Complementary use of gas chromatography–mass spectrometry, gas chromatography–atomic emission detection and nuclear magnetic resonance for identification of pharmaceutically related impurities of unknown structures

The complementary use of gas chromatography–mass spectrometry (GC–MS), gas chromatography–atomic emission detection (GC–AED) and nuclear magnetic resonance (NMR) spectroscopy is demonstrated by the identification of four major by-products in a sample from an exploratory attempt to synthesise 1,3-dichloro-5-(difluoromethoxy)benzene. GC–MS was used for straightforward identification of the target compound and one of the impurities. By employing GC–AED, the sample was screened for heteroatoms in the analysed molecules and determination of the partial empirical formula of one sample component was carried out. The combined spectroscopic data obtained from the MS and AED experiments facilitated structure elucidation of two of the additional by-products. Finally, identification of the last unknown component could be obtained by combining spectral information from GC–MS, GC–AED and NMR data acquired after isolation of the impurity from the sample.