Characterization and Quantitation of N-Nitroso Duloxetine Impurity in Duloxetine Hydrochloride Drug Substance

Abstract

The nitrosamine family of chemicals is a large group of carcinogens found in human diets and other environmental media. In animal experiments, it has been shown that N-nitroso compounds can cause cancer, hence the presence of nitrosamine impurities are important to evaluate and need to be quantified. This work shows the content of N-nitroso duloxetine in duloxetine (DXT) hydrochloride, before proceeding to the quantification of impurity, the impurity standard must be well characterized by analytical techniques and it places a vigorous role, i.e. N-nitroso DXT molecular weight conformed by mass spectral data and the atoms connectivity was confirmed by NMR spectral data (1H, 13C, COSY, HSQC and HMBC) and thermal analyses (DSC and TGA) were also performed. In N-nitroso DXT, two sets of signals were typically observed, indicating the presence of asymmetric N-nitroso DXT, concluding with drift functional theory (DFT) for E-, Z-isomers related to the nitroso group in N-nitroso DXT. The medical agency recommends a specified limit of 0.83 ppm for the acceptable intake (AI) and the maximum daily dosage. The determination of N- itroso DXT was performed by liquid chromatography mass spectrometry (LC-MS) followed by electron spray ionization with triple quadrupole.