A the recent CRGC/FDA meeting, Dr. Diaa Shakleya presented a study on the screening and effectiveness of potential scavengers to prevent Nitroso-API formation.
This week a team from FDA published “Bumetanide as a Model NDSRI Substrate: N-nitrosobumetanide impurity formation and its inhibition in bumetanide tablets”
Is there any comparative data for the formulation without the presence of any of the modifiers? e.g. the starting level of nitrosamine at time zero and then whether the level increases or decreases with time at 40/75.
I find it interesting that there is still such a prevalence of nitrosamine with the different scavenger molecules at time zero, with ascorbic seeming to have the biggest potential impact, but it may be that the level of formation in the “standard” formulation is far in excess of this.
There is a decrease in level over time with all of the acids added, including the HCl, but a slight increase with the NaHCO3 (from a much lower, inhibited/controlled starting point). Is this instability of the n-nitrosobumetanide in the presence of the acid, breaking down quicker than the rate of formation of new nitrosamine, rather than them acting as scavengers or inhibitors?
What I could comment is that the rate of formation of this nitrosamine by the “acid route” is from both sides, you could form the nitrosamine, but the nitrosamine could form back the amine. This could happen again and again unless there is a nucleophilic trap in the middle and while the acid is not “depleted”. This is more relevant for drug susbstance synthesis. But could be at least a contributor here.
This is interesting. I want to refer to the example of N-methyl-N-nitrosoaniline. The aromatic nitrosamine formed once degraded in 28 days at 50 ◦C/75% RH without adding a scavenger. Fischer–Hepp rearrangement might happen, according to the literature. The stability of nitrosamines should be considered when considering scavengers’ effect.
