Oxidation of citalopram with sodium hypochlorite and chlorine dioxide: Influencing factors and NDMA formation kinetics

Article abstract of DOI:10.3390/molecules24173065

The highly prescribed antidepressant, citalopram, as one of newly emerging pollutants, has been frequently detected in the aquatic environment. Citalopram oxidation was examined during sodium hypochlorite (NaOCl) and chlorine dioxide (ClO₂) chlorination processes since conventional wastewater treatment plants cannot remove citalopram effectively. Citalopram has been demonstrated to form N-nitrosodimethylamine (NDMA) during chlorination in our previous study. Further investigation on NDMA formation kinetics was conducted in the present study. Influences of operational variables (disinfectant dose, pH value) and water matrix on citalopram degradation, as well as NDMA generation, were evaluated. The results indicated high reactivity of citalopram with NaOCl and ClO₂. NDMA formation included two stages during CIT oxidation, which were linear related with reaction time. NaOCl was more beneficial to remove CIT, but it caused more NDMA formation. Increasing disinfectant dosage promoted citalopram removal and NDMA formation. However, no consistent correlation was found between citalopram removal and pH. Contrary to the situation of citalopram removal, NDMA generation was enhanced when citalopram was present in actual water matrices, especially in secondary effluent. DMA, as an intermediate of citalopram chlorination, contributed to NDMA formation, but not the only way.

Full text of DOI:10.3390/molecules24173065

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molecules
Article
Oxidation of Citalopram with Sodium Hypochlorite
and Chlorine Dioxide: Influencing Factors and
NDMA Formation Kinetics
Juan Lv *, Yan Wang and Na Li
School of Environment and Architecture, University of Shanghai for Science and Technology,
Shanghai 200093, China
* Correspondence: lujuan@usst.edu.cn; Tel.: +86-21-5527-5979
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 17 July 2019; Accepted: 22 August 2019; Published: 23 August 2019
Abstract: The highly prescribed antidepressant, citalopram, as one of newly emerging pollutants,
has been frequently detected in the aquatic environment. Citalopram oxidation was examined
during sodium hypochlorite (NaOCl) and chlorine dioxide (ClO2) chlorination processes since
conventional wastewater treatment plants cannot remove citalopram effectively. Citalopram has been
demonstrated to form N-nitrosodimethylamine (NDMA) during chlorination in our previous study.
Further investigation on NDMA formation kinetics was conducted in the present study. Influences
of operational variables (disinfectant dose, pH value) and water matrix on citalopram degradation,
as well as NDMA generation, were evaluated. The results indicated high reactivity of citalopram with
NaOCl and ClO2. NDMA formation included two stages during CIT oxidation, which were linear
related with reaction time. NaOCl was more beneficial to remove CIT, but it caused more NDMA
formation. Increasing disinfectant dosage promoted citalopram removal and NDMA formation.
However, no consistent correlation was found between citalopram removal and pH. Contrary to the
situation of citalopram removal, NDMA generation was enhanced when citalopram was present
in actual water matrices, especially in secondary effluent. DMA, as an intermediate of citalopram
chlorination, contributed to NDMA formation, but not the only way.
Keywords: citalopram; N-nitrosodimethylamine; sodium hypochlorite; chlorine dioxide; oxidation;
influencing factor; kinetics
1. Introduction
A higher prevalence of psychiatric disorders and increasing awareness of mental health issues
caused the number of prescriptions for psychiatric pharmaceuticals, particularly antidepressants,
promptly increasing [
Selective serotonin reuptake inhibitors (SSRIs) antidepressants, which are also used to treat psychiatric
disorders, panic disorder, and social phobia, have been widely marketed since the mid-1980s [ ].
1]. Depression will be the world’s second most frequent illness by 2020 [2].
3
Recently, as a new class of emerging pollutants, antidepressants have caused worldwide concern due
to their persistence and acute toxicity to aquatic life [4].
As a representative of SSRIs, citalopram (1-(3-dimethyaminopropyl-1-(4-fluoro-phenyl(-5-
phthalancarbonitrile, CIT) is highly prescribed in USA [
the world [ ]. Between 12% and 23% of CIT is excreted unaltered in the urine due to the incomplete
disintegration in human body [ ]. Human excretion and disposal of unused or expired drugs in
5], Northern Europe [6,7], and elsewhere in
8
9
toilets may be the major input of CIT in the wastewater [10]. Wastewater treatment plants (WWTPs)
cannot remove personal care products (PPCPs) residues and metabolites effectively since conventional
WWTPs are not specifically designed to remove pharmaceutical and PPCPs. Styrishave B. et al. [11
]
Molecules 2019, 24, 3065; doi:10.3390/molecules24173065
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revealed that abiotic degradation of CIT in the aquatic environment was low, and the removal of CIT
was primarily due to sorption in the WWTPs. Lajeunesse et al. [12] reported that primary treatment
and trickling filter/solids contact has limited capacity to remove antidepressants from sewage, and the
removing efficiencies of CIT were between 3.5% and 48% from the study of five WWTPs in Canada.
Besides that, the active metabolites and conjugates of psychoactive drugs could be transformed to
their parent compounds during the treatment processes, thus causing the CIT concentration in effluent
to be even higher than that in influent [13,14]. Consequently, WWTPs have been considered to
be the major environment source of CIT to the surrounding aquatic environment. Several studies
carried out in different countries reported the presence of CIT in different environmental matrices,
including wastewater effluent (21–520 ng/L) [15], surface (2000 ng/L–8000 ng/L) [16], and ground water
(40–90 ng/L) [17], in the order of ng/L [18] to µg/L.
The poor removal efficiency of CIT by conventional wastewater treatment has prompted some
studies demonstrating that advanced oxidation processes (AOPs) were efficient at eliminating CIT,
including O3, ClO2, UV, and Fenton oxidation [19,20]. It indicated that chemical oxidation could
lead to CIT breakdown. Actually, ClO2 process is not only used as AOP, but also used as a powerful
disinfectant in the WWTPs. Chlorination has been the most popular disinfection process for drinking
water and wastewater because of strong oxidizing ability. Usually, disinfection is required as the last
process step in WWTPs. CIT is still exposed to disinfection process due to the inefficient removal of
CIT during the activated sludge process. However, there is limited information regarding the behavior
of CIT during disinfection of wastewater.
Besides that, it cannot be ignored that one dimethylamine (DMA) group was contained in the
structure of CIT (Table 1). It has been demonstrated that PPCPs containing DMA groups could be the
potential precursors of N-nitrosodimethylamine (NDMA) with a high NDMA molecular conversion
during chloramines and chlorination disinfection [21,22]. As a typical nitrosamine, NDMA is a
suspected carcinogen with higher potency than trihalomethanes [23]. NDMA has been regulated
at the ng/L level in drinking water in California, Ontario, and the European Union (EU) due to its
frequent detection in the aquatic environment [24–26]. In our previous study [27], NDMA generation
from seven psychoactive pharmaceuticals (including CIT) chlorination was revealed during sodium
hypochlorite (NaOCl) and chlorine dioxide (ClO2) disinfection processes. It is important to understand
the factors that may affect CIT degradation and NDMA formation in order to control the NDMA level
after CIT chlorination in both drinking water and wastewater.
Table 1. Chemical structure and pKa [8] of citalopram (1-(3-dimethyaminopropyl-1-(4-fluoro-phenyl(-5-
phthalancarbonitrile (CIT)).
Compound Investigated
Molecular Structure
pKa
CAS
N
F
Citalopram
9.59
59729-33-8
O
N
In this study, we investigated the characterizations of CIT oxidation during NaOCl and ClO2
chlorination processes. The kinetics of NDMA generation from CIT degradation was also clarified.
Furthermore, the effects of disinfectant dosage, pH, and water matrix on CIT and NDMA formation
were assessed in order to better control NDMA generation.

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2. Results and Discussion
2.1. Effect of CIT Concentration
As shown in Figure 1, the rapid elimination of CIT was observed once the chlorination process
started, which was affected by the initial concentration of CIT. All of the CIT removal efficiencies
exceeded 90% in 10 min., and then reached to 100% in 40 min. The control test results indicated the
hydrolysis of CIT was negligible during the oxidation (Figure S1). It means that both NaOCl and
ClO2 were effective on CIT degradation. Obviously, the removal of CIT was influenced by the initial
concentration of CIT. It indicated that the disinfectant was insufficient to remove CIT rapidly when the
initial amount of CIT was increased. Thus, it appeared that the degradation rate of CIT was decreased
as the initial concentration increase. When comparing the C/C0 curves during the first 10 min. reaction
when CIT treated by NaOCl with that treated by ClO2, it indicated that NaOCl was more beneficial in
removing CIT, especially when the CIT concentration was higher (32 µM).
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
0.8μM
3.2μM
16μM
32μM
0.8μΜ
3.2μΜ
16μΜ
32μΜ
0
10
20
30
40
0
10
20
30
40
Time (min)
Time (min)
1.0
0.8
0.6
0.4
0.2
0.0
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0.8μΜ
3.2μΜ
16μΜ
32μΜ
0.8μM
3.2μM
16μM
32μM
linear fit of stage 1
linear fit of stage 2
linear fit of stage1
linear fit of stage2
0
2
4
6
8
10
0
2
4
6
8
10
Time (d)
(a)
Time (d)
(b)
Figure 1. CIT removal and N-nitrosodimethylamine (NDMA) formation during CIT oxidation with
NaOCl ( ) and ClO2 ( ) at different initial concentrations of CIT ([NaOCl] = [ClO2] = 1 mM, pH = 7.0)
a
b
(Black dash lines represent linear fit of the first stage of NDMA generation, red dash lines represent
linear fit of the second stage of NDMA generation).
Furthermore, NDMA formation also proceeded during CIT oxidation. According to the results of
NDMA concentration calculated using the equation (1) (Section 3.2), all of the NDMA molar yields were
above 2%. More CIT being present in the solution caused more NDMA generation when CIT reacted
with NaOCl. NDMA concentration after 10-day CIT oxidation with NaOCl increased from 0.88
µM to
1.26 M as the CIT concentration increased from 0.8 M to 32 M. However, when 32 M CIT was
µ
µ
µ
µ
treated by ClO2, the amount of NDMA was lower than that under other conditions. It indicated that
the dosage of the disinfectant limited the NDMA formation. Furthermore, the profiles of NDMA
concentration presented two stages. NDMA was formed quickly during the first day of reaction
(stage 1). More than half of NDMA amount appeared at the first stage of reaction. Afterwards, the

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NDMA concentration slowly increased during the rest of the 10-day oxidation (stage 2). Two kinetic
models for NDMA formation were obtained by linear fits (Table S1), respectively, and all of the R2
values were above 0.9. For example, the generation rates of NDMA during NaOCl process went down
from 5.35
×
10−12 M/s ~ 7.65
×
10−12 M/s to 5.32
×
10−13 M/s ~ 7.96
×
10−13 M/s when CIT was treated
by NaOCl (Table S1). However, the profiles of NDMA concentration remained on an upward trend.
Obviously, the contact time of CIT with disinfectant made a great influence on NDMA formation,
especially at the stage 1. Since residual chlorine is persistent during drinking water delivery, it means
that even a trace level of CIT presents in the drinking water might cause prolonged NDMA generation
during the long distance water supply system. It is useful to pay attention to the risk of NDMA
generation when CIT was distributed in raw water.
It is noteworthy that the CIT removal efficiencies reached nearly 100% just in 40 min. under
the same test condition. The same phenomenon was also observed under other reaction conditions,
including oxidation by ClO2 (Figure 1). In other words, NDMA generation still conducted, even if
CIT was completely removed. It indicated that CIT decomposition did not directly result in NDMA
formation. Some intermediate products from CIT decomposition also contributed to NDMA generation.
It suggested that different NDMA precursors took part in the reaction, causing NDMA formation
to appear in two stages. In addition, it seems that CIT treated by NaOCl tended to produce more
NDMA than that treated by ClO2. It also indicated that ClO2 was a proper disinfectant for controlling
NDMA formation.
2.2. Effect of Disinfectant Dose
Effort was also made on the effect of disinfectant dose on CIT removal and NDMA formation
kinetics since high reactivity of CIT during chlorination was identified (Figure 2). Apparently, increasing
NaOCl concentration promoted CIT degradation. Especially at the first 5 min. of reaction, CIT removal
efficiency was enhanced from 72.1% to 92.3% as the dosage of NaOCl increased from 0.1 mM to
2 mM. ClO2 concentration just made little improvement on CIT removal. Overall, CIT was completely
removed in 40 min., even though the ClO2 dosage was only 0.1 mM.
However, increasing disinfectant dosages distinctly enhanced NDMA formation. The NDMA
formation proceeded for 10 days in all cases, even if CIT was totally removed during 40 min. It also
indicated that CIT decomposition caused NDMA generation through several steps. Two stages of
NDMA generation were still observed, as Figure 2 shows. Moreover, increasing the disinfectant
concentration enhanced NDMA generation from the intermediate products of CIT degradation, not
only the production of NDMA, but also the rate of generation (Table S2). When the dosage of NaOCl
increased from 0.1 mM to 2 mM, the rates of NDMA generation increased from 2.06
×
10−12 M/s to
1.20
×
10−11 M/s at stage 1 of NDMA generation (Table S2). Especially, there was little difference
among the CIT removal efficiencies under given conditions, when CIT was treated by ClO2 (Figure 2b).
However, the correlation of NDMA generation became poorer when the dosage of ClO2 decreased
to 0.1 mM (Table S2). Furthermore, NDMA concentration at the end of 10-day reaction increased
from 0.23 µM to 1.21 µM, owing to ClO2 concentration increased from 0.1 mM to 2 mM. It means that,
although CIT could be removed efficiently, the transformation products could not be ignored, even
when low dose disinfectant was supplied. The mixture of stable products, such as NDMA, might pose
their own environmental and health risks.
2.3. Effect of pH Value on CIT Chlorination
A wide range of pH values (from 6 to 10) was tested to obtain deeper insight into the effect of
pH on CIT removal and NDMA formation. All of the tests at different pH values showed the rapid
oxidation of CIT during the first 10 min. of reaction (Figure 3). There was little difference in the curves
of CIT removal efficiencies at different pH value. As described earlier, it seems that NaOCl was more
beneficial for removing CIT. Consequently, more NDMA formation was observed during CIT oxidation
with NaOCl. The pH value also had little influence on NDMA. Furthermore, there was just a little