An analytical team from Merck just published a methodology to overcome one of the biggeest challenge of ion suppresion due high concentrations of DMF.
Publication: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5270312
Abstract: The presence of nitrosamines in pharmaceutical products presents significant challenges for the industry, primarily due to the potential carcinogenic risks they pose to patients. Among these, NNitrosodimethylamine (NDMA) has garnered attention as one of the first nitrosamines identified in products like Valsartan, Ranitidine, and Metformin. NDMA is a polar compound with weak retention on most stationary phases, making it susceptible to matrix interferences. A prevalent issue is the co-elution of NDMA and N,N-dimethylformamide (DMF), a common solvent and precursor for NDMA. DMF is typically present in much higher concentrations, which can lead to false positives and an overestimation of NDMA concentration due to interference from 15N DMF and 13C DMF. Conversely, elevated DMF concentrations can induce ion suppression, resulting in false negatives. Consequently, accurately quantifying NDMA remains a challenge, even when utilizing high-resolution or tandem mass spectrometry techniques. To address these issues, we developed a robust HPLC-MS method employing an Evosphere AQUA column, which enables good separation of NDMA from DMF and other sample matrices. This method permits accurate quantification of NDMA in the presence of DMF at concentrations up to 1,000,000 times greater. We achieved a detection limit of 0.1 ng/mL using a single quadrupole mass spectrometer, such as QDa, which corresponds to 1 ng/g relative to a 100 mg/mL Metformin HCl sample concentration. The method has been successfully validated according to ICH guidelines, demonstrating specificity, sensitivity, accuracy, precision, and robustness. The application of this method was further illustrated through the analysis of NDMA in Metformin drug products including both immediate release and extended release formulations.
