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Article(id=1239250710408253602, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239250701583446236, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2024.04.14, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1680537600000, receivedDateStr=2023-04-04, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773389993525, onlineDateStr=2026-03-13, pubDate=1714406400000, pubDateStr=2024-04-30, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773389993525, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773389993525, creator=13701087609, updateTime=1773389993525, updator=13701087609, issue=Issue{id=1239250701583446236, tenantId=1146029695717560320, journalId=1205117023404326918, year='2024', volume='44', issue='4', pageStart='553', pageEnd='736', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773389991422, creator=13701087609, updateTime=1773390513217, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239252890213209050, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239250701583446236, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239252890213209051, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239250701583446236, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=671, endPage=677, ext={EN=ArticleExt(id=1239250710794129579, articleId=1239250710408253602, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Determination of related substances in oxytocin for injection by HPLC-principal component self-control with correction factor, columnId=1206272757852074373, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Safety Monitoring, runingTitle=null, highlight=null, articleAbstract=
Objective:

To determine seven impurities in oxytocin for injection and investigate the limit values.

Methods:

HPLC and principal component self-control with correction factor were adopted. The determination was performed on a Waters Xbridge C18 column(150 mm×4.6 mm, 5 μm). The mobile phase consisted of 0.1 mol·L-1 dihydrogen phosphate solution (adjusted to pH 5.4)-acetonitrile (90∶10, phase A), and acetonitrile (phase B) with gradient elution at a flow rate of 1.5 mL·min-1. The column temperature was maintained at 32 ℃, and the detection wavelength was set at 220 nm. The injection volume was 100 μL. The linear equations of oxytocin, impurities Ac-Oxy, Oxy[Glu4], Oxy[+Gly10], Oxy[-NH2], Oxy[trisulfide], Oxy[cis-dimer] and Oxy[trans-dimer] were drawn. The correction factors of each impurity related to oxytocin were calculated by slope. The contents of impurities in 3 batches of oxytocin for injection were determined and compared with the results of impurity reference method.

Results:

The limits of quantification for seven impurities were 2.75-5.66 ng, while the detection limits were 1.38-2.83 ng. The linear ranges of seven impurities were 0.03-3.40 μg·mL-1 with good linearity(r>0.999). The correction factors of Ac-Oxy, Oxy[Glu4] and Oxy[-NH2] were 1.1, while the correction factors of Oxy[+Gly10] and Oxy[trisulfide] were 1.2 and 0.9, respectively. The correction factors of Oxy[cis-dimer] and Oxy[trans-dimer] were both 1.3. The seven impurities were determined in 3 batches of samples by principal component self-control with correction factor. The contents of impurity Ac-Oxy were 0.96%, 0.93% and 1.01%, respectively. The contents of impurity Oxy[Glu4] were 0.07%, 0.06% and 0.08%, respectively. The contents of impurity Oxy[+Gly10] were 0.07%, 0.04% and 0.04%, respectively. The contents of impurity Oxy[-NH2] were 0.09%, 0.05% and 0.07%, respectively. The contents of impurity Oxy[trans-dimer] were 0.27%, 0.18% and 0.22%, respectively. The maximum single impurity contents were 0.18%-0.19%, while the total impurity contents were 1.88%-2.06%. Compared the results measured by principal component self-control with correct factor method and the impurity reference method, there was no significant difference between two methods (p>0.05).

Conclusion:

The method is proved to be simple, repeatable and accurate for the content determination of related substances in oxytocin for injection.

, correspAuthors=Li-ming TANG, 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=Ping LIU, Jun-pei FAN, Jian-qin GU, Jie SUN, Xiu-xiu DOU, Li-ming TANG), CN=ArticleExt(id=1239250711628796121, articleId=1239250710408253602, tenantId=1146029695717560320, journalId=1205117023404326918, language=CN, title=高效液相色谱加校正因子主成分对照法测定注射用缩宫素中有关物质的含量, columnId=1206272758036623764, journalTitle=药物分析杂志, columnName=安全监测, runingTitle=null, highlight=null, articleAbstract=
目的：

测定缩宫素原料药中7个杂质的有关物质含量并对其限度进行探讨。

方法：

采用高效液相色谱加校正因子的主成分自身对照法进行测定。采用Waters Xbridge C18(150 mm×4.6 mm，5 μm)色谱柱，以0.1 mol·L-1磷酸盐缓冲液(pH 5.4)-乙腈(90∶10)为流动相A，乙腈为流动相B，梯度洗脱，流速1.5 mL·min-1，柱温32 ℃，检测波长220 nm，进样量100 μL。绘制缩宫素和杂质Ac-缩宫素、[Glu4]缩宫素、[+Gly10]缩宫素、缩宫素[-NH2]、[trisulfide]缩宫素、[cis-dimer]缩宫素和[trans-dimer]缩宫素的线性方程，以斜率计算7个杂质相对于缩宫素的校正因子，测定3批缩宫素原料药中各杂质含量，并与杂质对照品外标法测得的结果进行比较。

结果：

7个缩宫素杂质的定量限在2.75~5.66 ng，检测限在1.38~2.83 ng。各杂质质量浓度在0.03~3.40 μg·mL-1范围内，与相应的峰面积均呈良好线性(r>0.999)。相对于缩宫素，Ac-缩宫素、[Glu4]缩宫素和缩宫素[-NH2]的校正因子为1.1，[+Gly10]缩宫素的校正因子为1.2，[trisulfide]缩宫素的校正因子为0.9，[cis-dimer]缩宫素和[trans-dimer]缩宫素的校正因子为1.3。采用加校正因子的主成分自身对照法，测得3批缩宫素原料药中杂质Ac-缩宫素的含量分别为0.96%、0.93%和1.01%；杂质[Glu4]缩宫素的含量分别为0.07%、0.06%和0.08%；杂质[+Gly10]缩宫素的含量分别为0.07%、0.04%和0.04%；杂质缩宫素[-NH2]的含量分别为0.09%、0.05%和0.07%；杂质[trans-dimer]缩宫素的含量分别为0.27%、0.18%和0.22%。其他单个最大杂质含量为0.18%~0.19%，总杂质含量为1.88%~2.06%。比较采用加校正因子的主成分自身对照法和外标法测得的结果，2种方法的测定结果无统计学差异(p>0.05)。

结论：

本方法操作简单，可重复性高，能准确、有效地测定缩宫素中有关物质的含量。

, correspAuthors=唐黎明, authorNote=null, correspAuthorsNote=
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1.杂质Oxy[Glu4](impurity Oxy[Glu4])　2.杂质Oxy[+Gly10] (impurity Oxy [+Gly10])　3.缩宫素(oxytocin)　4.杂质Ac-Oxy(impurity Ac-Oxy)

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1.杂质Oxy[Glu4](impurity Oxy[Glu4])　2.杂质Oxy[-NH2](impurity Oxy[-NH2])　3.杂质Oxy[+Gly10](impurity Oxy[+Gly10])　4.缩宫素(oxytocin)　5.杂质Ac-Oxy(impurity Ac-Oxy)　6.杂质Oxy[trans-dimer](impurity Oxy[trans-dimer])

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The names and structures of seven impurities of oxytocin

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编号
(number)		名称
(name)		结构式
(structure)
1Ac-缩宫素(Ac-Oxy)Ac-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2(1，6二硫键)(Disulfide Bridge：1-6)
2[Glu4]缩宫素(Oxy[Glu4])Cys-Tyr-Ile-Glu-Asn-Cys-Pro-Leu-Gly-NH2(1，6二硫键)(Disulfide Bridge：1-6)
3[+Gly10]缩宫素(Oxy[+Gly10])Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-Gly-NH2(1，6二硫键)(Disulfide Bridge：1-6)
4缩宫素[-NH2] (Oxy[-NH2])Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly
5[trisulfide]缩宫素(Oxy[trisulfide])Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2(1，6-三硫键)(Trisulfide Bridge：1-6)
6[cis-dimer]缩宫素(Oxy[cis-dimer])Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2(1，1二硫键/6，6-二硫键) (Disulfide Bridge：1-1/Disulfide Bridge：6-6)
7[trans-dimer]缩宫素(Oxy[trans-dimer])Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2(1，6二硫键/1，6-二硫键)(Disulfide Bridge：1-6/Disulfide Bridge：1-6)
), ArticleFig(id=1239250718507455056, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250710408253602, language=CN, label=表1, caption=

缩宫素原料药中的7个杂质名称及结构式

, figureFileSmall=null, figureFileBig=null, tableContent=
编号
(number)		名称
(name)		结构式
(structure)
1Ac-缩宫素(Ac-Oxy)Ac-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2(1，6二硫键)(Disulfide Bridge：1-6)
2[Glu4]缩宫素(Oxy[Glu4])Cys-Tyr-Ile-Glu-Asn-Cys-Pro-Leu-Gly-NH2(1，6二硫键)(Disulfide Bridge：1-6)
3[+Gly10]缩宫素(Oxy[+Gly10])Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-Gly-NH2(1，6二硫键)(Disulfide Bridge：1-6)
4缩宫素[-NH2] (Oxy[-NH2])Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly
5[trisulfide]缩宫素(Oxy[trisulfide])Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2(1，6-三硫键)(Trisulfide Bridge：1-6)
6[cis-dimer]缩宫素(Oxy[cis-dimer])Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2(1，1二硫键/6，6-二硫键) (Disulfide Bridge：1-1/Disulfide Bridge：6-6)
7[trans-dimer]缩宫素(Oxy[trans-dimer])Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2(1，6二硫键/1，6-二硫键)(Disulfide Bridge：1-6/Disulfide Bridge：1-6)
), ArticleFig(id=1239250718616506967, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250710408253602, language=EN, label=Tab.2, caption=

Mobile phase gradient elution program for determination of related substances

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时间
(time)/min		流动相比例(ratio of mobile phase)/%
流动相(mobile phase) A流动相(mobile phase) B
0955
0~1095→855→15
10~1285→7515→25
12~157525
15~15.175→9525→5
15.1~18955
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有关物质测定流动相梯度洗脱程序

, figureFileSmall=null, figureFileBig=null, tableContent=
时间
(time)/min		流动相比例(ratio of mobile phase)/%
流动相(mobile phase) A流动相(mobile phase) B
0955
0~1095→855→15
10~1285→7515→25
12~157525
15~15.175→9525→5
15.1~18955
), ArticleFig(id=1239250718905913954, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250710408253602, language=EN, label=Tab.3, caption=

The linear equations and the relative correction factors of oxytocin and seven impurities

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		线性范围
(linear range)/(μg·mL-1)		线性方程
(regression equation)		r相对校正因子
(relative correction factor)
混合线性系列溶液Ⅰ
(mixed linear solution Ⅰ)
(n=4)		缩宫素(oxytocin)0.02~1.10Y=6.417 6×104X-65.040 41.0001.0
Ac-Oxy0.03~1.65Y=5.805 6×104X+4.380 4×1030.999 91.1
Oxy[Glu4]0.03~1.79Y=5.586 6×104X-0.816 11.0001.1
Oxy[+Gly10]0.03~1.68Y=5.220 3×104X-465.833 31.0001.2
Oxy[-NH2]0.03~1.67Y=5.869 6×104X-71.186 71.0001.1
Oxy[trisulfide]0.03~1.66Y=7.173 5×104X+188.408 61.0000.9
混合线性系列溶液Ⅱ
(mixed linear solution Ⅱ)
(n=8)		缩宫素(oxytocin)0.06~3.00Y=6.275 7×104X-877.412 91.0001.0
Oxy[cis-dimer]0.07~3.30Y=4.865 4×104X-2.138 1×1030.999 91.3
Oxy[trans-dimer]0.07~3.40Y=4.679 1×104X-2.085 4×1030.999 71.3
), ArticleFig(id=1239250719019160166, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250710408253602, language=CN, label=表3, caption=

缩宫素及7个杂质的线性方程及相对校正因子

, figureFileSmall=null, figureFileBig=null, tableContent=
化合物
(compound)		线性范围
(linear range)/(μg·mL-1)		线性方程
(regression equation)		r相对校正因子
(relative correction factor)
混合线性系列溶液Ⅰ
(mixed linear solution Ⅰ)
(n=4)		缩宫素(oxytocin)0.02~1.10Y=6.417 6×104X-65.040 41.0001.0
Ac-Oxy0.03~1.65Y=5.805 6×104X+4.380 4×1030.999 91.1
Oxy[Glu4]0.03~1.79Y=5.586 6×104X-0.816 11.0001.1
Oxy[+Gly10]0.03~1.68Y=5.220 3×104X-465.833 31.0001.2
Oxy[-NH2]0.03~1.67Y=5.869 6×104X-71.186 71.0001.1
Oxy[trisulfide]0.03~1.66Y=7.173 5×104X+188.408 61.0000.9
混合线性系列溶液Ⅱ
(mixed linear solution Ⅱ)
(n=8)		缩宫素(oxytocin)0.06~3.00Y=6.275 7×104X-877.412 91.0001.0
Oxy[cis-dimer]0.07~3.30Y=4.865 4×104X-2.138 1×1030.999 91.3
Oxy[trans-dimer]0.07~3.40Y=4.679 1×104X-2.085 4×1030.999 71.3
), ArticleFig(id=1239250719144989293, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250710408253602, language=EN, label=Tab.4, caption=

The determination results of related substances

, figureFileSmall=null, figureFileBig=null, tableContent=
杂质
(impurity)		相对保留时间
(relative retention time)		含量(content)/%
批号1(lot No.1)批号2(lot No.2)批号3(lot No.3)
ⅠⅡⅠⅡⅠⅡ
Ac-Oxy1.260.960.910.930.881.010.95
Oxy[Glu4]0.820.070.070.060.060.080.08
Oxy[+Gly10]0.950.070.090.040.050.040.05
Oxy[-NH2]0.870.090.080.050.050.070.06
Oxy[trans-dimer]1.580.270.320.180.210.220.26
), ArticleFig(id=1239250719224681074, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250710408253602, language=CN, label=表4, caption=

有关物质测定结果

, figureFileSmall=null, figureFileBig=null, tableContent=
杂质
(impurity)		相对保留时间
(relative retention time)		含量(content)/%
批号1(lot No.1)批号2(lot No.2)批号3(lot No.3)
ⅠⅡⅠⅡⅠⅡ
Ac-Oxy1.260.960.910.930.881.010.95
Oxy[Glu4]0.820.070.070.060.060.080.08
Oxy[+Gly10]0.950.070.090.040.050.040.05
Oxy[-NH2]0.870.090.080.050.050.070.06
Oxy[trans-dimer]1.580.270.320.180.210.220.26
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高效液相色谱加校正因子主成分对照法测定注射用缩宫素中有关物质的含量
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刘萍 , 范俊沛 , 顾建琴 , 孙杰 , 窦秀秀 , 唐黎明 *
药物分析杂志 | 安全监测 2024,44(4): 671-677
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药物分析杂志 | 安全监测 2024, 44(4): 671-677
高效液相色谱加校正因子主成分对照法测定注射用缩宫素中有关物质的含量
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刘萍 , 范俊沛, 顾建琴, 孙杰, 窦秀秀, 唐黎明*
作者信息
  • 上海市食品药品检验研究院，上海 201203

    • Tel：(021)50798172；E-mail：

通讯作者:

* Tel：(021)50798172；E-mail：
Determination of related substances in oxytocin for injection by HPLC-principal component self-control with correction factor
Ping LIU , Jun-pei FAN, Jian-qin GU, Jie SUN, Xiu-xiu DOU, Li-ming TANG*
Affiliations
  • Shanghai Institute for Food and Drug Control, Shanghai 201203, China
出版时间: 2024-04-30 doi: 10.16155/j.0254-1793.2024.04.14
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摘要
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目的：

测定缩宫素原料药中7个杂质的有关物质含量并对其限度进行探讨。

方法：

采用高效液相色谱加校正因子的主成分自身对照法进行测定。采用Waters Xbridge C18(150 mm×4.6 mm，5 μm)色谱柱，以0.1 mol·L-1磷酸盐缓冲液(pH 5.4)-乙腈(90∶10)为流动相A，乙腈为流动相B，梯度洗脱，流速1.5 mL·min-1，柱温32 ℃，检测波长220 nm，进样量100 μL。绘制缩宫素和杂质Ac-缩宫素、[Glu4]缩宫素、[+Gly10]缩宫素、缩宫素[-NH2]、[trisulfide]缩宫素、[cis-dimer]缩宫素和[trans-dimer]缩宫素的线性方程，以斜率计算7个杂质相对于缩宫素的校正因子，测定3批缩宫素原料药中各杂质含量，并与杂质对照品外标法测得的结果进行比较。

结果：

7个缩宫素杂质的定量限在2.75~5.66 ng，检测限在1.38~2.83 ng。各杂质质量浓度在0.03~3.40 μg·mL-1范围内，与相应的峰面积均呈良好线性(r>0.999)。相对于缩宫素，Ac-缩宫素、[Glu4]缩宫素和缩宫素[-NH2]的校正因子为1.1，[+Gly10]缩宫素的校正因子为1.2，[trisulfide]缩宫素的校正因子为0.9，[cis-dimer]缩宫素和[trans-dimer]缩宫素的校正因子为1.3。采用加校正因子的主成分自身对照法，测得3批缩宫素原料药中杂质Ac-缩宫素的含量分别为0.96%、0.93%和1.01%；杂质[Glu4]缩宫素的含量分别为0.07%、0.06%和0.08%；杂质[+Gly10]缩宫素的含量分别为0.07%、0.04%和0.04%；杂质缩宫素[-NH2]的含量分别为0.09%、0.05%和0.07%；杂质[trans-dimer]缩宫素的含量分别为0.27%、0.18%和0.22%。其他单个最大杂质含量为0.18%~0.19%，总杂质含量为1.88%~2.06%。比较采用加校正因子的主成分自身对照法和外标法测得的结果，2种方法的测定结果无统计学差异(p>0.05)。

结论：

本方法操作简单，可重复性高，能准确、有效地测定缩宫素中有关物质的含量。

缩宫素  /  有关物质检测  /  高效液相色谱法  /  加校正因子的主成分自身对照法  /  已知杂质
Objective:

To determine seven impurities in oxytocin for injection and investigate the limit values.

Methods:

HPLC and principal component self-control with correction factor were adopted. The determination was performed on a Waters Xbridge C18 column(150 mm×4.6 mm, 5 μm). The mobile phase consisted of 0.1 mol·L-1 dihydrogen phosphate solution (adjusted to pH 5.4)-acetonitrile (90∶10, phase A), and acetonitrile (phase B) with gradient elution at a flow rate of 1.5 mL·min-1. The column temperature was maintained at 32 ℃, and the detection wavelength was set at 220 nm. The injection volume was 100 μL. The linear equations of oxytocin, impurities Ac-Oxy, Oxy[Glu4], Oxy[+Gly10], Oxy[-NH2], Oxy[trisulfide], Oxy[cis-dimer] and Oxy[trans-dimer] were drawn. The correction factors of each impurity related to oxytocin were calculated by slope. The contents of impurities in 3 batches of oxytocin for injection were determined and compared with the results of impurity reference method.

Results:

The limits of quantification for seven impurities were 2.75-5.66 ng, while the detection limits were 1.38-2.83 ng. The linear ranges of seven impurities were 0.03-3.40 μg·mL-1 with good linearity(r>0.999). The correction factors of Ac-Oxy, Oxy[Glu4] and Oxy[-NH2] were 1.1, while the correction factors of Oxy[+Gly10] and Oxy[trisulfide] were 1.2 and 0.9, respectively. The correction factors of Oxy[cis-dimer] and Oxy[trans-dimer] were both 1.3. The seven impurities were determined in 3 batches of samples by principal component self-control with correction factor. The contents of impurity Ac-Oxy were 0.96%, 0.93% and 1.01%, respectively. The contents of impurity Oxy[Glu4] were 0.07%, 0.06% and 0.08%, respectively. The contents of impurity Oxy[+Gly10] were 0.07%, 0.04% and 0.04%, respectively. The contents of impurity Oxy[-NH2] were 0.09%, 0.05% and 0.07%, respectively. The contents of impurity Oxy[trans-dimer] were 0.27%, 0.18% and 0.22%, respectively. The maximum single impurity contents were 0.18%-0.19%, while the total impurity contents were 1.88%-2.06%. Compared the results measured by principal component self-control with correct factor method and the impurity reference method, there was no significant difference between two methods (p>0.05).

Conclusion:

The method is proved to be simple, repeatable and accurate for the content determination of related substances in oxytocin for injection.

oxytocin  /  related substances  /  HPLC  /  principal component self-control with correct factor  /  known impurities
刘萍, 范俊沛, 顾建琴, 孙杰, 窦秀秀, 唐黎明. 高效液相色谱加校正因子主成分对照法测定注射用缩宫素中有关物质的含量. 药物分析杂志, 2024 , 44 (4) : 671 -677 . DOI: 10.16155/j.0254-1793.2024.04.14
Ping LIU, Jun-pei FAN, Jian-qin GU, Jie SUN, Xiu-xiu DOU, Li-ming TANG. Determination of related substances in oxytocin for injection by HPLC-principal component self-control with correction factor[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (4) : 671 -677 . DOI: 10.16155/j.0254-1793.2024.04.14
正文
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缩宫素(oxytocin)，又名催产素，是一种由6个氨基酸组成的环状结构与3个氨基酸组成的侧链结构构成的具有生物活性的多肽产品[1]。临床主要用于促进分娩和引产，也可用于防治产后出血。缩宫素最初由动物神经垂体中提取制得，自20世纪50年代开始逐步采用液相法完成了缩宫素的全合成。国内的缩宫素注射剂目前多以合成缩宫素为原料[2-3]。
因环境温度和pH的变化，缩宫素在制备和贮藏过程中较易产生杂质，如脱酰胺杂质、乙酰化杂质、三硫化物等[4]。不同杂质引入药物成品都可能导致临床用药安全问题，因此在缩宫素的原料药合成和制剂阶段均需对缩宫素有关物质的含量进行严格控制。目前，2020年版《中华人民共和国药典》[5]、美国药典(USP 43-NF 38)[6]和欧洲药典(EP 11.0)[7]等国内外药典均只对注射用缩宫素的单一杂质和总杂质量进行限制，并未涉及不同杂质的具体限值。现有的国内缩宫素相关物质研究也大多局限于此[1，8]。缩宫素注射液有杂质个数多和变化多[8]的特点，且因制备工艺不同，不同企业缩宫素原料药中的杂质也各不相同[9-11]，这就提示相关部门应尽快制定具有针对性的质量标准，更精准、有效地控制缩宫素原料药中的主要杂质，提升产品的质量和安全性。
王振平等[4]于2020年发布了缩宫素多种杂质的高效液相色谱(HPLC)分离方法。该方法采用HPLC法即可对缩宫素原料及制剂中的相关杂质进行有效分离和含量测定。本研究在该方法基础上进一步测定了其中7个杂质(见表1)的含量。通过加校正因子的主成分自身对照法，探讨线性范围的选择对缩宫素不同杂质限度的影响，并与杂质外标法结果进行比较，检验该方法的实用性和可靠性。为保证缩宫素临床用药安全，修订有关物质限值标准提供了重要的参考依据。
1　仪器与试药
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1.1　仪器
1260型高效液相色谱仪(Agilent公司)；Waters Xbridge C18(150 mm×4.6 mm，5 μm)色谱柱；XS205DU型电子分析天平(0.01 mg，Mettler Toledo公司)；MettlerSevenEasy pH仪(Mettler Toledo公司)。
1.2　试药
缩宫素工作对照品(批号160191204，含量87.3%)、Ac-Oxy对照品(批号16A200603，含量92.0%)、Oxy[Glu4]对照品(批号16A190809，含量91.8%)、Oxy[+Gly10]对照品(批号16A190808，含量89.4%)、Oxy[-NH2]对照品(批号16A191214，含量92.4%)、Oxy[trisulfide]对照品(批号PA4408，含量89.6%)、Oxy[cis-dimer]对照品(批号16A190811F，含量91.2%)、Oxy[trans-dimer]对照品(批号PA4407，含量96.4%)及三批缩宫素原料药(批号160200911、160200912和160200913)均来自上海上药第一生化药业有限公司。乙腈为色谱纯，水为超纯水，其他试剂均为分析纯。
2　方法与结果
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2.1　色谱条件
采用Waters Xbridge C18(150 mm×4.6 mm，5 μm)色谱柱，以0.1 mol·L-1磷酸二氢钠溶液(取磷酸二氢钠46.8 g，加入超纯水2 000 mL，用1 mol·L-1氢氧化钠溶液调节pH至5.4，加超纯水至3 000 mL)-乙腈(90∶10)为流动相A，乙腈为流动相B，梯度洗脱(洗脱程序见表2)，流速1.5 mL·min-1，柱温32 ℃，检测波长220 nm，进样量100 μL。
2.2　溶液的制备
2.2.1　缩宫素对照品储备液
称取缩宫素工作对照品适量，2份，分别置于50 mL量瓶中，用稀释液(超纯水)定量稀释，制得缩宫素对照品储备液1(约0.2 mg·mL-1)和储备液2(约0.3 mg·mL-1)。
2.2.2　杂质对照品储备液
称取7个杂质对照品适量，分别置于50 mL量瓶中，用超纯水定量稀释，制成约0.3 mg·mL-1的单一杂质溶液，作为各杂质对照品储备液。
2.2.3　供试品溶液
称取缩宫素原料药适量，精密称定，加超纯水溶解并稀释制成每1 mL中约含0.02 mg的溶液，即得。
2.2.4　自身对照溶液
精密量取供试品溶液1 mL，置于100 mL量瓶中，用超纯水稀释至刻度，摇匀，即得。
2.2.5　系统适用性溶液
称取杂质Oxy[Glu4]、Oxy[+Gly10]、Ac-Oxy的对照品与缩宫素工作对照品适量，加超纯水溶解制成每1 mL中约含Oxy[Glu4] 0.2 μg、Oxy[+Gly10] 0.2 μg、Ac-Oxy 0.2 μg和缩宫素20 μg的混合溶液，即得。
2.2.6　混合线性溶液
取缩宫素对照品储备液1和5个杂质(Ac-Oxy、Oxy[Glu4]、Oxy[+Gly10]、Oxy[-NH2]、Oxy[trisulfide])的对照品储备液各2 mL，置于同一20 mL量瓶中，加超纯水稀释至刻度，摇匀，即得混合线性溶液Ⅰ；取该溶液逐步稀释，加超纯水制成缩宫素浓度约为供试品溶液浓度0.1%、0.4%、1.0%、6.0%、40%、60%、100%，5个杂质约为供试品溶液浓度0.15%、0.6%、1.5%、9.0%、60%、90%、150%的混合线性系列溶液Ⅰ(n=7)。另取缩宫素对照品储备液2和2个杂质(Oxy[cis-dimer]和Oxy[trans-dimer])的对照品储备液各2 mL，置于同一20 mL量瓶中，加超纯水定量稀释制成缩宫素约0.03 mg·mL-1的混合线性溶液Ⅱ，取该溶液逐步稀释，制成缩宫素和2个杂质浓度约为供试品溶液浓度0.3%、0.45%、0.75%、1.5%、3.0%、6.0%、12%、15%的混合线性系列溶液Ⅱ(n=8)。
2.3　方法专属性试验
取稀释液(超纯水)和系统适用性溶液各100 μL，注入液相色谱仪，色谱图见图1。如图可见该方法专属性良好，缩宫素主峰与相邻杂质峰分离度均符合要求。
2.4　检测限和定量限
取缩宫素对照品储备液1和5个杂质(Ac-Oxy、Oxy[Glu4]、Oxy[+Gly10]、Oxy[-NH2]、Oxy[trisulfide])的对照品储备液适量，逐级稀释，最低分别稀释至10 000倍和20 000倍，作为定量限和检测限溶液。取杂质Oxy[cis-dimer]和Oxy[trans-dimer]的对照品储备液适量，逐级稀释，最低分别稀释至6 000倍和12 000倍，作为定量限和检测限溶液。按“2.1”项下色谱条件进样，记录色谱图。以信号约为基线噪音的3倍时测得的浓度作为检测限，以信号约为基线噪音的10倍时测得的浓度作为定量限。结果显示，缩宫素的定量限与检测限分别为1.84 ng与0.92 ng；杂质Ac-Oxy的定量限与检测限分别为2.75 ng与1.38 ng；杂质Oxy[Glu4]的定量限与检测限分别为2.99 ng与1.50 ng；杂质Oxy[+Gly10]的定量限与检测限分别为2.81 ng与1.41 ng；杂质Oxy[-NH2]的定量限与检测限分别为2.79 ng与1.40 ng；杂质Oxy[trisulfide]的定量限与检测限分别为2.76 ng与1.38 ng；杂质Oxy[cis-dimer]的定量限与检测限分别为5.49 ng与2.75 ng；杂质Oxy[trans-dimer]的定量限与检测限分别为5.66 ng与2.83 ng。
2.5　线性关系和相对校正因子考察
取“2.2.6”项下混合线性系列溶液Ⅰ(n=7)和混合线性系列溶液Ⅱ(n=8)各100 μL，按照“2.1”项下色谱条件进样测定，记录色谱图，以质量浓度(X，μg·mL-1)为横坐标，峰面积(Y)为纵坐标，得缩宫素及7个杂质的线性回归方程。以7个杂质的回归方程斜率计算7个杂质相对于缩宫素的校正因子。根据杂质在供试品中的含量确定计算相对校正因子时适合的线性范围，选择供试品溶液浓度0.15%~9.0%作为混合线性系列溶液Ⅰ的线性范围(n=4)，供试品溶液浓度0.30%~15.0%作为混合线性系列溶液Ⅱ的线性范围(n=8)，得到7个杂质线性回归方程及相对校正因子，见表3。结果表明，各杂质浓度在相应的线性范围内，与峰面积均呈良好的线性关系(r>0.999)。
2.6　溶液的稳定性
取混合线性系列溶液Ⅰ(n=7)的7个浓度溶液和混合线性系列溶液Ⅱ(n=8)的8个浓度溶液，按“2.1”项下色谱条件进样测定，在10 ℃进样器内放置24 h后再次测定。混合线性系列溶液中各杂质的线性斜率和相对缩宫素的校正因子无明显变化，表明混合线性系列溶液于10 ℃放置时，在24 h内稳定性良好。
2.7　精密度试验
2.7.1　进样精密度
分别取缩宫素对照品储备液1和7个杂质的对照品储备液，加超纯水逐级稀释至浓度分别为供试品溶液浓度1.0%和1.5%的溶液。按“2.1”项下色谱条件，将上述溶液连续进样6次，计算峰面积的RSD。结果显示缩宫素峰面积的RSD为0.23%，各杂质峰面积的RSD均<5%，该方法进样精密度良好。
2.7.2　中间精密度
分别以不同实验人员(2人)、不同仪器(Agilent 1260和Waters e2695液相色谱仪)按“2.1”项下条件，检测并计算缩宫素和7个杂质的线性回归方程及相对校正因子。结果表明7个杂质相对于缩宫素的校正因子基本一致。该方法的中间精密度良好。
2.8　有关物质检测结果
将3批缩宫素原料药按照“2.2.3”和“2.2.4”项下方法，制成供试品溶液和自身对照溶液，取100 μL注入液相色谱仪，记录色谱图。供试品溶液色谱图中如有杂质峰，分别按加校正因子的主成分自身对照法和杂质外标法计算各杂质含量。3批缩宫素原料药的有关物质含量测定结果见表4。供试品溶液和自身对照溶液图谱见图2。
运用统计软件SPSS 19.0，通过单因素方差分析对2种方法得出的有关物质含量结果进行比较。结果显示2种方法计算所得的结果不存在统计学差异(p>0.05)。3批缩宫素原料药的其他单个最大杂质分别为0.18%、0.19%和0.19%，杂质总量分别为2.03%、1.88%和2.06%。
3　讨论
收起
3.1　线性范围的选择
本研究发现，缩宫素和杂质的线性范围选择对含量结果和相对校正因子有较大影响。由于7个杂质在缩宫素原料药中的实际含量较低，单个最大杂质均在2.0%以内，因此选择供试品溶液浓度0.15%~9.0%作为杂质的线性范围(n=4)。但是在研究过程中发现，杂质Oxy[cis-dimer]和Oxy [trans-dimer]的定量限分别为5.49 ng和5.66 ng，在供试品溶液浓度0.15%水平无法准确定量。同时，取4个点拟合线性曲线可能过少，造成这2个杂质的线性曲线斜率极不稳定。因此，本研究重新选择供试液溶液浓度0.3%~15.0%的8个点对杂质Oxy[cis-dimer]和Oxy[trans-dimer]进行线性拟合，双人双仪器考察后发现这2个杂质的相对校正因子均为1.3，方法稳定，可重复性较原方法有了显著提高。
由于缩宫素杂质个数多，检测限和定量限各有不同，因此在计算相对校正因子时，应根据杂质的自身特点建立不同范围的线性回归方程[12]。本研究发现当相对校正因子的范围为0.9~1.1时，取较少的浓度个数(n<6)进行线性拟合时不会对结果产生显著影响。但是当相对校正因子>1.2时，拟合个数越少越容易造成线性斜率剧烈变化。综上，在采用加相对校正因子的主成分对照法时，必须根据实际情况针对不同杂质配制相应的混合线性系列溶液，保证试验结果的稳定性和可靠性。
3.2　有关物质限度的确定及测定结果比较
本研究检测了同一厂家生产的3批缩宫素原料药，杂质Ac-Oxy的结果范围为0.93%~1.01%，杂质Oxy[Glu4]的结果范围为0.06%~0.08%，杂质Oxy[+Gly10]的结果范围为0.04%~0.07%，杂质Oxy[-NH2]的结果范围为0.05%~0.09%，杂质Oxy[trans-dimer]的结果范围为0.18%~0.27%，杂质Oxy[cis-dimer]和Oxy[trisulfide]均未检出。其他单个最大杂质的结果范围为0.18%~0.19%，杂质总量为1.88%~2.06%。该结果提示杂质Ac-Oxy和杂质Oxy[trans-dimer]的含量高于其他杂质，而其他单个最大杂质均在0.5%以内。
在确定有关物质的含量限度时，主要参考化学药物杂质研究的技术指导原则[13]和2020年版《中华人民共和国药典》[5]。药典规定各单一杂质的峰面积不得大于总峰面积的0.02倍(2.0%)，杂质峰面积之和不得大于总峰面积的0.05倍(5.0%)。该标准没有区分原料药中的不同杂质，制定的限度较为宽松，且在计算时没有纳入各杂质的相对校正因子。加校正因子的主成分自身对照法适用于已知杂质[14]。当杂质的响应与主成分响应不同时，不引入校正因子测得的杂质含量可能与药品中真正的杂质含量不一致[15]。因此，本研究建议应当在标准中添加缩宫素常见杂质(如乙酰化缩宫素杂质Ac-Oxy)的相对校正因子，使得标准更具有针对性。
杂质Ac-Oxy在原料药中的含量高于其他单一杂质，且与杂质Oxy[trisulfide](相对保留时间为1.29)相邻出峰。在结合药典后本研究建议可以将标准定为杂质Ac-Oxy和杂质Oxy[trisulfide]的峰面积之和不得大于对照溶液主峰面积的2倍(2.0%)。杂质Oxy[trans-dimer]的限度定为不得大于对照溶液主峰面积(1.0%)。其他单个杂质峰面积不得大于对照溶液主峰面积的0.5倍(0.5%)，各杂质峰面积之和不得大于对照溶液主峰面积的3倍(3.0%)。该标准在药典的基础上进行了进一步扩展和界定，具有良好的实用价值。
4　结论
收起
本研究建立了注射用缩宫素中缩宫素和7个杂质的线性回归方程，计算了各杂质相对缩宫素的相对校正因子。采用加校正因子的主成分自身对照法，对3批缩宫素原料药的有关物质含量进行了测定，并与杂质外标法进行比较。结果提示该方法准确、可靠，可重复性高，对提高我国现有的缩宫素质量标准具有一定参考意义。
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2024年第44卷第4期
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doi: 10.16155/j.0254-1793.2024.04.14
  • 接收时间：2023-04-04
  • 首发时间：2026-03-13
  • 出版时间：2024-04-30
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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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