Evaluation and Measurement of Potential Genotoxic Impurities in Empagliflozin Active Pharmaceutical Ingredient Using Tandem Liquid Chromatography Mass Spectrometer, Accompanied by an Advanced Greenness Assessment
Abstract
Empagliflozin (EPG) is a glycemic control antidiabetic agent used to in patients with Type 2 diabetes and in individuals with established heart failure with reduced ejection fraction. In this study, four potential genotoxic impurities alkyl sulfonate esters, such as methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), isopropyl methanesulfonate (IPMS), and (2‐chloro‐5‐iodophenyl)(4‐(dimethylamino)phenyl)methanone, were identified by reviewing the synthetic pathway of EPG. At present, no appropriate techniques have been created for the threshold of toxicological concern level of isolation and quantification of these four contaminations in EPG. Two ionization techniques, such as atmospheric pressure chemical ionization (APCI), were employed for MMS, EMS, and IPMS (Method 1), whereas electrospray ionization (ESI) was used for the (2‐chloro‐5‐iodophenyl)(4‐(dimethylamino)phenyl)methanone impurity (Method 2) to evaluate their analytical suitability. In APCI positive‐ion mode, the three alkyl sulfonate esters produced stable and selective ion‐monitoring (SIM) mass transitions as [M + NH
4
]
+
. In contrast, (2‐chloro‐5‐iodophenyl)(4‐(dimethylamino)phenyl)methanone showed superior sensitivity under ESI conditions in positive‐polarity multiple reaction monitoring mode. The developed methods are both efficient and practical for the detection and quantification of these potential genotoxic impurities, thereby supporting the safe use of EPG. Validation results demonstrated…
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