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 ((18)O) into the structure with LC-MS, in which the experiment was carried out in a medium prepared with heavy oxygen water to label (18)O during the hydrolysis.
Analytical and Quality Evaluation Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo, 1-12-1, Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan. ueyama.eiji.s2@daiichisankyo.co.jp
Eiji
E
Ueyama
Fumie
F
Takahashi
Jyunji
J
Ohashi
Tomonori
T
Konse
Naoyuki
N
Kishi
Kenji
K
Kano
D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004095:Dihydropyridines / Q000032:analysis / Q000378:metabolism*; D005609:Free Radicals / Q000032:analysis / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D019999:Pharmaceutical Solutions / Q000032:analysis / Q000378:metabolism
D004095:Dihydropyridines; D005609:Free Radicals; D019999:Pharmaceutical Solutions; D001383:Azetidinecarboxylic Acid; C061679:azelnidipine