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NDMA formation from amine-based pharmaceuticals e

Impact from prechlorination and water matrix

Ruqiao Shen*, Susan A. Andrews

Department of Civil Engineering, University of Toronto, 35 St. George St., Toronto, Ontario, Canada M5S 1A4

a r t i c l e i n f o

Article history:

Received 1 October 2012

Received in revised form

6 February 2013

Accepted 8 February 2013

Available online 17 February 2013

Keywords:

NDMA

Prechlorination

Ranitidine

Sumatriptan

NOM

* Corresponding author. Tel.: þ1 4169783141;E-mail addresses: shenruqiao@yahoo.com

0043-1354/$ e see front matter ª 2013 Elsevhttp://dx.doi.org/10.1016/j.watres.2013.02.017

a b s t r a c t

The presence of N-nitrosodimethylamine (NDMA) in drinking water is most commonly

associated with the chloramination of amine-based precursors. One option to control the

NDMA formation is to remove the precursors via pre-oxidation, and prechlorination is

among the most effective options in reducing NDMA formation. However, most of the

findings to-date are based on single-precursor scenarios using the model precursor

dimethylamine (DMA) and natural organic matter (NOM), while few studies have consid-

ered the potential interactions between water matrix components and the target pre-

cursors when investigating the prechlorination impact. Specifically, little is known for the

behaviour of amine-based pharmaceuticals which have recently been reported to

contribute to NDMA formation upon chloramination. This work demonstrates that pre-

chlorination can affect both the ultimate NDMA conversion and the reaction kinetics from

selected pharmaceuticals, and the nature and extent of the impact was compound-specific

and matrix-specific. In the absence of NOM, the NDMA formation from most pharma-

ceuticals was reduced upon prechlorination, except for sumatriptan which showed a

consistent increase in NDMA formation with increasing free chlorine contact time. In the

presence of NOM, prechlorination was shown to enhance initial reactions by reducing the

binding between NOM and pharmaceuticals, but prolonged prechlorination broke down

NOM into smaller products which could then form new bonds with pharmaceuticals and

thus inhibit their further conversion into NDMA.

ª 2013 Elsevier Ltd. All rights reserved.

1. Introduction drinking water (Health Canada, 2010). USEPA also placed it on

The presence of N-nitrosodimethylamine (NDMA) in drinking

water has been commonly associated with the disinfection

process, especially chloramination. NDMA is a highly muta-

genic compound and a potential human carcinogen, with a

10�6 lifetime cancer risk associated with a drinking water

concentration of 0.7 ng/L (EPA IRIS, 1993). The exposure to

NDMA through drinking water has become a concern espe-

cially for utilities that apply chloramine as the secondary

disinfectant. Health Canada has recently proposed a

maximum acceptable concentration for NDMA of 40 ng/L in

fax: þ1 4169783674..cn (R. Shen), sandrews@

ier Ltd. All rights reserve

the drinking water contaminant candidate list 3 (CCL3)

together with four other nitrosamines (USEPA, 2009). NDMA is

currently regulated in drinking water in several provinces and

states across North America, including Ontario (9 ng/L; MOE,

2003), Massachusetts (10 ng/L; MassDEP, 2004), and Califor-

nia (10 ng/L; OEHHA, 2006).

During drinking water treatment processes, NDMA is most

commonly formed via the slow reaction between chloramines

(especially dichloramine) and amine-based precursors

(Schreiber and Mitch, 2006a). NDMA is also formed through a

nitrosation mechanism at acidic pH (Choi and Valentine,

civ.utoronto.ca (S.A. Andrews).d.

wat e r r e s e a r c h 4 7 ( 2 0 1 3 ) 2 4 4 6e2 4 5 7 2447

2003), but this mechanism is of less importance in drinking

water due to the generally low nitrite concentrations and the

neutral/basic pH. Moreover, ozonation can also lead to the

formation of NDMA (Andrzejewski et al., 2008; Oya et al.,

2008); an especially high yield was observed for dime-

thylsulfamide, a degradation product of the fungicide toly-

fluanid (Schmidt and Brauch, 2008).

Early studies on NDMA typically used the model precursor

dimethylamine (DMA; Gerecke and Sedlak, 2003) and natural

organic matter (NOM; Chen and Valentine, 2007; Dotson et al.,

2007; Gerecke and Sedlak, 2003; Mitch and Sedlak, 2004),

however chloramination of these precursors typically gave

low yields of NDMA and thus cannot always account for all of

the precursors present in natural waters. More recently,

higher levels of NDMA formation have been associated with

wastewater-impacted surface water (Krasner, 2009; Schreiber

and Mitch, 2006b; Shah et al., 2012), indicating the contribu-

tion from anthropogenic compounds. Several studies have

linked NDMA formation to quaternary amines used in per-

sonal care products (Kemper et al., 2010), pharmaceuticals and

pesticides (Le Roux et al., 2011, 2012a b; Shen and Andrews,

2011a,b), as well as some amine-based polymers and resins

(Kohut and Andrews, 2003; Mitch and Sedlak, 2004; Najm and

Trussell, 2001; Wilczak et al., 2003). Mitch and Schreiber (2008)

have proposed that the NDMA formation from tertiary amines

proceeds via a chlorine transfer reaction to release the DMA

which is then subsequently oxidized to NDMA. However,

NDMA formed fromDMA alone cannot explain the high yields

from some tertiary amines such as ranitidine. A recent study

by Le Roux et al. (2012b) has proposed an alternative mecha-

nism for NDMA formation from chloramination of ranitidine,

which involves a direct substitution on the DMA group of ra-

nitidine and can well explain its high yield of NDMA.

In practice, chloramine is usually used as the secondary

disinfectant following primary disinfection (e.g., Cl2, UV, and

O3). Moreover, instead of using preformed monochloramine,

most utilities that perform chloramination typically apply free

chlorine first, followed by the addition of ammonia to form

chloramine on site. Compared with chloramine alone, the

application of pre-oxidation may modify or destroy the pre-

cursors and release transformation products that may or may

not react with the subsequent secondary disinfectant.

Generally, the application of preoxidation prior to chlor-

amination has been reported to reduce the NDMA formation

from DMA and NOM. Preoxidation processes have included

prechlorination (Chen and Valentine, 2008; Charrois and

Hrudey, 2007; Mitch et al., 2010), O3 and O3/H2O2 (Chen and

Valentine, 2008; Pisarenko et al., 2012), ClO2 (Lee et al., 2007),

ferrate (Lee et al., 2008), and KMnO4 (Chen and Valentine,

2008). Among all the options, ozone and chlorine were found

to be most effective in reducing NDMA formation (Shah et al.,

2012). However, oxidation of precursors does not necessarily

lead to the reduction in NDMA formation. In some cases,

prechlorination may increase NDMA formation at lower ex-

posures due to insufficient oxidation (Chen and Valentine,

2008; Shah et al., 2012). It has also been observed that UV

and UV/H2O2 pretreatment have increased the NDMA forma-

tion from amine-based polymers (e.g., polyDADMAC, epi-

DMA), possibly due to the increased degradation of the poly-

mers releasing more NDMA precursors (Harvey, 2009). More

recently, Radjenovic et al. (2012) have reported that the

oxidation products of the pharmaceutical tramadol by UV and

UV/H2O2 have higher NDMA formation potentials (FPs) than

the parent compound. Thus, the impact of preoxidation on the

formation of NDMA requires further investigation.

Currently, most of the findings regarding the preoxidation

impact have been based on DMA and NOM. Several studies

used treated wastewater as a “precursor pool”, but few specific

compounds have been studied separately, especially

pharmaceutical-based precursors. Moreover, very little infor-

mation is available in terms of how the preoxidation process

might affect the NDMA formation kinetics. This study in-

vestigates the impact of prechlorination on the NDMA for-

mation from eight selected pharmaceuticals, especially the

impact on their reaction kinetics. The eight pharmaceuticals

were selected because of their relatively high NDMA FPs

among the twenty pharmaceuticals and personal care prod-

ucts (PPCPs) tested in a previous study by the authors (Shen

and Andrews, 2011a). This work also compares the prechlori-

nation impact with and without the presence of NOM, and

looks into how the interactions in between NOM, pharma-

ceuticals, and free chlorine could affect the NDMA formation

from selected pharmaceuticals. Relatively high pharmaceu-

tical concentrations (6.8e11.1 mg/L) compared with their ex-

pected environmental levels were applied in this study in

order to be able tomeasure the differences in NDMA formation

under different disinfection conditions. However, Shen and

Andrews (2011b) demonstrated that the NDMA formation ki-

netics in a real water matrix was relatively independent of the

initial pharmaceutical concentration because chloramine was

present in large excess relative to the pharmaceutical con-

centrations; therefore similar reaction kinetics are expected

for selected pharmaceuticals at their environmental levels.

Findings from this work could be of particular concern for

water reuse processes where much higher concentrations of

pharmaceuticals might be subjected to chloramination.

2. Materials and methods

Chemical structures of the eight selected pharmaceuticals are

illustrated in Fig. 1. The pharmaceuticals (25 nM of each) were

dosed into selected water matrices (raw, not filtered) individ-

ually and subjected to different disinfection strategies. The

chloramination experiments (preformed chloramine) were

carried out under the same simulated distribution system

(SDS) conditions as applied in Shen and Andrews (2011b). The

sequential disinfection experiments (prechlorination fol-

lowed by chloramination) employedmodified SDS conditions,

where a sodiumhypochlorite (NaClO) solutionwas first added,

followed by the addition of ammonia chloride (NH4Cl) to form

chloramine after a range of target free chlorine contact times

(0.5e120 min). The resulting chloramine concentration at the

point of NH4Cl addition was the same as that which was

applied in the preformed chloramination experiments for

each matrix (i.e., 2.5 � 0.2 mg/L plus the 24 h chloramine de-

mand for eachmatrix). The initial free chlorine dosage and the

NH4Cl dosage for each matrix were determined via pre-

liminary chlorine/chloramine demand tests (see details in

Supporting Information). All of the other conditions remained

Fig. 1 e Structures of selected pharmaceuticals.

wat e r r e s e a r c h 4 7 ( 2 0 1 3 ) 2 4 4 6e2 4 5 72448

the same as the SDS conditions (i.e., 21 � 1 �C; pH ¼ 7.0 � 0.1;

Cl2: N mass ratio ¼ 4.2:1). Further details concerning the

preparation of stock solutions, working solutions, and the

NDMA analysis have been described in Shen and Andrews

(2011a,b).

NDMA-FPs and kinetics evaluations were both conducted

under the (modified) SDS conditions described above. The 24 h

NDMA-FPwas determined for all eight pharmaceuticals in lab-

gradeMQ (Milli-Q�, MilliPore, Etobicoke, Ontario) water, where

samples (dosed with pharmaceuticals) and blanks (water ma-

trix only) were both prepared in triplicate. The NDMA forma-

tion kinetics was monitored for ranitidine and sumatriptan,

where samples were prepared in triplicate along with one

blank control (using the respective water matrix) at each time

point. Error bars in all graphs demonstrate the variability due

to multiple formation potential tests (n ¼ 3 unless otherwise

specified) under the same reaction conditions.

The kinetic experiments were performed in three water

matrices; the basic water quality parameters for each source

are summarized in Table 1. Lake Ontario water and Otonabee

River water samples were taken from the influent of two

drinking water treatment plants in September 2011 and

January 2012, respectively. The methods for measuring these

basic water quality parameters have been described in Shen

and Andrews (2011b). Use of raw water instead of partially-

treated water as the experimental matrix provided the study

Table 1 e Water matrix source and basic water quality measu

Water matrix Water source TOC (mg/L)

Milli-Q� (MQ) MilliPore; Etobicoke, Ontario 0 7.5

Lake Lake Ontario Ajax, Ontario 2.3 � 0.1a 8.2

River Otonabee River, Peterborough,

Ontario

6.2 � 0.1 7.8

a These basic water quality parameters (except for turbidity) were mea

months) and the values here are the average and standard deviation of 5

b Turbidity was recorded at the water treatment plant on the day of sam

with the maximum amount of unmodified NOM for the cur-

rent investigations. Future studies could employ partially-

treated water to account for the removal or modification of

someNOM fromvarious treatment processes or process trains.

In order to better characterize the water matrix, NOM

components in each raw water source were analysed using

size-exclusion liquid chromatography-organic carbon detec-

tion (LC-OCD) at the University of Waterloo (ON, Canada). The

LC-OCD uses a size-exclusion column to separate the hydro-

philic NOM fractions. The hydrophobic matter does not elute

within the limited measuring time of 120 min, and thus is

calculated as “DOCminus hydrophilic DOC”. A typical LC-OCD

chromatograph for surface water is shown in Fig. S1 in

Supporting Information. The major hydrophilic NOM frac-

tions are eluted in the order of biopolymers, humics, building

blocks, low-molecular-weight (LMW) acids, and LMW neu-

trals. Further details about the LC-OCD system are described

by Huber et al. (2011). Proprietary software was used for data

acquisition and processing (ChromCalc, DOC-LABOR, Karls-

ruhe, Germany). The LC-OCD results for the selected water

matrices are summarized in Table 2. In addition, several

chlorine- and/or chloramine-treated water samples (lake and

river; from the blank controls) were collected along with the

kinetic experiments to investigate the potential change of

NOM upon the disinfection treatment. The chlorine/chlora-

mine residual was quenched with sodium thiosulfate

rements.

pH Alkalinity(mg/L)

UV254 (cm�1) SUVA

(L/mg-m))Turbidityb

(NTU)

� 0.1 1.8 � 0.3 0.000 0.0 0.0

� 0.1 95.4 � 1.8 0.023 � 0.002 1.0 � 0.1 0.67

� 0.1 94.9 � 2.9 0.162 � 0.002 2.6 � 0.1 0.46

sured every week during the sample storage period (no more than 2

e10 measurements.

pling.

Table 2 e LC-OCD results for the selected water matrices (Unit: mg/L carbon).

Watermatrix

DOC HydrophobicDOC

HydrophilicDOC

Hydrophilic DOC fractions

Biopolymers Humics Building blocks LMW neutrals LMW acids

MQ 0.07 0.03 0.04 0.01 0.000 0.003 0.02 0.004

Lake 2.20 0.20 2.00 0.34 0.90 0.46 0.19 0.10

River 5.90 0.20 5.70 0.34 3.82 0.72 0.62 0.20

wat e r r e s e a r c h 4 7 ( 2 0 1 3 ) 2 4 4 6e2 4 5 7 2449

(Na2S2O3) at the dosage of twice the stoichiometric ratio of

chlorine (personal communication, University of Waterloo);

the samples were then filtered through a 0.45 mm filter paper

and shipped to University of Waterloo for LC-OCD analysis.

Samples were stored at 4 �C for no more than one week prior

to the analysis.

3. Results and discussion

3.1. Prechlorination impacts in MQ water

3.1.1. 24 h NDMA-FP upon prechlorinationTo begin investigating the impacts of prechlorination, 24 h

NDMA-FPs following sequential chlorine and chloramine

Fig. 2 e 24 h NDMA-FP from eight pharmaceuticals upon seque

water).

disinfection were determined for eight selected pharmaceu-

ticals in MQ water (Fig. 2). The 0 min pre-Cl condition repre-

sents the use of preformed chloramine. In general, the NDMA

formation from most of the pharmaceuticals (except for su-

matriptan and diltiazem) decreased with increasing pre-

chlorination contact time ( p-value < 0.0001 except for

doxylamine ( p-value ¼ 0.0034); ANOVA analysis, 95% confi-

dence level). However, the rate and degree of reduction in

NDMA formation varied among the different compounds. For

example, ranitidine and nizatidine responded very quickly to

chlorine, with a 50% reduction in NDMA formation achieved

by 0.5 min and 3 min of prechlorination, respectively. For

tetracycline, a similar amount of reduction required 30 min of

prechlorination. For the three structurally similar H1-antihis-

tamines (carbinoxamine, chlorphenamine, and doxylamine),

ntial chlorination and chloramination disinfection (MQ

wat e r r e s e a r c h 4 7 ( 2 0 1 3 ) 2 4 4 6e2 4 5 72450

no significant reduction was observed until the chlorine con-

tact time increased to 60e120 min. Sumatriptan was the only

pharmaceutical showing consistently increasing NDMA for-

mation as the prechlorination contact time increased ( p-

value < 0.0001). For diltiazem, a very short chlorine contact

time (30 s) seemed to reduce the NDMA formation, but further

increases in chlorine contact time increased the NDMA for-

mation to levels approaching those observed when preformed

monochloramine was used. Detailed calculations for the sta-

tistical analyses are provided in Supporting Information

(Table S2).

These initial tests showed that not all of the NDMA for-

mation potential of the target compounds was destroyed by

prechlorination. Further testingwould focus on ranitidine and

sumatriptan as representatives of pharmaceuticals that

showed either decreases or increases in NDMA formation,

respectively, following prechlorination.

3.1.2. NDMA formation kinetics upon prechlorinationIn order to further investigate the impact of prechlorination

on NDMA reaction kinetics, the NDMA formation was moni-

tored over time for ranitidine and sumatriptan following

sequential chlorination and chloramination (Fig. 3). Markers

in the figures represent the measured NDMA molar conver-

sion values and the lines represent model-predictions.

The three-parameter kinetic model used was of the form:

Y ¼ q

1þ 10k�ðLag�tÞ

where Y is the NDMAmolar conversion at given reaction time

(t); q is the ultimate NDMA molar conversion; Lag is the time

required to achieve 50% of the ultimate molar conversion and

thus associated with the length of the initial lag phase; k is the

pseudo-first order reaction rate constant. Further details

about the model have been discussed in Shen and Andrews

(2011b). The 0 min prechlorination time represents the use

of preformed chloramine.

The formation kinetics results were in good agreement

with the 24 h formation potential results (Fig. 2). NDMA for-

mation from ranitidine was significantly reduced upon pre-

chlorination even with a short free chlorine contact time at

3 min, and no further reduction was achieved as the free

chlorine contact time increased. In contrast, the ultimate

NDMA conversion from sumatriptan increased with free

Fig. 3 e NDMA formation kinetics from ranitidine and sumatript

MQ water (Error bars represent the maximum and minimum v

chlorine contact time, and the initial lag phase was reduced

upon prechlorination. The estimated model parameters for

both compounds are shown in Table S3 in Supporting

Information, and the associated analytical analyses on the

estimated model parameters are summarized in Tables S4

and S5.

3.2. Prechlorination impacts in real water matrices

Previously, the authors demonstrated that water matrix

components could slow down the initial NDMA formation

from pharmaceuticals (i.e., much longer initial lag phase with

the presence of NOM), while they had less impact on the ul-

timate NDMAmolar conversion (Shen andAndrews, 2011b). In

the present work, the impact of prechlorination on the NDMA

formation kinetics was also investigated in natural water

samples dosed with selected pharmaceuticals. Some studies

have reported the possible impact of bromide ion on NDMA

formation (Chen et al., 2010; Le Roux et al., 2012a; Valentine

et al., 2005); however, the bromide levels in the waters

selected for this work (Lake Ontario, w40 mg/L (Comerton

et al., 2006); Otonabee River, <11.4 mg/L (Woodbeck, 2007))

aremuch lower comparedwith the concentrations reported to

be significant in literature (mg/L). Therefore the role of bro-

mide ion in the NDMA formation from selected pharmaceu-

ticals is not investigated in this study. The results for

ranitidine and sumatriptan in water from Lake Ontario and

the Otonabee River are summarized in Figs. 4 and 5, respec-

tively. Similar to Fig. 3, markers represent the measured

NDMA molar conversion values and the lines represent

model-predicted conversions. The estimated model parame-

ters in different water matrices are included in Table S3 for

easier comparison with similar data determined using MQ

water; similarly, the associated statistical analyses on the

model parameters are provided in Tables S4 and S5.

For ranitidine, prechlorination impacts observed in the

lake water (Fig. 4) showed similar trends to those that were

observed in MQ water (Fig. 3); the ultimate NDMA formation

was significantly reduced upon prechlorination, and increases

in free chlorine contact time did not cause further reductions

in NDMA formation.Moreover, the initial lag period in the lake

water was significantly shortened by more than half upon

prechlorination, and the estimated model parameters in MQ

an upon sequential chlorine and chloramine disinfection in

alues under the same reaction conditions (n [ 2)).

Fig. 4 e NDMA formation kinetics from ranitidine upon sequential chlorine and chloramine disinfection in Lake Ontario and

Otonabee River water.

wat e r r e s e a r c h 4 7 ( 2 0 1 3 ) 2 4 4 6e2 4 5 7 2451

and lake water were comparable with each other when pre-

chlorination was applied at the same contact time (Table S3).

Previously, a NOMepharmaceutical binding hypothesis was

proposed to explain the initial lag phase observed in realwater

matrices (Shen and Andrews, 2011b). The results here suggest

that chlorination may destroy some of the binding between

NOM and ranitidine and thus enhance the initial reaction

between ranitidine and chloramine to form NDMA.

However, the results in the river water were quite different

for ranitidine. Upon 3 min prechlorination, the ultimate

NDMA molar conversion was reduced by 23% and the initial

lag period was shortened from 31 h to 4 h. When the chlorine

contact time further increased to 10 min, the NDMA conver-

sion was significantly inhibited to 12.5%, and very little NDMA

(molar conversion less than 3%) was detected at longer chlo-

rine contact times. It is not likely that prolonged chlorination

simply destroyed the NDMA precursor (ranitidine in this case)

because similar results would have been obtained in MQ and

the lake water. Considering the NOMeranitidine binding

theory, the results suggest that prolonged chlorination might

further break down the NOM to form smaller products which

may rebind with ranitidine and thus inhibit the NDMA for-

mation. However, it is still unclear why this “rebinding” was

Fig. 5 e NDMA formation kinetics from sumatriptan upon seque

and Otonabee River water.

not observed in the lake water. One possible explanation

could be the much higher TOC level in the river water, thus

more NOMeranitidine complexes were formed.

Sumatriptan’s response to prechlorination in naturalwater

matrices (Fig. 5) was quite different compared with that

observed in MQ water (Fig. 3), except for the common trend in

all of the matrices of a reduced initial lag phase upon pre-

chlorination. However, unlike the consistently increasing

NDMA conversion from sumatriptan in MQwater, there was a

maximum NDMA molar conversion observed upon 30 min of

prechlorination. Further increases in chlorine contact time

reduced the ultimate molar conversion. This phenomenon

might also be explained by the proposed rebinding theory that

prolonged chlorination could breakdown NOM molecules to

smaller products and thus enhance their rebinding with su-

matriptan, as will be discussed further in Section 3.3.3.

In summary, prechlorination was shown to affect both the

ultimate NDMA conversion (q) and the reaction kinetics (Lag

and k). As compared in Fig. 6, the impact was both compound-

specific and matrix-specific, thus requiring case-by-case

investigation. Currently, most studies have found that pre-

chlorination with enough CT (concentration � contact time)

has, in general, been able to reduce the NDMA formation.

ntial chlorine and chloramine disinfection in Lake Ontario

Fig. 6 e Comparison of the kinetic model parameters upon sequential chlorine and chloramine disinfection in three water

matrices (Error bars represent the 95% confidence interval).

wat e r r e s e a r c h 4 7 ( 2 0 1 3 ) 2 4 4 6e2 4 5 72452

However, only single-precursor scenarios have been consid-

ered in most studies, i.e., NOM or DMA as the only precursor.

This work suggests that the potential interactions between

NOM and other precursors could also affect NDMA formation.

Moreover, an enhanced NDMA formation rate upon prechlori-

nation has not been reported previously, which is a new

contribution to the field.

3.3. NOMepharmaceuticaleCl2 interactions

Both free chlorine and NOM have been shown to individually

affect the conversion of selected pharmaceuticals into NDMA.

Since systems involving free chlorine, NOM, and the target

pharmaceuticals are more complicated, it is important to

investigate the interactions in between them to further

understand the impact from matrix components as well as

prechlorination.

3.3.1. NOMepharmaceutical interactionsIn the absence of prechlorination, the matrix components

were found to slow down the initial NDMA formation (i.e.,

longer initial lag phases were associated with higher TOC and

SUVA), while they had less impact on the ultimate NDMA

molar conversion (Fig. 6, pre-Cl ¼ 0 min). The results are in

good agreement with a previous study by the authors (Shen

and Andrews, 2011b), where the potential interactions be-

tween NOM and selected pharmaceuticals have been dis-

cussed. The formation of NOMepharmaceutical complexes is

most likely due to the electrostatic attraction between the

negatively charged NOM surface (De Ridder et al., 2011) and

the positively charged amines. Although there is no direct

wat e r r e s e a r c h 4 7 ( 2 0 1 3 ) 2 4 4 6e2 4 5 7 2453

spectroscopic evidence to confirm such binding in the

aqueous phase, the NOMepharmaceutical binding hypothesis

has been suggested by other researchers to explain the

enhanced pharmaceutical removal during treatment pro-

cesses like coagulation and membrane filtration (Ballard and

Mackay, 2005; Diemert, 2012; Stackelberg et al., 2007; Vieno

et al., 2006; Westerhoff et al., 2005). A recent study by Ding

et al. (2012) has developed an efficient solid phase extraction

method to determine the association of a variety of pharma-

ceuticals with dissolved humic acids, in which two of the

pharmaceuticals studied had the DMA functional group in

their structures. The difference in their affinity with NOMwas

well explained by the different amounts of positively charged

sites in the pharmaceuticals (e.g., amine groups) and nega-

tively charged sites in the humic acids (i.e., carboxylic and

phenolic moieties). Although the concentrations applied in

Ding et al. (2012) were relatively high (i.e., 100e2500 mg/L of

pharmaceuticals; 40e80 mg/L of NOM) compared with the

levels of pharmaceuticals and NOM in natural waters, their

study proves the possibility of binding between amine-based

pharmaceuticals and NOM in the aqueous phase.

3.3.2. Cl2epharmaceutical interactionsResults from this work showed that prechlorination can either

increase or decrease NDMA formation from selected phar-

maceuticals. Because the NDMA formation can be described

as an electrophilic reaction on the nitrogen atom of the amine

group (Mitch and Schreiber, 2008), theoretically chlorination

could enhance the reaction if it enhances the electron density

on the amine group, and vice versa. Therefore, it is important

to evaluate the different reactivity of selected pharmaceuti-

cals towards free chlorine in order to determine how the final

NDMA conversion will be affected by prechlorination.

Table 3 e Comparison of chlorine reactivity towards ranitidine

Ranitidine

DMA group protonated on the parent

compound at given pH (7.0 � 0.1)?

w94%

Primary chlorine attack site of the

parent compound

Sulphur

Possible fragmentation upon chlorination? Yes

DMA group protonated on the breakdown

product(s) at given pH (7.0 � 0.1)?

w92%

Primary chlorine attack site(s) of the

breakdown product(s)

DMA

Electron density of DMA group increased? No

Ultimate NDMA molar conversion

upon prechlorination

Reduced

Moreover, the DMA group is not the only functional group on

the pharmaceuticals that could react with chlorine. If the

groups close to the DMA group are modified upon chlorina-

tion, they may also impact the electron density of the amine

group, and thus affect the NDMA conversion. Among the eight

pharmaceuticals being tested, ranitidine and sumatriptan had

relatively highNDMA conversions but showed opposite trends

when being subjected to prechlorination. Thus the following

discussion mainly focuses on these two pharmaceuticals.

Deborde and von Gunten (2008) have reviewed the kinetics

and mechanisms for the chlorination of organic compounds.

Generally, rate constants for the reaction of chlorine with

sulphur-moieties are typically 1e2 orders of magnitude higher

thanwith amines. According to this review, themost potential

attack site of chlorine on ranitidine would be the sulphur,

forming ranitidine sulfoxide (S]O). Then the ranitidine sulf-

oxide may go through CeS fragmentation upon further chlo-

rination, resulting in the formation of smallermolecules (Table

3). The CeS fragmentation upon chlorination was confirmed

by Le Roux et al. (2012b) for ranitidine, and the breakdown

product (5-(dimethylaminomethyl)-2-furanmethanol (DFUR))

is still a potential NDMA precursor, with NDMA molar con-

version being reported from 50% to 80% upon preformed

chloramination (Schmidt et al., 2006; Le Roux et al., 2012a).

However, the DMA group on DFUR may now become the pri-

mary chlorine attack site. Abia et al. (1998) also proposed a

reaction mechanism for the chlorination of tertiary amines,

including an elementary step in which a positive charge is

developed on theN-atom via a chlorine transfer. This supports

the results of a previous study which has suggested that pre-

chlorination can significantly reduce the NDMA formation

fromDMA due to the partially formed Cl-DMA that inhibits the

electrophilic attack on the amine group (Schreiber and Mitch,

and sumatriptan.

Sumatriptan

w100%

C2 site of the indole ring

No

/

/

Yes

Enhanced

wat e r r e s e a r c h 4 7 ( 2 0 1 3 ) 2 4 4 6e2 4 5 72454

2005). Le Roux et al. (2012b) have also suggested that the

chlorine attack on the amine group could reduce the NDMA

conversion from ranitidine because it limited the direct sub-

stitution on the DMA group.

Unlike ranitidine, the NDMA conversion from sumatriptan

was enhanced upon prechlorination. As indicated in Table 3,

the sulphur moiety of sumatriptan is already fully oxidized

(eSO2), therefore the proposed CeS fragmentation for raniti-

dine may not occur. Moreover, the DMA group is almost

completely protonated at pH 7 (pKa ¼ 9.6; 99.8% protonated),

while the chlorine reaction is only significant with neutral

amines (reaction rate constants in the range of

101e102 M�1 s�1 at pH 7 (Deborde and von Gunten, 2008)). As a

result, the DMA group may not be the primary chlorine attack

site of sumatriptan at the given reaction conditions. In addi-

tion, Xu et al. (2001) have suggested that the C2 position of

indole can be activated for oxidationwhen the C3 site has an R

group. In the case of chlorination, the C2 position could be

substituted with chlorine (Gilow and Burton, 1981) and the

reactionwould occur very fast, with a conservative estimation

of the reaction rate constants to be at least in the range of

101e102 M�1 s�1 at pH 7 (Lin and Carlson, 1984). The

substituted chlorine on the C2 position may then increase the

electron density at C3 position due to the conjugation effect

between the double bond and the lone electron pair on the Cl

(Carey, 2008), thus enhancing NDMA formation from suma-

triptan. Although this reaction is plausible from the literature

cited above, it would benefit from mass spectral confirmation

of the intermediate species which, unfortunately, was not

possible as part of the current study.

In summary, twomajor factors should be considered when

evaluating the effect of prechlorination on the NDMA con-

version from amine-based pharmaceuticals: i) if the DMA

group on these pharmaceuticals is the primary chlorine attack

site; ii) if the DMA group is protonated (pHepKa relevant).

Table 3 compares the differences in the chlorine reactivity

towards ranitidine and sumatriptan.

Usually chlorine would cause a small modification on the

parent compound rather than a complete oxidation. The

Fig. 7 e Potential interactions in between NO

modification may change the pharmaceutical reactivity to-

wards the subsequent chloramine, but it could also change

their binding potential with NOM which would affect the

availability of the pharmaceuticals as well. For example, if

chlorination increases the electron density on the amine

group of sumatriptan (Table 3), it will not only enhance the

NDMA conversion from sumatriptan (i.e., favouring the elec-

trophilic attack), but also reduce the binding with the nega-

tively charged NOM surface thus improving the initial

reaction. The latter might also contribute to the much short-

ened initial lag phase for sumatriptan upon prechlorination in

lake and river water (Fig. 5).

3.3.3. Cl2eNOM interactionsChlorine can also react with NOM and modify its surface

properties, which would then affect the binding potential

between NOM and pharmaceuticals. The potential in-

teractions between chlorine and NOM were investigated via

LC-OCD analysis. Water samples were collected along with

the chloramination and sequential disinfection experiments

(from the blank control samples in each set of kinetic exper-

iments) to investigate the potential change of NOM compo-

nents upon the treatment.

For the rawwater samples used in this study (lake and river

water), the majority of NOM was hydrophilic (more than 90%

of the total DOC), and the major fractions were humic sub-

stances (HS) and building blocks (accounting for 70%e80% of

the total hydrophilic NOM). In general, DOC was not removed

by chlorination or chloramination at the applied reaction

conditions, but there were changes in the major NOM frac-

tions (i.e., HS and building blocks). Typically, degradation of

HS was observed to lead to the formation of building blocks,

and further breakdown of building blocks would lead to the

increase in LMW fractions (data not shown). At the employed

reaction conditions, free chlorine itself did not change any

NOM fractions significantly; however, it facilitated the trans-

formation of HS into building blocks when NH4Cl was added

subsequently to form chloramine. For example, following

120 min of prechlorination, the HS in lake water started to

M, pharmaceuticals, and free chlorine.

wat e r r e s e a r c h 4 7 ( 2 0 1 3 ) 2 4 4 6e2 4 5 7 2455

degrade after 2 h of NH4Cl addition. However, without pre-

chlorination, the reduction in HS occurred only after 4 h of

chloramination (Fig. S2, top left).

This trendwas further confirmed in the river water (Fig. S2,

bottom two). The application of prechlorination enhanced the

degradation of HS, and the reduction was improved as the

chlorine contact time increased. Compared with preformed

chloramine (i.e., pre-Cl ¼ 0 min), there were more building

blocks formed when prechlorination was applied; as chlor-

amination contact time increased, the building blocks first

increased (from the breakdown of HS) and then decreased

subsequently (further breakdown to LMW fractions). Specif-

ically, the highest increase in building blocks occurred at

30 min of prechlorination followed by chloramination; this is

in agreement with the kinetic experiments for sumatriptan in

lake and river water, where the maximum NDMA molar

conversion was also observed upon 30 min of prechlorination

(Fig. 5). It was proposed that prolonged prechlorination may

destroy some NOM fractions and the breakdown products

may rebind with the pharmaceutical and thus inhibit its

conversion into NDMA. The LC-OCD results suggest that pro-

longed chlorine contact time does lead to early breakdown of

building blocks, yielding more LMW molecules which may

rebind with pharmaceuticals and inhibit their further con-

version into NDMA.

Fig. 7 summarizes the possible interactions in between

NOM, pharmaceuticals, and free chlorine. Without the appli-

cation of prechlorination, the presence of NOM usually does

not affect the ultimate NDMA conversion, but will affect the

reaction rate due to the formation of NOMepharmaceutical

complexes. However, free chlorine could affect both the

NDMA conversion and the reaction rate by altering the prop-

erties of the pharmaceuticals and/or NOM, as well as the

binding potential between the two.

4. Conclusions

Previous research that looked into prechlorination effects

mostly considered the single-precursor scenarios, while very

few took into consideration the interactions between matrix

components and the precursors. Moreover, little is known in

terms of the prechlorination impact on the NDMA formation

kinetics. This work demonstrates that prechlorination affects

both the ultimateNDMA conversion and the reaction rate, and

investigates how the interactions in between NOM, pharma-

ceuticals, and free chlorine could affect the NDMA formation.

The prechlorination impact is compound-specific and

matrix-specific, requiring case-by-case investigation. In gen-

eral, prechlorination tends to reduce the NDMA conversion

from ranitidine while it increases that from sumatriptan. In

the presence of NOM, prechlorination may enhance the initial

reaction by breaking the binding between NOM and pharma-

ceuticals, but prolonged prechlorinationmay also break down

NOM into smaller products which may rebind with pharma-

ceuticals and thus inhibit its further conversion into NDMA. In

addition, an enhanced NDMA formation rate upon prechlori-

nation has not been reported previously.

Inmost cases, it would be expected that applying sufficient

prechlorination may help reducing the maximum NDMA

concentration at the farther end of the distribution system.

However, for certain precursors like the amine-based phar-

maceuticals studied in this work, short prechlorination

sometimes might break the binding between NOM and pre-

cursors and thus enhance the initial reaction, resulting higher

level of NDMA within the sections with shorter water age.

Therefore, a good NDMA control strategy would require

knowledge about the sourcewater, the precursor property, the

treatment applied at the plant, the size of the distribution

system, as well as the location of households and water age.

Acknowledgement

This researchwasfinancially supportedby theCanadianWater

Network, the Natural Sciences and Engineering Research

Council of Canada, and the Ontario Research Fund. Special

thanks are dedicated to Richard Jones and John Armour in the

water treatment plants for their assistance in water sampling.

Appendix A. Supplementary data

Supplementary data related to this article can be found at

http://dx.doi.org/10.1016/j.watres.2013.02.017.

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