Betrixaban is an oral anticoagulant drug, recently approved by the Food and Drug Administration (FDA), for the treatment of Venous Thromboembolism. Its FDA approval is expected to exponentially increase its medical use which necessitates understanding its fate in the environment. This study investigated the fate of betrixaban during disinfection with monochloramine (NH2Cl), free chlorine, and ozone as well as its N-Nitrosodimethylamine (NDMA) formation potential with these oxidants. Betrixaban revealed an NDMA yield of >1% upon monochloramination. An increase in NH2Cl dosage, contact time, and pH significantly increased betrixaban degradation and NDMA formation. Although the highest yield of NDMA was observed at basic pH, the formation of NDMA was still significant (yield ~0.3%) at circumneutral pH. This study revealed a new potent precursor of NDMA, indicating that monochloramination of waters containing betrixaban can lead to the formation of NDMA and other disinfection by-products (DBPs) such as dichloroacetonitrile (DCAN) and dimethylformamide (DMF). Moreover, betrixaban showed a complete degradation with 5 mM free chlorine over seven days with 0.01% NDMA yield. The degradation of betrixaban, in the presence of 0.3 mM ozone, increased from 40% after 1 minute to almost complete degradation after 6 minutes of contact time, with no observed NDMA formation. DMF was detected as a prominent DBP of chlorination and ozonation of betrixaban. The kinetic studies revealed that the reaction of betrixaban with NH2Cl and ozone followed pseudo-first-order reaction kinetics while no reaction kinetics was obtained for chlorination of betrixaban due to its complete removal within initial two minutes of the reaction. As the use of betrixaban will widen, and its presence in the environment, including in wastewater and surface waters, will increase, its DBPs’ formation risks in the environment will also increase. Our study highlights these risks and, through a detailed investigation of contributing factors, kinetics, and reaction mechanism, provides useful information to mitigate such risks. 

Reactivity and <i>N</i>-nitrosodimethylamine formation potential of betrixaban with monochloramine, chlorine, and ozone

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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Reactivity and N-nitrosodimethylamine formation potential of betrixaban with monochloramine, chlorine, and ozone