Reaction of Nicardipine with Nitrous Acid or tert -Butylnitrite Produces Nicardipine Pyridine Analog and Nicardipine Oxime Derivatives, Rather Than N -Nitroso Nicardipine

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-MS n 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.