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Article(id=1200383180432863941, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200383177295515678, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-0050, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1705420800000, receivedDateStr=2024-01-17, revisedDate=1713196800000, revisedDateStr=2024-04-16, acceptedDate=null, acceptedDateStr=null, onlineDate=1764123252255, onlineDateStr=2025-11-26, pubDate=1723392000000, pubDateStr=2024-08-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764123252255, onlineIssueDateStr=2025-11-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764123252255, creator=13701087609, updateTime=1764123252255, updator=13701087609, issue=Issue{id=1200383177295515678, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='8', pageStart='2183', pageEnd='2416', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764123251508, creator=13701087609, updateTime=1764225076631, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200810262870741499, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200383177295515678, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200810262870741500, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200383177295515678, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2337, endPage=2342, ext={EN=ArticleExt(id=1200383180814545614, articleId=1200383180432863941, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Separation and determination of chiral and achiral impurities in glimepiride tablets by supercritical fluid chromatography, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Separation and determination of chiral and achiral impurities in glimepiride tablets by supercritical fluid chromatography. Chiral and achiral impurities were separated on a ACQUITY UPC2 TrefoilTM CEL1 column (150 mm × 3.0 mm, 2.5 μm) maintained at 30 ℃ with the mobile phase containing a mixture of CO2 and methanol-isopropanol (1∶1) at 1 mL·min-1, and the detection wavelength was set at 228 nm. The back pressure was set at 13.8 MPa. The injection volume was 5 μL. In the chromatogram of the system suitability solution, the peaks elute in the following order: impurity Ⅳ, impurity Ⅴ, glimepiride, impurity Ⅲ, impurity Ⅰ and impurity Ⅱ. The six substances were separated successfully in 6 min using the proposed method with a resolution factor of 2.9, 1.6, 3.0, 2.0, 6.4. The impurity Ⅰ-Ⅴ detection limit (S/N = 3) was 0.17, 0.10, 0.06, 0.15, 0.10 μg·mL-1, respectively. Good linear relationship was established between the peak response and the concentration in the range of 0.48-51.30 μg·mL-1 for all impurities. The spiked recovery of impurity Ⅰ-Ⅴ was found to be acceptable for 99.9%, 98.9%, 102.1%, 100.1%, 96.3% (n = 9), respectively. The related substance and assay results of 11 sample batches are consistent with the results obtained using the HPLC method in the Chinese Pharmacopoeia. Compared to the two HPLC methods in the Chinese Pharmacopoeia, the established supercritical fluid chromatography method can simultaneously separate glimepiride and its 5 impurities in a single run, and it has the following advantages: simplified sample preparation, greatly reducing the volumes of organic solvents, environmentally friendly, high accuracy and good reproducibility. It can be employed for the quality control of the chiral and achiral impurities in glimepiride tablets.

, correspAuthors=Li-ju YU, Ming DENG, 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=Han CHEN, Li-ju YU, Yan-hua FENG, Si-li LIU, Li-li HUANG, Jian-ping ZHU, Ming DENG), CN=ArticleExt(id=1200383181619852004, articleId=1200383180432863941, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=超临界流体色谱法同时测定格列美脲片中手性和非手性杂质含量, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

建立了一种超临界流体色谱法同时分离和测定格列美脲片中手性和非手性杂质的含量。本方法选用Waters TrefoilTM CEL1色谱柱(150 mm × 3.0 mm, 2.5 μm); 流动相A (CO2)-流动相B (甲醇-异丙醇, 1∶1), 梯度洗脱, 流速为1 mL·min-1; 检测器波长为228 nm; 柱温: 30 ℃; 背压: 13.8 MPa; 进样量: 5 μL。系统适用性溶液中出峰顺序, 依次为杂质Ⅳ、顺式异构体(杂质Ⅴ)、格列美脲、杂质Ⅲ、杂质Ⅰ和杂质Ⅱ, 6个成分在6 min内完全分离, 分离度依次为2.9、1.6、3.0、2.0、6.4。杂质Ⅰ~Ⅴ的检出限分别为0.17、0.10、0.06、0.15、0.10 μg·mL-1; 线性范围均在0.48~51.30 μg·mL-1, 平均加标回收率分别为99.9%、98.9%、102.1%、100.1%、96.3% (n = 9)。11批次样品有关物质和含量测定结果与中国药典HPLC方法的测定结果基本一致。相较于中国药典两种HPLC方法, 建立的超临界流体色谱方法能一次同时分离格列美脲及其5个杂质, 具有前处理简单、极大幅度减少有机溶剂使用量、对环境友好、准确度高、重现性好等优点。本方法可同时测定格列美脲中手性和非手性杂质含量。

, correspAuthors=庾莉菊, 邓鸣, authorNote=null, correspAuthorsNote=
*庾莉菊, Tel: 86-10-53851601, E-mail: ;
邓鸣, Tel: 86-771-5828428, E-mail:
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No.Molecular formula /relative molecular massChP 2020USPEP 11.0BP 2024JP 18th
1 C19H25N3O6S/423.48 Impurity Ⅰ - - - -
2 C18H23N3O6S/409.46 Impurity Ⅱ Glimepiride related compound C; glimepiride urethane Impurity C Impurity C -
3 C16H21N3O4S/351.42 Impurity Ⅲ Glimepiride related compound B; glimepiride sulfonamide Impurity B Impurity B -
4 C24H34N4O5S/490.62 Impurity Ⅳ Glimepiride related compound D; glimepiride 3-isomer Impurity D Impurity D -
5 C24H34N4O5S/490.62 Impurity Ⅴ Glimepiride related compound A; glimepiride cis-isomer Impurity A Impurity A cis-Isomer
), ArticleFig(id=1201107067407917668, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200383180432863941, language=CN, label=Table 1, caption=

Impurities information of glimepiride in different pharmacopeias. -: Not listed specified impurities in the pharmacopeias

, figureFileSmall=null, figureFileBig=null, tableContent=
No.Molecular formula /relative molecular massChP 2020USPEP 11.0BP 2024JP 18th
1 C19H25N3O6S/423.48 Impurity Ⅰ - - - -
2 C18H23N3O6S/409.46 Impurity Ⅱ Glimepiride related compound C; glimepiride urethane Impurity C Impurity C -
3 C16H21N3O4S/351.42 Impurity Ⅲ Glimepiride related compound B; glimepiride sulfonamide Impurity B Impurity B -
4 C24H34N4O5S/490.62 Impurity Ⅳ Glimepiride related compound D; glimepiride 3-isomer Impurity D Impurity D -
5 C24H34N4O5S/490.62 Impurity Ⅴ Glimepiride related compound A; glimepiride cis-isomer Impurity A Impurity A cis-Isomer
), ArticleFig(id=1201107067495998055, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200383180432863941, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
AnalyteLinear range/μg·mL-1Calibration curverCorrection factorLOD/μg·mL-1LOQ/μg·mL-1
Glimepiride 0.50-49.65 Y = 14 639x + 3 316.6 0.999 9 1 / /
Impurity Ⅰ 0.50-50.30 Y = 17 030x + 1 172.6 0.999 9 0.86 0.17 0.58
Impurity Ⅱ 0.48-48.30 Y = 17 064x - 873.73 0.999 9 0.86 0.10 0.34
Impurity Ⅲ 0.51-50.70 Y = 19 115x + 4 486.3 0.999 9 0.77 0.06 0.21
Impurity Ⅳ 0.51-51.30 Y = 11 326x + 2 526.7 0.999 9 1.29 0.15 0.51
Impurity Ⅴ 0.51-50.90 Y = 16 829x + 1 172.6 0.999 9 0.87 0.10 0.32
), ArticleFig(id=1201107067579884140, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200383180432863941, language=CN, label=Table 2, caption=

The calibration curve, linear range, regression, LOD, LOQ of glimepiride and five impurities

, figureFileSmall=null, figureFileBig=null, tableContent=
AnalyteLinear range/μg·mL-1Calibration curverCorrection factorLOD/μg·mL-1LOQ/μg·mL-1
Glimepiride 0.50-49.65 Y = 14 639x + 3 316.6 0.999 9 1 / /
Impurity Ⅰ 0.50-50.30 Y = 17 030x + 1 172.6 0.999 9 0.86 0.17 0.58
Impurity Ⅱ 0.48-48.30 Y = 17 064x - 873.73 0.999 9 0.86 0.10 0.34
Impurity Ⅲ 0.51-50.70 Y = 19 115x + 4 486.3 0.999 9 0.77 0.06 0.21
Impurity Ⅳ 0.51-51.30 Y = 11 326x + 2 526.7 0.999 9 1.29 0.15 0.51
Impurity Ⅴ 0.51-50.90 Y = 16 829x + 1 172.6 0.999 9 0.87 0.10 0.32
), ArticleFig(id=1201107067705713262, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200383180432863941, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No.LotUPC2/%HPLC/%
Impurity ⅢOther total impurityGlimepirideImpurity ⅢOther total impurityGlimepiride
S1 62101736 0.14 0.16 100.6 0.13 0.19 99.3
S2 62102736 0.14 0.26 101.5 0.13 0.22 99.0
S3 62007717 0.18 0.16 99.5 0.19 0.21 98.3
S4 621027401 0.23 0.13 99.4 0.19 0.17 99.4
S5 62102739 0.14 0.15 97.5 0.14 0.13 100.0
S6 621027403 0.14 0.10 99.5 0.12 0.09 98.2
S7 62102701 0.14 0.13 96.3 0.11 0.10 97.1
S8 202011121 0.33 0.47 100.3 0.33 0.93 99.9
S9 20210203 0.24 0.20 97.2 0.26 0.21 99.7
S10 210114 0.09 0.78 97.4 0.14 0.58 97.7
S11 201110 0.19 0.25 94.0 0.19 0.23 101.4
), ArticleFig(id=1201107067844125297, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200383180432863941, language=CN, label=Table 3, caption=

The result of related substances and assay in glimepiride tablets employing UPC2 and HPLC

, figureFileSmall=null, figureFileBig=null, tableContent=
No.LotUPC2/%HPLC/%
Impurity ⅢOther total impurityGlimepirideImpurity ⅢOther total impurityGlimepiride
S1 62101736 0.14 0.16 100.6 0.13 0.19 99.3
S2 62102736 0.14 0.26 101.5 0.13 0.22 99.0
S3 62007717 0.18 0.16 99.5 0.19 0.21 98.3
S4 621027401 0.23 0.13 99.4 0.19 0.17 99.4
S5 62102739 0.14 0.15 97.5 0.14 0.13 100.0
S6 621027403 0.14 0.10 99.5 0.12 0.09 98.2
S7 62102701 0.14 0.13 96.3 0.11 0.10 97.1
S8 202011121 0.33 0.47 100.3 0.33 0.93 99.9
S9 20210203 0.24 0.20 97.2 0.26 0.21 99.7
S10 210114 0.09 0.78 97.4 0.14 0.58 97.7
S11 201110 0.19 0.25 94.0 0.19 0.23 101.4
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超临界流体色谱法同时测定格列美脲片中手性和非手性杂质含量
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陈瀚 1 , 庾莉菊 2, * , 奉艳花 1 , 刘思莉 3 , 黄丽丽 1 , 朱健萍 1 , 邓鸣 1, *
药学学报 | 研究论文 2024,59(8): 2337-2342
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药学学报 | 研究论文 2024, 59(8): 2337-2342
超临界流体色谱法同时测定格列美脲片中手性和非手性杂质含量
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陈瀚1, 庾莉菊2, * , 奉艳花1, 刘思莉3, 黄丽丽1, 朱健萍1, 邓鸣1, *
作者信息
  • 1.广西壮族自治区药品检验研究院, 广西 南宁 530021
  • 2.中国食品药品检定研究院, 国家药品监督管理局重点实验室-化学药品质量研究与评价重点实验室, 北京 102629
  • 3.桂林医学院药学院, 广西 桂林 541199

通讯作者:

*庾莉菊, Tel: 86-10-53851601, E-mail: ;
邓鸣, Tel: 86-771-5828428, E-mail:
Separation and determination of chiral and achiral impurities in glimepiride tablets by supercritical fluid chromatography
Han CHEN1, Li-ju YU2, * , Yan-hua FENG1, Si-li LIU3, Li-li HUANG1, Jian-ping ZHU1, Ming DENG1, *
Affiliations
  • 1. Guangxi Institute for Drug Control, Nanning 530021, China
  • 2. National Institutes for Food and Drug Control, Key Laboratory of National Medical Products Administration-Key Laboratory of Research and Evaluation of Chemical Drug Quality, Beijing 102629, China
  • 3. College of Pharmacy, GuiLin Medical University, Guilin 541199, China
出版时间: 2024-08-12 doi: 10.16438/j.0513-4870.2024-0050
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摘要
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建立了一种超临界流体色谱法同时分离和测定格列美脲片中手性和非手性杂质的含量。本方法选用Waters TrefoilTM CEL1色谱柱(150 mm × 3.0 mm, 2.5 μm); 流动相A (CO2)-流动相B (甲醇-异丙醇, 1∶1), 梯度洗脱, 流速为1 mL·min-1; 检测器波长为228 nm; 柱温: 30 ℃; 背压: 13.8 MPa; 进样量: 5 μL。系统适用性溶液中出峰顺序, 依次为杂质Ⅳ、顺式异构体(杂质Ⅴ)、格列美脲、杂质Ⅲ、杂质Ⅰ和杂质Ⅱ, 6个成分在6 min内完全分离, 分离度依次为2.9、1.6、3.0、2.0、6.4。杂质Ⅰ~Ⅴ的检出限分别为0.17、0.10、0.06、0.15、0.10 μg·mL-1; 线性范围均在0.48~51.30 μg·mL-1, 平均加标回收率分别为99.9%、98.9%、102.1%、100.1%、96.3% (n = 9)。11批次样品有关物质和含量测定结果与中国药典HPLC方法的测定结果基本一致。相较于中国药典两种HPLC方法, 建立的超临界流体色谱方法能一次同时分离格列美脲及其5个杂质, 具有前处理简单、极大幅度减少有机溶剂使用量、对环境友好、准确度高、重现性好等优点。本方法可同时测定格列美脲中手性和非手性杂质含量。

超临界流体色谱  /  格列美脲  /  有关物质  /  顺式异构体  /  含量测定

Separation and determination of chiral and achiral impurities in glimepiride tablets by supercritical fluid chromatography. Chiral and achiral impurities were separated on a ACQUITY UPC2 TrefoilTM CEL1 column (150 mm × 3.0 mm, 2.5 μm) maintained at 30 ℃ with the mobile phase containing a mixture of CO2 and methanol-isopropanol (1∶1) at 1 mL·min-1, and the detection wavelength was set at 228 nm. The back pressure was set at 13.8 MPa. The injection volume was 5 μL. In the chromatogram of the system suitability solution, the peaks elute in the following order: impurity Ⅳ, impurity Ⅴ, glimepiride, impurity Ⅲ, impurity Ⅰ and impurity Ⅱ. The six substances were separated successfully in 6 min using the proposed method with a resolution factor of 2.9, 1.6, 3.0, 2.0, 6.4. The impurity Ⅰ-Ⅴ detection limit (S/N = 3) was 0.17, 0.10, 0.06, 0.15, 0.10 μg·mL-1, respectively. Good linear relationship was established between the peak response and the concentration in the range of 0.48-51.30 μg·mL-1 for all impurities. The spiked recovery of impurity Ⅰ-Ⅴ was found to be acceptable for 99.9%, 98.9%, 102.1%, 100.1%, 96.3% (n = 9), respectively. The related substance and assay results of 11 sample batches are consistent with the results obtained using the HPLC method in the Chinese Pharmacopoeia. Compared to the two HPLC methods in the Chinese Pharmacopoeia, the established supercritical fluid chromatography method can simultaneously separate glimepiride and its 5 impurities in a single run, and it has the following advantages: simplified sample preparation, greatly reducing the volumes of organic solvents, environmentally friendly, high accuracy and good reproducibility. It can be employed for the quality control of the chiral and achiral impurities in glimepiride tablets.

supercritical fluid chromatography  /  glimepiride  /  related substance  /  cis-isomer  /  assay
陈瀚, 庾莉菊, 奉艳花, 刘思莉, 黄丽丽, 朱健萍, 邓鸣. 超临界流体色谱法同时测定格列美脲片中手性和非手性杂质含量. 药学学报, 2024 , 59 (8) : 2337 -2342 . DOI: 10.16438/j.0513-4870.2024-0050
Han CHEN, Li-ju YU, Yan-hua FENG, Si-li LIU, Li-li HUANG, Jian-ping ZHU, Ming DENG. Separation and determination of chiral and achiral impurities in glimepiride tablets by supercritical fluid chromatography[J]. Acta Pharmaceutica Sinica, 2024 , 59 (8) : 2337 -2342 . DOI: 10.16438/j.0513-4870.2024-0050
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格列美脲片是第三代磺酰脲类口服抗糖尿病药, 收载于《中华人民共和国药典》 (2020年版, ChP 2020)[1]二部、《美国药典》 (USP)[2]、《英国药典》(2024年版, BP 2024)[3]和《日本药典》 (18版, JP 18th)[4], 主药格列美脲收载于ChP 2020[5]、USP[6]、BP 2024[7]、JP 18th[8]和《欧洲药典》 (11版, EP 11.0)[9]。格列美脲及其杂质的结构见图 1, 各国药典杂质信息见表 1。在临床上应用的有确切疗效的是格列美脲反式异构体, 各国药典均采用正相HPLC控制格列美脲样品中的顺式异构体, 采用反相HPLC用于非手性杂质和含量测定的控制。国内文献[10-14]报道的格列美脲的分析策略基本与药典类似, 均需要两种液相方法, 用反相HPLC测定格列美脲样品的含量或非手性杂质, 用正相HPLC测定其顺式异构体, 但在色谱条件和样品制备等方面尚略有差异。国外有文献[15]报道反相液相色谱方法同时分析格列美脲样品中非手性杂质和顺式异构体, 格列美脲和其顺式异构体分离度仅为1.3, 且分析时长达到90 min。综合各国药典收载的方法和相关文献报道, 采用HPLC分离分析格列美脲中的非手性杂质和顺式异构体, 存在分离度低、有机试剂消耗高和分析时间较长等问题, 有待进一步提高。
超临界流体色谱法(supercritical fluid chromatography, SFC) 或超高效合相色谱法(ultra performance convergence chromatography, UPC2) 被视为是一种与HPLC相正交的色谱方法, 其优势在于分离对映异构体或结构相近的化合物[16-18], 广泛应用于制药、食品、化工等诸多领域。超临界状态的流体(常用二氧化碳) 的极性相当于正己烷[19], 流动相中加入不同比例的甲醇、乙醇等助溶剂能使其流体溶剂强度增大, 可应用于从非极性化合物到极性化合物的分离[20]。金薇等[21]用超临界流体色谱法分析了格列美脲顺式异构体, 但并未分离分析药典中控制的非手性杂质。国外亦未见超临界流体色谱法同时分离分析格列美脲的手性和非手性杂质方面的报道。本文建立6 min内能够同时测定格列美脲手性和非手性杂质的方法, 对格列美脲原料和制剂的质量控制均具有重要意义。
材料与方法
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仪器与试剂  Waters Acquity UPC2超高效合相色谱仪, PDA光电二极管阵列检测器(沃特世科技上海有限公司), XP205DR型十万分之一电子天平[梅特勒-托利多国际贸易(上海) 有限公司]。TrefoilTM系列色谱柱如下: ACQUITY UPC2 TrefoilTM AMY1、CEL1、CEL2, 色谱柱规格均为150 mm × 3.0 mm, 2.5 μm。甲醇、乙醇、乙腈、异丙醇均为色谱纯[赛默飞世尔科技(中国) 有限公司], 三氟乙酸为色谱纯(上海麦克林生化科技股份有限公司), 二乙胺、三乙胺和氨水为分析纯(国药集团化学试剂有限公司), 高纯二氧化碳纯度为99. 999% (广西瑞达化工科技有限公司)。
实验材料  格列美脲对照品(批号100674-201904, 纯度99.7%)、格列美脲杂质Ⅰ对照品(批号: 100781-201902)、格列美脲杂质Ⅱ对照品(批号: 101371-201501)、格列美脲杂质Ⅲ对照品(批号: 100675-201603)、格列美脲杂质Ⅳ对照品(批号: 101372-202002)、格列美脲杂质Ⅴ对照品(批号: 101373-201501) 均购自于中国食品药品检定研究院, 格列美脲片均为我院抽检样品, 生产企业1七批(S1~S7), 选取S6做方法学考察样品, 生产企业2一批(S8), 生产企业3一批(S9), 生产企业4两批(S10-S11)。
超临界流体色谱条件  色谱柱采用ACQUITY UPC2 TrefoilTM CEL1 (150 mm × 3.0 mm, 2.5 μm); 流动相A为二氧化碳, B为甲醇-异丙醇(1∶1), 梯度洗脱: 0~5 min, 72% A; 5~6 min, 72%~68% A; 6~8 min, 72%~68% A; 8~8.5 min, 68%~72% A; 8.5~10 min, 72% A。流速: 1 mL·min-1; 柱温: 30 ℃; 背压: 13.8 MPa; 检测波长: 228 nm; 进样量: 5 μL。
有关杂质溶液的制备
供试品溶液  取格列美脲片, 研细, 取细粉适量(约相当于格列美脲2 mg), 置10 mL量瓶中, 加甲醇适量, 超声使格列美脲溶解并定量稀释制成0.2 mg·mL-1的溶液。
对照溶液  精密量取供试品溶液1 mL, 置100 mL量瓶中, 用甲醇稀释至刻度, 摇匀, 即得。
对照品贮备溶液  精密称取格列美脲对照品10 mg, 加甲醇适量, 超声使格列美脲溶解并定量稀释制成20 μg·mL-1的溶液, 得格列美脲对照品贮备溶液。精密称取杂质Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ对照品各10 mg, 加甲醇适量, 超声使各杂质溶解并定量稀释制成20 μg·mL-1的溶液, 得混合杂质对照品贮备溶液。
混合对照溶液  精密量取格列美脲对照品贮备溶液和混合杂质对照品贮备溶液各1 mL, 置10 mL量瓶中, 用甲醇稀释至刻度, 摇匀, 即得。
系统适用性溶液  取格列美脲对照品约2 mg, 精密量取混合杂质对照品贮备溶液1 mL, 置10 mL量瓶中, 用甲醇稀释至刻度, 摇匀, 即得。
含量测定溶液的制备
供试品溶液  取格列美脲片20片, 研细, 精密称定, 取细粉适量(约相当于格列美脲10 mg), 加甲醇适量, 超声使格列美脲溶解并定量稀释制成40 μg·mL-1的溶液。
对照品溶液  取格列美脲对照品适量, 精密称定, 加甲醇适量, 超声使格列美脲溶解并定量稀释制成40 μg·mL-1的溶液。
专属性考察  分别取空白溶剂、系统适用性溶液、混合对照溶液和供试品溶液按“超临界流体色谱条件”进样检测, 记录色谱图。
线性范围、检出限和定量限  精密称取杂质Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ和格列美脲对照品各10 mg, 用甲醇制成质量浓度分别为99.30、100.60、96.60、101.40、102.60和101.80 μg·mL-1的混合溶液, 加甲醇稀释2、5、10、20、50、100和200倍, 得到不同浓度的线性溶液1~7, 按“超临界流体色谱条件”进样, 记录色谱图, 以峰面积(Y) 为纵坐标, 质量浓度(x, μg·mL-1) 为横坐标, 进行线性回归, 计算相关系数。线性溶液7进样5 μL, 以信噪比为3和10时, 计算杂质Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ的检测限和定量限。
精密度  取“有关杂质溶液的制备”项下系统适用性溶液按“超临界流体色谱条件”重复进样6次, 记录色谱图, 计算各待测物峰面积的RSD值。
重复性  取S6格列美脲片, 按“有关杂质溶液的制备”项下方法配制供试品溶液, 平行制备6份, 按“超临界流体色谱条件”测定。计算杂质Ⅲ及其他总杂含量的RSD值。
准确度  取S6格列美脲片, 研细, 取细粉适量(约相当于格列美脲2 mg), 置10 mL量瓶中, 共9份, 分为3组, 每组各加入“线性范围”项下线性2溶液0.8、1.0、1.2 mL, 加甲醇适量, 超声使格列美脲溶解, 放冷, 用甲醇稀释至刻度, 摇匀, 滤过, 取续滤液, 即得。按“超临界流体色谱条件”测定。记录色谱图及峰面积, 进行各待测物平均回收率计算。
稳定性  取“有关杂质溶液的制备”项下系统适用性溶液, 分别于配制后的0、2、4、6、10、15、20 h, 按“超临界流体色谱条件”进样, 记录色谱图, 计算各待测物峰面积RSD。
方法优化  考察了流速、进样量、背压和温度等参数的变动, 对格列美脲及5个杂质包括分离度、保留时间、峰型和拖尾因子等在内的色谱行为的影响。
统计学分析  采用GraphPad Prism 9进行统计学分析, 对两种方法测定结果分别做配对t检验, 比较两组之间的统计学差异, P < 0.05被认为数据之间存在显著性差异。
结果
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1 含量测定方法学考察
1.1 专属性
测得典型色谱图如图 2所示, 系统适用性溶液中出峰顺序依次为杂质Ⅳ、杂质Ⅴ、格列美脲、杂质Ⅲ、杂质Ⅰ及杂质Ⅱ, 分离度依次为2.9、1.6、3.0、2.0、6.4。样品中的杂质、空白溶剂均未干扰测定。
1.2 线性范围、检测限和定量限
格列美脲和5个杂质的线性回归方程、相关系数、检测限(LOD) 和定量限(LOQ) 结果见表 2, 均显示出良好的线性关系。
1.3 精密度
杂质Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ和格列美脲峰面积的相对标准偏差(RSD) 分别为1.7%、1.9%、1.3%、2.0%、2.1%和1.9%。结果表明仪器进样精密度良好。
1.4 重复性
杂质Ⅲ含量为0.14%, RSD为2.7%; 其他总杂含量为0.11%, RSD为3.5%。结果表明该方法重复性良好。
1.5 准确度
杂质Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ的平均回收率分别为99.9%、98.9%、102.1%、100.1%、96.3% (n = 9), 其RSD为1.6%、1.6%、1.4%、1.8%、1.5%。结果表明该方法准确度良好。
1.6 稳定性
杂质Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ和格列美脲峰面积的RSD分别为2.0%、2.5%、1.4%、2.3%、2.6%和2.2%。结果表明系统适用性溶液在20 h内稳定性良好。
1.7 方法优化
分别考察了0.8、1.0、1.5和2.0 mL·min-1 4种流速, 流速增加, 各杂质峰的保留时间提前, 当流速为1.5 mL·min-1以上时, 峰2与峰3、峰4和峰5的分离度逐渐降低, 不能完全分离, 0.8 mL·min-1时峰6出峰较晚, 拖尾因子较高, 故选择1.0 mL·min-1流速。
分别考察了1、2、5、10 μL进样量条件, 进样量为1、2 μL时, 各杂质峰响应较低; 进样量为5 μL时, 峰形对称且响应较好, 进样量为10 μL时, 峰形明显变宽, 峰2与峰3达不到基线分离, 故进样量选择5 μL。
分别考察了11.7、13.8和15.8 MPa等背压条件, 背压增大, 各杂质峰的保留时间均提前, 15.8 MPa下, 峰2与峰3达不到基线分离, 11.7 MPa下, 峰6拖尾因子不如13.8 MPa, 故背压为13.8 MPa。
分别考察了25、30、35、40 ℃等柱温条件, 结果发现, 柱温对6种物质有双向选择影响, 随柱温升高, 峰3、4出峰加快, 峰5、6保留时间增加, 峰1、2保留时间基本不变, 在35、40 ℃下峰2与峰3达不到基线分离, 在25 ℃下峰4与峰5达不到基线分离, 最佳柱温为30 ℃。
2 UPC2与HPLC的测定结果比较
取11批样品分别按“有关杂质溶液的制备”和“含量测定溶液的制备”项下方法配制, 按“超临界流体色谱条件”测定。采用ChP2020 HPLC方法测定其有关物质和含量, 11批格列美脲片有关物质和含量测定结果见表 3。两种方法测定的杂质Ⅲ、其他总杂和格列美脲含量结果分别做配对t检验, P值分别为0.720 0、0.620 2、0.471 4, 均无显著性差异。两种方法的杂质Ⅲ含量基本一致; 总体上其他总杂含量虽有差异, 但都在药典规定范围内。两种方法的测定结果基本一致, 可互为补充。
讨论
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本实验选取了6种色谱柱并结合6种溶剂进行初筛, 色谱柱分别是: Waters Trefoil AMY1、CEL1和CEL2, Daicel CHIRALPAK IA-3、IB-3和IH-3; 6种溶剂分别是: 甲醇、乙腈、乙醇、异丙醇、甲醇-异丙醇(1∶1)、乙醇-乙腈(1∶1)。结果显示: 在其他色谱条件不变的情况下, ①在甲醇-异丙醇(1∶1) 下CEL1色谱柱能出6个色谱峰, IB-3色谱柱分离出4个峰; ②在甲醇条件下CEL1分离出5个峰, CEL2和IH-3色谱柱分离出4个色谱峰; ③其余溶剂在色谱柱分离效果均不理想; 故最终选择CEL1色谱柱继续进行优化。
为获得最佳分离效果, 进一步优化助溶剂, 主要从以下三方面进行考察: ①改变助溶剂甲醇-异丙醇混合比例, 考察了甲醇-异丙醇(2∶1) 和甲醇-异丙醇(1∶2); ②针对格列美脲这一弱碱性化合物, 加入碱性添加剂, 考察甲醇-异丙醇(1∶1) 分别加入0.1%二乙胺、0.1%三乙胺和0.1%氨水; ③筛选其他添加剂, 考察甲醇-异丙醇(1∶1) 加入0.1%三氟乙酸, 以分离度和拖尾因子为指标筛选各助溶剂, 结果显示甲醇-异丙醇(1∶1) 效果最好。
本方法可在6 min内将格列美脲及其手性杂质和4个非手性杂质完全分离, 准确度高、重现性好, 适用于格列美脲片的有关物质、含量测定。相对ChP2020收载的格列美脲顺式异构体、有关物质、含量测定等HPLC方法而言, 新建的UPC2方法可同时测定顺式异构体、有关物质和含量测定, 结果与ChP2020 HPLC测定结果基本一致, 达到一测多评的效果, 可作为HPLC的互补方法, 具有快速准确, 分离效率高、环境友好的优势。本工作的开展为中国药典2020年版通则方法超临界流体色谱法在具体品种中的应用提供了实践案例, 也为绿色化学在手性和非手性杂质分离领域增添了应用实例。
作者贡献: 陈瀚、庾莉菊和邓鸣设计实验; 陈瀚、奉艳花、刘思莉和黄丽丽进行实验数据采集及处理; 朱健萍进行样品收集和相关资源保障; 陈瀚、庾莉菊和邓鸣撰写、修改论文。
利益冲突: 所有作者均声明本研究内容不存在利益冲突。
基金
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  • 中国食品药品检定研究院学科带头人培养基金(2021X3)
  • 广西药品监督管理局科研计划项目(桂药监科自[2022]038号(直属))
文献
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2024年第59卷第8期
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doi: 10.16438/j.0513-4870.2024-0050
  • 接收时间：2024-01-17
  • 首发时间：2025-11-26
  • 出版时间：2024-08-12
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  • 收稿日期：2024-01-17
  • 修回日期：2024-04-16
基金
中国食品药品检定研究院学科带头人培养基金(2021X3)
广西药品监督管理局科研计划项目(桂药监科自[2022]038号(直属))
作者信息
    1.广西壮族自治区药品检验研究院, 广西 南宁 530021
    2.中国食品药品检定研究院, 国家药品监督管理局重点实验室-化学药品质量研究与评价重点实验室, 北京 102629
    3.桂林医学院药学院, 广西 桂林 541199

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*庾莉菊, Tel: 86-10-53851601, E-mail: ;
邓鸣, Tel: 86-771-5828428, E-mail:
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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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