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Article(id=1239973081536582025, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239973077845603299, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2024-0130, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1709136000000, receivedDateStr=2024-02-29, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773562220224, onlineDateStr=2026-03-15, pubDate=1730304000000, pubDateStr=2024-10-31, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773562220224, onlineIssueDateStr=2026-03-15, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773562220224, creator=13701087609, updateTime=1773562220224, updator=13701087609, issue=Issue{id=1239973077845603299, tenantId=1146029695717560320, journalId=1205117023404326918, year='2024', volume='44', issue='10', pageStart='1647', pageEnd='1826', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773562219344, creator=13701087609, updateTime=1773563041495, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239976526251356920, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239973077845603299, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239976526251356921, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239973077845603299, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1807, endPage=1815, ext={EN=ArticleExt(id=1239973082492883343, articleId=1239973081536582025, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Molecular weight distribution and n value of nonoxynol were determined by ultra-high performance liquid chromatography with tandem quadrupole time-of-flight mass spectrometry*, columnId=1206272758774821315, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Standard Deliberation, runingTitle=null, highlight=null, articleAbstract=
Objective:

To develop an ultra-high performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q TOF MS) approach to investigate the molecular weight distribution and n value of nonoxynol oligomers，and to study several batches of samples produced domestically or abroad.

Methods:

The mobile phase was 0.1% trifluoroacetic acid aqueous solution(A)-0.1% trifluoroacetic acid in acetonitrile(B) with linear gradient elution at a flow rate of 0.3 mL·min-1. The column was Techmate STV SUNSHELL Peptide C18 (100 mm×2.1 mm，2.6 μm，300 Å) and installed in a 60 ℃ column oven. Injection volume was 5 μL. A tandem quadrupole time-of-flight mass spectrometer with Dual ESI as ion source and argon as collision gas were used for detection in positive ion mode with a collection range of m/z 50-3 000. ChemDraw 19.0 software was used to draw the relevant structure，and MassHunter PCDL Manager software was used to build the database and edit the calculation formula.

Results:

The weight average molecular weight and number average molecular weight of 6 batches nonoxynol drug substance produced domestically or abroad were determined by the newly established method，and the range of n average value in the structure was obtained. The results showed that the weight average molecular weight and number average molecular weight were different between domestic and foreign products and also between different batches produced by same manufacturer. The n value of structure basis also varies. The weight average molecular weight ranges were 664.6 to 686.8 (n value was about 10)，and number average molecular weight ranges were 677.1 to 715.5 (n value was about 11).

Conclusion:

The molecular weight distribution and n value of such oligomer drugs need to be controlled in the production process and quality specifications. The newly established method has high sensitivity，precision and reproducibility，can be qualified for the needs of determining molecular weight distribution and n value of nonoxynol，and provides insight in determination of molecular weight distribution of such oligomers. This study also provides a data supplement for the improvement and revision of the standards of Chinese Pharmacopoeia.

, correspAuthors=Cheng-gang LIANG, 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=Wei ZHANG, Hui ZHANG, Zhi-guo HAN, Ming-hui SUN, Cheng-gang LIANG), CN=ArticleExt(id=1239973084669727216, articleId=1239973081536582025, tenantId=1146029695717560320, journalId=1205117023404326918, language=CN, title=超高效液相色谱-串联四极杆飞行时间质谱法测定壬苯醇醚分子量分布及n值*, columnId=1206272758971953622, journalTitle=药物分析杂志, columnName=标准研讨, runingTitle=null, highlight=null, articleAbstract=
目的：

研究并建立超高效液相色谱-串联四极杆飞行时间质谱法测定壬苯醇醚低聚物的分子量分布及n值，并用国内外多批次壬苯醇醚样品进行考察。

方法：

采用Techmate STV SUNSHELL Peptide C18 (100 mm×2.1 mm，2.6 μm，300 Å)色谱柱，以0.1%三氟乙酸水溶液(A)-0.1%三氟乙酸乙腈溶液(B)为流动相，线性梯度洗脱，流速0.3 mL·min-1，柱温60 ℃，进样量5 μL。采用串联四极杆飞行时间质谱检测器，离子源为Dual ESI，氩气为碰撞气，以正离子模式，采集范围m/z 50~3 000进行检测。采用ChemDraw19.0软件绘制相关结构，通过MassHunter PCDL Manager软件建立数据库，并编辑计算公式。

结果：

用新建立的方法对国内外生产的6批壬苯醇醚原料药的重均分子量及数均分子量进行了测定，并计算得到结构中n值的范围，结果发现国内外产品之间以及同一企业不同批次产品之间的重均分子量及数均分子量均有一定差异；产品结构中的n值也各不相同。数均分子量范围在664.6~686.8(n值约为10)；重均分子量范围在677.1~715.5(n值约为11)。

结论：

此类低聚物药物的分子量分布及n值亟需在生产过程及质量标准中增加控制；新建立的方法灵敏度高，精密度和重现性好，可以满足测定壬苯醇醚原料药的分子量分布及n值的需要，为此类低聚物分子量分布的测定提供了解决方案，同时为《中华人民共和国药典》标准提高及修订提供了依据。

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Tel：（010）53851619；E-mail：

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ArticleFig(id=1239977438344704065, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=CN, label=图4, caption=壬苯醇醚（批号100112-201603）UPLC-Q TOF MS图

A.一级质谱图(MS)　B.总离子流图(TIC)

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A.PEG 1000(PEG 1000)　B.壬苯醇醚(nonoxynol，batch No. 190801)

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A.PEG Mn　B. PEG MW

, figureFileSmall=5TJv+P/0pX8KmKGHoINg4w==, figureFileBig=zac0ouEwWjEa5MumMe3RFQ==, tableContent=null), ArticleFig(id=1239977438973849706, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=EN, label=Tab.1, caption=

MWD test results of PEG 600

, figureFileSmall=null, figureFileBig=null, tableContent=
名称
（name）		分子式
（molecular formula）		相对保留时间
（relative retention time）		相对分子质量
（relative molecular mass）		m/z偏差
（deviation）/×10-6		离子强度
（ion strength）
PEG(6)C12H26O73.951282.167 4305.157 9-1.72265 076
PEG(7)C14H30O84.133326.191 4327.200 5-8.131 031 691
PEG(8)C16H34O94.266370.218 9388.253 5-3.792 793 332
PEG(9)C18H38O104.365414.244 5432.279 6-4.735 900 306
PEG(10)C20H42O114.448458.270 1476.306 7-5.78 381 981
PEG(11)C22H46O124.531502.295 1503.305 7-7.579 140 633
PEG(12)C24H50O134.597546.320 5569.314 2-8.5413 520 815
PEG(13)C26H54O144.647590.347 4591.357 8-6.6812 948 868
PEG(14)C28H58O154.713634.373 3652.408 1-6.7510 620 204
PEG(15)C30H62O164.763678.399 6701.392 2-6.138 000 700
PEG(16)C32H66O174.813722.426 1740.462-5.345 693 092
PEG(17)C34H70O184.846766.452 6784.485 4-4.742 649 212
PEG(18)C36H74O194.895810.479 2828.514 5-4.011 397 847
PEG(19)C38H78O204.945854.502 3855.508 6-7.38644 256
PEG(20)C40H82O214.978898.529 3916.561 6-6.16282 195
PEG(21)C42H86O225.011942.558965.549 8-3.21103 608
PEG(22)C44H90O235.045986.581 51 004.613 3-5.8742 453
), ArticleFig(id=1239977439095484529, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=CN, label=表1, caption=

PEG 600分子量分布测定结果

, figureFileSmall=null, figureFileBig=null, tableContent=
名称
（name）		分子式
（molecular formula）		相对保留时间
（relative retention time）		相对分子质量
（relative molecular mass）		m/z偏差
（deviation）/×10-6		离子强度
（ion strength）
PEG(6)C12H26O73.951282.167 4305.157 9-1.72265 076
PEG(7)C14H30O84.133326.191 4327.200 5-8.131 031 691
PEG(8)C16H34O94.266370.218 9388.253 5-3.792 793 332
PEG(9)C18H38O104.365414.244 5432.279 6-4.735 900 306
PEG(10)C20H42O114.448458.270 1476.306 7-5.78 381 981
PEG(11)C22H46O124.531502.295 1503.305 7-7.579 140 633
PEG(12)C24H50O134.597546.320 5569.314 2-8.5413 520 815
PEG(13)C26H54O144.647590.347 4591.357 8-6.6812 948 868
PEG(14)C28H58O154.713634.373 3652.408 1-6.7510 620 204
PEG(15)C30H62O164.763678.399 6701.392 2-6.138 000 700
PEG(16)C32H66O174.813722.426 1740.462-5.345 693 092
PEG(17)C34H70O184.846766.452 6784.485 4-4.742 649 212
PEG(18)C36H74O194.895810.479 2828.514 5-4.011 397 847
PEG(19)C38H78O204.945854.502 3855.508 6-7.38644 256
PEG(20)C40H82O214.978898.529 3916.561 6-6.16282 195
PEG(21)C42H86O225.011942.558965.549 8-3.21103 608
PEG(22)C44H90O235.045986.581 51 004.613 3-5.8742 453
), ArticleFig(id=1239977439175176305, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=EN, label=Tab.2, caption=

MWD calculated results of PEG

, figureFileSmall=null, figureFileBig=null, tableContent=
名称（name）Mn测定值（measured Mn）Mn报告值（COA Mn）Mw测定值（measured Mw）Mw报告值（COA Mw）
PEG 400403.4397409.1434
PEG 600572.3560594.4601
PEG 10001 030.59761 061.21 010
PEG 15001 503.61 4801 522.81 530
PEG 20002 009.02 0502 057.12 110
), ArticleFig(id=1239977439250673784, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=CN, label=表2, caption=

PEG分子量分布计算结果

, figureFileSmall=null, figureFileBig=null, tableContent=
名称（name）Mn测定值（measured Mn）Mn报告值（COA Mn）Mw测定值（measured Mw）Mw报告值（COA Mw）
PEG 400403.4397409.1434
PEG 600572.3560594.4601
PEG 10001 030.59761 061.21 010
PEG 15001 503.61 4801 522.81 530
PEG 20002 009.02 0502 057.12 110
), ArticleFig(id=1239977439330365564, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=EN, label=Tab.3, caption=

MWD and n value Results of nonoxynol

, figureFileSmall=null, figureFileBig=null, tableContent=
批号（batch No.）Mn测定值（measured Mn）n值（n value）Mw测定值（measured Mw）n值（n value）
100112-201603672.610.3715.211.2
R06910670.410.2703.811.0
1.0664.610.1677.110.4
190801668.210.2704.111.0
190905686.810.6715.511.3
191101680.210.5713.911.2
), ArticleFig(id=1239977439426834561, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=CN, label=表3, caption=

壬苯醇醚分子量分布及n值计算结果

, figureFileSmall=null, figureFileBig=null, tableContent=
批号（batch No.）Mn测定值（measured Mn）n值（n value）Mw测定值（measured Mw）n值（n value）
100112-201603672.610.3715.211.2
R06910670.410.2703.811.0
1.0664.610.1677.110.4
190801668.210.2704.111.0
190905686.810.6715.511.3
191101680.210.5713.911.2
), ArticleFig(id=1239977439514914949, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=EN, label=Tab.4, caption=

MWD results of PEG

, figureFileSmall=null, figureFileBig=null, tableContent=
名称（name）Mn测定值（measured Mn）Mn报告值（COA Mn）Mw测定值（measured Mw）Mw报告值（COA Mw）
PEG 300427.92269439.88330
PEG 400481.82397504.04434
PEG 600669.85560698.39601
PEG 10001 009.289761 047.241 010
PEG 15001 485.561 4801 529.811 530
PEG 20001 748.022 0501 841.852 110
), ArticleFig(id=1239977439615578252, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=CN, label=表4, caption=

PEG分子量分布计算结果

, figureFileSmall=null, figureFileBig=null, tableContent=
名称（name）Mn测定值（measured Mn）Mn报告值（COA Mn）Mw测定值（measured Mw）Mw报告值（COA Mw）
PEG 300427.92269439.88330
PEG 400481.82397504.04434
PEG 600669.85560698.39601
PEG 10001 009.289761 047.241 010
PEG 15001 485.561 4801 529.811 530
PEG 20001 748.022 0501 841.852 110
), ArticleFig(id=1239977439728824462, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=EN, label=Tab.5, caption=

NWD results of nonoxynol

, figureFileSmall=null, figureFileBig=null, tableContent=
批号（batch No.）Mn测定值（measured Mn）n值（n value）Mw测定值（measured Mw）n值（n value）
100112-201603698.6010.9728.5111.5
R06910690.8410.7714.9511.2
1.0732.2911.6764.4012.4
190801699.2310.9733.1611.7
190905674.8010.3701.5510.9
191101677.0010.4704.9211.0
), ArticleFig(id=1239977439804321939, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=CN, label=表5, caption=

壬苯醇醚分子量分布计算结果

, figureFileSmall=null, figureFileBig=null, tableContent=
批号（batch No.）Mn测定值（measured Mn）n值（n value）Mw测定值（measured Mw）n值（n value）
100112-201603698.6010.9728.5111.5
R06910690.8410.7714.9511.2
1.0732.2911.6764.4012.4
190801699.2310.9733.1611.7
190905674.8010.3701.5510.9
191101677.0010.4704.9211.0
), ArticleFig(id=1239977439863042200, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=EN, label=Tab.6, caption=

Comparison of the results of determination of n value of nonoxynol by different methods

, figureFileSmall=null, figureFileBig=null, tableContent=
批号
（batch No）		n值（n value）
MALDI-TOF MSUPLC-TOF MS
MnMwMnMw
100112-20160310.911.510.311.2
R0691010.711.210.211.0
1.011.612.410.110.4
19080110.911.710.211.0
19090510.310.910.611.3
19110110.411.010.511.2
), ArticleFig(id=1239977439946928282, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239973081536582025, language=CN, label=表6, caption=

不同方法测定壬苯醇醚n值结果比较

, figureFileSmall=null, figureFileBig=null, tableContent=
批号
（batch No）		n值（n value）
MALDI-TOF MSUPLC-TOF MS
MnMwMnMw
100112-20160310.911.510.311.2
R0691010.711.210.211.0
1.011.612.410.110.4
19080110.911.710.211.0
19090510.310.910.611.3
19110110.411.010.511.2
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超高效液相色谱-串联四极杆飞行时间质谱法测定壬苯醇醚分子量分布及n值*
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张伟 1 , 张慧 1 , 韩治国 2 , 孙明辉 3 , 梁成罡 1, **
药物分析杂志 | 标准研讨 2024,44(10): 1807-1815
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药物分析杂志 | 标准研讨 2024, 44(10): 1807-1815
超高效液相色谱-串联四极杆飞行时间质谱法测定壬苯醇醚分子量分布及n值*
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张伟1 , 张慧1, 韩治国2, 孙明辉3, 梁成罡1, **
作者信息
  • 1.中国食品药品检定研究院激素室 国家药品监督管理局化学药品质量研究与评价重点实验室，北京 102629
  • 2.安捷伦科技有限公司，北京 100102
  • 3.布鲁克科技有限公司，北京 100081

    • Tel：（010）53851619；E-mail：

通讯作者:

** Tel：（010）53851638；E-mail：
Molecular weight distribution and n value of nonoxynol were determined by ultra-high performance liquid chromatography with tandem quadrupole time-of-flight mass spectrometry*
Wei ZHANG1 , Hui ZHANG1, Zhi-guo HAN2, Ming-hui SUN3, Cheng-gang LIANG1, **
Affiliations
  • 1.Division of Hormone, National Institutes for Food and Drug Control, NMPA Key Laboratory for Quality Research and Evaluation of Chemical Drugs, Beijing 102629, China
  • 2.Agilent Technology Co., Ltd., Beijing 102629, China
  • 3.Bruker Technology Co., Ltd., Beijing 100081, China
出版时间: 2024-10-31 doi: 10.16155/j.0254-1793.2024-0130
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摘要
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目的：

研究并建立超高效液相色谱-串联四极杆飞行时间质谱法测定壬苯醇醚低聚物的分子量分布及n值，并用国内外多批次壬苯醇醚样品进行考察。

方法：

采用Techmate STV SUNSHELL Peptide C18 (100 mm×2.1 mm，2.6 μm，300 Å)色谱柱，以0.1%三氟乙酸水溶液(A)-0.1%三氟乙酸乙腈溶液(B)为流动相，线性梯度洗脱，流速0.3 mL·min-1，柱温60 ℃，进样量5 μL。采用串联四极杆飞行时间质谱检测器，离子源为Dual ESI，氩气为碰撞气，以正离子模式，采集范围m/z 50~3 000进行检测。采用ChemDraw19.0软件绘制相关结构，通过MassHunter PCDL Manager软件建立数据库，并编辑计算公式。

结果：

用新建立的方法对国内外生产的6批壬苯醇醚原料药的重均分子量及数均分子量进行了测定，并计算得到结构中n值的范围，结果发现国内外产品之间以及同一企业不同批次产品之间的重均分子量及数均分子量均有一定差异；产品结构中的n值也各不相同。数均分子量范围在664.6~686.8(n值约为10)；重均分子量范围在677.1~715.5(n值约为11)。

结论：

此类低聚物药物的分子量分布及n值亟需在生产过程及质量标准中增加控制；新建立的方法灵敏度高，精密度和重现性好，可以满足测定壬苯醇醚原料药的分子量分布及n值的需要，为此类低聚物分子量分布的测定提供了解决方案，同时为《中华人民共和国药典》标准提高及修订提供了依据。

超高效液相色谱-串联四极杆飞行时间质谱法  /  基质辅助激光解析串联飞行时间质谱技术  /  壬苯醇醚  /  低聚物  /  数据库  /  分子量分布  /  n值
Objective:

To develop an ultra-high performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q TOF MS) approach to investigate the molecular weight distribution and n value of nonoxynol oligomers，and to study several batches of samples produced domestically or abroad.

Methods:

The mobile phase was 0.1% trifluoroacetic acid aqueous solution(A)-0.1% trifluoroacetic acid in acetonitrile(B) with linear gradient elution at a flow rate of 0.3 mL·min-1. The column was Techmate STV SUNSHELL Peptide C18 (100 mm×2.1 mm，2.6 μm，300 Å) and installed in a 60 ℃ column oven. Injection volume was 5 μL. A tandem quadrupole time-of-flight mass spectrometer with Dual ESI as ion source and argon as collision gas were used for detection in positive ion mode with a collection range of m/z 50-3 000. ChemDraw 19.0 software was used to draw the relevant structure，and MassHunter PCDL Manager software was used to build the database and edit the calculation formula.

Results:

The weight average molecular weight and number average molecular weight of 6 batches nonoxynol drug substance produced domestically or abroad were determined by the newly established method，and the range of n average value in the structure was obtained. The results showed that the weight average molecular weight and number average molecular weight were different between domestic and foreign products and also between different batches produced by same manufacturer. The n value of structure basis also varies. The weight average molecular weight ranges were 664.6 to 686.8 (n value was about 10)，and number average molecular weight ranges were 677.1 to 715.5 (n value was about 11).

Conclusion:

The molecular weight distribution and n value of such oligomer drugs need to be controlled in the production process and quality specifications. The newly established method has high sensitivity，precision and reproducibility，can be qualified for the needs of determining molecular weight distribution and n value of nonoxynol，and provides insight in determination of molecular weight distribution of such oligomers. This study also provides a data supplement for the improvement and revision of the standards of Chinese Pharmacopoeia.

UPLC-Q TOF MS  /  MALDI-TOF MS  /  nonoxynol  /  oligomer  /  database  /  molecular weight distribution  /  n value
张伟, 张慧, 韩治国, 孙明辉, 梁成罡. 超高效液相色谱-串联四极杆飞行时间质谱法测定壬苯醇醚分子量分布及n值*. 药物分析杂志, 2024 , 44 (10) : 1807 -1815 . DOI: 10.16155/j.0254-1793.2024-0130
Wei ZHANG, Hui ZHANG, Zhi-guo HAN, Ming-hui SUN, Cheng-gang LIANG. Molecular weight distribution and n value of nonoxynol were determined by ultra-high performance liquid chromatography with tandem quadrupole time-of-flight mass spectrometry*[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (10) : 1807 -1815 . DOI: 10.16155/j.0254-1793.2024-0130
正文
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分子量分布（molecular weight distributon，MWD）是表征聚合分子特征非常重要的指标之一，与聚合产物的物理化学性质乃至生物学特性密切相关，是聚合物类药物质控的重要项目，可直接影响药物的安全性与有效性。壬苯醇醚（nonoxynol-9）是一种非离子型表面活性剂，作为杀精剂在世界范围内使用已有60多年，2020年版《中华人民共和国药典》（以下简称《中国药典》）、USP 43以及EP 10.0均有收载[1]。工业中，壬苯醇醚是通过壬基苯酚和环氧乙烷在碱性条件下缩聚而成的无水低聚化合物[2]，结构式见图1。
壬苯醇醚的分子式为C9H19C6H4（OCH2CH2）nOH，结构中具有乙二醇重复性结构，中美两国药典壬苯醇醚各论中均描述本品为n平均值为9[3-5]的混合物，但质量标准中对具体n值却是未做控制。这势必造成各生产企业产品之间，甚至每个企业各批产品之间的物质组成不尽相同，从而导致作为同种药品，理化性质甚至生物学性质存在差异，使用同一规格同一剂量的药品可能在临床上存在有效性或安全性不同的现象。事实上，当壬苯醇醚的n值为4、9、10、15或30时，随着聚合度的增加，其性状就会由无色液体→无色至淡黄色粘稠液体→乳白色油状物→乳白色固体不断变化。据一项体外活性研究[6]，在不同的壬基苯氧基衍生物（n值在11~15）中，对壬基苯氧基聚乙二醇醚，即壬苯醇醚-9（n平均值为9）才是最有效的杀精剂。因此，有理由推断，作为一种药物在临床使用，该类聚合物的聚合程度（分子量分布或n值）在不同企业或不同批次产品间的不同，可直接影响着临床用药的安全与有效[7]。
近年来，测定聚合物分子量的新技术、新方法层出不穷，凝胶色谱法(GPC)与多种检测器联用，如示差折光检测器(RID)、多角度激光光散射检测器(MALLSD)等，用于高分子聚合物的分子量分布研究与控制已经常见[8-10]，另外，作为进一步发展的基质辅助激光解析串联飞行时间质谱(MALDI-TOF MS)技术可测定难挥发，高极性，热不稳定分子，特别是生物大分子的分子量也有文献报道[11-12]。但对于测定壬苯醇醚这类结构中具有重复结构但聚合度较低的化合物分子量，上述方法均存在缺陷，测定结果会有一定误差，这将在文末讨论中详细介绍。另外，对于此类低聚物分子量的相关研究相对文献报到较少，中美两国药典收载的此类品种也基本未对聚合度进行控制。药检药监相关部门已经认识到这类药物的这一质控漏洞，正在力图尽早完善质量标准。
本研究就是以《中国药典》和USP收载的壬苯醇醚为研究对象，建立了超高效液相色谱-串联四极杆飞行时间质谱法（UPLC-Q TOF MS法）测定壬苯醇醚分子量分布及n值，研究过程中采用ChemDraw19.0软件绘制相关化合物结构，通过MassHunter PCDL Manager软件建立数据库，并编辑计算公式。方法中以聚乙二醇（PEG）系列对照品对新方法测定出的分子量分布及n值进行了结果验证，并与基质辅助激光解析串联飞行时间质谱法（MALDI-TOF MS法）进行对比分析，同时用建立的新方法对国内外壬苯醇醚原料药进行考察。本文最后还对几种测定分子量的方法进行探讨。本研究为低聚物分子量分布的测定提供了解决方案，同时为《中国药典》标准提高及修订提供了数据依据。
1　仪器与试药
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Agilent 1260超高效液相色谱-Agilent 6230 TOF飞行时间质谱串联系统（Agilent公司），用于方法的建立；MassHunter PCDL Manager建库软件和MassHunter Qualitative Analysis分析软件（Agilent公司）；Waters Acquity I-Class超高效液相色谱-Waters Synapt G2-Si飞行时间质谱串联系统（Waters公司），用于中间精密度考察；UNIFI分析软件（Waters公司）；Autoflex max基质辅助激光解析串联飞行时间质谱仪（Bruker公司）；Polytools分析软件（Bruker公司）；ChemDraw19.0（CambridgeSoft公司）；METTLER AG245十万分之一电子天平（Metler Roledo公司）；Milli-Q超纯水仪（Millipore公司）；Techmate STV SUNSHELL Peptide C18（100 mm×2.1 mm，300 Å，2.6 μm）（Techmate公司）。
壬苯醇醚对照品（批号100112-201603，含量99.3%），中国食品药品检定研究院；壬苯醇醚对照品（批号R06910，含量99.3%），USP；苯醇醚对照品（EP，批号1.0）；壬苯醇醚原料药均来自药大制药有限公司；PEG 300（批号BCBZ5867，GPC级）、PEG 400（批号BCCB9061，GPC级）、PEG 600（批号BCCB4732，GPC级）、PEG 1000（批号BCBZ5870，GPC级）、PEG 1500（批号BCCC7318，GPC级）、PEG 2000（批号BCCC7307，GPC级），均购自Sigma公司；Peptide Calibration StandardⅡ（批号0000386956，相对分子质量范围700~3 500），Bruker公司；α-氰基-4-羟基肉桂酸（HCCA，批号10222613，10 mg·支-1），Sigma公司；乙腈（质谱级），Merck公司、三氟乙酸（TFA，质谱级），Merck公司；试验所用溶液均用电阻率为18.2 MΩ·cm的去离子水配制。
2　方法与结果
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2.1　UPLC-Q TOF MS法测定壬苯醇醚分子量分布及n值
2.1.1　溶液的配制
2.1.1.1　PEG对照品溶液
分别称取PEG 400、PEG 600、PEG 1000、PEG 2000的对照品适量，分别加水溶解并稀释制成每1 mL中约含0.5 mg的溶液，即得。
2.1.1.2　壬苯醇醚供试品溶液
分别称取壬苯醇醚对照品及原料药适量，分别加水溶解并稀释制成每1 mL中约含0.5 mg的溶液，即得。
2.1.2　色谱-质谱条件
采用Techmate STV SUNSHELL Peptide C18 (100 mm×2.1 mm，300 Å，2.6 μm)色谱柱，柱温60 ℃，以0.1%TFA水溶液(A)-0.1%TFA乙腈(B)为流动相，线性梯度洗脱(0~1 min，95%A；1~7 min，95%A→60%A；7~8 min，60%A→5%A；8~9 min，5%A；9~9.5 min，5%A→95%A；9.5~11 min，95%A)，流速0.3 mL·min-1，进样量5 μL。
采用飞行时间质谱检测器，Agilent 6230 TOF：离子源为Dual ESI；脱溶剂气温度300 ℃；脱溶剂气流速8 L·min-1；雾化器压力276 kPa；毛细管电压3 800 V；碎裂电压125 V；正离子模式；采集范围MS Scan m/z 50~3 000。Waters Synapt G2-Si：离子源为ESI；脱溶剂气温度300 ℃；脱溶剂气流速800 L·h-1；雾化器压力500 kPa；毛细管电压3 000 V；碰撞能30 V；正离子模式；采集范围MS Scan m/z 50~3 000。
2.1.3　数据库的建立及计算公式编辑
采用ChemDraw19.0软件绘制PEG系列结构、壬苯醇醚系列结构，见图2，命名为PEG(1)、PEG(2)~PEG(60)，RBCM(1)、RBCM(2)~RBCM(30)，并将所有结构文件及分子量通过MassHunter PCDL Manager和UNIFI软件分别建立数据库。
通过MassHunter Qualitative Analysis分析软件进行数均分子量(Mn)及重均分子量(Mw)计算公式的编辑，公式(1)、公式(2)；n值计算见公式(3)；其中，Mass代表质荷比，Strength代表离子强度，220.35为壬基苯酚相对分子质量。
2.1.4　PEG对照品溶液测定
取“2.1.1”项下PEG对照品溶液（PEG 400、PEG 600、PEG 1000、PEG 1500、PEG 2000），按“2.1.2”项下色谱-质谱条件进行分析，通过“2.1.3”项下分析软件计算公式进行计算，与对照品附带检测报告（采用SEC/GPC法，通过PSS WINGPC软件进行数据分析得到的分析报告）分子量分布结果进行对比。典型图谱见图3，测定结果见表1，计算结果见表2。
2.1.5　重复性
取PEG 600对照品，按“2.1.1.1”项下方法平行配制6份对照品溶液，按“2.1.2”项下色谱-质谱条件进行分析，通过“2.1.3”项下分析软件计算公式进行计算。结果6份PEG 600对照品溶液的Mn平均值为573.3，RSD为0.19%；Mw平均值为594.2，RSD为0.18%，说明新建立的方法具有较好的重复性。
2.1.6　中间精密度
取PEG 600对照品，按“2.1.1”项下方法平行配制6份对照品溶液，按“2.1.2”项下色谱-质谱条件，用不同品牌型号仪器（安捷伦公司Agilent 1260超高效液相色谱-Agilent 6230 TOF飞行时间质谱串联系统；沃特世公司Waters Acquity I-Class超高效液相色谱-Waters Synapt G2-Si飞行时间质谱串联系统）分别进行分析，通过“2.1.3”项下分析软件计算公式进行计算。结果12份PEG 600对照品溶液的Mn平均值为572.2，RSD为0.66%；Mw平均值为595.0，RSD为0.57%，说明新建立的方法具有较好的精密度。
2.1.7　壬苯醇醚供试品溶液测定
取“2.1.1”项下壬苯醇醚供试品溶液，按“2.1.2”项下色谱-质谱条件进行分析，通过“2.1.3”项下分析软件计算公式进行计算，典型图谱见图4，计算结果见表3。
2.2　MALDI-TOF-MS测定壬苯醇醚分子量分布及n值
2.2.1　溶液的配制
2.2.1.1　基质溶液
取HCCA 1支，加乙腈-水-三氟乙酸(50：47.5：2.5)1 mL使溶解，摇匀，即得。
2.2.1.2　PEG对照品溶液
称取PEG 300、PEG 400、PEG 600、PEG 1000、PEG 1500、PEG 2000各约0.01 mg，分别加基质溶液10 μL使溶解，混匀，即得。
2.2.1.3　壬苯醇醚供试品溶液
称取壬苯醇醚对照品及原料药各约0.01 mg，分别加基质溶液10 μL使溶解，混匀，即得。
2.2.2　质谱条件
采用反射模式；电压极性为正极；扫描范围m/z 50~3 500；离子源1电压19.7 kV；离子源2电压18.44 kV；单次扫描信号累加500次。
2.2.3　样品测定
取“2.2.1.3”项下壬苯醇醚供试品溶液5 μL，按“2.2.2”项下条件测定，采用Polytools软件进行分析计算，通过公式(3)计算n值，典型图谱见图5，计算结果见表4、5。
3　讨论
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3.1　示差折光检测器测定
本研究选用凝胶色谱法（GPC）串联示差折光检测器测定PEG混合对照品溶液（取PEG 400、PEG 600、PEG 1000适量，加水配制成含各组分均为0.5 mg·mL-1的溶液），选取TSKgel G2000SWxl色谱柱对PEG混合对照品溶液进行分离，发现由于PEG分子量差异较小，各组分无法有效分离，且灵敏度较低，见图6，因此该方法不适于测定此类低聚物的分子量。
3.2　多角度激光检测器测定
跟据仪器企业介绍，MALLS检测器测定分子量时，该仪器自身具有5%的误差，也不能准确测定低聚物的分子量分布以及n值。
3.3　2种质谱检测器的差异
采用MALDI-TOF MS技术，在测定低聚化合物PEG时，在低分子量和高分子量端测定值会偏离报告值，见图7，本研究建立方法测定结果与PEG的COA结果基本一致，分析原因主要是由于离子源对待测样品的离子化原理不同导致[13]。MALDI是一种软电离技术，用激光照射样品与基质形成的共结晶薄膜，基质吸收能量电离，将质子转移到样品上，从而使样品发生电离的过程。样品的电离程度取决于基质的选择、待测样品的物理化学特性以及分子量大小，该技术具有一定的质量歧视效应[14]；UPLC-TOF MS常被用于PEG修饰的生物大分子聚合度检测[15]，本研究采用ESI源，液相中的待测分子变成气相离子（气溶胶）时不会受到外部能量的激发而发生裂解，适用于极性、大分子有机物，待测分子离子化程度高。
MALDI-TOF MS法与UPLC-TOF MS法测定的壬苯醇醚n值结果见表6。
通过表6数据对比可知，2种方法测定的壬苯醇醚n值在10.1~11.6（按Mn计算）和10.4~12.4范围内（按Mw计算），这与中美两国药典标准对壬苯醇醚的定义描述n的平均值为9有一些差异，原因应该与不同的测定方法、原理以及仪器设备的分辨率、精密度有关。
本研究为此类分子中具有重复结构的低聚物分子量分布的测定提供了解决方案，同时为药典标准提高及修订提供依据。
基金
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  • *国家药典委员会药品标准制修订研究课题(2023H048)
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2024年第44卷第10期
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doi: 10.16155/j.0254-1793.2024-0130
  • 接收时间：2024-02-29
  • 首发时间：2026-03-15
  • 出版时间：2024-10-31
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  • 收稿日期：2024-02-29
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*国家药典委员会药品标准制修订研究课题(2023H048)
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    1.中国食品药品检定研究院激素室 国家药品监督管理局化学药品质量研究与评价重点实验室，北京 102629
    2.安捷伦科技有限公司，北京 100102
    3.布鲁克科技有限公司，北京 100081

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2种不同金属材料的力学参数
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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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