目的 建立可监控米拉贝隆原料中3种具有警示结构的苯胺类杂质(MLB-IM-K、MLB-IM-L、MLB-3-IM01)含量的方法。方法 采用高效液相色谱法(HPLC)-QDa色谱系统,XBridge Shield RP18柱(4.6 mm×150 mm,3.5 μm),流动相为乙腈-0.01 moL·L-1乙酸铵溶液(用乙酸调节pH值至6.5)(30∶70);流速:0.8 mL·min-1,柱温:35 ℃,进样体积:10 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:600 ℃,采集速率:每秒10点,气流量:20 L·min-1;采集时间:12 min。结果 3种目标苯胺类杂质在0.02~0.2 μg·mL-1内(相当于主成分的0.000 7%~0.007%水平;3种目标杂质的总量限度为0.01%),线性关系均良好(r≥0.998 0),回收率介于95.6%~110.8%,检测限和定量限分别低于0.003、0.01 μg·mL-1(相当于0.000 3%),能较好的满足目标杂质的检测灵敏度要求。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,可用于米拉贝隆原料中潜在苯胺类具有警示结构杂质的残留量监控。
Abstract
OBJECTIVE To establish an original method for determination of three anilines with alerting structure(MLB-IM-K, MLB-IM-L and MLB-3-IM01) in mirabegron drug substance. METHODS The Waters Acquity HPLC-QDa system was applied, with the XBridge Shield RP18 column(4.6 mm×150 mm,3.5 μm) maintained at 35 ℃. Mobile phase consist of acetonitrile/0.01 moL·L-1 ammonium acetate solution(pH 6.5, adjusted by acetic acid)(30∶70) at a flow rate of 0.8 mL·min-1. The injection volumes were 10 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 12 min. RESULTS Three anilines all showed good linearity (r≥ 0.998 0) in the range of 0.02-0.2 μg·mL-1(equivalent to 0.000 7%-0.007% of mirabegron, meanwhile the total limit for the three anilines was 0.01%). Their recoveries were between 95.6%-110.8%(ideal range:80%-120%), and their limits of detection and quantitation were all below 0.003 μg·mL-1 and 0.01 μg·mL-1(0.000 3%), respectively, fulfilling the sensitivity requirements for trace control of the target impurities. 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 anilines in mirabegron drug substances.
关键词
高效液相色谱法 /
QDa检测器 /
米拉贝隆 /
苯胺 /
杂质
{{custom_keyword}} /
Key words
HPLC /
QDa detector /
mirabegron /
aniline /
impuritie
{{custom_keyword}} /
中图分类号：
R917
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] LAM S,HILAS O. Pharmacologic management of overactive bladder[J]. Clin Interv Aging,2007,2(3):337-345.
[2] TANG Q D, GONG P. Mirabegron[J]. Chin J Med Chem(中国药物化学杂志), 2012, 22(6):544.
[3] CHONG T, CHEN Q. Clinical application of mirabegron in the treatment of overactive Bladder[J]. J Shandong Univ Health Sci(山东大学学报医学版),2018,56(3):6-11.
[4] ICH harmonised tripartite guideline. M7: Assessment and control of DNA reactive(mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk[S]. 2014: 9.
[5] ZHANG J, ZHANG Y J, NIE B. Advances in control strategies and methods for genotoxic impurities in drug research & development[J]. Chin J Pharm(中国医药工业杂志), 2018,49(9):1203-1220.
[6] ZHANG L, TAN Z M, JIAO H R, et al. Synthesis of related substance of mirabegron[J]. Chin J Pharm(中国医药工业杂志), 2014, 45(1): 9-12.
[7] DING Y M, PU Y W, WU J, et al. Determination of related substances in mirabegron by HPLC[J]. Chin J Pharm Anal(药物分析杂志), 2016, 36(8): 1439-1445.
[8] Astellas Medical Net. Betanis® Tablets 25 mg·50 mg (87259)[EB/OL].[2021-10-13][2023-02-17]. https://www.pmda.go.jp/PmdaSearch/iyakuSearch.
[9] ZHANG Y M, HE Y, LI Y L, et al. Simultaneous determination of six diterpenoid alkaloids in Fuzilizhong pills by HPLC coupled with QDA mass detector[J]. Chin J Pharm Anal(药物分析杂志), 2018, 38(7): 1248-1253.
[10] CAO L, HU Y, ZHANG Y, et al. Determination of the contents of lactulose and related substances in lactulose oral solution by UPLC-QD[J]. Chin J Mod Appl Pharm(中国现代应用药学),2021, 38(12): 1493-1496.
[11] HE J, QU F W, ZHANG J, et al. γ-Aminobutyric acid in blood is determined by upper high performation liquid chromatography/QDa detection[J]. Chin J Anal Lab (分析试验室), 2015,34(9): 1022-1025.
[12] WANG W B, YU C F, ZHANG F, et al. Analysis of N-linked glycan profile of therapeutic antibodies by UPLC-Qda MS[J]. Chin Pharm J(中国药学杂志), 2018, 53(3): 223-227.
[13] SHI Y, WEI F, LU B J, 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(中国中药杂志), 2020, 45(21): 5232-5237.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
国家药品监督管理局化学药品杂质谱研究重点实验室开放课题资助(NMPA-KLIPCD-2020-06);北京市科委、中关村管委会专项课题资助(Z211100003421042)
{{custom_fund}}
PDF(956 KB)
