This discussion is related to FDA has learned that N-Nitrosobumetanide can form as a degradation
impurity in some formulations of bumetanide during shelf-life. While the details of its
formation are not fully understood, the N-Nitrosobumetanide may result from
reaction of the bumetanide API with trace levels of nitrite and/or nitrate in the
formulation. The nitrosation is believed to occur at the nitrogen of the N-butyl side
chain to form 3-(butyl(nitroso)amino)-4-phenoxy-5-sulfamoylbenzoic acid (CAS#
2490432-02-3).
I believe either zero or ppb level of Nitrate/Nitrite containing excipients would solve the issue.
I’m interested in this topic. When I asked Dr. Urquhart about the conversion factor of nitrosation for the drug product, he advised me to be careful with aniline type amine. According to him, aniline works like a “sponge” for nitrite due to its low basicity. Bumetanide looks like the typical case!!
To mitigate nitrosamine contamination risk, controlling the nitrite content in excipients is one way. The other way is to add antioxidants such as ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E) in the formulation, as FDA recommended. And Dr. Urquhart advised me the addition of primary amines like glycine, which was in the model case of not the tablet but the solution, might not be appropriate due to the basicity of the amine.
Anyway, we should assess the API with aniline carefully, I think.
