目的: 对乌拉地尔注射液有关物质进行结构鉴定,为工艺优化和质量控制提供参考。方法: 采用ACQUITY UHPLC® HSS C18（50 mm×2.1 mm,1.7 μm）色谱柱,以0.1% 甲酸水- 乙腈为流动相,梯度洗脱, 对乌拉地尔强制降解溶液中的有关物质进行分离,采用四极杆/ 静电场轨道阱高分辨质谱法（Q-Orbitrap HRMS 法）进行检测,结合其精确相对分子质量、质谱裂解规律和化学反应理论,推测有关物质的结构。结果: 共发现了23 个有关物质,根据其来源主要分为3 类：合成过程的副产物5 个（有关物质1、6、15、19 和22）、合成过程的中间体2 个（有关物质5 和7）、氧化降解产物16 个（有关物质2~4、8~14、16~18、20~21、23。强制降解试验证明乌拉地尔对强酸、强碱、高温、光照相对较为稳定,氧化条件对乌拉地尔的影响较大。结论: UHPLC-Q-Orbitrap HRMS 技术能有效鉴定乌拉地尔中的有关物质,能够为其生产工艺的优化和质量控制提供参考。
Objective： To identify the structure of related substances of urapidil injection. Methods： The separation of urapidil and its related substances was carried out on ACQUITY UHPLC® HSS C18（ 50 mm×2.1 mm, 1.7 μm） column,using 0.1% formic acid water and acetonitrile as the mobile phase,The quadrupole/electrostatic field orbitrap high-resolution mass spectrometry（ UHPLC-Q-Orbitrap HRMS） was used for detection. Combined with the precise relative molecular mass,fragmentation rule and chemical reaction theory,the structure of the relevant substances was speculated. Results： A total of 23 related substances were identified,which were mainly divided into 3 categories according to their sources：5 synthetic by-products（ related substances 1,6,15,19 and 22）,and 2 synthetic intermediates（related substances 5 and 7）,16 oxidative degradation products（ related substances 2-4,8-14,16-18,20-21,23） . The forced degradation test proved that urapidil was relatively stable to strong acids,strong alkali,high temperatures and light,while oxidation condition had a greater impact on urapidil. Conclusion： UHPLC-Q-Orbitrap HRMS technology can effectively identify the relevant substances in urapidil,which is significant for its production process optimization and quality control.
[1] BUCH J.Urapidil,a dual-acting antihypertensive agent:current usage considerations[J].Adv Ther,2010,27(7):426
[2] IL’IN SA.Urapidil as a drug of choice for decreasing arterial pressure in surgical practice[J].Angiol Sosud Khir,2017,23(4): 147
[3] MINUSHKINA LO.Treatment of hypertensive emergencies and malignant hypertension:the possibility of using urapidil[J]. Kardiologiia,2014,54(11):70
[4] SALVETTI M,PAINI A,BERTACCHINI F,et al.Acute blood pressure elevation:therapeutic approach[J].Pharmacol Res,2018,130:180
[5] KIRSTEN R,NELSON K,NEFF J,et al.Pharmacodynamics and pharmacokinetics of three different doses of urapidil infused in hypertensive patients[J].Eur J Clin Pharmacol,1986,30(5): 549
[6] BAKER R.High-performance liquid chromatography-ultraviolet method for the simultaneous determination of potential synthetic and hydrolytic impurities in urapidil fumarate[J].J Chromatogr,1987, 393(3):447
[7] 邱凯锋,姚少毅,邓丽华.高效液相色谱法测定乌拉地尔缓释胶囊的含量及有关物质[J].中国医院药学杂志,2011,31(23): 1983
QIU KF,YAO SY,DENG LH.Determination of urapidil sustained release capsules and related substances by HPLC[J].Chin J Hosp Pharm,2011,31(23):1983
[8] 王嫦鹤,焦艳,杜珊,等.HPLC 法测定乌拉地尔不同制剂中的有关物质[J].西北药学杂志,2013,28(3):254
WANG CH,JIAO Y,DU S,et al.Analysis of the related substances in different urapidil preparations by HPLC[J].Northwest Pharm J, 2013,28(3):254
[9] 阎卉,姜峰,王成港.RP-HPLC 法测定盐酸乌拉地尔注射液含量和有关物质[J].天津药学,2007,19(4):7
YAN H,JIANG F,WANG CG.Determination of urapidil hydrochloride injection and related substances by RP-HPLC[J]. Tianjin Pharm,2007,19(4):7
[10] 贾雪冬,李卓伦,杨彦涛,等.基于UHPLC-Q-Orbitrap HRMS 的甲磺酸阿帕替尼有关物质结构鉴定[J].药物分析杂志,2020, 40(10):1848
JIA XD,LI ZL,YANG YT,et al.Structural identification of related substances of apatinib mesylate based on UHPLC-Q-Orbitrap HRMS[J].Chin J Pharm Anal,2020,40(10):1848
[11] 梅芊,李倚天,杨博涵,等.UHPLC-Q-Orbitrap HRMS 法测定盐酸二甲双胍及其片剂中遗传毒性杂质的含量[J].中国药物评价,2020,37(5):353
MEI Q,LI QT,YANG BH,et al.Determination of genotoxic impurity in metformin hdrochloride and its tablets by UHPLC-Q-Orbitrap HRMS[J].Chin J Drug Eval,2020,37(5):353
[12] 梅芊,李茜,刘英.柱前衍生化UHPLC-Q-Orbitrap HRMS 法测定乙酰唑胺及其胶囊剂中肼的含量[J].药物分析杂志,2020,40(8):1467
MEI Q,LI Q,LIU Y.Determination of hydrazine in acetazolamide and its capsules by UHPLC-Q-Orbitrap HRMS with precolumn derivatization[J].Chin J Pharm Anal,2020,40(8):1467
[13] 杨彦涛,李卓伦,王松,等.UHPLC-Q-Orbitrap HRMS 法鉴定盐酸阿扎司琼中的有关物质[J].药物分析杂志,2019,39(9): 1625
YANG YT,LI ZL,WANG S,et al.Identification of related substances in azasetron hydrochloride by UHPLC-Q-Orbitrap HRMS[J].Chin J Pharm Anal,2019,39(9):1625
[14] 周军红. 乌拉地尔的合成和多晶型分析[D].天津:天津大学, 2006
ZHOU JH.The Synthesis of Urapidil and Analyse of Its Polymorphic Forms[D].Tianjin:Tianjin University,2006
[15] 许佑君,杨治旻,蒋清乾,等.乌拉地尔的合成[J]. 中国医药工业杂志,2000,31(7):294
XU YJ,YANG ZM,JIANG QQ,et al.Synthesis of urapidil[J]. Chin J Pharm,2000,31(7):294
[16] 李雯,吴桂英,马晓青,等.乌拉地尔的合成改进[J].高校化学工程学报,2013,27(1):131
LI W,WU GY,MA XQ,et al.Improvement of the synthesis of urapidil[J].J Chem Eng Chin Univ,2013,27(1):131
