基于气相色谱-质谱法测定塞来昔布中磺酸酯类基因毒性杂质的残留量

doi:10.19586/j.2095-2341.2023.0138

生物技术进展 ›› 2024, Vol. 14 ›› Issue (1): 85-93.DOI: 10.19586/j.2095-2341.2023.0138

• 生物制品研发与技术专题 • 上一篇下一篇

基于气相色谱-质谱法测定塞来昔布中磺酸酯类基因毒性杂质的残留量

赵晨阳¹(), 刘晓梦²(), 邢亮彬¹, 李亚丽¹, 赵立新¹, 艾连峰³^,⁴(), 哈婧²()

^1.河北省药品审评中心，石家庄 050091
^2.河北科技大学化学与制药工程学院，石家庄 050018
^3.石家庄海关技术中心，石家庄 050051
^4.河北医科大学公共卫生学院，石家庄 050017

收稿日期:2023-10-26 接受日期:2023-11-15 出版日期:2024-01-25 发布日期:2024-02-05
通讯作者: 艾连峰,哈婧
作者简介:赵晨阳E-mail: vivosunny@163.com
刘晓梦E-mail: liuxmleo@126.com第一联系人：赵晨阳和刘晓梦为共同第一作者。
基金资助:
河北省市场监督管理局科研计划项目(2021YJ13);河北省卫生厅科研项目(20210700)

Determination of Sulfonate Genotoxic Impurity Residues in Celecoxib Based on Gas Chromatography-mass Spectrometry Method

Chenyang ZHAO¹(), Xiaomeng LIU²(), Liangbin XING¹, Yali LI¹, Lixin ZHAO¹, Lianfeng AI³^,⁴(), Jing HA²()

^1.Hebei Provincial Drug Review Centre，Shijiazhuang 050091，China
^2.College of Chemical and Pharmaceutical Engineering，Hebei University of Science and Technology，Shijiazhuang 050018，China
^3.Shijiazhuang Customs Technology Center，Shijiazhuang 050051，China
^4.College of Public Health，Hebei Medical University，Shijiazhuang 050017，China

Received:2023-10-26 Accepted:2023-11-15 Online:2024-01-25 Published:2024-02-05
Contact: Lianfeng AI,Jing HA

摘要/Abstract

摘要：

为了建立一种测定塞来昔布原料药及其制剂中塞来昔布磺酸甲酯和塞来昔布磺酸乙酯残留量的气相色谱-质谱(gas chromatography-mass spectrometry, GC-MS)分析方法，采用碘化钠衍生-顶空进样，将两杂质衍生成碘甲烷和碘乙烷，DB624毛细管色谱柱(60 m×0.25 mm, 1.4 μm)分离，氦气为载气，质谱检测器检测。塞来昔布磺酸甲酯和塞来昔布磺酸乙酯均在10~500 ng·mL^-1浓度范围内线性关系良好；回收率在80.87%~106.52%，RSD小于10%；定量限均为10 ng·mL^-1。所有塞来昔布样品中均未检测出塞来昔布磺酸甲酯和塞来昔布磺酸乙酯杂质。该方法简便准确，可用于塞来昔布中塞来昔布磺酸甲酯和塞来昔布磺酸乙酯2个磺酸酯类基因毒性杂质的检测。

关键词: 塞来昔布, 塞来昔布磺酸甲酯, 塞来昔布磺酸乙酯, 基因毒性杂质, 气相色谱-质谱法

Abstract:

A gas chromatography-mass spectrometry （GC-MS） method was developed for the determination of methyl celecoxib sulfonate and ethyl celecoxib sulfonate residues in celecoxib APIs and their formulations. The two impurities were derivatised into iodomethane and iodoethane by sodium iodide derivatisation with headspace injection， and separated on a DB-624 capillary column （60 m×0.25 mm， 1.4 μm）， with helium as the carrier gas and detected by mass spectrometry detector. Both methyl celecoxib sulfonate and ethyl celecoxib sulfonate showed good linearity in the concentration range of 10~500 ng·mL^-1； the recoveries were in the range of 80.87%~106.52% with the RSDs less than 10%； and the limits of quantification （LOQs） were both 10 ng·mL^-1. Methyl celecoxib sulfonate and ethyl celecoxib sulfonate impurities were not detected in any of the celecoxib samples. The method is simple and accurate， which can be used for the detection of genotoxic impurities of two sulfonate esters， methyl celecoxib sulfonate and ethyl celecoxib sulfonate， in celecoxib.

Key words: celecoxib, methyl celecoxib sulfonate, ethyl celecoxib sulfonate, genotoxic impurities, GC-MS

中图分类号:

Q789

赵晨阳, 刘晓梦, 邢亮彬, 李亚丽, 赵立新, 艾连峰, 哈婧. 基于气相色谱-质谱法测定塞来昔布中磺酸酯类基因毒性杂质的残留量[J]. 生物技术进展, 2024, 14(1): 85-93.

Chenyang ZHAO, Xiaomeng LIU, Liangbin XING, Yali LI, Lixin ZHAO, Lianfeng AI, Jing HA. Determination of Sulfonate Genotoxic Impurity Residues in Celecoxib Based on Gas Chromatography-mass Spectrometry Method[J]. Current Biotechnology, 2024, 14(1): 85-93.

图/表 11

参考文献 22

1	许俊来.塞来昔布联合甲氨蝶呤治疗类风湿关节炎患者的临床效果[J].临床合理用药杂志,2022,15(9):125-127.
	XU J L. Clinical effect of celecoxib combined with methotrexate on patients with rheumatoid arthritis[J]. Chin. J. Clin. Ration. Drug Use, 2022, 15(9): 125-127.
2	ZHANG L, LI M, WANG W, et al.. Celecoxib alleviates denervation-induced muscle atrophy by suppressing inflammation and oxidative stress and improving microcirculation[J/OL]. Biochem. Pharmacol., 2022, 203: 115186[2023-11-07]. .
3	KRASSELT M, BAERWALD C. Celecoxib for the treatment of musculoskletal arthritis[J]. Expert Opin. Pharmacother., 2019,18: 1-14.
4	KISHORE N, RAJA M D, KUMAR C S, et al.. Lipid carriers for deliverof celecoxib: in vitro, in vivo assessment of nanomedicine in rheumatoid arthritis[J]. Eur. J. Lipid Sci. Technol., 2015, 118(6): 949-958.
5	冯蕊,陈冠军,刘莉,等.LC-MS法测定塞来昔布中2个苯肼类基因毒性杂质[J].中国新药杂志,2021,30(2):182-186.
	FENG R, CHEN G J, LIU L, et al.. Determination of two phenylhydrazine-like genotoxic impurities in celecoxib by LC-MS[J]. Chin. J. N. Drugs, 2021, 30(2): 182-186.
6	KAUSAR N, ULLAH S, KHAN M A, et al.. Celebrex derivatives: synthesis, α-glucosidase inhibition, crystal structures and molecular docking studies[J/OL]. Bioorg. Chem., 2021, 106: 104499[2023-11-07]. .
7	CHOI J S, LEE D H, AHN J B, et al.. Therapeutic effects of celecoxib polymeric systems in rat models of inflammation and adjuvant-induced rheumatoid arthritis[J/OL]. Mater. Sci. Eng. C Mater. Biol. Appl., 2020, 114: 111042[2023-11-07]. .
8	NOZOHOURI S, SHAYANFAR A, CÁRDENAS Z J, et al.. Solubility of celecoxib in N-methyl-2-pyrrolidone+water mixtures at various temperatures: experimental data and thermodynamic analysis[J]. Korean J. Chem. Eng., 2017, 34(5): 1435-1443.
9	孔凯丽.米诺膦酸原料药中基因毒性杂质的分析[J].山东化工,2022,51(10):100-103.
	KONG K L. Analysis of genotoxic impurity in minodronic acid API[J]. Shandong Chem. Ind., 2022, 51(10): 100-103.
10	KALAUZ A, KAPUI I. Determination of potentially genotoxic impurities in crotamiton active pharmaceutical ingredient by gas chromatography[J/OL]. J. Pharm. Biomed. Anal., 2022, 210: 114544[2023-11-07]. .
11	葛雨琦,叶晓霞,乐健,等.N-亚硝胺类基因毒性杂质毒性与检测方法研究进展[J].药物分析杂志,2020,40(1):83-89.
	GE Y Q, YE X X, LE J, et al.. Research progress on toxicity and detection methods of N-nitrosamines genotoxic impurities[J]. Chin. J. Pharm. Anal., 2020, 40(1): 83-89.
12	杨竹,杭太俊,郭晓迪,等.N-亚硝胺类基因毒性杂质的研究进展[J].药学与临床研究,2020,28(4):270-274.
	YANG Z, HANG T J, GUO X D, et al.. A review of research progress on N-nitrosamine genotoxic impurities[J]. Pharm. Clin. Res., 2020, 28(4): 270-274.
13	FU X, WANG X, XIA Z, et al.. Preparation of dummy molecularly imprinted polymers for selective extraction of aromatic amine genotoxic impurities[J/OL]. J. Chromatogr. A, 2022, 1685: 463617[2023-11-07]. .
14	LI S, DONG L, TANG K, et al.. Simultaneous and trace level quantification of two potential genotoxic impurities in valsartan drug substance using UPLC-MS/MS[J/OL]. J. Pharm. Biomed. Anal., 2022, 212: 114630[2023-11-07]. .
15	韩佳芮,徐艳梅,郝丽娟,等.药物中磺酸酯类基因毒性杂质测定方法研究进展[J].化学分析计量,2023,32(6):104-108.
	HAN J R, XU Y M, HAO L J, et al.. Research progress in the determination of genotoxic impurities of sulfonates[J]. Chem. Anal. Meterage, 2023, 32(6): 104-108.
16	盛蕖,张涵,万悦,等.固相萃取与气相色谱⁃质谱法联用测定食用植物油和含脂肪食品中氯丙醇酯的方法验证研究[J].生物技术进展,2023,13(1):22-29.
	SHENG Q, ZHANG H, WAN Y, et al.. Method validation research for the determination of chloropropanol esters in edible vegetable oil and fatty food by solid-phase extraction and gas chromatography-mass spectrometry[J]. Curr. Biotechnol., 2023, 13(1): 22-29.
17	鲁晶晶,冯芳.磺酸酯类基因毒性杂质研究进展[J].广州化工,2019,47(9):20-22.
	LU J J, FENG F. Research progress on genotoxic impurities of sulfonate esters in medicines[J]. Guangzhou Chem. Ind., 2019, 47(9): 20-22.
18	于瑞董,俞海荣,杨杰,等.药物中基因毒性杂质磺酸酯类分析方法的研究近况[J].海峡药学,2019,31(8):122-125.
	YU R D, YU H R, YANG J, et al.. Advances in studies on analytical techniques for sulfonate esters in pharmaceuticals[J]. Strait Pharm. J., 2019, 31(8): 122-125.
19	European Pharmacopoeia Commission. European Pharmacopoeia[M] 9th ed. Strasbourg: Council of Europe, 2017.
20	ICH M7(R1). Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk[EB/OL]. [2023-11-07] .
21	NAKKA S, MUCHAKAYALA S K, MANABOLU SURYA S B. A sensitive UPLC-MS/MS method for the simultaneous assay and trace level genotoxic impurities quantification of SARS-CoV-2 inhibitor-Molnupiravir in its pure and formulation dosage forms using fractional factorial design[J/OL]. Results Chem, 2023, 6: 101019[2023-11-07]. .
22	MULLANGI S, RAVINDHRANATH K, YARALA M R, et al.. A sensitive LC-MS/MS method for the determination of potential genotoxic impurities in cinnarizine[J]. Ann. Pharm. Fr., 2023, 81(1): 74-82.

待测物	衍生后实测物	保留时间/min	定量离子/(m·z^-1)	定性离子/(m·z^-1)
塞来昔布磺酸甲酯	碘甲烷	8.43	142	127
塞来昔布磺酸乙酯	碘乙烷	12.83	156	127

待测物	衍生后实测物	保留时间/min	定量离子/(m·z^-1)	定性离子/(m·z^-1)
塞来昔布磺酸甲酯	碘甲烷	8.43	142	127
塞来昔布磺酸乙酯	碘乙烷	12.83	156	127

放置时间/h	塞来昔布磺酸甲酯			塞来昔布磺酸乙酯
放置时间/h	样品溶液	标准品溶液	样品加标溶液	样品溶液	标准品溶液	样品加标溶液
0	未检出	953	858	未检出	657	545
2	未检出	1 015	842	未检出	585	502
4	未检出	938	926	未检出	615	493
8	未检出	974	821	未检出	604	505
12	未检出	995	850	未检出	587	487
24	未检出	919	811	未检出	532	445
RSD (%)		3.72	4.77		6.89	6.51

放置时间/h	塞来昔布磺酸甲酯			塞来昔布磺酸乙酯
放置时间/h	样品溶液	标准品溶液	样品加标溶液	样品溶液	标准品溶液	样品加标溶液
0	未检出	953	858	未检出	657	545
2	未检出	1 015	842	未检出	585	502
4	未检出	938	926	未检出	615	493
8	未检出	974	821	未检出	604	505
12	未检出	995	850	未检出	587	487
24	未检出	919	811	未检出	532	445
RSD (%)		3.72	4.77		6.89	6.51

方法条件	塞来昔布磺酸甲酯		塞来昔布磺酸乙酯
方法条件	浓度/(ng·mL^-1)	RSD/%	浓度/(ng·mL^-1)	RSD/%
进样口温度210 ℃	20.18	5.98	18.37	8.61
进样口温度230 ℃	19.35	7.21	19.07	5.93
流速1.1 mL·min^-1	19.04	4.81	18.52	3.82
流速1.3 mL·min^-1	19.47	9.42	17.97	4.56
起始柱温35 ℃	18.67	3.87	18.55	7.11
起始柱温45 ℃	19.24	6.14	18.71	4.53

基于气相色谱-质谱法测定塞来昔布中磺酸酯类基因毒性杂质的残留量

Determination of Sulfonate Genotoxic Impurity Residues in Celecoxib Based on Gas Chromatography-mass Spectrometry Method

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

图/表 11

参考文献 22

相关文章 1

编辑推荐

Metrics

本文评价

成分	样品含量/(ng·mL^-1)	加入量/(ng·mL^-1)	测得量/(ng·mL^-1)	回收率/%	RSD/%
塞来昔布磺酸甲酯	0	10	8.61	86.14	7.69
		20	21.30	106.52	6.18
		50	48.18	96.37	4.01
塞来昔布磺酸乙酯	0	10	8.09	80.87	5.42
		20	18.31	91.55	7.18
		50	44.93	89.86	5.29