANG, Yu-ting LU, Min SONG, Tai-jun HANG**
Affiliations
  • Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
出版时间: 2024-01-31 doi: 10.16155/j.0254-1793.2024.01.09
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摘要
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目的：

基于二维高效液相色谱-四极杆-飞行时间串联质谱技术(2D-LC-Q TOF/MS)，鉴定喷昔洛韦乳膏有关物质的结构。

方法：

采用ODS(250 mm×4.6 mm，5 μm)色谱柱，以0.15%甲酸10 mmol·L-1甲酸铵缓冲溶液-乙腈为流动相，进行一维梯度洗脱，对喷昔洛韦乳膏及其依照ICH原则强制降解样品的有关物质进行分离，并分别富集各有关物质；再采用Phenomenex Luna SCX(250 mm×4.6 mm，5 μm)色谱柱，以0.1%甲酸20 mmol·L-1甲酸铵缓冲溶液-乙腈为流动相，进行二维梯度洗脱，实现各有关物质与喷昔洛韦乳膏基质的良好分离。利用电喷雾正离子化-四极杆-飞行时间串联质谱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，并解析鉴定其结构。

结果：

在所建立的2D-LC-Q TOF/MS分析条件下，喷昔洛韦与其有关物质分离良好，检测出喷昔洛韦乳膏及其强制降解样品中21个主要有关物质。根据其色谱保留行为、光谱特征、质谱特征及与其他核苷类药物已知有关物质的差异，结合合成和制剂工艺路线分析，可鉴定出它们的结构，它们均为首次被鉴定出的有关物质。

结论：

研究结果为喷昔洛韦乳膏的质量控制提供了参考依据。

喷昔洛韦  /  有关物质  /  结构鉴定  /  强制降解  /  二维高效液相色谱-四极杆-飞行时间串联质谱技术
Objective:

To identify the structures of the related substances in penciclovir cream by two-dimensional liquid chromatography quadrupole time-of-flight tandem mass spectrometry (2D-LC-Q TOF/MS) technique.

Methods:

The first-dimension separation of the related substances in penciclovir cream and its stressed samples according to ICH were carried out on an ODS (250 mm×4.6 mm, 5 μm) column with gradient elution by 0.15% formic acid 10 mmol·L-1 ammonium formate buffer solution and acetonitrile as mobile phases, and each related substance was enriched separately. The second-dimension gradient elution was performed on a Phenomenex Luna SCX (250 mm×4.6 mm, 5 μm) column with 0.1% formic acid 20 mmol·L-1 ammonium formate buffer solution and acetonitrile as mobile phases for each of the related substances to achieve good separation with the matrix of penciclovir cream. The accurate mass and elemental composition of the parent ions and their product ions of the related substances were determined by positive electrospray-ionization quadrupole time-of-flight high resolution mass spectrometry, and the structures of all the related substances were elucidated.

Results:

Under the established 2D-LC-Q TOF/MS analytical conditions, penciclovir and its related substances were adequately separated, and 21 major related substances were detected and identified in the penciclovir cream and its stressed samples. According to their chromatographic retention behavior, spectral characteristics, mass spectrometry characteristics and their differences from other known related substances of nucleoside drugs and combing with synthesis and formulation process route, their structures can be identified all of which were identified for the first time.

Conclusion:

The results can provide reference for the quality control of penciclovir cream.

penciclovir cream  /  related substances  /  structural identification  /  stressed degradation  /  2D-LC-Q TOF/MS
Abbosova Zokirjonovna Diyorakhon, 王李杰, 陆宇婷, 宋敏, 杭太俊. 喷昔洛韦乳膏有关物质的二维色谱-质谱联用鉴定*. 药物分析杂志, 2024 , 44 (1) : 89 -100 . DOI: 10.16155/j.0254-1793.2024.01.09
Abbosova Zokirjonovna Diyorakhon, Li-jie WANG, Yu-ting LU, Min SONG, Tai-jun HANG. Identification of the related substances in penciclovir cream by two-dimensional LC-MS techniques*[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (1) : 89 -100 . DOI: 10.16155/j.0254-1793.2024.01.09
正文
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喷昔洛韦(9-[4-羟基-3-(羟甲基)-丁基]-鸟嘌呤)是1990年开发上市的开环核苷类抗病毒药物。喷昔洛韦既是DNA聚合酶抑制剂[1]，又能直接参与到病毒的复制过程中，终止DNA链的合成和延长，达到抑制病毒增殖的目的。喷昔洛韦主要有抗单纯疱疹病毒、带状疱疹病毒和EB病毒的作用，并对耐药阿昔洛韦的病毒有效[2]。喷昔洛韦胃肠道吸收较差，口服生物利用度仅为5%~10%，主要以软膏剂用于娇嫩皮肤的疱疹治疗[3]。
喷昔洛韦原料药及其制剂暂未有药典收载，已有文献仅报道了喷昔洛韦的有关物质检查方法[4-5]，但喷昔洛韦乳膏杂质谱的全面研究尚未见报道。在乳膏制剂样品有关物质的质谱测定时，需要排除基质的干扰，既可通过溶剂提取、冷冻滤除或固相萃取等前处理方式[6-7]，也可通过二维液相色谱法排除基质的干扰[8-9]。
本研究建立了适用于喷昔洛韦有关物质检查的2D-LC-Q TOF/MS分析方法，实现有关物质与乳膏基质的良好分离，并测定了喷昔洛韦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[10-11]与反应机理，经综合解析，鉴定了各有关物质的结构，可为喷昔洛韦乳膏的质量控制提供参考。
1 材料
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1.1 试药与试剂
喷昔洛韦乳膏(重庆华邦制药有限公司，批号011210030，规格1%)。甲酸铵、甲酸、盐酸、氢氧化钠(AR级，南京化学试剂有限公司)，乙腈(HPLC级，MERCK公司)，去离子水(市售，娃哈哈纯净水)，过氧化氢(AR级，南京化学试剂有限公司)，碘化钠(HPLC级，萨恩化学技术有限公司)。
1.2 仪器
LC-30AD高效液相色谱仪(配SPD-M30A检测器)-岛津LCMS-9030四极杆飞行时间质谱仪、Lab-Solutions数据处理系统(岛津公司)、LC-10AT高效液相色谱仪(配SPD-10A检测器)(岛津公司)；BS21S十万分之一电子分析天平(Sartorius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)；PL-ELS 2100 蒸发光散射检测器(聚合物实验室)。
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(约相当于喷昔洛韦10 mg)，精密称定，置10 mL量瓶中，加水约5 mL，超声使溶解，加水定量稀释制成每1 mL中约含1 mg的溶液，取出后放置至室温，5 000 r·min-1离心10 min，取下层澄清液体，滤过，取续滤液，即得。
2.1.2 对照溶液
精密量取供试品溶液适量，用水定量稀释制成每1 mL中约含1 μg的溶液，即得。
2.1.3 强制降解试验溶液
精密称取本品适量(约相当于喷昔洛韦10 mg)，加4.0 mol·L-1盐酸1 mL并于40 ℃水浴放置10 d；或加4 mol·L-1氢氧化钠溶液1 mL并于40 ℃水浴放置1 d；或加30%过氧化氢溶液1 mL并于40 ℃水浴放置1 d；或于120 ℃烘箱中放置1 d；或加水1 mL并于90 ℃水浴放置8 d；或加水1 mL并于4 500 lx光照放置10 d；或4 500 lx光照放置10 d。分别加水5 mL (酸处理溶液需先加4.0 mol·L-1氢氧化钠1 mL、碱处理溶液需先加4.0 mol·L-1盐酸1 mL中和，放冷)，超声使溶解，再加水稀释至10 mL，摇匀，置于-80 ℃中冷冻2 h。取出后放置至室温，5 000 r·min-1离心10 min，取下层澄清液体，滤过，取续滤液，即得采用不同方法制备的强制降解试验溶液。同法配制空白溶液。
2.2 色谱-质谱条件
2.2.1 一维色谱条件
采用十八烷基硅烷键合硅胶Shim-pack Scepter C18-120(250 mm×4.6 mm，5 μm)为填充剂的色谱柱；以0.15%甲酸10 mmol·L-1甲酸铵缓冲溶液-乙腈(99∶1)为流动相A，以0.15%甲酸10 mmol·L-1甲酸铵缓冲溶液-乙腈(50∶50)为流动相B，进行线性梯度洗脱(A-B)：0 min (100∶0)→25 min(80∶20)→50 min(0∶100)→55 min (0∶100)→56 min(100∶0)→65 min(100∶0)；流速1.0 mL·min-1；柱温25 ℃；检测波长254 nm；进样体积10 μL。
2.2.2 二维色谱条件
采用阳离子交换键合硅胶Phenomenex Luna SCX(250 mm×4.6 mm，5 μm)为填充剂的色谱柱；以0.1%甲酸20 mmol·L-1甲酸铵缓冲溶液为流动相A，以乙腈为流动相B，进行线性梯度洗脱(A-B)：0 min(95∶5)→5 min(80∶20)→10 min(80∶20)→10.1 min(95∶5)→15 min(95∶5)；流速1.5 mL·min-1；柱温25 ℃；紫外检测器检测波长254 nm；蒸发光散射检测器检测参数为雾化器温度90 ℃，漂移管温度90℃，氮气流速1.00 L·min-1；进样体积10 μL。
2.2.3 质谱条件
化合物19、23采用大气压化学电离源负离子模式。其余有关物质均采用电喷雾离子源正离子模式。质谱参数：采用碘化钠溶液(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，脱溶剂离子传输管温度300 ℃，氩气CID能量5~35 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
取强制降解试验溶液，按“2.2.1”项一维色谱条件进样检测。结果表明，建立的一维液相色谱分析法，适用于喷昔洛韦乳膏有关物质液相色谱检查。采用0.1%自身对照法计算有关物质的含量，按保留时间由短到长顺序对主要有关物质进行识别和编号(图1)。
强制降解试验结果表明，喷昔洛韦乳膏对高温条件比较敏感，全部降解条件下共分离并检出除主成分外的23个化合物，其中21个为喷昔洛韦有关物质(相对含量均超过0.1%)，化合物19、23为辅料及辅料降解杂质。喷昔洛韦乳膏中检出3个有关物质(图1-b，有关物质8、15、22)；酸破坏形成2个主要降解产物(图1-i，有关物质13、22)；氧化破坏形成4个主要降解产物（图1-g，有关物质1、2、6、9)；高温干法破坏形成12个主要降解产物(图1-c，有关物质3、4、6、7、10、11、14、16、18、20、21、22)；高温湿法破坏形成6个主要降解产物(图1-d，有关物质5、7、10、12、17、18)。研究建立的有关物质检查条件对于不同强制降解试验样品有关物质的检测均物料平衡(表1)。
3.2 二维液相色谱条件的建立
采用一维色谱分析方法对样品直接进行质谱测定。结果发现总离子流图中有响应很大的相对分子质量相差44的乳膏基质聚乙二醇簇峰，干扰有关物质检测(图2)。故利用乳膏基质与喷昔洛韦及其有关物质在阳离子交换色谱柱上保留行为的差异，进行二维液相色谱分离，排除基质对样品中有关物质质谱测定的干扰。
因乳膏基质无紫外吸收，故在二维液相色谱方法摸索时，取供试品溶液，采用高效液相色谱(配SPD-10A检测器)串联蒸发光散射检测器(ELSD)确定乳膏基质、喷昔洛韦及其有关物质的出峰位置。最终确定了如“2.2.2”所示的二维液相色谱条件，保证基质与各有关物质分离良好(图3)。
按“2.2.1”项下色谱条件，每次进样100 μL，分别收集23个馏分，重复3次，将收集的溶液冻干，再用0.1%甲酸20 mmol·L-1甲酸铵-乙腈(95∶5)100 μL复溶，即分别得到喷昔洛韦各有关物质溶液。并按“2.2.2”所述色谱条件进行分析。各有关物质在二维液相色谱中保留时间适宜，与基质分离良好(图4)。
3.3 有关物质的结构鉴定
按“2.2.2”所述色谱条件，采用高效液相色谱(配SPD-M30A检测器)串联高分辨质谱仪Q-TOF测定富集得到的各有关物质溶液，可得到各有关物质的母离子及子离子的准确质量和元素组成、其二级质谱特征碎片以及DAD图，并通过与喷昔洛韦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5、6及表2。
3.3.1 鸟嘌呤核苷类药物已知有关物质的结构鉴定
目前，各国药典暂未收录喷昔洛韦的有关物质，但可参考相关文献[12-13]，根据喷昔洛韦和其他含鸟嘌呤结构化合物的质谱裂解特征(图7)，对喷昔洛韦有关物质的结构进行分析鉴定。鸟嘌呤核苷类药物的MS/MS裂解具有如下规律：(1)鸟嘌呤核苷类药物的支链易断裂，生成特征碎片离子m/z 152.05(C5H6N5O+)，其为鸟嘌呤[M+H]+离子的准确离子质量，表明这些有关物质均含有鸟嘌呤结构；(2)m/z 152.05又可裂解为m/z 135.03(C5H3N4O+)、m/z 110.03 (C4H4N3O+)的碎片离子，分别与鸟嘌呤[M+H]+离子脱去NH3和碳二亚胺相应。
3.3.2 未知有关物质的确证
聚乙二醇是乳膏制剂中常用的辅料之一，可降解为甲醛、甲酸[14]和多种过氧化物[15]，这些辅料降解产物可进一步参与喷昔洛韦的降解反应，产生新的有关物质，在有关物质解析时应加以考虑。
根据各有关物质的色谱保留特征、光谱特征、质谱特征及其与喷昔洛韦、阿昔洛韦、鸟嘌呤的差异，结合合成和制剂工艺路线分析，可鉴定其结构，并根据有关物质来源，进行归类分析。
3.3.2.1 氧化破坏产生的降解杂质
有关物质1是喷昔洛韦的特征氧化降解杂质；有关物质7是喷昔洛韦的高温干法、高温湿法、氧化降解杂质。测得其[M+H]+的准确离子质量分别为270.120 6、270.119 6，与离子式C10H16N5O4+相应；与喷昔洛韦元素组成相比，是多1个O元素的同分异构体。有关物质6也是喷昔洛韦的特征氧化降解杂质，测得其[M+H]+的准确离子质量为286.116 3，与离子式C10H16N5O5+相应。有关物质1的二级质谱碎片离子m/z 227.114 7 (C9H15N4O3+)与[M+H]+脱去异氰酸相应；m/z 168.052 5 (C5H6N5O2+)与[M+H]+中性丢失侧链和1分子H2O相应。由DAD图(图8)可知，有关物质1的共轭结构与喷昔洛韦相差较大，即母核结构发生了改变。有关物质1的色谱保留极弱，极性很大。根据喷昔洛韦的结构特点，其C-4、C-5受双键共轭作用影响[16]，在过氧化氢和甲酸的存在下，易生成双羟化加成产物。故推测有关物质1应为喷昔洛韦侧链脱去1分子H2O，C-4、C-5被羟基化而形成的有关物质。有关物质7的二级质谱碎片离子m/z 252.110 4(C10H14N5O3+)、m/z 234.099 4(C10H12N5O2+)与[M+H]+连续失去1分子H2O相应。DAD图表明，有关物质7在292 nm有一吸收峰，由于嘌呤的富电子特性，羟基自由基会攻击活性较高的8位，此位点易氧化，故推测有关物质7应为喷昔洛韦8位氧化成酮（即共轭羟基亚胺）得到的有关物质。有关物质6与有关物质7相比，多1个O原子，且极性更大，推测有关物质6是在氧化条件下，喷昔洛韦8位氧化成酮，3位叔胺形成氮氧化物得到的有关物质。
有关物质2为喷昔洛韦的氧化降解杂质。测得其[M+H]+的准确离子质量为215.114 4，与离子式C8H15N4O3+相应；与喷昔洛韦元素组成相比，少C2HN。有关物质2的DAD图与喷昔洛韦相差较大，共轭结构发生显著改变。碎片离子中无m/z 152.05 (C5H6N5O+)，说明有关物质2的结构不含鸟嘌呤母核。碎片离子m/z 197.102 1(C8H13N4O2+)与[M+H]+丢失1分子H2O相应。碎片离子m/z 113.040 6(C3H5N4O+)与有关物质1的碎片离子m/z 113.045 8 (C3H5N4O+)元素组成相同，二级质谱图中含有碎片m/z 85.065 1 (C5H9O+)均证明此有关物质结构中仍保留喷昔洛韦侧链。故推测在强氧化条件下，喷昔洛韦3位发生氮氧化，嘧啶环脱去CO，咪唑环丢失1分子HCN变成三元环，最终生成有关物质2(图6)。
3.3.2.2 7/9位同分异构体杂质
有关物质3、4、14、16为喷昔洛韦的特征高温干法降解杂质。测得有关物质3和4的[M+H]+的离子准确质量分别为344.158 2、344.155 9，是与离子式C13H22N5O6+相应的同分异构体。测得有关物质14和16的[M+H]+的离子准确质量为400.182 6、400.182 4，是与离子式C16H26N5O7+相应的同分异构体。有关物质3和4、有关物质14和16这2对同分异构体的二级质谱图、DAD图均分别两两相似，保留时间也接近，推测其共轭结构也两两相似。由文献可知[17]，对于鸟嘌呤核苷类药物，当化合物母核相同、侧链相同时，鸟嘌呤7位氮连接侧链，化合物的极性强于9位侧链连接。故推测喷昔洛韦有关物质3和4、有关物质14和16均含有鸟嘌呤母核，但侧链取代位置不同(7位或9位)的同分异构体，根据其碎片特征推定相应结构式（图6）。以有关物质16为例进行结构解析。其MS/MS的碎片离子m/z 298.115 3(C11H16N5O5+)、m/z 280.141 8 (C11H14N5O4+)与[M+H]+中性丢失侧链2-乙烯基丙烷-1，3-二醇、进一步脱去1分子H2O相应。碎片离子m/z 224.080 0 (C8H10N5O3+)、m/z 206.068 8 (C8H8N5O2+)别是在m/z 298.115 3的基础上脱去乙醇和CO、再进一步脱去1分子H2O。观察喷昔洛韦及其有关物质可知，其二级质谱碎片中大都不含m/z 178.073 1 (C7H8N5O+)，可知喷昔洛韦侧链碳碳键不易断裂，故推测有关物质16二级质谱碎片中的该碎片是氨基所连支链的碳氧键断裂所得。故推测喷昔洛韦原有侧链连接在7位或9位，断裂后的支链之间发生反应或断裂后的支链与聚乙二醇降解产物反应，生成新的支链，氨基端与新支链连接，生成同分异构体：有关物质14和16。
3.3.2.3 侧链变化产生的杂质
有关物质5和10主要为喷昔洛韦的高温湿法降解杂质。测得其[M+H]+准确离子质量分别为312.131 6、312.130 3，是与离子式C12H18N5O5+相应的同分异构体；且与喷昔洛韦元素组成相比，多C2H2O2。有关物质5的碎片离子m/z 254.125 9 (C10H16N5O3+)与[M+H]+脱去甲醛和CO相应。有关物质5、10共同的MS/MS主要特征碎片离子m/z 266.127 0 (C11H16N5O3+)与[M+H]+脱去H2O和CO相应；碎片离子m/z 210.062 9 (C7H8N5O3+)、m/z 192.057 2 (C7H6N5O2+)与[M+H]+脱去2-乙烯基丙烷-1，3-二醇、进一步脱去1分子H2O相应。二者都存在碎片离子m/z 85.06，推测它们仍保留喷昔洛韦原侧链结构。虽然有关物质10和5的碎片离子相似，但二者的色谱保留时间相差约7 min，表明二者极性有明显差异。故推测有关物质10和5不是7/9位同分异构体，而是氨基所连侧链不同的异构体。根据二者元素组成与极性大小，推测有关物质5为喷昔洛韦2位氨基连接乙酸形成的有关物质(图6)；有关物质10为喷昔洛韦2位氨基与聚乙二醇降解产物羟基乙酸反应形成的酰胺有关物质(图6)。
有关物质12、17为喷昔洛韦高温湿法降解杂质，有关物质21为喷昔洛韦的高温干法降解杂质。根据三者的元素组成及二级质谱特征碎片，推测三者均是以鸟嘌呤为母核，但2位氨基连接不同支链的有关物质（图6）。以有关物质21为例，其MS/MS主要特征碎片离子m/z 442.232 0(C19H32N5O7+)、m/z 310.152 3(C13H20N5O4+)、m/z 266.125 4 (C11H16N5O3+)，均为其[M+H]+离子所连乙二醇长链在不同位置断裂产生。碎片离子m/z 266.125 4的元素组成表明有关物质21仍保留喷昔洛韦的基本结构，进一步脱去1分子H2O生成m/z 248.114 5（C11H14N5O2+）。碎片离子m/z 208.085 9表明乙二醇长链与氨基相连，否则无法形成此碎片离子。故推测有关物质21为喷昔洛韦2位氨基连接乙二醇长链而形成的有关物质。
3.3.2.4 与甲醛反应得到的杂质
由喷昔洛韦的合成工艺可知，在合成过程中可能有多聚甲醛参与反应。有关物质8、9、11、13分别是为喷昔洛韦的工艺杂质、氧化降解杂质、高温干法降解杂质、特征酸降解杂质。根据各个有关物质的元素组成、保留时间、二级质谱特征碎片，可推测有关物质8、9、11、13的结构如图6所示。以有关物质13为例进行说明，其MS/MS主要特征碎片离子m/z 115.075 5 (C6H11O2+)与[M+H]+中性丢失鸟嘌呤相应，提示有关物质13由鸟嘌呤和准确离子质量为115.075 5的支链构成，同时也可推出多余的1个C原子连接在侧链上。碎片离子m/z 236.115 6 (C10H14N5O2+)、m/z 206.104 7 (C9H12N5O+)与[M+H]+接连丢失1分子甲醛相应；碎片离子m/z 152.056 3 (C5H6N5O+)是由母核与侧链之间的C-N键断裂而形成。碎片离子m/z 206.104 7 (C9H12N5O+)含碳原子数比鸟嘌呤多4，可以由此推测侧链氧原子的位置。二级质谱图中丰度最高的碎片离子m/z 83.049 1 (C5H7O+)由m/z 115.075 5 (C6H11O2+)中性丢失1分子甲醇得到。又因有关物质13极性较小，推测在酸性条件下，甲醛与喷昔洛韦侧链两羟基反应成环得到的有关物质13。
3.3.2.5 单乙酰化喷昔洛韦
有关物质15为喷昔洛韦乳膏的工艺杂质。测得其[M+H]+离子的准确质量为296.136 5，与离子式C12H18N5O4+相应；与喷昔洛韦元素组成相比，多C2H2O。MS/MS主要特征碎片离子m/z 254.129 7 (C10H16N5O3+)与[M+H]+脱去乙烯酮相应，存在此碎片离子也表明其结构中可能保留喷昔洛韦母核结构。由喷昔洛韦的合成路线可知，侧链先乙酰化再与2-氨基-6-氯鸟嘌呤反应，产物再经过酸水解最终得到喷昔洛韦，若水解反应不完全，则易产生有关物质15。观察强制降解试验结果可知，有关物质15在强酸、强碱条件下，发生降解而含量下降，但其余条件均较稳定，也与该酯键在酸、碱条件下易水解特征相应(图6)。
3.3.2.6 二聚体杂质
有关物质18、20、22分别为喷昔洛韦的工艺杂质和多种条件下的降解杂质。根据元素组成、质谱特征可知，有关物质18、20、22均含有2个鸟嘌呤母核，并根据剩余的碳原子与氧原子数以及极性大小的不同，可推测有关物质18、20、22的结构为喷昔洛韦经不同程度甲醛缩合的产物（图6）。以有关物质22为例，对二聚体杂质进行结构解析。有关物质22的MS/MS主要特征碎片离子m/z 152.057 0 (C5H6N5O+)与鸟嘌呤[M+H]+相应；碎片离子m/z 254.125 0 (C10H16N5O3+)证明此有关物质保留喷昔洛韦母核结构，m/z 266.127 6 (C11H16N5O3+)与[M+H]+脱去1分子喷昔洛韦相应。又因有关物质22极性较弱、保留较强，故推测1分子喷昔洛韦与甲醛发生反应生成席夫碱(亚胺中间体)，另1分子喷昔洛韦再亲核进攻此亚胺中间体而形成有关物质22[18]。
3.3.2.7 辅料及其降解杂质
化合物19是酸、碱破坏条件下产生的杂质，同时酸碱破坏条件下化合物23不存在，其余条件下化合物23均存在，且化合物19、23含量均较大，故推测是化合物19是由化合物23降解得到。
采用电喷雾离子源正离子模式测定化合物19、23，发现无质谱信号，又因它们的DAD图与喷昔洛韦相差较大，且化合物23在样品中的含量较高，故怀疑其是具有紫外吸收的乳膏辅料。化合物23的保留较强，极性较弱，故换用APCI源正/负离子模式测定。结果显示，化合物19、23在APCI负离子模式有响应。
测得化合物23[M-H]-离子的准确质量为151.040 2，与离子式C8H7O3-相应。MS/MS主要特征碎片离子136.016 2 (C7H4O3·-)、92.026 3 (C6H4O·-)与[M-H]-脱去甲基自由基并进一步脱去CO2相应。测得化合物19[M-H]-的准确离子质量为137.024 2，与离子式C7H5O3-相应。MS/MS主要特征碎片离子93.034 3 (C6H5O-)与[M-H]-脱去CO2相应。化合物19、23的DAD图可知，它们分别在254、255 nm处有最大吸收。故推测化合物23为辅料对羟基苯甲酸甲酯、化合物19为辅料降解产物对羟基苯甲酸(图6)。
4 讨论
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在建立的2D-LC-Q TOF/MS条件下，喷昔洛韦与各有关物质均得到有效的分离，共检测到23个化合物，经鉴定，21个有关物质均为本文首次鉴定的未知有关物质，其余2个为辅料和辅料降解杂质。根据喷昔洛韦及其有关物质的结构和相关裂解途径，总结了喷昔洛韦的有关物质来源。
在合成过程中，甲醛与喷昔洛韦反应生成有关物质8；有关物质15为合成过程中生成的单乙酰化喷昔洛韦；甲醛参与反应，2个分子喷昔洛韦易发生聚合，生成有关物质22。在氧化条件下，鸟嘌呤C-4、C-5位被羟基化得到有关物质1；鸟嘌呤3位发生氮氧化同时嘧啶环丢失CO、咪唑环丢失HCN得到有关物质2；喷昔洛韦8位氧化成酮，形成有关物质7，在此基础上，喷昔洛韦3位叔胺发生氮氧化，则形成有关物质6；喷昔洛韦3位氮氧化，且侧链与甲醛反应形成有关物质9。在酸性条件下，甲醛与喷昔洛韦侧链两羟基反应成环得到有关物质13。在高温干法条件下，3位叔胺发生氮氧化反应，氨基与断裂的支链碎片连接，喷昔洛韦原有侧链连接在7位或9位，得到同分异构体：有关物质3和4；氨基与聚乙二醇降解产物羟基乙酸反应生成酰胺，得到有关物质10；喷昔洛韦侧链末端与醛基相连，形成有关物质11；氨基与断裂后的支链连接，喷昔洛韦原有侧链连接在7位或9位，得到同分异构体：有关物质14和16；有关物质13与喷昔洛韦通过次甲基连接生成有关物质18；有关物质22与乙醛反应生成有关物质20；喷昔洛韦与乙二醇链反应生成有关物质21。在高温湿法条件下，氨基与聚乙二醇的降解产物乙酸反应生成有关物质5；喷昔洛韦侧链末端的1个羟基被氧化成羧基，与喷昔洛韦的氨基相连生成有关物质12；氨基与甲酸乙酯相连生成有关物质17。化合物23为添加的防腐剂对羟基苯甲酸甲酯，在酸、碱条件下化合物23降解为化合物19对羟基苯甲酸。本研究的结果表明，喷昔洛韦乳膏在高温下易和辅料聚乙二醇反应，在生产以及储存时应加以注意。
基金
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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(NMPA-KLIPCD-2020-03)
文献
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doi: 10.16155/j.0254-1793.2024.01.09
  • 接收时间：2023-05-11
  • 首发时间：2026-03-16
  • 出版时间：2024-01-31
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  • 收稿日期：2023-05-11
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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(NMPA-KLIPCD-2020-03)
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    中国药科大学药物分析系，南京 210009

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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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