1-(4-Aminophenyl)-3-Morpholinopiperidin-2-One: A Process Related Impurity of Apixaban- An Anticoagulant Drug

ABSTRACT

Introduction: Apixaban is an anticoagulant drug act by direct inhibition of factor Xa. Apixaban is used for the treatment and prevention of blood clots and stroke in people with nonvalvular atrial fibrillation. In this report, we describe the identification of a process-related impurity observed during the preparation of apixaban, an anticoagulant drug. Objectives: The primary objective of this study was to isolate, purify, and characterize an unknown process impurity observed during the synthesis of Apixaban. Materials and Methods: All the reagents and solvents required for the synthesis were obtained from commercial vendors and had the desired purity of >98%. Isolation of unknown impurity was carried out using Flash Chromatography, Puriflash 5.250 using acetonitrile/water as eluent in gradient mode. The column used in Puriflash is YMC- Triart Prep-C18 250×20 mm, 10 μ. NMR spectra of the synthesized compounds were recorded on Bruker 400 MHz spectrometers with TMS as the internal standard. Chemical shift is represented with δ in parts per million. Mass spectra were recorded with a XEVO-TQSmicro#QEE0233 LC Mass Spectrometer. The IR spectra of synthesized compounds were recorded on Perkin Elmer Spectrum IR ES Version 10.6.0 by using the KBr pellet method. The purity of apixaban and its intermediates was determined by HPLC using an area normalization method. Results: As a part of the investigation, we isolated the impurity by column chromatography with >96% purity and analyzed the sample of impurity by LC-MS, IR, and NMR spectroscopy. The LC-MS analysis coupled with IR and NMR analysis suggested that the impurity is 1-(4-aminophenyl)-3- morpholinopiperidin-2-one, generated during preparation of Apixaban intermediate (APN-05). The impurity is a reduced form of APN-05, possibly formed due to reduction of the ring double bond of dihydropyridin-2(1H)-one moiety of APN-05. The genotoxic assessment of the impurity revealed its probability to exhibit genotoxic properties.

KEYWORDS

• Apixaban
• Process-related impurity
• Structural alert
• Genotoxic impurity
• Root cause
• investigation

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• DOI10.5530/ijper.20261932Copy

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