Mechanistic study on degradation of azelnidipine solution under radical initiator-based oxidative conditions

We identified four degradants (Dg-A, Dg-B, Dg-C, Dg-D) of azelnidipine to be generated under radical initiator-based oxidative conditions and proposed the mechanistic pathway for their formation. 2,2′-Azobisisobutyronitrile was used as a radical initiator. There appeared to be two major pathways in the oxidation of the 1,4-dihydropyridine moiety. One was initiated by hydrogen abstraction from the C-4 position of the dihydropyridine ring, followed by hydrogen abstraction from the N-1 position, leading to aromatization of the dihydropyridine ring and Dg-A generation. The other was initiated by hydrogen abstraction from the N-1 position of the dihydropyridine ring followed by oxidation and hydrolysis to yield Dg-B. Furthermore, Dg-B was subjected to hydrolysis to generate Dg-C and Dg-D. It has been revealed that the rate of the Dg-B degradation was predominantly governed by the water content of the solvent used. Water participation in Dg-B degradation was proved by monitoring the incorporation of heavy oxygen atom (18O) into the structure with LC–MS, in which the experiment was carried out in a medium prepared with heavy oxygen water to label 18O during the hydrolysis.

► A stability-indicating method that can realize the separation of all of the oxidative degradates of azelnidipine has been developed. ► The structure of the four major degradates of AZ generated under AIBN-initiated oxidation conditions has been characterized, and the mechanistic pathways have been proposed. ► An oxidation experiment with heavy oxygen water as an oxygen tracer has proved water molecule participation in the Dg-B generation step.