کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1222584 | 1494670 | 2012 | 7 صفحه PDF | دانلود رایگان |
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.
Journal: Journal of Pharmaceutical and Biomedical Analysis - Volume 61, 5 March 2012, Pages 277–283