Nitrosamine formation in lidocaine active pharmaceutical ingredients and drug products

N-nitrosamine compounds have long been known for their carcinogenic properties, but they came into the focus of the pharmaceutical industry in 2018 when N-nitrosodimethylamine was detected in the active ingredient Valsartan. Since then, there has been a growing literature on the formation of N-nitrosamines in pharmaceutical products. In our study Lidocaine semi-solid and liquid pharmaceutical formulations were tested with a limit of 26.5-53.0 ppb N-nitrosodiethylamine (NDEA) and 100-200 ppb N-nitroso-desethyl lidocaine. It was found that the lidocaine active ingredient degrades to the secondary amine precursors of these nitrosamines at elevated temperatures and that the formation of nitrosamines is feasible in the drug products where the excipients contain trace amounts of nitrite. Nitrite was detected at ppb level in the excipients of the formulations, while diethylamine and desethyl lidocaine were detected at ppm level during the degradation of the active substance. The nitrosamine formation was investigated at their respective production temperatures (ointment: 70 °C/3 h; injection: 125 °C/15 min), and the NDEA and N-nitroso-desethyl lidocaine contents were measured by GC-MS and HPLC-MS. The formation of nitrosamines in the drug formulations was found to be not only time, temperature, and nitrite dependent but was also different in the base and salt form of the API and in the studied semi-solid and liquid pharmaceutical formulations. These experiments have proven to be a useful tool for predicting nitrosamine formation in lidocaine pharmaceutical formulations and can be used as a basis for making recommendations to reduce nitrosamine concentrations.