Synthesis and detection of potential genotoxic impurities in nebivolol hydrochloride
WANG Yi-xuan
HUANG Hai-wei
HU Xiao-wen
ZHANG Cai-yu
YU Li-ju
YUAN Song
CHEN Hua
Abstract：Objective:To obtain impurity reference substance by synthesizing N-nitroso nebivolol,and to establish and compare analytical methods for determination of N-nitroso nebivolol in API. Methods:The structure of synthetic product was identified by HRMS,1 H-NMR,and 13 C-NMR. The content was determined by DSC. The reference substance was studied using three analytical methods of UPLC,ultra-high performance liquid chromatography triple quadrupole mass spectrometry ( UPLC-QQQ),and high performance liquid chromatograph quadrupole time-of-flight mass spectrometry ( UPLC Q-TOF) . Results:The compound was identified as N-nitroso nebivolol and the average result of DSC assay was 99.26％. The limit of detection ( LOD) and the limit of quantitation ( LOQ) of UPLC Q-TOF are 30 and 60 ng·mL-1 respectively. The LOD of UPLC-QQQ and UPLC are 1 and 7.5 ng·mL-1,the LOQ are 3 and 15 ng·mL-1,the range of calibration cure are 3～300 and 15～300 ng·mL-1 respectively. The recoveries meet the requirements at the range of 98.13％～105.93％ and 86.75％～92.01％,respectively. Conclusion:The synthesis method is feasible. The method using UPLC Q-TOF is capable for limit detection while methods using UPLC-QQQ and UPLC are suitable for quantitative analysis. These three analytical methods are all convenient and exclusive,providing references for quality control of different requirements.
Keywords：nebivolol hydrochloridegenotoxic impurityUPLC-MS/MSassaynitrosamine drug substance-related impurities
Publication Date：2025-01-14
Online Publishing Date：2026-08-14(First online date of this platform, not the publication date of the document)
Pages：7( 73-79 )