Process-dependent N-nitroso-ketamine formation during ketamine active pharmaceutical ingredient manufacturing: part I impact of process design, solvent selection, and activated carbon.

内容摘要

Activated carbon is commonly used in certain manufacturing steps of active pharmaceutical ingredients (APIs) to remove impurities, unwanted by-products and color. For ketamine hydrochloride, due to the presence of a secondary amine moiety in the API, high-energy nitroxide species from activated carbon present a risk of introducing N-nitroso-ketamine, a potential carcinogen and nitrosamine impurity of regulatory concern. The current study examined the impact of activated carbon contact on nitrosamine formation during API manufacturing, using either a ketamine hydrochloride salt or ketamine base form. After contact with the activated carbon slurry, N-nitroso-ketamine formation from ketamine hydrochloride salt in the aqueous phase was low and most of the formed N-nitroso-ketamine was adsorbed onto the activated carbon. In contrast, filtering ketamine base in ethyl acetate through an activated carbon cartridge generated markedly higher levels of N-nitroso-ketamine, with approximately half of the generated N-nitroso-ketamine eluting from the activated carbon. Solvent selection strongly influenced nitrosamine formation, with N-nitroso-ketamine formation from ketamine hydrochloride salt in acetonitrile substantially increased, whereas formation increased only slightly in ethyl acetate, and was completely inhibited in methanol. Notably, while activated carbon and organic solvents can facilitate N-nitroso-ketamine formation, they were not the primary determining factors. Rather, an unidentified nitrosating agent appears to play a central role in N-nitroso-ketamine formation. Collectively, these findings provide process-specific insights to inform API manufacturing process design and help mitigate the risk of introducing N-nitrosamine impurities when designing or optimizing API manufacturing processes for ketamine and potentially other secondary amine-containing APIs.