Synthesis of Nitroso Derivatives of Dihydropyridine Calcium Channel Blockers

Regulatory authorities issued guidance on acceptable intake limits for nitrosoamine drug substance-related impurities. However, the formation of these potential nitrosamine contaminants in the dihydropyridine class of drugs has not been clearly established. In this work, the nitrosation of six dihydropyridine calcium channel blockers was investigated under a set of conditions. The nitrosation products were isolated and characterized by MS, NMR, and XRD. The results show that nitrosation occurred on the carbon atom instead of the nitrogen atom. Nifedipine exhibited the highest reactivity via oxidative aromatization and reduction to produce a C-nitroso compound. Treatment with nitrite in either 1 M hydrochloric acid or 30% acetic acid resulted mainly in pyridine products via oxidation. In contrast, the other dihydropyridine derivatives studied generated C-nitrosated products in addition to aromatized products upon treatment with butyl nitrite. The findings provide direct evidence to rule out the possibility of N-nitroso impurities being present in the dihydropyridine class of drug substances and products.