Understanding Aqueous Nitrosation Kinetics of 4-Substituted Piperidines To Risk Assess Pharmaceutical Processes and Products

In this work, the rates of aqueous nitrosation of 4-phenylpiperidine hydrochloride, 4-(naphthalen-1-yl)piperidine hydrochloride, 4-phenylpiperidin-4-ol, and 4-(naphthalen-1-yl)piperidin-4-ol were investigated and subsequently compared to the previously reported experimental initial rate of nitrosation of dimethylamine (DMA). At low concentrations of the investigated amines, the nitrosation rate of DMA was approximately 1 order of magnitude faster than that of the investigated bulkier amines. At higher amine concentrations, this disparity becomes more pronounced for 4-(naphthalen-1-yl)piperidine hydrochloride due to its limited solubility in water, resulting in nitrosation rates 3–4 orders of magnitude lower than that of DMA. Experiments and simulation results from a solution phase kinetic model indicate that nearly neutral to basic conditions (i.e., pH > 6) prevent nitrosation of the investigated amines under the investigated conditions. The solution phase kinetic model was then used to simulate the potential nitrosamine formation that could occur in an oral solid dosage formulation containing 4-(naphthalen-1-yl)piperidine hydrochloride. According to the simulation results, the risk of 4-(naphthalen-1-yl)piperidine nitrosation should be classified as low.