A GC-MS/MS Method for Trace Level Quantification of Six Nitrosamine Impurities (NDMA, NDEA, NEIPA, NDIPA, NDPA, and NDBA) in Commercially Used Organic Solvents: Dichloromethane, Ethyl Acetate, Toluene, and O-xylene

Abstract

Nitrosamines, the probable carcinogens have been reported with Angiotensin II Receptor Blocker (ARB) drugs, Ranitidine, and other medicines. Solvents play a vital role in the pharmaceutical industry in the separation, purification, and cleaning process for manufacturing APIs and drug products. According to the FDA and EMA, solvents used in the drug manufacturing process are potential root causes of Nitrosamine impurities. Hence, monitoring nitrosamines in solvents is an essential step for manufacturers.A sensitive direct injection GC-MS/MS, an essential analytical tool for low-level nitrosamine quantification in solvents, was developed by utilizing multiple reactions monitoring mode (MRM) for the simultaneous determination of six nitrosamines, namely, NDMA, NDEA, NEIPA, NDIPA, NDPA and NDBA in common solvents such as dichloromethane, ethyl acetate, toluene, and o-xylene. NDMA-d6 was used as an internal standard.The FDA reported a combined direct injection method for nitrosamine impurity assay by GC-MS/MS, which had several challenges for commercial-grade solvents in terms of interferences and resolution of unknown impurities and nitrosamine peaks. A novel method was developed to optimize the critical parameters of GC-MS/MS according to the solvent samples. The method validation was performed through the following parameters, sensitivity, linearity, accuracy, precision, specificity, and stability. The quantification of nitrosamines in commercial-grade solvents ranged from 100 ppb to 8000 ppb with respect to the sample concentration of 25 mg/mL with good sensitivity in LOQ level. The quantification ranged from 5 ppb (for NDMA, NDEA, NEIPA, NDIPA, NDPA) and 13 ppb (NDBA) to 2000 ppb with respect to the sample concentration of 100 mg/mL for analytical grade solvents with good sensitivity in the proposed method. Hence, it will be useful to quantify the low-level nitrosamines in commercial-grade solvents as well as analytical-grade solvents.