The determination of two analogues of 4-(azidomethyl)-1,1'-biphenyl as potential genotoxic impurities in the active pharmaceutical ingredient of several sartans containing a tetrazole group

Abstract

4'-(azidomethyl)-[1,1'-biphenyl]-2-carbonitrile (GTI-azide-1) and 5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole (GTI-azide-2) are potentially genotoxic impurities that can be present at trace levels in the active pharmaceutical ingredients and drug products of sartans containing a tetrazole group. A method of high-performance liquid chromatography coupled with mass spectrometry, that allows the determination of those genotoxic impurities at sub-ppm level relative to the active pharmaceutical ingredient, was developed.The method utilises a very efficient liquid chromatograph Waters Acquity I-Class coupled with a highly sensitive tandem mass spectrometer Xevo TQ-XS. The separation was achieved on a column Acquity UPLC BEH Shield RP18 1.7 μm employing a linear elution gradient. The mass spectrometer was used with a heated electrospray ionization. The method was found to be sufficient in terms of sensitivity, linearity, precision, accuracy, selectivity and robustness and is easily applicable in the pharmaceutical quality control environment. The method allows for accurate quantification of both impurities GTI-azide-1 and GTI-azide-2 at levels below 1/10th of the specification limit, which is crucial in the context of pharmaceutical analysis. The limit of quantification was determined to be 0.033 ppm and 0.025 ppm for GTI-azide-1 and GTI-azide-2, respectively.