Transformation of ranitidine during water chlorination and ozonation: Moiety-specific reaction kinetics and elimination efficiency of NDMA formation potential
Graphical abstract
Introduction
To cope with the stringent regulations governing disinfection by-products (DBPs), such as trihalomethanes (THMs) and haloacetic acids (HAAs), in chlorinated drinking water, chloramines have been increasingly used as an alternative disinfectant in the distribution systems of some countries [1]. Although chloramine disinfection is effective in minimizing the formation of regulated DBPs (e.g., THMs and HAAs), it is associated with the formation of N-nitrosamines [2], [3]. Among the N-nitrosamine family, N-nitrosodimethylamine (NDMA) has received the most attention due to its frequent occurrence and high carcinogenic potency [2], [3]. Even though NDMA is not regulated yet, guideline values or notification levels are set at low ng/L ranges in some countries [4], [5].
Dimethylamine and tertiary amines containing N,N-dimethylamine moiety are known to produce NDMA during chloramination [2], [3]. While the molar yields of NDMA formation from dimethylamine and most tertiary amines are less than 3%, a subset of tertiary amines, however, have been shown to form NDMA at considerably higher yields (e.g., 20%–90%) [2], [3]. Ranitidine, a common anti-acid drug, is a representative example and has a tertiary amine with N,N-dimethyl and N-methylfuran groups (Fig. 1). The molar NDMA yield of ranitidine ranges from 60%–90% upon chloramination [6], [7], [8]. A molar NDMA yield of 78% and 84% was also reported for N,N-dimethyl-thiophene-2-methylamine and N,N-dimethyl-benzylamine, respectively [7]. Tertiary amines with N,N-dimethyl and N-isopropyl groups also form high NDMA (23%–84%), such as pharmaceutical methadone [9] and N,N-dimethyl-isopropylamine [7] (see Fig. S1 for the structures). Studies have shown that the β aromatic or isopropyl groups can easily leave from the key reaction intermediate of the reaction between the tertiary amines and monochloramine, leading to a higher NDMA yield [6], [10]. In this study, the term “potent NDMA precursor” will be used to refer to the precursors with activated tertiary amine moieties forming >20% molar NDMA compared to the “regular NDMA precursors” having <3% molar NDMA.
Due to population growth and urbanization, drinking water resources worldwide are increasingly affected by the discharge of municipal or industrial wastewaters. Studies have shown that municipal wastewater effluents contain much higher concentrations of NDMA precursors compared to pristine natural waters [2], [3]. While the exact sources and structural identities of the NDMA precursors are still unclear [11], potent NDMA precursors from tertiary amine-based pharmaceuticals, such as ranitidine [12], [13], [14] and methadone [9], or other structurally related compounds are likely to constitute a significant fraction of the total NDMA precursor pool of municipal wastewater effluents.
Pre-oxidation with chlorine, ozone, and some other oxidants has been tested to decrease the NDMA formation in the post chloramination process by transforming the key structural moieties of NDMA precursors. The pre-oxidation of natural waters affected by wastewater discharge showed significant decreases in the NDMA formation potential (NDMA-FP), especially for ozonation and chlorination [15], [16], [17], [18]. Even though the results of these studies are valuable for assessing pre-oxidation efficiency for NDMA formation control, their generalized applications to other waters can sometimes be limited due to the complex, uncharacterized nature of the NDMA precursors. In addition, the previous studies mainly focused on drinking water matrices, and the pre-oxidation efficiency for wastewater effluent matrices is currently poorly understood.
Pre-oxidation has also been tested for deactivating various specific NDMA precursors, such as amine-based pharmaceuticals and water treatment polymers. After the oxidation, the NDMA-FP decreased significantly for several compounds [15], [19], [20]. However, the NDMA-FP sometimes did not decrease or even increase, depending on the type of precursors/oxidants or treatment conditions [19], [20], [21], [22], [23], which requires further investigations. Reductions in the NDMA-FP after ozonation or chlorination have been reported for some potent NDMA precursors, including ranitidine [19], [20], [24]. Nevertheless, it is still difficult to design oxidation processes that are generally applicable to various NDMA precursors or water matrices due to the lack of principle-based reaction kinetics and stoichiometric information. This is critical in determining optimal oxidant dose and contact time (i.e., oxidation exposure) to maximize NDMA precursor mitigation with the formation of the regulated DBPs under control.
This study aims to assess the efficiency of pre-chlorination and pre-ozonation to deactivate potent NDMA precursors using ranitidine as a representative compound. Reaction kinetics and stoichiometric factors were determined for each structural moiety of ranitidine (Fig. 1) and the corresponding NDMA-FP elimination. The elimination of ranitidine and the deactivation of its NDMA-FP were determined in simulated water treatment conditions using natural water and wastewater effluent samples and discussed with the chemical kinetics models.
Section snippets
Standards and reagents
All chemicals and solvents were purchased from various commercial suppliers and used as received. The details regarding the preparation of the oxidants are provided in SI-Text-1.
Chlorination and ozonation
Oxidation experiments with chlorine and ozone were performed in batch reactors with sample volumes ranging from 20 to 500 mL. Sample solutions were treated with a range of oxidant doses by adding the chlorine or ozone stock solution. After complete oxidant consumption or quenching of the residual oxidant by thiosulfate
Chlorine
Fig. 2 shows pH-dependent second-order rate constants for the reaction of free available chlorine (i.e., HOCl/OCl−, hereafter referred to as FAC) with ranitidine (kFAC-RAN) and its sub-structural moieties, such as thioether (kFAC-thioether), N,N′-dimethylnitro-acetamidine (kFAC-acetamidine, hereafter referred to as acetamidine), tertiary amine (kFAC−3°amine), and dimethyl-furan (kFAC-furan, hereafter referred to as furan). Each moiety-specific rate constant was experimentally determined (see
Conclusions
• FAC reacts rapidly with the acetamidine and thioether moieties of ranitidine (kFAC > 108 M−1 s−1 at pH 7). Nevertheless, these reactions do not lead to the reduction of the NDMA-FP. The reaction of FAC with the tertiary amine moiety of ranitidine is also considerable (kFAC = 3 × 103 M−1 s−1 at pH 7) and leads to the significant reduction of the NDMA-FP.
• Ozone reacts rapidly with all four moieties of ranitidine (kO3 = 1.5 × 105 M−1 s−1 − 1.6 × 106 M−1 s−1 at pH 7), and the reaction of ozone with the tertiary amine
Acknowledgements
This study was supported by the Mid-Career Researcher Program (NRF-2013R1A2A2A03068929) through the National Research Foundation of Korea funded by the Ministry of Science ICT & Future Planning.
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These authors contributed equally to this work.