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

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 61; pp. 277 - 283
• Main Authors: Ueyama, Eiji, Takahashi, Fumie, Ohashi, Jyunji, Konse, Tomonori, Kishi, Naoyuki, Kano, Kenji
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 05.03.2012; Elsevier
• Subjects: AIBN; Analysis; Analytical, structural and metabolic biochemistry; Azetidinecarboxylic Acid - analogs & derivatives; Azetidinecarboxylic Acid - analysis; Azetidinecarboxylic Acid - metabolism; Biological and medical sciences; Chemistry, Pharmaceutical - methods; Degradation product; Dihydropyridines - analysis; Dihydropyridines - metabolism; Free Radicals - analysis; Free Radicals - metabolism; Fundamental and applied biological sciences. Psychology; General pharmacology; Heavy oxygen water; hydrogen; hydrolysis; Medical sciences; monitoring; Oxidation; Oxidation-Reduction; Oxidative Stress - physiology; oxygen; Pharmaceutical Solutions - analysis; Pharmaceutical Solutions - metabolism; Pharmacology. Drug treatments; solvents; Stability; water content; AIBN; Oxidation; Stability; Heavy oxygen water; Degradation product; Oxygen; Calcium antagonist; Metabolism; Azelnidipine; Heavy water; Dihydropyridine derivatives; Pharmacokinetics; Physicochemical properties
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2011.12.001

► 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. 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.