Process-related impurities of eplerenone: determination and characterisation by HPLC methods and Raman spectroscopy

• Published in: Journal of pharmaceutical and biomedical analysis 2018-09, Vol.159, p.466-476
• Main Authors: Filip, Katarzyna, Łaszcz, Marta, Leś, Andrzej, Chmiel, Justyna
• Format: Article
• Language: English
• Subjects: Chromatography, High Pressure Liquid - methods; Drug Contamination; Eplerenone; Eplerenone - analysis; High-performance liquid chromatography (HPLC), reversed-phase (RP); Process-related impurites; Raman spectroscopy (RS); Spectrum Analysis, Raman - methods; Stereoisomer; Stereoisomerism
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2018.07.028

[Display omitted] •Development and validation of RP and HPLC methods for impurity profiling of eplerenone API and it’s starting material.•Application of Raman spectroscopy as a fast method for the diagnostics and characterization of the isomers during the synthesis.•The bands assignment supported by the quantum chemical calculations. Two novel high-performance liquid chromatography methods for the determination of process-related impurities of eplerenone drug substance and the designated starting material were developed and validated. Process impurities, including stereoisomers of eplerenone and the intermediate, were controlled using a Kromasil C18 column (250 mm x 4.6 mm; particle size 5 μm), under gradient conditions. Simple mobile phases: water and acetonitrile, as well as a PDA detector set at 240 nm were used. In order to control the stereochemical purity of the starting material (SM) in the eplerenone synthesis the polysaccharide-based Kromasil 5-AmyCoat chiral stationary phase was applied. To confirm the identity of the process-related impurities (nine compounds) Raman Spectroscopy (RS), as a fast and convenient method, was applied. Differences in the wavenumbers of CC and CO stretching vibrations were the most distinctive features for the identification by means of RS. The bands assignment was supported by quantum mechanical computations. For one pair of the epimers containing the hydroxyl group the O-H…O bond geometry was correlated with the wavenumbers of stretching vibrations of this group. Wherever possible, experimental results were compared with literature data.