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.