Synthesis and Physicochemical Characterization of the Process-Related Impurities of Eplerenone, an Antihypertensive Drug

• Published in: Molecules (Basel, Switzerland) Switzerland), 2017-08, Vol.22 (8), p.1354
• Main Authors: Dams, Iwona, Białońska, Agata, Cmoch, Piotr, Krupa, Małgorzata, Pietraszek, Anita, Ostaszewska, Anna, Chodyński, Michał
• Format: Article
• Language: English
• Subjects: Analytical methods; Antihypertensive Agents - chemistry; Antihypertensives; Chromatography, High Pressure Liquid; Contaminants; crystal structure; Dehydration; Drug Contamination; eplerenone; High resolution; hypertension; Impurities; Infrared spectroscopy; Ionization; Ions; Magnetic Resonance Spectroscopy; Mass spectrometry; Mass spectroscopy; Molecular Structure; NMR; Nuclear magnetic resonance; Nuclear reactions; Oxidation; Pharmacology; Production methods; Quality control; selective aldosterone blocker; Side reactions; Single crystals; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Infrared; spectroscopic methods; Spectroscopy; Spironolactone - analogs & derivatives; Spironolactone - chemistry; steroids; X-ray diffraction
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules22081354

Two unknown impurities were observed during the process development for multigram-scale synthesis of eplerenone (Inspra ). The new process-related impurities were identified and fully characterized as the corresponding (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-9,11-dichloroeplerenone derivatives and . Seven other known but poorly described in the literature eplerenone impurities, including four impurities A, B, C and E listed in the European Pharmacopoeia 8.4 were also detected, identified and fully characterized. All these contaminants result from side reactions taking place on the steroid ring C of the starting 11α-hydroxy-7α-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone ( ) and the key intermediate (7α,17α)-9(11)-enester , including epimerization of the C-7 asymmetric center, oxidation, dehydration, chlorination and lactonization. The impurities were isolated and/or synthesized and fully characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their ¹H- and C-NMR signals were fully assigned. The molecular structures of the eight impurities, including the new (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-9,11-dichloroeplerenone related substances and , were solved and refined using single-crystal X-ray diffraction (SCXRD). The full identification and characterization of these impurities should be useful for the quality control and the validation of the analytical methods in the manufacture of eplerenone.