Hello Nitrosamines teams,
The N-Nitrosonicardipine impurity has been added to the FDA list with a AI 1500ng/d. We have requiered the synthesis of this impurity to 2 suppliers but they are not abble to produce it and proposed us to send a report describing the chemical tests done to synthetise it. As this impurity has been listed do you think that a standard reference is available ? Or it’s only based on the nicardipine structure ? Thanks in advance for your experience on this type of subject.
1 Like
This impurity cannot be formed; see the discussion in the related topic:
N-nitroso-amlodipine ; N-nitroso-felodipine ; synthesis not successfull but still listed by FDA and EMA as NDSRIs
Therefore a detailed failure report (including NMR and mass spectra of the other products obtained) should be sufficient.
7 Likes
Not the first time we have seen that. It may be a good idea for the regulatory agencies to add a vetting process.
2 Likes
Sciandra,
Yes, this impurity cannot be formed due to the structural arrangements of the molecule. We got FDA acceptance for this communication. You can also proceed by this way.
4 Likes
Reaction of Nicardipine with Nitrous Acid Produces Nicardipine Pyridine Analog and Nicardipine Oxime Derivatives, rather than N-Nitroso Nicardipine-Pub
6 Likes
https://pubs.acs.org/doi/10.1021/acs.oprd.5c00436
Reaction of Nicardipine with Nitrous Acid or tert-Butylnitrite Produces Nicardipine Pyridine Analog and Nicardipine Oxime Derivatives, Rather Than N-Nitroso Nicardipine
Abstract
During a recent impurity profiling study of nicardipine, the potential presence of a hypothetical nitrosamine drug substance-related impurity (NDSRI), “N-nitroso nicardipine”, became a critical focal point for the study due to the presence of a “secondary amine” group in the 1,4-dihydropyridine core structure of the drug molecule. In this study, nicardipine was reacted with nitrous acid or tert-butylnitrite to prepare N-nitroso nicardipine but to no avail. Instead, the major reaction product formed is nicardipine pyridine analog, a known oxidative degradant of nicardipine. Two minor reaction products were also formed, which were determined to be the oxime derivatives of nicardipine based on the evidence obtained from LC-MSn and 1D/2D nuclear magnetic resonance (NMR) spectroscopy. The oximes are isomeric to the hypothetical “N-nitroso nicardipine”, which could easily be mistaken as N-nitroso nicardipine. The formation mechanism for the oximes is proposed, and the reason why N-nitroso nicardipine could not be obtained is explained.
3 Likes