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.
QIN Yong-xiang, XU Hong-xia, SHEN Zong-yong, GUO Xin, LIU Zhi, SUN Yue-jun, WANG Ming-juan, YUAN Wei-feng, MENG Min, MA Ang, LIU Yu-jing
. Determination of notrobenzenes impurities with alerting structures in mirabegron by UPLC-QDa mass spectrometry method*[J]. Chinese Journal of Pharmaceutical Analysis, 2022
, 42(10)
: 1792
-1800
.
DOI: 10.16155/j.0254-1793.2022.10.12
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