卡贝缩宫素注射液有关物质检测方法的建立与验证

陈一淼; 张翔; 吴锦慧; 黄玉晔

doi:10.11665/j.issn.1000-5048.2024062603

卡贝缩宫素注射液有关物质检测方法的建立与验证

陈一淼¹,
张翔²,
吴锦慧^1, ,,
黄玉晔^1, ,

1.
南京大学医学院, 南京210093
2.
常州四药制药有限公司, 常州213004

详细信息

通讯作者:
吴锦慧: Tel：025-83592629　E-mail：wuj@nju.edu.cn

黄玉晔: Tel：15850683155　 E-mail：hyyzijing@163.com

中图分类号: R917
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- 文章访问数: 23
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- PDF下载量: 12
出版历程
- 收稿日期: 2024-06-25
- 刊出日期: 2025-02-24

Establishment and validation of the determination method for the related substances in carbetocin injection

1.
Medical School, Nanjing University, Nanjing 210093
2.
Changzhou Siyao Pharmaceutical Co., Ltd., Changzhou 213004, China

摘要

摘要:
建立一种HPLC分析方法用于卡贝缩宫素注射液中有关物质的测定。采用Waters Xbridge C₁₈色谱柱（150 mm×3 mm，3.5 μm），0.30 mg/mL乙酸铵-19%乙腈水溶液为流动相A，流动相A-乙腈（1∶1）为流动相B，检测波长为220 nm，在60 ℃的柱温下，以0.8 mL/min的流速进行梯度洗脱。对该方法的系统适用性、专属性、线性及范围、准确度等进行了验证，结果表明卡贝缩宫素注射液的9个杂质在各自浓度范围内与峰面积呈现良好的线性关系（R²>0.999），该方法的精密度良好（RSD<5%）。本法适用于同时检测卡贝缩宫素注射液中药物及其9个杂质，可为该制剂的质量控制提供理论依据。
- 卡贝缩宫素注射液 /
- 有关物质 /
- 高效液相色谱法
Abstract:
An HPLC analytical method was developed to determine the related substances in carbetocin injection. The method was performed on a Waters Xbridge C₁₈ column (150 mm×3 mm, 3.5 μm) with 0.30 mg/mL ammonium acetate-19% acetonitrile aqueous solution as mobile phase A and mobile phase A-acetonitrile (1∶1) as mobile phase B. The detection wavelength was 220 nm. Gradient elution was performed at the flow rate of 0.8 mL/min and the column temperature of 60℃. The method was validated for system applicability, specificity, linearity and range, accuracy, with the results that the 9 impurities of carbetocin injection showed good linearity (R²>0.999) with peak area in their respective concentration range, and that the method had good precision (RSD<5%). This method is suitable for the simultaneous determination of carbetocin and its 9 impurities in carbetocin injection and can provide a theoretical basis for the quality control of the carbetocin injection.
- carbetocin injection /
- related substances /
- high performance liquid chromatography

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Figure 1. Structure of carbetocin（CBT ）

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Figure 2. Structure of impurities of carbetocin

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Figure 3. Chromatogram of impurity location test

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Figure 4. Degradation of injection under acid(A)，base(B)，oxidation(C)，heat(D) and light(E) stress condition

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Figure 5. Curve of impurity retention time at different concentrations of ammonium acetate

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Figure 6. Chromatogram of carbetocin and related impurities in optimal method

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Figure 7. Curves of impurity retention time at different content of PIC-B8

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Table 1 Results of degradation study

Test	Condition	Assay of API/%	Recovery/%
Acid	10 mol/L HCl for 2 h at 40℃	91.97	100.23
Base	5 mol/L NaOH for 5 min（r.t.）	93.23	99.61
Oxidation	10% H₂O₂ for 20 min（r.t.）	90.03	99.23
Light	(5000±500) lx for 9 d at 25℃	99.52	102.73
Heat	60℃ for 9 d	99.02	102.81

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Table 2 Results of linearity test

Compd.	Regression equation of linearity	R²	Linear range/（μg/mL）
Imp1	y=46213x+15.342	0.9999	0.0338–1.6921
Imp2	y=44862x–78.524	0.9999	0.0145–0.7229
Imp3	y=46632x–1.724	0.9999	0.0172–0.8613
Imp4	y=44852x–117.09	0.9999	0.0349–1.7455
Imp5	y=46795x+84.166	0.9999	0.0146–0.7290
Imp6	y=47865x–150.3	0.9999	0.0143–0.7158
Imp7	y=44998x–206.24	0.9997	0.0148–0.7392
Imp8	y=54607x–108.38	0.9999	0.0150–0.7503
Imp9	y=39031x+14.874	0.9999	0.1014–0.7603

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参考文献(17)

[1]	Borovac-Pinheiro A, Pacagnella RC, Cecatti JG, et al. Postpartum hemorrhage: new insights for definition and diagnosis[J]. Am J Obstet Gynecol, 2018, 219(2): 162-168. doi: 10.1016/j.ajog.2018.04.013
[2]	Stämpfli D, Dommrich R, Orbach-Zinger S, et al. An explorative analysis of pharmacovigilance data of oxytocin and its analogue carbetocin, with a focus on haemodynamic adverse effects[J]. Int J Clin Pharm, 2023, 45(4): 922-928. doi: 10.1007/s11096-023-01587-9
[3]	Liu CY, Tan XY, Zhu DM. The clinical application analysis of carbetoxine in the prevention of bleeding after cesarean section[J]. Heilongjiang Med J(黑龙江医学), 2023, 47(07): 792-794.
[4]	Yan JY. The Effect of carbetocin and carboprost tromethamine in the treatment of postpartum hemorrhage due to uterine contraction and their influence on the lactation function of the parturient[J]. Med Inf (医学信息), 2020, 33(21): 146-148.
[5]	Zhang HH. Prescription process development and quality research of carbetocin injection(卡贝缩宫素注射液处方工艺开发及质量研究)[D]. Nanjing: Nanjing University, 2019.
[6]	Yin LN, Huang YY, Wang C, et al. Development of a novel and stability indicating RP-HPLC-UV method for simultaneous analysis of carbetocin and ten impurities in carbetocin injection products[J]. Chromatographia, 2021, 84(10): 967-978. doi: 10.1007/s10337-021-04083-2
[7]	Wang SS. Application of two-dimensional liquid chromatography-mass spectrometry in related substances research of peptide drugs(二维液相色谱-质谱联用技术在多肽类药物有关物质研究中的应用)[D]. Nanjing: Nanjing University, 2021.
[8]	Yang L, Yang G, Deng T. Analysis on clinical application rationality for carbetocin injection[J]. J China Prescr Drug (中国处方药), 2023, 21(3): 68-71.
[9]	Widmer M, Piaggio G, Nguyen TMH, et al. Heat-stable carbetocin versus oxytocin to prevent hemorrhage after vaginal birth[J]. N Engl J Med, 2018, 379(8): 743-752. doi: 10.1056/NEJMoa1805489
[10]	Armbruster D, Burke T, Weeks A. Heat-stable carbetocin to prevent postpartum hemorrhage[J]. N Engl J Med, 2018, 379(24): 2380-2381. doi: 10.1056/NEJMc1812692
[11]	Cook JR, Saxena K, Taylor C, et al. Cost-effectiveness and budget impact of heat-stable carbetocin compared to oxytocin and misoprostol for the prevention of postpartum hemorrhage (PPH) in women giving birth in India[J]. BMC Health Serv Res, 2023, 23(1): 267. doi: 10.1186/s12913-023-09263-4
[12]	Sanz-Nebot V, Garcés A, Barbosa J. Investigation of crudes of synthesis of carbetocin by liquid chromatography coupled to electrospray ionization mass spectrometry[J]. J Chromatogr A, 1999, 833(2): 267-275. doi: 10.1016/S0021-9673(98)01053-X
[13]	Sanz-Nebot V, Toro I, Garcés A, et al. Separation and identification of peptide mixtures in a synthesis crude of carbetocin by liquid chromatography/electrospray ionization mass spectrometry[J]. Rapid Commun Mass Spectrom, 1999, 13(23): 2341-2347. doi: 10.1002/(SICI)1097-0231(19991215)13:23<2341::AID-RCM795>3.0.CO;2-9
[14]	Zhang H, Yang HX, Liang CG, et al. HPLC analysis of carbetocin and its related impurities[J]. Chin J Pharm Anal (药物分析杂志), 2007, 27(10): 1553-1555.
[15]	Malm M, Madsen I, Kjellström J. Development and stability of a heat-stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle-income countries[J]. J Pept Sci, 2018, 24(6): e3082. doi: 10.1002/psc.3082
[16]	Lin SY, Jeng SL. Comparison of ion-pairing and ion-suppressing liquid chromatographic methods for the determination of pyrimethamine and ormetoprim in chicken feed[J]. J Chromatogr Sci, 2002, 40(6): 331-336. doi: 10.1093/chromsci/40.6.331
[17]	Molnár I, Horváth C. Separation of amino acids and peptides on non-polar stationary phases by high-performance liquid chromatography[J]. J Chromatogr, 1977, 142: 623-640. doi: 10.1016/S0021-9673(01)92073-4