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Article(id=1198656212058342313, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198656209390764948, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0161, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1676390400000, receivedDateStr=2023-02-15, revisedDate=1684598400000, revisedDateStr=2023-05-21, acceptedDate=null, acceptedDateStr=null, onlineDate=1763711510909, onlineDateStr=2025-11-21, pubDate=1697040000000, pubDateStr=2023-10-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763711510909, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763711510909, creator=13701087609, updateTime=1763711510909, updator=13701087609, issue=Issue{id=1198656209390764948, tenantId=1146029695717560320, journalId=1189982191388893191, year='2023', volume='58', issue='10', pageStart='2835', pageEnd='3150', issueExtLink='null', onlineDate='null', pubDate='1697040000000', pubDateStr='2023-10-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763711510274, creator='13701087609', updateTime=1763711659007, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1198656833280897539, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198656209390764948, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198656833280897540, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198656209390764948, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=3082, endPage=3089, ext={EN=ArticleExt(id=1198656212381303732, articleId=1198656212058342313, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Determination of deuterium incorporation of new drug donafenib tosilate by two methods of LC-MS with natural isotope abundance correction and 1H NMR relative quantitative method, columnId=null, journalTitle=Acta Pharmaceutica Sinica, columnName=null, runingTitle=null, highlight=null, articleAbstract=

An LC-MS method with natural isotope abundance correction and a 1H NMR relative quantitative method were established to determine the deuterium incorporation of donafenib tosilate, a new deuterated drug molecule. First, the peak areas of isotopic impurities (non-deuterated and incompletely deuterated impurities) and deuterated drug were recorded through the single ion monitoring (SIM) mode of the established LC-MS method and then corrected in terms of the natural isotope abundance offered by ChemDraw soft, removing the nature isotope interference from 13C, 37Cl, etc. The corrected areas were subsequently used to calculate mol% of isotopologues (D0, D1, D2, D3) and Atom% D, namely, deuterium incorporation. In addition, a 1H qNMR experiment was conducted with the aromatic proton at δ 8.63 and the residual proton of isotopic impurities at δ 2.79 as quantitative peaks. The mixture of DMSO-d6 and D2O (10∶1) was employed as the solvent to change the spin-coupling between the residual proton and active hydrogen so that the residual proton could be measured as the single peak, and the sensitivity was greatly improved. The acquisition parameters were also optimized, and Atom% 1H and the deuterium incorporation were then calculated. The two methods were applied to samples of three commercial batches, and the testing results were almost consistent. Both methods proved accurate, sensitive, fast and independent of standard substances and accurate weighing, which could be applied to the determination of the deuterium incorporation of donafenib tosilate and provide a reference for other deuterated drugs.

, authors=null, authorsList=Yi-wen HUANG, Yang WU, Xia-ju CHENG, Qi XU, Yan-mei LI, Ye-fei QIAN, authorCompany=null, correspAuthors=Ye-fei QIAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2023 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, fund=null), CN=ArticleExt(id=1198656215149543435, articleId=1198656212058342313, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=LC-MS法结合天然同位素校正和1H NMR相对定量法2种方法测定氘代新药甲苯磺酸多纳非尼的氘代率, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

测定氘代抗肿瘤新药甲苯磺酸多纳非尼中氘同位素杂质(包括非氘代和不完全氘代杂质) 的含量, 并计算氘原子百分比, 即氘代率。建立液相色谱-质谱(LC-MS) 法通过选择离子扫描模式测定各氘同位素杂质及氘代药物峰面积, 并根据ChemDraw软件给出的天然同位素分布对峰面积进行校正, 消除13C、37Cl等天然同位素干扰, 通过校正后的峰面积计算各氘同位素杂质的相对含量, 继而计算药物氘代率; 并采用非氘代杂质对照品对该方法下天然同位素分布、氘同位素杂质与氘代药物的摩尔相对响应因子、基质效应等进行验证。另采用1H定量核磁共振波谱技术(1H qNMR), 以δ 8.63的总芳香1H峰和δ 2.79的氘同位素杂质残留1H峰为定量峰, 采用氘代二甲基亚砜-重水(10∶1) 混合溶剂, 改变活泼氢对残留1H的偶合裂分, 使其以单峰的形式参与定量, 提高方法灵敏度, 并优化采集参数, 测定1H原子百分比, 继而计算药物氘代率。结果表明, 在建立的LC-MS方法下, 天然同位素化合物相对丰度的实测值与理论值的相对偏差均小于15%; 氘同位素杂质与氘代药物的摩尔响应因子基本一致; 方法无基质效应。建立的1H qNMR方法定量限低至0.1%。将建立的2种方法用于3批商业化样品的测定, 测定结果基本一致。建立的LC-MS法结合天然同位素校正和1H NMR相对定量法2种方法均准确、快速、灵敏, 且无需准确称量, 无需任何对照品, 可用于甲苯磺酸多纳非尼氘代率的测定, 也为其他氘代药物氘代率的测定提供了新思路。

, authors=null, authorsList=黄逸文, 吴杨, 程侠菊, 许奇, 李艳梅, 钱叶飞, authorCompany=null, correspAuthors=钱叶飞, authorNote=null, correspAuthorsNote=
*钱叶飞, Tel: 86-512-67079940, E-mail:
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A: <i>m/z</i> 465.1; B: <i>m/z</i> 466.1; C: <i>m/z</i> 467.1; D: <i>m/z</i> 468.1 , figureFileSmall=xY1UwDv6wcdPGILYHBnjFw==, figureFileBig=zE1RXe8iO8XgZf7SpqQGlg==, tableContent=null), ArticleFig(id=1198960245998453336, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198656212058342313, language=EN, label=null, caption=null, figureFileSmall=IKy8vY8nU/+xSrKy2LWGQA==, figureFileBig=QhVA9NqDDDAmo9y1xpc7Yg==, tableContent=null), ArticleFig(id=1198960246124282467, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198656212058342313, language=CN, label=Figure 4, caption= Extract ion chromatograms of the sample solution: A: <i>m/z</i> 465.1; B: <i>m/z</i> 466.1; C: <i>m/z</i> 467.1; D: <i>m/z</i> 468.1 , figureFileSmall=IKy8vY8nU/+xSrKy2LWGQA==, figureFileBig=QhVA9NqDDDAmo9y1xpc7Yg==, tableContent=null), ArticleFig(id=1198960246275277427, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198656212058342313, language=EN, label=null, caption=null, figureFileSmall=o9ICm/bgeseJ+MrHfAIPVA==, figureFileBig=8k7AhMYRgU8hhueJrbb8Zg==, tableContent=null), ArticleFig(id=1198960246422078080, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198656212058342313, language=CN, label=Figure 5, caption= Typical <sup>1</sup>H NMR spectra of sample solutions. 1: <i>δ</i> 2.79 quantitative peak; 2: <i>δ</i> 8.63 quantitative peak , figureFileSmall=o9ICm/bgeseJ+MrHfAIPVA==, figureFileBig=8k7AhMYRgU8hhueJrbb8Zg==, tableContent=null), ArticleFig(id=1198960246539518597, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198656212058342313, language=EN, label=null, caption=null, figureFileSmall=bAArRq2WeU6kHK4iSS93DQ==, figureFileBig=y2b12+JAFosBliSiBDYeXg==, tableContent=null), ArticleFig(id=1198960246661153423, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198656212058342313, language=CN, label=Figure 6, caption= <sup>1</sup>H NMR spectra of D<sub>0</sub> reference solutions of 1 mg·mL<sup>-1</sup>: (A) with D<sub>2</sub>O; (B) without D<sub>2</sub>O. 1: <i>δ</i> 2.79 methyl <sup>1</sup>H peak; 3: <i>δ</i> 8.78 amide <sup>1</sup>H peak; 4: H<sub>2</sub>O peak , figureFileSmall=bAArRq2WeU6kHK4iSS93DQ==, figureFileBig=y2b12+JAFosBliSiBDYeXg==, tableContent=null), ArticleFig(id=1198960246904423070, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198656212058342313, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Concentration/ng·mL-1 [M+H+1]+ [M+H+2]+ [M+H+3]+
Measured value Relative deviation Measured value Relative deviation Measured value Relative deviation
0.521 7 < LOQ / < LOQ / < LOQ /
1.043 26.5% 7.8% 35.6% 0.3% < LOQ /
2.608 24.8% 1.2% 35.8% 0.8% < LOQ /
5.217 24.3% 0.8% 35.9% 1.1% 9.4% 14.9%
7.825 24.1% 1.7% 35.9% 1.1% 9.3% 13.8%
10.43 24.7% 0.8% 36.3% 2.2% 9.1% 11.6%
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Measured value and relative deviation of the natural abundance of D0 reference

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Concentration/ng·mL-1 [M+H+1]+ [M+H+2]+ [M+H+3]+
Measured value Relative deviation Measured value Relative deviation Measured value Relative deviation
0.521 7 < LOQ / < LOQ / < LOQ /
1.043 26.5% 7.8% 35.6% 0.3% < LOQ /
2.608 24.8% 1.2% 35.8% 0.8% < LOQ /
5.217 24.3% 0.8% 35.9% 1.1% 9.4% 14.9%
7.825 24.1% 1.7% 35.9% 1.1% 9.3% 13.8%
10.43 24.7% 0.8% 36.3% 2.2% 9.1% 11.6%
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Added amount/μg Determined amount/μg Recovery/% Average/% RSD/%
0.251 5 0.254 3 101.1 104.7 3.2
0.251 5 0.270 9 107.7
0.251 5 0.265 1 105.4
0.503 0 0.498 5 99.1 100.9 1.7
0.503 0 0.508 0 101.1
0.503 0 0.515 6 102.5
0.754 5 0.826 9 109.6 107.4 1.8
0.754 5 0.800 5 106.1
0.754 5 0.804 3 106.6
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Results of recovery testing

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Added amount/μg Determined amount/μg Recovery/% Average/% RSD/%
0.251 5 0.254 3 101.1 104.7 3.2
0.251 5 0.270 9 107.7
0.251 5 0.265 1 105.4
0.503 0 0.498 5 99.1 100.9 1.7
0.503 0 0.508 0 101.1
0.503 0 0.515 6 102.5
0.754 5 0.826 9 109.6 107.4 1.8
0.754 5 0.800 5 106.1
0.754 5 0.804 3 106.6
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Lot LC-MS 1H qNMR
Mol% D0 Mol% D1 Mol% D2 Mol% D3 Atom% D Atom% 1H Atom% D
220605 0.15 0.03 0.45 99.36 99.67 0.41 99.59
220801 0.13 0.06 0.42 99.40 99.70 0.23 99.77
221102 0.13 0.03 0.39 99.45 99.72 0.25 99.75
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Determination results of samples by two methods

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Lot LC-MS 1H qNMR
Mol% D0 Mol% D1 Mol% D2 Mol% D3 Atom% D Atom% 1H Atom% D
220605 0.15 0.03 0.45 99.36 99.67 0.41 99.59
220801 0.13 0.06 0.42 99.40 99.70 0.23 99.77
221102 0.13 0.03 0.39 99.45 99.72 0.25 99.75
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LC-MS法结合天然同位素校正和1H NMR相对定量法2种方法测定氘代新药甲苯磺酸多纳非尼的氘代率
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黄逸文 1 , 吴杨 1 , 程侠菊 2 , 许奇 1 , 李艳梅 2 , 钱叶飞 1, *
药学学报 | 研究论文 2023,58(10): 3082-3089
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药学学报 |研究论文 2023 , 58 (10) : 3082 -3089
LC-MS法结合天然同位素校正和1H NMR相对定量法2种方法测定氘代新药甲苯磺酸多纳非尼的氘代率
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黄逸文1, 吴杨1, 程侠菊2, 许奇1, 李艳梅2, 钱叶飞1, *
作者信息
  • 1.苏州市药品检验检测研究中心, 江苏 苏州 215104
  • 2.苏州大学生物医学研究院, 江苏省感染与免疫重点实验室, 江苏 苏州 215127
通讯作者:
*钱叶飞, Tel: 86-512-67079940, E-mail:
Determination of deuterium incorporation of new drug donafenib tosilate by two methods of LC-MS with natural isotope abundance correction and 1H NMR relative quantitative method
Yi-wen HUANG1, Yang WU1, Xia-ju CHENG2, Qi XU1, Yan-mei LI2, Ye-fei QIAN1, *
Affiliations
  • 1. Suzhou Institute for Drug Control, Suzhou 215104, China
  • 2. Jiangsu Key Laboratory of Infection and Immunity, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215127, China
出版时间: 2023-10-12 doi: 10.16438/j.0513-4870.2023-0161
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摘要
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测定氘代抗肿瘤新药甲苯磺酸多纳非尼中氘同位素杂质(包括非氘代和不完全氘代杂质) 的含量, 并计算氘原子百分比, 即氘代率。建立液相色谱-质谱(LC-MS) 法通过选择离子扫描模式测定各氘同位素杂质及氘代药物峰面积, 并根据ChemDraw软件给出的天然同位素分布对峰面积进行校正, 消除13C、37Cl等天然同位素干扰, 通过校正后的峰面积计算各氘同位素杂质的相对含量, 继而计算药物氘代率; 并采用非氘代杂质对照品对该方法下天然同位素分布、氘同位素杂质与氘代药物的摩尔相对响应因子、基质效应等进行验证。另采用1H定量核磁共振波谱技术(1H qNMR), 以δ 8.63的总芳香1H峰和δ 2.79的氘同位素杂质残留1H峰为定量峰, 采用氘代二甲基亚砜-重水(10∶1) 混合溶剂, 改变活泼氢对残留1H的偶合裂分, 使其以单峰的形式参与定量, 提高方法灵敏度, 并优化采集参数, 测定1H原子百分比, 继而计算药物氘代率。结果表明, 在建立的LC-MS方法下, 天然同位素化合物相对丰度的实测值与理论值的相对偏差均小于15%; 氘同位素杂质与氘代药物的摩尔响应因子基本一致; 方法无基质效应。建立的1H qNMR方法定量限低至0.1%。将建立的2种方法用于3批商业化样品的测定, 测定结果基本一致。建立的LC-MS法结合天然同位素校正和1H NMR相对定量法2种方法均准确、快速、灵敏, 且无需准确称量, 无需任何对照品, 可用于甲苯磺酸多纳非尼氘代率的测定, 也为其他氘代药物氘代率的测定提供了新思路。

氘代药物  /  甲苯磺酸多纳非尼  /  氘代率  /  液相色谱-质谱法  /  同位素分布  /  1H定量核磁共振波谱法

An LC-MS method with natural isotope abundance correction and a 1H NMR relative quantitative method were established to determine the deuterium incorporation of donafenib tosilate, a new deuterated drug molecule. First, the peak areas of isotopic impurities (non-deuterated and incompletely deuterated impurities) and deuterated drug were recorded through the single ion monitoring (SIM) mode of the established LC-MS method and then corrected in terms of the natural isotope abundance offered by ChemDraw soft, removing the nature isotope interference from 13C, 37Cl, etc. The corrected areas were subsequently used to calculate mol% of isotopologues (D0, D1, D2, D3) and Atom% D, namely, deuterium incorporation. In addition, a 1H qNMR experiment was conducted with the aromatic proton at δ 8.63 and the residual proton of isotopic impurities at δ 2.79 as quantitative peaks. The mixture of DMSO-d6 and D2O (10∶1) was employed as the solvent to change the spin-coupling between the residual proton and active hydrogen so that the residual proton could be measured as the single peak, and the sensitivity was greatly improved. The acquisition parameters were also optimized, and Atom% 1H and the deuterium incorporation were then calculated. The two methods were applied to samples of three commercial batches, and the testing results were almost consistent. Both methods proved accurate, sensitive, fast and independent of standard substances and accurate weighing, which could be applied to the determination of the deuterium incorporation of donafenib tosilate and provide a reference for other deuterated drugs.

deuterated drug  /  donafenib tosilate  /  deuterium incorporation  /  liquid chromatography-mass spectrometry  /  isotope distribution  /  1H quantitative nuclear magnetic resonance
黄逸文, 吴杨, 程侠菊, 许奇, 李艳梅, 钱叶飞. LC-MS法结合天然同位素校正和1H NMR相对定量法2种方法测定氘代新药甲苯磺酸多纳非尼的氘代率. 药学学报, 2023 , 58 (10) : 3082 -3089 . DOI: 10.16438/j.0513-4870.2023-0161
Yi-wen HUANG, Yang WU, Xia-ju CHENG, Qi XU, Yan-mei LI, Ye-fei QIAN. Determination of deuterium incorporation of new drug donafenib tosilate by two methods of LC-MS with natural isotope abundance correction and 1H NMR relative quantitative method[J]. Acta Pharmaceutica Sinica, 2023 , 58 (10) : 3082 -3089 . DOI: 10.16438/j.0513-4870.2023-0161
正文
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氘代药物是将药物分子上处于特定代谢部位的1个或多个氢原子(1H) 用氘原子(D) 替代所获得的药物分子。相比于D修饰前的药物分子, 氘代药物具有改善药代动力学特性、减少毒性代谢产物、稳定分子手性结构等优势[1, 2]。自2017年全球首个氘代药物—氘代丁苯那嗪片获FDA批准上市以来, 氘代药物越来越成为药物设计与开发的新策略和新选择[3-5]。
甲苯磺酸多纳非尼(donafenib tosilate) 是由我国自主研发并拥有自主知识产权的1类创新药, 于2021年通过优先审评审批程序被国家药监局批准上市, 用于既往未接受过全身系统性治疗的不可切除肝细胞癌患者的治疗, 是全球第二个、国产第一个获批上市的氘代药物。甲苯磺酸多纳非尼是将甲苯磺酸索拉非尼(sorafenib tosilate) 21位甲基的3个1H, 用D替换而形成的新分子, 该氘代位点涉及药物的氧化、水解、去甲基和葡糖醛酸化等多个代谢途径(图 1)。相比未氘代分子, 甲苯磺酸多纳非尼有更高的稳态血药峰浓度和血浆暴露量, 更低的毒性代谢产物, 临床上表现出更高的抗肿瘤活性和安全性[6]。
氘代药物的合成策略主要分为从氘代合成砌块出发, 经多步化学反应制备的氘池合成法, 以及在催化剂和氘源作用下直接对化合物进行氘代修饰的同位素交换法[1, 7]。对于多原子氘代的氘代药物, 如甲苯磺酸多纳非尼(D3), 在合成过程中会产生非氘代(D0) 和不完全氘代(D1、D2) 多种氘同位素杂质。因此, 氘代药物修饰位点的D原子百分数, 即氘代率, 是影响其安全性及有效性的关键质量属性。然而氘代药物和氘同位素杂质理化性质几乎相同, 常规色谱方法无法进行分离测定。
目前氘代药物氘代率的测定方法还鲜有报道, 仅有文献[8-11]报道了在同位素稀释质谱法中作为内标使用的“氘标记化合物”的氘标记率, 即同位素丰度的测定, 以及各类“氘代试剂”的氘代率的测定[12-16]。传统的测定方法是气体同位素质谱法, 但需要复杂的前处理将样品转化为气体样品后通过气体同位素质谱仪进行分析。目前使用最广泛的是基于有机质谱的质量簇法[8-10]和1H定量核磁共振波谱法(1H qNMR)[12-16]。质量簇法是通过色谱-质谱联用技术或通过蠕动泵直接将样品引入低分辨质谱仪, 通过全扫描模式获得的质谱图中各氘同位素化合物的峰强度计算D同位素丰度。然而质量簇法在实际应用中有很多不足, 如需要通过多次归一化和解线性方程组将质谱数据去卷积, 标记的D越多, 方程组求解越复杂; 不同的样品浓度、峰的前沿、中部和拖尾处等不同位置、不同的质谱图数量等条件下得到的同位素分布均有较大差异; 且很难对方法的定量限等进行定量评价。Tian等[11]通过用四级杆轨道阱高分辨质谱结合流动注射进样, 无需解方程组去卷积, 即可直接测定氘标记化合物的同位素丰度。但该方法对仪器精度和仪器状态要求很高, 在不同的仪器质量数偏差及测量允许偏差下, 测定结果有较大差异, 且同样很难对方法的定量限等进行定量评价。另有文献[14-18]采用1H qNMR结合内标或外标物将氢谱中的定量峰以D0或其他某一种氘同位素杂质的形式用于计算氘代分子中同位素杂质的绝对含量, 继而计算氘代率。但对于多原子氘代分子, 定量峰实际是由各氘同位素杂质组成的混合物产生的质子峰, 因此这种1H NMR定量法测定的氘代率是不准确的。且NMR因灵敏度相对较低、信号强度与摩尔浓度直接相关、积分对定量峰信噪比要求较高等因素[19], 在用于测定氘代药物这类分子量较大的化合物中的微量杂质时有一定的困难。Marriott等[20]则采用红外光谱法对氘代甲胺的氘代率进行测定, 但需要各氘同位素杂质对照品且仍需结合液质联用(LC-MS) 法建立化学计量学模型。
本研究采用LC-MS法通过选择离子扫描模式(single ion monitoring, SIM) 获得的色谱数据代替质谱数据, 测定多纳非尼中各氘化合物峰面积, 并根据ChemDraw软件给出的天然同位素分布对峰面积进行校正, 消除13C、37Cl等天然同位素干扰, 通过校正后各峰面积直接计算各氘同位素杂质的相对含量, 继而计算药物氘代率; 另外, 本研究基于混合氘代溶剂, 改变活泼氢对氘同位素杂质残留1H的偶合裂分, 使其以单峰的形式参与定量, 提高方法灵敏度, 并优化采集参数, 建立了无需任何内标或外标物的1H NMR相对定量法计算氘代率。本研究建立的2种方法的方法学参数可定量评价, 测定结果基本一致, 可相互佐证, 互为补充; 且具有操作和计算简便、分析时间短、无需准确称量、无需对照品的优势, 也为其他氘代药物氘代率的测定提供了新思路。
材料与方法
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仪器  Waters Acquity I-Class高效液相色谱仪配Xevo TQ-S质谱检测器(美国Waters公司); Bruker AVANCE III 500 MHz核磁共振波谱仪, 配5 mm BBO探头(瑞士Bruker公司); XSE205DU型电子天平(瑞士Mettler-Toledo公司)。
试药与试剂  甲苯磺酸多纳非尼样品(批号220605、220801、221102) 和对照品(批号351-040-1, 纯度99.9%) 由苏州泽璟生物制药股份有限公司提供; D0杂质对照品(甲苯磺酸索拉非尼, 批号ML220615-17, 纯度98.7%) 购自美国Stanford Analytical Chemicals Inc.; 甲酸铵、甲酸、甲醇、乙腈均为LC-MS级, 购自德国Merck公司; 氘代二甲基亚砜(DMSO-d6, 含0.03%四甲基硅烷, 批号C14673655) 和重水(D2O, 批号C13267037) 均购自上海麦克林生化科技有限公司。
LC-MS测定法
供试品溶液制备  取甲苯磺酸多纳非尼适量, 加甲醇溶解并稀释制成浓度约为0.5 μg·mL-1的供试品溶液。
色谱与质谱条件  以Waters sunfire C18 (150 mm × 2.1 mm, 3.5 μm) 为色谱柱, 0.005 mol·L-1甲酸铵水溶液(用甲酸调pH为2.5)-乙腈(1∶1) 为流动相, 柱温35 ℃, 流速0.3 mL·min-1, 进样量2 μL; ESI电离源, 正离子模式, 喷雾电压3.0 kV, 锥孔电压20 V, SIM模式, 监测离子m/z 465.1、466.1、467.1、468.1。
氘代率的计算  通过SIM模式采集供试品溶液中各氘同位素杂质(D0, D1, D2) 及氘代药物(D3) [M+H]+ (扣除甲苯磺酸根后m/z分别为465.1、466.1、467.1、468.1) 的色谱图, 峰面积分别记为A0、A1、A2、A3。
由于天然同位素的存在, 峰面积A1、A2、A3受到D0、D1、D2等的天然同位素化合物的干扰。根据ChemDraw软件给出的D0、D1、D2、D3的各天然同位素化合物理论相对丰度(图 2, 扣除甲苯磺酸根), 按公式1~4对峰面积A0、A1、A2、A3进行校正, 校正后的峰面积分别记为CA0、CA1、CA2、CA3。
$\mathrm{C} A_0=A_0$
$\mathrm{C} A_1=A_1-24.5 \% \mathrm{C} A_0$
$\mathrm{C} A_2=A_2-24.5 \% \mathrm{C} A_1-35.5 \% \mathrm{C} A_0$
$\mathrm{C} A_3=A_3-24.5 \% \mathrm{C} A_2-35.5 \% \mathrm{C} A_1-8.2 \% \mathrm{C} A_0$
通过校正后的峰面积, 分别按公式5、6计算得到各氘化合物的摩尔百分含量Xn (n = 0, 1, 2, 3) 和最终的氘代率Atom% D。
$X_n=\frac{\mathrm{C} A_n}{\mathrm{C} A_0+\mathrm{C} A_1+\mathrm{C} A_2+\mathrm{C} A_3} \times 100 \%$
$ \text { Atom } \% \mathrm{D}=\frac{1 X_1+2 X_2+3 X_3}{3} \times 100 \% $
峰面积校正参数的验证  取D0杂质对照品适量, 加甲醇溶解并稀释制成浓度为0.5、1.0、2.5、5.0、7.5、10 ng·mL-1的系列溶液(分别相当于供试品浓度的0.1%、0.2%、0.5%、1.0%、1.5%、2.0%), 按“色谱与质谱条件”记录D0对照品各天然同位素化合物峰面积, 计算实测相对丰度。并计算在不同浓度下, D0各天然同位素化合物相对丰度的实测值与ChemDraw软件理论值的相对偏差。
氘同位素杂质与氘代药物摩尔相对响应因子的验证  取上述系列浓度的D0对照品溶液, 按“色谱与质谱条件”记录峰面积A0。将质量浓度换算为摩尔浓度(mol·L-1) 后, 以摩尔浓度为横坐标, 峰面积为纵坐标, 计算D0线性回归方程。另取高丰度D3对照品适量, 加甲醇溶解并稀释制成质量浓度为0.25、0.4、0.5、0.6、0.75、1.0 μg·mL-1的系列溶液(分别相当于供试品浓度的50%、80%、100%、120%、150%、200%), 按“色谱与质谱条件”记录峰面积A3。将质量浓度换算为摩尔浓度(mol·L-1) 后, 以摩尔浓度为横坐标, 峰面积为纵坐标, 计算D3线性回归方程。并计算D0与D3线性方程斜率(k) 的比值。
基质效应的考察  由于各氘化合物在色谱系统无法分离, 共洗脱进入离子源, 且样品中各氘同位素杂质的实际含量很低, 因此有必要考察高浓度的D3对微量的氘同位素杂质的竞争性抑制, 即基质效应。
取高丰度D3对照品适量, 加甲醇溶解并稀释制成质量浓度为0.5 μg·mL-1的基质溶液。另取D0杂质对照品适量, 加基质溶液溶解并稀释制成质量浓度为0.5、1.0、2.5、5.0、7.5、10 ng·mL-1的系列溶液, 按“色谱与质谱条件”记录峰面积A0。将质量浓度换算为摩尔浓度(mol·L-1) 后, 以摩尔浓度为横坐标, 峰面积为纵坐标, 计算基质匹配标准曲线方程的k值。通过与不加基质的D0对照品标准曲线方程k值进行比较, 评价方法的基质效应[21]。
LC-MS法其他方法学验证
专属性  各氘化合物在色谱系统无法分离, LC-MS法专属性主要考察空白溶剂在各提取离子通道下对各氘化合物的测定有无干扰。分别取甲醇空白溶液、供试品溶液, 按“色谱与质谱条件”测定, 分别记录m/z 465.1、466.1、467.1、468.1的提取离子色谱图。
线性与范围  见“氘同位素杂质与氘代药物摩尔相对响应因子的验证”项下。
检测限与定量限  将D0杂质对照品用甲醇逐级稀释, 按“色谱与质谱条件”记录峰面积A0, 以信噪比(S/N) 约为10时相应的浓度作为定量限(LOQ) 浓度, 以S/N约为3时相应的浓度作为检测限(LOD) 浓度。
重复性  取同一批供试品, 按LC-MS测定法的供试品溶液制备方法平行制备6份供试品溶液, 按“色谱与质谱条件”测定, 计算供试品中各氘化合物摩尔百分含量和氘代率测定值的RSD (n = 6)。
回收率  取同一批供试品适量, 加D0杂质对照品配制成加标浓度分别为2.5、5.0、7.5 ng·mL-1 (分别相当于供试品浓度的0.5%、1.0%、1.5%) 的加标供试品溶液, 每个浓度平行制备3份, 按“色谱与质谱条件”测定, 计算D0的加标回收率。
耐用性  将建立的色谱条件在流速(0.3 ± 0.1 mL·min-1)、柱温(35 ± 5 ℃)、流动相pH (2.5 ± 0.2) 等发生变动时, 取供试品溶液进行测定, 计算供试品中各氘化合物摩尔百分含量及供试品氘代率, 考察方法耐用性。
1H qNMR测定法
供试品溶液制备  取甲苯磺酸多纳非尼约100 mg, 加DMSO-d6 1 mL使溶解, 再加入D2O 100 μL, 混匀后转移0.5 mL至5 mm核磁管中, 待测。
NMR采集参数  采用90°脉冲(脉冲序列为zg), 测试温度298 K, 谱宽(SWH) 10 000 Hz, 采样时间(AQ) 3.28 s, 弛豫延迟时间(D1) 15 s, 脉冲宽度(P1) 9.4 μs, 采样点数(TD) 64 k, 空扫次数(DS) 2次; 扫描次数(NS) 64次。
数据处理参数  线宽因子(LB) 0.3 Hz, 图谱点数(SI) 与TD一致。
氘代率的计算  将供试品溶液按NMR采集参数进行采样, 对采集得到的氢谱依次进行傅里叶变换、相位校正和基线校正。
以δ 2.79的1H峰作为氘同位素杂质的特征定量峰, 积分值记为Ax。以δ 8.63的芳香1H峰(1H) 作为各氘化合物总定量峰, 积分值记为As。分别按公式7、8计算D修饰位点残留1H的Atom% 1H和最终的氘代率Atom% D。
$ \mathrm{A}\mathrm{t}\mathrm{o}\mathrm{m}\mathrm{\%}{}^{1}\mathrm{H}=\frac{{A}_{x}}{3{A}_{s}}\times 100\mathrm{\%} $
$ \mathrm{A}\mathrm{t}\mathrm{o}\mathrm{m}\mathrm{\%}\mathrm{ }\mathrm{D}=(1-\frac{{A}_{x}}{3{A}_{s}})\times 100\mathrm{\%} $
1H qNMR方法学验证
线性与范围  取D0杂质对照品适量, 加DMSO-d6溶解并稀释制成浓度为0.1、0.2、0.5、1.0、1.5、2.0 mg·mL-1的线性溶液(分别相当于供试品浓度的0.1%、0.2%、0.5%、1.0%、1.5%、2.0%), 分别取1 mL后加入D2O 100 μL, 混匀后转移0.5 mL至5 mm核磁管中, 待测, 按NMR采集参数测定。以待测物浓度为横坐标, δ 2.79定量峰与溶剂自带的四甲基硅烷内标峰的面积比为纵坐标, 计算回归方程。
定量限  取上述系列浓度的待测D0杂质对照品溶液, 按NMR采集参数测定, 以S/N约为150时相应的浓度作为LOQ浓度。
重复性  取同一批供试品, 按1H qNMR测定法的供试品溶液制备方法平行制备6份待测供试品溶液, 按NMR采集参数测定, 计算Atom% 1H和氘代率测定值的RSD (n = 6)。
回收率  精密称取同一批供试品100 mg各9份, 分为3组, 每组分别精密加入“线性与范围”项下0.5、1.0、1.5 mg·mL-1的D0杂质对照品溶液(分别相当于供试品浓度的0.5%、1.0%、1.5%) 1 mL使溶解, 加入D2O 100 μL混匀后转移0.5 mL至5 mm核磁管中, 按NMR采集参数测定, 计算D0的加标回收率。
结果与讨论
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1 LC-MS测定法
1.1 峰面积校正参数的验证
由于13C、37Cl等天然同位素的存在, 峰面积A1、A2、A3除了包含各自所代表的D1、D2、D3, 又包含了其他天然同位素化合物。具体来说: A0仅包含[D0+H]+; A1除包含[D1+H]+, 还包含了来自D0的天然同位素化合物[D0+H+1]+的贡献; A2除包含[D2+H]+, 还包含了[D1+H+1]+和[D0+H+2]+的贡献; A3除包含[D3+H]+, 还包含了[D2+H+1]+、[D1+H+2]+和[D0+H+3]+的贡献。需根据天然同位素化合物的相对丰度予以校正扣除。
D0对照品各天然同位素化合物相对丰度的实测值以及与ChemDraw软件的理论值的相对偏差详见表 1。在不同浓度条件下, D0各天然同位素化合物相对丰度的实测值与理论值的相对偏差均 < 15%, 表明本研究建立的方法各天然同位素化合物相对丰度测定值准确, 且可用理论相对丰度作为校正参数对各氘化合物峰面积进行校正。
1.2 氘同位素杂质与氘代药物摩尔相对响应因子的验证
D0和D3线性回归方程分别为y = 2.033 × 1013 x - 1 007.6 (r = 0.999 9)和y = 1.936 × 1013 x + 480 702 (r = 0.999 4), k的比值为1.05。表明低浓度(限度浓度附近) 的氘同位素杂质与高浓度(供试品浓度附近) 的D3色谱峰信号响应因子基本一致, 摩尔相对响应因子近似为1, 可用各氘化合物校正后峰面积直接计算各氘化合物的摩尔百分含量。
1.3 基质效应的考察
基质匹配标准曲线方程与不加基质的标准曲线方程k的比值为103%, 在90%~110%范围内, 表明基质干扰较低, 可以忽略不计。
1.4 LC-MS法其他方法学验证
1.4.1 专属性
空白溶液和供试品溶液各提取离子色谱图分别见图 3、4。结果表明, 空白溶剂在各提取离子通道下均不干扰供试品中各氘化合物的测定。
1.4.2 线性与范围
氘同位素杂质和D3的线性范围分别在0.5~10 ng·mL-1和0.25~1.0 μg·mL-1内时峰面积与质量浓度线性关系良好。
1.4.3 检测限与定量限
LOQ浓度结果为0.5 ng·mL-1, 相当于供试品浓度的0.1%。LOD浓度结果为0.15 ng·mL-1, 相当于供试品浓度的0.03%。表明方法灵敏度满足检测要求。
1.4.4 重复性
供试品中各氘化合物摩尔百分含量测定值的RSD (n = 6) 分别为2.0% (D0)、9.7% (D1)、3.8% (D2)、0.02% (D3), 供试品氘代率测定值RSD (n = 6) 为0.005%。表明方法重复性良好。
1.4.5 回收率
3个浓度水平下D0的加标回收率结果见表 2, 表明方法准确度较高。
1.4.6 耐用性
在流速、柱温、流动相pH等发生变动时, 供试品中各氘化合物摩尔百分含量及供试品氘代率的测定值基本无变化, 方法耐用性良好。
2 1H qNMR测定法
2.1 1H qNMR方法的建立与优化
2.1.1 定量峰的选择
由于各氘同位素杂质除在δ 2.79处显示21位的残留甲基1H外, 其他各质子峰和D3几乎重合, 因此以δ 2.79的1H峰作为氘同位素杂质的特征定量峰。另选一芳香1H峰作为各氘化合物的总定量峰。相比其他芳香1H峰, 18位δ 8.63的芳香1H峰裂分相对简单(双峰), 且与其他信号峰分离度良好, 因此作为各氘化合物总定量峰。样品典型性图谱见图 5。
2.1.2 样品制备的选择
由于氘同位素杂质含量较低, 为提高方法灵敏度, 样品的制备首先考虑样品溶解度。筛选了常用的氘代溶剂如DMSO-d6、氘代氯仿、氘代甲醇、D2O等, 甲苯磺酸多纳非尼在DMSO-d6中溶解度最大(> 200 mg·mL-1), 但样品浓度过高, 溶液黏度变大, 磁场均匀性变差和弛豫增快导致谱图分辨率下降。经筛选以DMSO-d6为溶剂制成100 mg·mL-1的供试品溶液。
以DMSO-d6为溶剂制备1.0% (限度浓度) 的D0杂质对照品溶液。21位的特征甲基1H与29位的N-H相连, N-H属于活泼氢, 通常由于分子间的快速交换, N-H对邻位C-H的偶合平均化, 不会造成裂分。但由于29位的N-H属于酰胺氢, 交换速度很慢, 会与邻位甲基1H有偶合作用, 使得δ 2.79甲基1H峰裂分为双峰, 同时δ 8.78酰胺1H峰也被甲基1H裂分为四重峰(图 6B)。为进一步提高氘同位素杂质的检测灵敏度, 尝试向样品溶液中加入100 μL D2O, 混匀, 使酰胺活泼氢与D2O充分交换, 结果酰胺氢峰几乎消失, 偶合作用减弱, 特征定量峰由双峰变为单峰, 灵敏度大幅提高(图 6A)。且单峰峰宽更窄, 积分值更准确。
另一方面, 加入D2O前, 来自样品或溶剂残留的H2O峰位于δ 3.43, 峰宽较宽, 对低浓度的氘同位素杂质δ 2.79定量峰的积分有一定干扰, 积分宽度的微小变化会对积分产生明显变化, 杂质浓度越低, 对积分影响越大。加入D2O后, 残留H2O峰向低场移动, 且峰宽明显变小, 对定量峰积分几乎没有影响(图 6A)。
2.1.3 采集参数的优化
D1是影响定量峰面积准确性的重要参数, D1不够会在激发核尚未完全回到低能态便开始下一次激发, 对响应信号强度产生较大影响, 继而增加定量误差, 但增加D1也会明显增加测试时间。为保证被积分的信号强度与原子核数目完全成正比, 且控制测试时间, 通常D1设置为5倍的纵向弛豫时间(T1)。不同化合物以及同一化合物中不同信号峰的T1均不同。通过反转恢复法测定供试品溶液中δ 2.79甲基1H峰和δ 8.63芳香1H峰的T1, 结果分别为1.096 s和2.669 s。取最大T1, D1设置为15 s。
与其他定量技术通常要求S/N ≥ 10不同, 欧洲药典对qNMR S/N的要求是≥ 150, 另有文献[22]推荐S/N ≥ 250。首先选择90°脉冲(脉冲序列zg) 作为测定脉冲, 因为该角度可在xy平面上产生最大磁化强度。S/N与NS增加倍数的平方根成正比, 但NS越大测试时间越长。尝试NS为16、32、64和128次, 当NS为64次时, 0.1%浓度水平的D0杂质对照品溶液特征定量峰S/N为263.4, 因此不再增加NS次数。
2.2 1H qNMR方法学验证
2.2.1 线性与范围
特征定量峰线性方程为y = 2.690 4 x - 0.042 8 (r = 0.999 9)。表明在0.1%~2.0%内, 氘同位素杂质特征定量峰响应与其质量浓度线性关系良好。
2.2.2 定量限
0.1 mg·mL-1的D0杂质对照品溶液δ 2.79定量峰S/N为263.4, 表明方法定量限低至0.1%。
2.2.3 重复性
Atom% 1H和氘代率测定值的RSD (n = 6) 分别为3.1%和0.004%。表明方法重复性良好。
2.2.4 回收率
3个浓度水平下D0的平均加标回收率分别为103.7%、99.4%、101.8%, RSD (n = 3) 分别为1.3%、1.8%、0.9%。
3 两种方法的比较
分别将2种方法用于3批商业化样品的测定, 每批样品平行测定6次取平均值, 结果(表 3) 表明, 2种方法氘代率测定结果基本一致, 可相互佐证, 互为补充。2种测定方法均准确、灵敏, 无需对照品, 且样品无需准确称量, 可消除称量误差。其中1H NMR相对定量法分析时间更短, 操作和计算更为简单。但是相比于LC-MS法可同时测定氘代率以及各氘同位素的摩尔百分含量, 1H NMR相对定量法仅可测定最终的氘代率。
结论
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本研究建立了LC-MS法结合天然同位素校正和基于混合氘代溶剂的1H NMR相对定量法2种方法用于测定氘代抗肿瘤新药甲苯磺酸多纳非尼的关键质量属性氘代率, 其质量标准控制在≥ 99.0%。3批商业化样品测定结果显示, 2种方法测定结果基本一致, 且均符合标准规定。其中LC-MS法结果表明氘同位素杂质主要以不完全氘代杂质D2为主, 其次是非氘代杂质D0, 各氘化合物的相对含量并不服从天然同位素化合物所遵从的二项式分布。本研究建立的2种方法具有方法学参数可定量评价; 操作和计算简便; 分析时间短; 无需准确称量; 无需任何对照品的优势, 也为其他氘代药物氘代率的测定提供了新思路。
致谢: 苏州泽璟生物制药股份有限公司对本研究给予了支持与帮助。
作者贡献: 黄逸文设计、操作实验和撰写论文; 吴杨参与实验和数据分析; 程侠菊参与实验设计; 许奇和李艳梅参与数据分析; 钱叶飞整体指导和修改论文。
利益冲突: 本研究内容无任何利益冲突。
基金
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  • 国家药品标准制修订研究课题(2022Y09)
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2023年第58卷第10期
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doi: 10.16438/j.0513-4870.2023-0161
  • 接收时间：2023-02-15
  • 首发时间：2025-11-21
  • 出版时间：2023-10-12
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  • 收稿日期：2023-02-15
  • 修回日期：2023-05-21
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国家药品标准制修订研究课题(2022Y09)
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    1.苏州市药品检验检测研究中心, 江苏 苏州 215104
    2.苏州大学生物医学研究院, 江苏省感染与免疫重点实验室, 江苏 苏州 215127

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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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