色谱-质谱联用技术鉴定环孢素A的有关物质

倪悦泠; 韩兴; 宋敏; 杭太俊

doi:10.11665/j.issn.1000-5048.20190407

色谱-质谱联用技术鉴定环孢素A的有关物质

中国药科大学药物分析系

计量
- 文章访问数: 542
- HTML全文浏览量: 14
- PDF下载量: 1006
出版历程
- 刊出日期: 2019-08-24

Identification of the related substances of cyclosporin A by LC-MS techniques

摘要

摘要: 采用Hypersil BDS C₁₈(100 mm×4.6 mm，2.4 μm)色谱柱，以乙腈-水-甲基叔丁基醚-甲酸(430∶520∶50∶1)为流动相进行等度洗脱，对环孢素A及其有关物质进行分离。在所建立的条件下，环孢素A及其有关物质分离良好，检测并鉴定出29个主要有关物质(9个工艺杂质，20个降解产物)，其中13个为欧洲药典中列出的已知杂质或其光学异构体，其余16个均为未知结构的有关物质。采用电喷雾正离子化-飞行时间质谱法(ESI-TOF/MS)测定各有关物质的准确质量和元素组成，三重四极杆串联质谱(ESI-MS/MS)测定其碎片离子特征，通过质谱解析鉴定了29个有关物质的结构。建立的色谱-质谱联用分析方法能有效地分离鉴定环孢素A中的有关物质，可用于其发酵过程的质量控制。
- 环孢素A /
- 有关物质 /
- 降解产物 /
- 结构鉴定 /
- 色谱-质谱联用
Abstract: To identify the related substances of cyclosporin A by LC-MS techniques, the separation of cyclosporin A and its related substances was carried out on a Hypersil BDS C₁₈(100 mm×4. 6 mm, 2. 4 μm)column with isocratic elution by a mixture of acetonitrile-water-MTBE and formic acid(430 ∶520 ∶50 ∶1)as the mobile phase. Cyclosporin A and its 29 related substances(9 process related and 20 degradants)were well separated under the established conditions. Among them, 13 were listed in EP and the rest 16 were unknown products having not been reported before. Electrospray positive ionization high resolution TOF/MS was used for the determination of the accurate mass and elemental composition of parent ions of all the components, and triple quadrupoles tandem mass was employed for the product mass spectra determination. Thence, the structures of all the 29 detected substances were successfully characterized through spectra elucidation and the fragmentation pathways analysis. The established LC-MS method was successfully employed for the separation and identification of the related substances of cyclosporin A and it is useful for its fermentation processes and quality control.
- cyclosporin A /
- related substances /
- degradation products /
- structure identification /
- LC-MS

HTML全文

参考文献(16)

[1]	Pang WZ,Wang ML,Han B.Quantitive analysis of domestic research literature on cyclosporin from 1995 to 2016[J].J Shijiazhuang Univ Appl Technol(石家庄职业技术学院学报),2017,29(2):39-41.
[2]	Chen YX,Wang J,Wei ZY,et al.Preparation and determination of cyclosporine ophthalmic emulsion[J].Pharm Today(今日药学),2017,27(1):24-29.
[3]	Zhan Y,Hu XY,Liu QS.Clinical effect and safety of cyclosporine A in the treatment of dry eyes:a systematic review[J].China Pharm(中国药业),2018,27(3):47-51.
[4]	Zhou TX,Zhu L,Xia HY,et al.HPLC-MS /MS determination of cyclosporine A in rat cornea [J].Chin J Pharm Anal(药物分析杂志),2013,33(2):263-267.
[5]	Hu NN,Zhang CX,Han X.Drug interaction and clinical application of cyclosporin A[J].Hebei Med J(河北医药),2016,38(9):1405-1408.
[6]	Emilia G,Messora C,Longo G,et al.Long-term salvage treatment by cyclosporin in refractory autoimmune haematological disorders[J].Br J Haematol,2015,93(2):341-344.
[7]	Dixit A,Chatterjee T,Mishra P,et al.Cyclosporin A in myelodysplastic syndrome:a preliminary report[J].Ann Hematol,2005,84(9):565-568.
[8]	Rojas CM, Borella E, Palma L, et al. Bronchiolitis obliterans organizing pneumonia in patients with autoimmune rheumatic diseases[J].Immunol Res,2015,61(1/2):97-103.
[9]	Lu JH,Nong WH.Preparation and quality control of cyclosporin A microemulsion soft gelatin capsule[J].Pharm Clin Res(药学与临床研究),2013,21(3):247-250.
[10]	Wei L,Li HY,Yin L.Preparation and quality control of cyclosporin A chitosan eye gels[J].China Pharm(中国药房),2009,20(28):2213-2215.
[11]	Li ZX,Zhang J.Preparation and quality control of cyclosporine A colloid suspensions for eye use[J].Chin J Hosp Pharm(中国医院药学杂志),2006,26(4):400-402.
[12]	Fu LW,Yang LY,Chen WP,et al.Cyclosporin pharmacokinetics following administration of capsules and Neoral in paediatric patients with lupus nephritis[J].Br J Haematol,2015,44(2):125-127.
[13]	Pieper JB,Dirikolu L,Campbell KL,et al.Evaluation of the effect of fluconazole on the pharmacokinetics of cyclosporin A in healthy dogs after a single dose and at steady-state[J].J Vet Pharmacol Ther,2017,40(3):304-308.
[14]	Bauer S,Störmer E,Johne A,et al.Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John′s wort in renal transplant patients[J].Br J Clin Pharmacol,2003,55(2):203-211.
[15]	Liang FM,Ni YL,Wang L,et al.Structural identification of the related substances of fusidic acid by LC-MS[J].J China Pharm Univ(中国药科大学学报),2018,49(3):322-332.
[16]	Han XC.Study on catalytic application of solid acid in the synthesis of acetal and ketal(固体酸在缩醛缩酮合成中的催化应用研究)[D].Qufu:Qufu Normal University,2011.