Reaction of Nicardipine with Nitrous Acid or <i>tert</i> -Butylnitrite Produces Nicardipine Pyridine Analog and Nicardipine Oxime Derivatives, Rather Than <i>N</i> -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-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.