Identification, synthesis, and characterization of thermal degradants of brivaracetam

AbstractImp-I∼III were observed for the first time after a 4-hour thermal degradation study of brivaracetam at 130 °C. These three degradants were prepared and purified through targeted and regiospecific synthesis, and were further characterized by 1D-NMR and 2D-NMR. After differentiation from other isomers, Imp-I was identified as (2S)-2-((3R)-2,5-dioxo-3-propylpyrrolidin-1-yl)butanamide; Imp-II was identified as (2S)-2-((3R,4S)-3-hydroxy-2-oxo-4-propylpyrrolidin-1-yl)butanamide; and Imp-III was identified as (S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide. Besides, in-silico toxicity prediction confirmed a high probability of non-mutagenicity of the three impurities. By preparing and characterizing the degradants, product stability of Brivaracetam under even extreme conditions was better understood, thus further ensuring product quality.Keywords: Brivaracetamcharacterizationdegradantsregioisomersynthesis Disclosure statementNo potential conflict of interest was reported by the author(s).Additional informationFundingThis work was supported by the State Key Laboratory of Anti-Infective Drug Development (Sunshine Lake Pharma Co., Ltd) under Grant [number 2015DQ780357] and Key-Area Research and Development Program of Guangdong Province under Grant [number 2022B1111050003].