Forced Oxidative Degradation Pathways of the Imidazole Moiety of Daclatasvir |
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| Affiliation: | 1. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China;2. Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China;3. National Experimental Teaching Demonstration Center of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China;1. Translational PKPD Research Group, Department of Pharmaceutical Biosciences, Associate Member of SciLife Lab, Uppsala University, Uppsala, Sweden;2. Department of Drug Metabolism and Pharmacokinetics, Early Respiratory, Inflammation and Autoimmunity, R&D Biopharmaceuticals, AstraZeneca R&D, Gothenburg, Sweden;1. Sciences Pharmaceutiques, Ecole Doctorale des Sciences et Technologie (EDST), Laboratoire de Valorisation des Ressources Naturelles et Produits de Santé (VRNPS), Université Libanaise, Beyrouth, Lebanon;2. Laboratoire de Pharmacie Galénique et Génie Pharmaceutique, Institut Charles Gerhardt, UMR 5253, Equipe MACS, UFR Sciences Pharmaceutiques et Biologiques, Université de Montpellier, France;3. Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Institut Charles Gerhardt, UMR 5253, EPHE, PSL, Equipe MACS, Ecole Nationale Supérieure de Chimie, Université de Montpellier, Montpellier, France;1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;2. Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan;3. Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan;4. School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia;5. Faculty of Pharmaceutical Sciences, Sojo University, 1-22-4 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan;1. Research Center Pharmaceutical Engineering GmbH (RCPE), Graz, Austria;2. University of Technology, Institute of Process and Particle Engineering, Graz Austria |
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| Abstract: | Daclatasvir hydrochloride (DCV) is the active pharmaceutical ingredient of Daklinza, a marketed product for the treatment of hepatitis C viral infection. The intrinsic stability of daclatasvir was evaluated via a forced degradation study. DCV was found to be stable in the solid state. In solution, its carbamate moiety is susceptible to basic hydrolysis, whereas its imidazole is liable to base-mediated autoxidation to form degradants 1 and 3, 7-8, respectively. The imidazole moiety can also be oxidized to form degradants 6-7 in the presence of hydrogen peroxide or azobisisobutyronitrile. The chloro-adduct degradant 9 was also observed in hydrogen peroxide solution. Furthermore, the imidazole moiety is sensitive to photodegradation in solution. Degradants 2-8 were observed in a solution of DCV exposed to high intensity light/UV light; the formation of degradants 2 and 5-8 was postulated through 4 degradation pathways. The degradants 3 and 4 were deemed to be secondary degradants of 7 and 5, respectively. |
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| Keywords: | forced conditions oxidation(s) photodegradation degradation products stability nuclear magnetic resonance (NMR) spectroscopy liquid chromatography–mass spectrometry (LC-MS) |
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