目的: 建立可监控米拉贝隆原料中残留风险最大的4个硝基苯类带基因毒警示结构杂质(MLB-1、MLB-2、MLB-1-IM01、MLB-2-IM01)含量的方法。方法: 采用UPLC-QDa质谱检测器系统,XBridge C18柱(150 mm×4.6 mm,3.5 μm),以乙腈-水-三氟乙酸(400∶600∶0.5)为流动相,流速0.8 mL·min-1,柱温35 ℃,进样体积2 μL;QDa检测器的参数设置:电喷雾离子化-正电离模式(ESI+),多反应监测模式(MRM),探头温度为600 ℃,采集速率10 点·s-1,气流量20 L·min-1;采集时间15 min。结果: 4个目标硝基苯类杂质在0.03~0.6 μg·mL-1浓度范围内(相当于主成分的0.000 3%~0.006%水平;4个目标杂质限度为0.003%,总量限度为0.01%)线性关系均良好(r≥0.997 3),回收率介于91.8%~119.1%,检测限和定量限分别低于0.1和0.25 μg·mL-1(相当于0.002 5%水平),能较好地满足目标杂质的检测灵敏度要求。采用拟定工艺生产的多批米拉贝隆样品中均未检出上述4个目标杂质(总量<0.001%,远低于限度规定的0.01%)。结论: 该方法灵敏度高,准确性好,在拟定限度范围内呈线性响应,可用于检测米拉贝隆原料中潜在硝基苯类基因毒杂质的残留量监控。
秦永香, 许红霞, 谌宗永, 郭鑫, 刘智, 孙跃军, 王明娟, 袁伟锋, 孟旻, 马昂, 刘宇晶
. UPLC-QDa质谱检测器法检测米拉贝隆中硝基苯类带基因毒警示结构杂质的含量*[J]. 药物分析杂志, 2022
, 42(10)
: 1792
-1800
.
DOI: 10.16155/j.0254-1793.2022.10.12
Objective: To establish an original method for determination of four nitrobenzenes with alerting structure (MLB-1, MLB-2, MLB-1-IM01 and MLB-2-IM01) most likely residue in mirabegron drug substance. Methods: The Waters Acquity UPLC-QDa mass detector system was applied, with the XBridge C18 column (150 mm×4.6 mm, 3.5 μm) maintaining at 35 ℃. Mobile phase consisted of 0.05% trifluoroacetic acid in acetonitrile-water (400∶600, v/v) at a flow rate of 0.8 mL·min-1. The injection volumes were 2 μL. The conditions of QDa detector were as follows: electrospray ionization mode positive (ESI+), multi-reaction monitoring (MRM) mode, probe temperature at 600 ℃, flow rate of nitrogen at 20 L·min-1, with the acquisition rate of 10 points·s-1 for 15 min. Results: Four nitrobenzenes all showed good linearity (r≥0.997 3) in the range of 0.03-0.6 μg·mL-1 (equivalent to 0.000 3%-0.006% of mirabegron,meanwhile the single and total limit for the four nitrobenzenes was 0.003% and 0.01%, respectively). Their recoveries were between 91.8%-119.1%, and their limits of detection and quantitation were all below 0.1 μg·mL-1 and 0.25 μg·mL-1 (0.002 5%), respectively, fulfilling the sensitivity requirements for detection of the target impurities. None of the four nitrobenzenes was detected in mirabegron produced with the proposed synthesis and purification process (total amount <0.001%, much lower than the limit of 0.01%). Conclusion: The original method established is sensitive, accurate and shows linear response in the range covering the proposed limit, demonstrating its suitability for trace control of nitrobenzenes in mirabegron drug substances.
[1] LAM S, HILAS O. Pharmacologic management of overactive bladder[J].Clin Interv Aging, 2007, 2(3): 337
[2] 唐启东, 宫平. 米拉贝隆[J].中国药物化学杂志, 2012, 22(6): 544
TANG QD, GONG P. Mirabegron[J].Chin J Med Chem, 2012, 22(6): 544
[3] 种铁, 陈琦. 米拉贝隆治疗膀胱过度活动症的临床应用[J].山东大学学报, 2018, 56(3): 6
CHONG T, CHEN Q. Clinical application of mirabegron in the treatment of overactive bladder[J].J Shandong Pharm Univ, 2018, 56(3): 6
[4] 张霁, 张英俊, 聂飚. 药物研发中基因毒性杂质的控制策略与方法探索进展[J].中国医药工业杂志, 2018, 49(9): 1203
ZHANG J, ZHANG YJ, NIE B. Advances in control strategies and methods for genotoxic impurities in drug research & development[J].Chin J Pharm, 2018, 49(9): 1203
[5] ICH指南. M7: 评估和控制药物中DNA反应性(致突变)杂质以限制潜在的致癌风险[S].2014: 9
ICH Harmonised Tripartite Guideline. M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk[S].2014: 9
[6] 章磊, 谭志敏, 焦慧荣, 等. 米拉贝隆有关物质的合成[J].中国医药工业杂志, 2014, 45(1): 9
ZHANG L, TAN ZM, JIAO HR, et al. Synthesis of related substance of mirabegron[J].Chin J Pharm, 2014, 45(1): 9
[7] 丁逸梅, 浦雨伟, 吴娟, 等. 米拉贝隆有关物质的HPLC法测定[J].药物分析杂志, 2016, 36(8): 1439
DING YM, PU YW, WU J, et al. Determination of related substances in mirabegron by HPLC[J].Chin J Pharm Anal, 2016, 36(8): 1439
[8] 张聿梅, 何轶, 李耀磊, 等. 高效液相色谱与QDA质谱串联同时测定附子理中丸中6个单酯及双酯型生物碱含量[J].药物分析杂志, 2018, 38(7): 1248
ZHANG YM, HE Y, LI YL, et al. Simultaneous determination of six diterpenoid alkaloids in Fuzilizhong pills by HPLC coupled with QDA mass detector[J].Chin J Pharm Anal, 2018, 38(7): 1248
[9] 曹琳, 胡樱, 章燕, 等. UPLC-QDa测定乳果糖口服溶液中乳果糖及其有关物质含量[J].中国现代应用药学, 2021, 38(12): 1493
CAO L, HU Y, ZHANG Y, et al. Determination of the contents of lactulose and related substances in lactulose oral solution by UPLC-QDa[J].Chin J Mod Appl Pharm, 2021, 38(12): 1493
[10] 何瑾, 屈凡伟, 张俊, 等. 超高效液相色谱/质谱法测定血液中γ-氨基丁酸[J].分析试验室, 2015, 34(9):1022
HE J, QU FW, ZHANG J, et al. γ-Aminobutyric acid in blood is determined by upper high performation liquid chromatography/QDa detection[J].Chin J Anal Lab, 2015, 34(9): 1022
[11] 王文波, 于传飞, 张峰, 等. 超高效液相色谱串联Qda质谱法检测单抗N糖的研究[J].中国药学杂志, 2018, 53(3): 223
WANG WB, YU CF, ZHANG F, et al. Analysis of N-linked glycan profile of therapeutic antibodies by UPLC-Qda MS[J].Chin Pharm J, 2018, 53(3): 223
[12] 石岩, 魏锋, 吕宝骏, 等. 基于UPLC-QDA的培植牛黄中胆汁酸类成分化学轮廓考察与测定研究[J].中国中药杂志, 2020, 45(21): 5232
SHI Y, WEI F, LÜ BJ, et al. Investigation of chemical profile of bile acids and determination of them in cultured Bovis Calculus with UPLC-QDA[J].China J Chin Mater Med, 2020, 45(21): 5232
[13] JAGADABI V, NAGENDRA KUMAR PV, MAHESH K, et al. A stability-indicating UPLC method for the determination of potential impurities and its mass by a new QDa mass detector in daclatasvir drug used to treat hepatitis C infection[J].J Chromatogr Sci, 2019, 57(1): 44
[14] MURALI KRP, SHYAMALA P, VENKATA NB, et al. Assay of tirofiban and identification of oxidative impurity in aqueous injection by using UPLC-PDA/QDa detectors[J].Ann Pharm Fr, 2022, 80(1): 35
[15] GARRIGUES JC, COURNAC M, OSWALD M, et al. Analysis of complex mixtures of polyglycerol fatty esters using liquid chromatography and high-resolution mass spectrometry: retention, structural and relative composition study[J].J Chromatogr A, 2020, 1616: 460792
