Chemosphere 85 (2011) 1430–1437
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Bromination of selected pharmaceuticals in water matrices F. Javier Benitez ⇑, Juan L. Acero, Francisco J. Real, Gloria Roldan, Francisco Casas Universidad de Extremadura, Departamento de Ingeniería Química, 06006 Badajoz, Spain
a r t i c l e
i n f o
Article history: Received 14 June 2011 Received in revised form 3 August 2011 Accepted 4 August 2011 Available online 8 September 2011 Keywords: Pharmaceuticals Bromination reaction Apparent and intrinsic rate constants Chlorination Water matrices
a b s t r a c t The bromination of five selected pharmaceuticals (metoprolol, naproxen, amoxicillin, phenacetin, and hydrochlorothiazide) was studied with these compounds individually dissolved in ultra-pure water. The apparent rate constants for the bromination reaction were determined as a function of the pH, obtaining the sequence amoxicillin > naproxen hydrochlorothiazide phenacetin metoprolol. A kinetic mechanism specifying the dissociation reactions and the species formed for each compound according to its pKa value and the pH allowed the intrinsic rate constants to be determined for each elementary reaction. There was fairly good agreement between the experimental and calculated values of the apparent rate constants, confirming the goodness of the proposed reaction mechanism. In a second stage, the bromination of the selected pharmaceuticals simultaneously dissolved in three water matrices (a groundwater, a surface water from a public reservoir, and a secondary effluent from a WWTP) was investigated. The pharmaceutical elimination trend agreed with the previously determined rate constants. The influence of the main operating conditions (pH, initial bromine dose, and characteristics of the water matrix) on the degradation of the pharmaceuticals was established. An elimination concentration profile for each pharmaceutical in the water matrices was proposed based on the use of the previously evaluated apparent rate constants, and the theoretical results agreed satisfactorily with experiment. Finally, chlorination experiments performed in the presence of bromide showed that low bromide concentrations slightly accelerate the oxidation of the selected pharmaceuticals during chlorine disinfection. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction Pharmaceuticals and personal care products (PPCPs) and endocrine disrupting compounds (EDCs) are frequently detected in aquatic environments worldwide (Huerta-Fontela et al., 2011). The presence of these pollutants in different water systems is attributed to their incomplete removal in wastewater treatment plants (WWTPs) which are not designed for this task. Consequently, these contaminants have spread into surface waters (Reemtsma et al., 2006; Sui et al., 2011; Ziylan and Ince, 2011) which are used as major sources of drinking water. Some pharmaceuticals are again not completely removed in drinking water treatment plants (DWTPs), and, although at low concentrations of the order of lg L1 to ng L1, have been identified in the resulting drinking waters (Ternes et al., 2002; Kim et al., 2007). To deal with this problem, different technologies have been proposed as potential alternatives for the more efficient degradation of these pollutants including the use of single oxidants such as UV radiation, ozone, or hydrogen peroxide, or combinations of oxidants in the so-called Advanced Oxidation Processes, such as O3/ H2O2, UV/H2O2, Fenton/photo-Fenton reactions and UV/TiO2. There ⇑ Corresponding author. Tel./fax: +34 924289384. E-mail address:
[email protected] (F.J. Benitez). 0045-6535/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.chemosphere.2011.08.022
are various reviews of these treatments in the recent literature (Ikehata et al., 2006; Esplugas et al., 2007; Sharma, 2008; Klavarioti et al., 2009; Lee and von Gunten, 2010). Despite their clear advantages, oxidation treatments have some drawbacks such as the generation of by-products, or that the toxicity is often incompletely eliminated. Another frequently used water oxidant treatment is, of course, chlorination. Indeed, 98% of the drinking water treatment plants in Europe use chlorination as one of their main disinfection steps. Chlorine disinfection is also applied to treated wastewater before re-use. Consequently, there are several studies in the literature dealing with the elimination of pharmaceuticals in waters by using chlorine (HOCl + OCl) (Lee and von Gunten, 2009; Quintana et al., 2010). There has also been recent interest in the involvement of bromination reactions in the oxidation of water pollutants, especially in waters with a high bromide (Br) content (Guo and Lin, 2009; Lee and von Gunten, 2009). In this process, bromine (HOBr + OBr) is produced from the oxidation of bromide with chlorine:
HOCl þ Br ! HOBr þ Cl
k ¼ 1:55 103 M1 s1
ð1Þ
The dissociation equilibrium HOBr/OBr has a pKa value of 8.9, which means that HOBr is a weaker acid than HOCl (pKa = 7.5).
F.J. Benitez et al. / Chemosphere 85 (2011) 1430–1437
Given the interest in this research field, we designed an overall study program focused on providing an overview of the fate of different frequent pharmaceutical contaminants during water chlorination treatments and the effect of bromide when it is also present. For this purpose, we selected five pharmaceutical compounds which have been found in different aquatic environments at concentrations in the range of ng L1 to lg L1 (Santos et al., 2010): the beta-blocker metoprolol (Met), the nonsteroidal antiinflammatory compound (NSAID) naproxen (Nap), the antibiotic amoxicillin (Amox), the thiazidic diuretic hydrochlorothiazide (Hctz), and the analgesic phenacetin (Phen). A first study considered the process of chlorination of these compounds in the absence of bromide (Acero et al., 2010). In order to establish the combined effect of chlorination and bromination processes, the present work considered the bromination process alone and chlorination in the presence of bromide. To this end, firstly, the selected model pharmaceuticals were subjected to reactions with bromine in UP water with the objective of determining the unknown apparent and intrinsic rate constants, and secondly, the bromination process of these compounds was studied in different water matrices with the aim of establishing the influence of the main operating variables. Finally, chlorination experiments were performed in the presence of low bromide concentrations to study the effect of bromide on the fate of the pharmaceuticals during water chlorination. A simple kinetic model was proposed for the bromination reactions of the selected pharmaceuticals which was validated by the experimental results with the real water matrices tested. 2. Materials and methods 2.1. Chemicals, stock solutions, and water matrices The selected pharmaceuticals and the reference compound 3methoxyphenol (used in combination with amoxicillin), were obtained from Sigma–Aldrich and were of the highest purity available (99%). Stock solutions of bromine were prepared by addition of 0.8 mM ozone solution to a 0.7 mM solution of potassium bromide at pH = 4, according to the procedure described by Pinkernell et al. (2000). Previously, concentrated ozone stock solutions were prepared by bubbling a gas mixture of oxygen-ozone through UP water (produced from a MilliQ – Millipore – water purification system) in a flask placed in an ice bath. Stock solutions of chlorine were prepared by diluting a commercial solution of sodium hypochlorite (4% active chlorine, Panreac). The three water matrices selected were two natural waters – a groundwater (PZ), and a surface water from the public drinking-water reservoir ‘‘Peña del Aguila’’ (PA) – and a secondary effluent collected from a WWTP located in the Extremadura Community (BA). The main water quality
Table 1 Quality parameters of the selected water matrices. Water matrices
Groundwater (PZ)
Reservoir (PA)
Secondary effluent (BA)
pH TOC (mg L1) A254 (cm1) Alkalinity (mg L1 CaCO3) Conductivity (lS cm1) Ammonia (mg N L1) Nitrate (mg N L1) Total nitrogen (mg N L1) Total phosphorus (mg L1)
7.5 <1 0.014 388
7.8 6.9 0.116 30
7.8 22.2 0.214 250
1716
128
650
0.4 5.2 5.9
1.6 0.7 2.4
13.5 17.5 32.0
0.157
0.569
2.150
1431
parameters are summarized in Table 1 One observes in the table that the sequence of the dissolved organic matter (DOM) content was: BA > PA > PZ. 2.2. Bromination and chlorination experiments In the first group of experiments, the pharmaceuticals (Ph) were individually dissolved in UP water at a constant temperature of 20 ± 0.2 °C. The bromination reactions of phenacetin, metoprolol, naproxen, and hydrochlorothiazide were conducted under pseudo-first-order conditions, in which the total bromine concentration was at least 10 times in excess with respect to the pharmaceutical concentration ([Br]0 P 5 mM vs. [Ph]0 = 1 lM). In these experiments, a 250 mL volume of pharmaceutical solution was prepared in a batch reactor, and the selected pH was adjusted using phosphoric acid/phosphate buffer (0.1 M). The experiments were started after addition to the solution of the appropriate volume of the bromine stock solution to obtain the desired initial concentration. At regular times, 2 mL samples were withdrawn and rapidly transferred to HPLC vials containing 10 lL of sodium thiosulfate (0.1 M) to stop the reaction. The residual pharmaceutical concentrations were analyzed directly by HPLC. In the specific case of the bromination of amoxicillin, given the fast reaction rate, competition kinetics was followed for the determination of the rate constants by including 3-methoxyphenol in the reactor as reference compound. In particular, amoxicillin and 3-methoxyphenol, both at initial concentrations of 1 lM, were previously dissolved in UP water in 20 mL flask reactors at the desired pH adjusted using phosphoric acid/phosphate buffer (10 mM). The reactions were initiated by injecting into each flask a variable volume of the bromine stock solution to achieve the desired initial bromine dose in the range 0.5–3 lM. Once the bromine had been totally consumed (24 h), the residual concentrations of amoxicillin and 3-methoxyphenol were determined. In the second group of experiments, the selected pharmaceuticals were dissolved together in the three selected water matrices in 100 mL flask reactors. The experiments were conducted at 20 ± 0.2 °C and the pH was adjusted to 7.0 with phosphoric acid/ phosphate buffer. The initial concentrations of the pharmaceuticals spiked in the water systems were 1 lM for each compound in all cases, and the runs were started by injecting the required volume of the bromine stock solution to reach a concentration of 30– 50 lM (5–8 mg L1). At regular reaction times, two samples were withdrawn from the reactor. The first was used to determine the remaining bromine concentration, and the second to assay the residual pharmaceuticals after quenching the reaction with thiosulfate. Finally, chlorination experiments were performed with PZ and BA waters in the presence of different bromide doses. These experiments were performed in 20 mL flask reactors at pH 7, 20 °C, initial dose of chlorine of 70 lM (5 mg L1), and varying the bromide dose in the range 0–3.75 lM (0–300 lg L1) as typically found in real waters. Residual concentrations of pharmaceuticals were determined after total chlorine consumption (24 h). 2.3. Analytical methods Concentrations of pharmaceuticals were measured by HPLC in a Waters Chromatograph equipped with a 996 Photodiode Array Detector and a Waters Nova-Pak C18 Column (3.9 mm i.d. 150 mm, 4 lm particle size). A gradient elution of methanol (A) and aqueous solution of phosphoric acid 1 102 M (B) was used by varying the percentage of A from 10% to 90% (in volume) over 30 min. The flow-rate was 1 cm3 min1, and detection was performed at 222, 226, 230, 226, and 240 nm for metoprolol, hydrochlorothiazide, naproxen, amoxicillin, and phenacetin, respectively. In
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the competition kinetics procedure, the concentrations of 3-methoxyphenol were also assayed by HPLC at 226 nm. Bromine stock solutions were standardized by direct photometric determination of the hypobromite at 329 nm, and chlorine stock solutions were assayed spectrophotometrically in the presence of excess iodide to form triiodine (e at 351 nm = 25 700 M1 cm1) (Bichsel and von Gunten, 1999). The ozone concentration of the stock solution was determined directly by measuring the UV absorbance at 258 nm (e = 3150 M1 cm1). The bromine concentration of the reaction samples was determined spectrophotometrically according to the ABTS [2,2-azino-bis(3-ethylbenzothiazoline)-6sulfonic acid diammonium salt] method (Pinkernell et al., 2000). The water quality parameters were determined according to the Standard Methods (Clesceri et al., 1989). 3. Results and discussion 3.1. Determination of bromination rate constants for the selected pharmaceuticals
ln
As has been reported previously in the study of the kinetics of bromination reactions of several organic compounds (Gallard et al., 2003; Acero et al., 2007), these reactions follow second-order kinetics (first-order with respect to bromine and first-order with respect to the organic compound). By considering in the present case that the target compounds are the selected pharmaceuticals, the reaction rate can be written as:
d½Ph ¼ kapp ½Pht ½Br2 t ¼ kobs ½Pht dt
ð2Þ
where [Ph]t and [Br2]t represent the total concentrations of the selected pharmaceutical and bromine (i.e., sum of concentrations of the different species present in the solution), respectively, and kapp is the apparent second-order rate constant. This rate constant usually shows a pH-dependence which can be explained by the presence of several species of both bromine and the pharmaceuticals in the aqueous solution. Specifically for bromine, it must be noted that hypobromous acid dissociates into hypobromite ion (OBr) with a pKa = 8.9, so that the aforementioned total concentration of bromine in the reaction is:
½Br2 t ¼ ½HOBr þ ½OBr
ð3Þ
Additionally, when [Br2]t is greatly in excess with respect to [Ph]t, a pseudo-first-order rate constant kobs can be introduced which is equal to kapp[Br2]t. Then, the second part of Eq. (2) can be integrated leading to:
ln
½Ph0 ¼ kobs t ¼ kapp ½Br2 t t ½Ph
the remaining bromination experiments, as this concentration was almost constant during the reaction time, kapp was determined directly by dividing the kobs rate constant by the total initial bromine concentration. Table 2A also lists the values obtained for kapp, and one can deduce from these that naproxen presented a much greater reactivity than the other three pharmaceuticals whose rate constants were in the same range, and depended on the pH. Since the bromination reaction of amoxicillin was too fast to measure the rate constant by using the pseudo-first-order kinetic method, competition kinetics was applied. 3-Methoxyphenol was selected as reference compound, since its rate constants with bromine are known (Guo and Lin, 2009), and are similar to those of amoxicillin. This competition kinetics model has been described in detail elsewhere (Acero et al., 2005; Lee and von Gunten, 2009), and the application of Eq. (4) to both the target (Ph) and the reference (R) compound concentrations leads to:
ð4Þ
Individual bromination experiments of the five selected pharmaceuticals in UP water were carried out with the aim of determining the second-order rate constants kapp. As was described in the Experimental Section, four of these pharmaceuticals (naproxen, metoprolol, phenacetin, and hydrochlorothiazide) presented intermediate or slow reactions with bromine. The evaluation of the kapp rate constant for these compounds was performed under pseudofirst-order conditions, with initial [Br2]t [Ph]t. Table 2A presents the results of these experiments performed by varying the pH as well as the initial bromine concentration at the specific pH = 7. The application of Eq. (4) and the subsequent regression analysis allowed the determination of kobs. In the experiments conducted at pH = 7 and 20 °C, in which the initial total bromine concentration was varied, a linear regression analysis of kobs values vs. [Br2]t provided the apparent second-order rate constants kapp. In
½Ph0 kapp ½R ln 0 ¼ ½Ph kapp-R ½R
ð5Þ
where kapp and kapp-R are the apparent bromination rate constants for the target and reference compounds, respectively. Table 2B lists the values of kapp-R for 3-methoxyphenol previously reported by Guo and Lin (2009). Plots of Eq. (5) using the experimental concentrations of amoxicillin and 3-methoxyphenol were subjected to a regression analysis, yielding the values of kapp for amoxicillin. These results are also given in Table 2B. As observed, the reaction rate for amoxicillin was much greater than those of the other pharmaceuticals, with values ranging between 2.35 104 M1 s1 at pH = 3 and 2.76 108 M1 s1 at pH = 9. These kapp values clearly confirmed the strong influence of pH on the apparent rate constants, which is explained by speciation of both bromine and the pharmaceuticals. Fig. 1 plots these kapp values vs. pH, showing the different reactivity of bromine towards each pharmaceutical in the pH range studied. The observed differences can be explained by taking into account the predominant species of each pharmaceutical involved in the reaction at each specific pH, which is a consequence of their pKa values, and also by considering the reactivity of each species towards the oxidant. In this sense, the dissociation of bromine must also be taken into account, with its pKa = 8.9. Nevertheless, OBr is much less reactive, so much so that its reactivity can be taken to be negligible compared to that of HOBr (Acero et al., 2005). Thus HOBr must be considered as the main oxidant in the bromination of organic compounds. The five selected pharmaceuticals can dissociate with increasing pH as a consequence of their pKa values. These values are given in the literature (Sangster, 1994; Acero et al., 2010), and are 2.6, 7.3, and 9.7 for amoxicillin; 9.7 for metoprolol; 4.2 for naproxen, 7.9 for hydrochlorothiazide, and 1.42 and 14.0 for phenacetin. The three dissociation constants of amoxicillin mean that four posþ sible species may be found depending on the pH: PhH3 , PhH2, = PhH , and Ph . Eq. (6) describes the consecutive dissociation reactions that could take place among these species: þ K a1
K a2
K a3
H
H
H
PhH3 ¢þ PhH2 ¢þ PhH ¢þ Ph
¼
ð6Þ
Metoprolol, naproxen, and hydrochlorothiazide have only a single pKa value, and consequently two species can be formed. Taking the nature of these compounds into account, it must be expected that the species of naproxen are neutral and anionic (PhH2, PhH), while those of metoprolol and hydrochlorothiazide þ are protonated and neutral (PhH3 , PhH2). Thus, and following the notation used in Eq. (6), their pKa values will be expressed as pKa1, in contrast to that of naproxen (pKa2). Finally, phenacetin
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F.J. Benitez et al. / Chemosphere 85 (2011) 1430–1437 Table 2A Apparent second-order rate constants kapp for the reactions of naproxen, phenacetin, metoprolol, and hydrochlorothiazide with bromine. [Pharmaceutical]0 = 1 lM. Naproxen
a
Phenacetin
[Br2]0 (mM)
pH
kapp 10
5 5 10 10 15 20 10 10
4.0 5.0 6.0 7.0 7.0 7.0 8.0 9.0
759 ± 14 150 ± 7 80 ± 4 25 ± 1a 25 ± 1a 25 ± 1a 2.3 ± 0.3 0.9 ± 0.2
2
(M
1
s
1
)
Metoprolol 1
[Br2]0 (mM)
pH
kapp (M
10 10 10 10 10 10 20 50 10 10
3.0 4.0 5.0 5.5 6.0 7.0 7.0 7.0 8.0 9.0
11 ± 1 5.8 ± 0.7 1.6 ± 0.6 1.5 ± 0.7 2.2 ± 0.6 7.3 ± 1.0a 7.3 ± 1.0a 7.3 ± 1.0a 29 ± 2 67 ± 8
s
1
)
Hydrochlorothiazide 1
[Br2] (mM)
pH
kapp (M
10 10 10 10 10 20 50 10 10
3.0 4.0 5.0 6.0 7.0 7.0 7.0 8.0 9.0
6.7 ± 0.9 4.4 ± 0.7 3.1 ± 0.5 3.7 ± 0.7 5.2 ± 0.8a 5.2 ± 0.8a 5.2 ± 0.8a 6.7 ± 0.9 8.2 ± 0.9
1
s
)
[Br2] (mM)
pH
kapp (M1 s1)
10 10 10 10 10 10 20 50 10 10 10
3.0 4.0 5.0 6.0 6.5 7.0 7.0 7.0 8.0 8.5 9.0
7.2 ± 0.5 4.67 ± 0.6 5.7 ± 0.6 3.0 ± 0.6 3.2 ± 0.8 8.1 ± 1.2a 8.1 ± 1.2a 8.1 ± 1.2a 47 ± 29 54 ± 3 14 ± 2
Values as a result of regression analysis.
Table 2B Apparent second-order rate constants (kapp) for the reactions of amoxicillin with bromine determined by competition kinetics.
a
Reference comp.
pH
kapp-R 104a (M1 s1)
Target comp.
pH
kapp 104 (M1 s1)
3-Methoxyphenol
3.0 4.0 5.0 6.0 7.0 8.0 9.0
7.7 7.8 9.1 22 151 1270 5200
Amoxicillin
3.0 4.0 5.0 6.0 7.0 8.0 9.0
2.4 ± 0.1 3.8 ± 0.1 5.2 ± 0.1 63 ± 1 671 ± 2 5810 ± 16 27 600 ± 94
Guo and Lin (2009).
has two dissociation constants, and consequently, three possible þ species: PhH3 , PhH2, and PhH. þ All of these four possible species of pharmaceuticals – PhH3 , = PhH2, PhH and Ph – can be oxidized by HOBr according to the general reaction: ki
Phspecies þ HOBr ! Products
ð7Þ
where the rate constant ki can be k1, k2, k3, or k4, depending on which species is being considered. As well as this set of reactions, each pharmaceutical in its protonated form can be degraded by the acid-catalyzed reaction of HOBr: þ PhH3
þ kc
þ HOBr þ H ! Products
ð8Þ
Therefore, and according to the bromination reactions corresponding to the rate constants k1–k4 and kc, the elimination of amoxicillin can be expressed by:
d½Ph þ ¼ k1 ½PhH3 ½HOBr þ k2 ½PhH2 ½HOBr þ k3 ½PhH ½HOBr dt ¼ þ þ k4 ½Ph ½HOBr þ kc ½PhH3 ½HOBr½Hþ
ð9Þ
By equating Eqs. (4) and (9), and taking into account the dissociation equilibria of hypobromous acid and of amoxicillin, the apparent second-order rate constant kapp for amoxicillin is given by the expression: n o 2 3 Hþ k1 ½Hþ þ k2 K a1 ½Hþ þ k3 K a1 K a2 þ k4 K a1HKþa2 K a3 þ kc ½Hþ Hþ þK HOBr ½ kapp ¼ ½Hþ 2 þ K a1 ½Hþ þ K a1 K a2 þ K a1 KHa2þ K a3 ½
ð10Þ For phenacetin, one must consider the rate constants k1, k2, k3, and kc, and consequently Eq. (10) reduces to:
kapp
n o ½Hþ k1 ½Hþ 2 þ k2 K a1 ½Hþ þ k3 K a1 K a2 þ kc ½Hþ 3 ½Hþ þK HOBr ¼ þ 2 þ þ K a1 ½H þ K a1 K a2 H
ð11Þ
Similarly, for metoprolol and hydrochlorothiazide, only k1, k2, and kc have to be taken into account, and the expression for kapp is:
kapp
n 2 o ½Hþ k1 Hþ þ k2 K a1 þ kc Hþ ½Hþ þK HOBr þ ¼ H þ K a1
ð12Þ
Finally, for naproxen, the rate constants considered have to be k2, k3, and kc, leading to:
kapp
n 2 o ½Hþ k2 Hþ þ k3 K a2 þ kc Hþ þ ½H þK HOBr þ ¼ H þ K a2
ð13Þ
The kinetic model represented by Eqs. (10)–(13) allows one to determine the intrinsic rate constants kc and ki (ki = k1, k2, k3, or k4) for the elementary reactions of each pharmaceutical species with each bromine species. For this purpose, the values of kapp, Ka1, Ka2, and Ka3 were introduced into the corresponding Eqs. (10)–(13) for each pharmaceutical, together with the concentration [H+] for the pH used. A non-linear least-squares regression analysis yielded the values of the intrinsic rate constants as listed in Table 3. Fig. 1 also represents these calculated values of kapp vs. pH. One observes that the agreement between the experimental (symbols) and the calculated (lines) values is quite good. One can conclude, therefore, that the proposed set of reactions is able to appropriately model the experimental values for the conditions being studied. Similarly to chlorine, bromine reacts mainly with activated aromatic rings and neutral amines. Thus, amoxicillin presents the highest reactivity since bromine can attack both the activated aromatic ring (phenol moiety) and the primary amine, with the attack on the acetamide also being possible, although at a slow reaction rate. From the reactivity profile of amoxicillin vs. pH (Fig. 1), the acid-catalyzed reaction between HOBr and protonated amoxicillin can occur only at low pH (below pH 3). Therefore the increase in magnitude of kapp beginning from pH 4 may be due to the deprotonation of amoxicillin (first the carboxyl group, then the primary amine, and finally the hydroxyl group of the phenolic moiety) to yield more nucleophilic species. The deprotonation of the carboxyl
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(a)
(b) 6
Metoprolol
1.6 1.4
Naproxen
5 4
1
log kapp
log kapp
1.2
0.8 0.6
3 2
0.4 1
0.2 0
0
2
4
6
8
0
10
0
2
4
(c)
(d)
Amoxicillin
9 8
log kapp
log kapp
6 5
10
8
10
Phenacetin
2.5
1.5 1 0.5
4
0
2
4
6
8
10
0
0
2
4
6
pH
pH
(e)
8
2
7
3
6
pH
pH
Hidrochlorothiazide
2 1.8 1.6
log kapp
1.4 1.2 1 0.8 0.6 0.4 0.2 0
0
2
4
pH
6
8
10
Fig. 1. pH dependence of the apparent rate constants for the bromination of the selected pharmaceuticals. Theoretical values (lines) calculated according to Eqs. (10)–(13): (a) metoprolol; (b) naproxen; (c) amoxicillin; (d) phenacetin; (e) hydrochlorothiazide.
Table 3 Intrinsic rate constants for the bromination of each pharmaceutical species.
a
Pharmaceuticala
k1 (M1 s1)
k2 (M1 s1)
k3 (M1 s1)
Metoprolol Naproxen Amoxicillin Phenacetin Hydrochlorothiazide
3.9 ± 0.2
104 ± 6 (2.1 ± 0.4) 104 (2.4 ± 0.4) 104 1.7 ± 0.2 58 ± 10
270 ± 30 (9.9 ± 1.5) 106 (7.4 ± 0.5) 107
(2.4 ± 0.4) 104 540 ± 60 3.3 ± 0.4
k4 (M1 s1)
kc (M2 s1)
(3.8 ± 1.2) 109
(2.8 ± 0.2) 103 <1 108 <1 107 <1 104 (4.2 ± 0.8) 103
pK values for the pharmaceuticals: 9.7 for metoprolol; 4.2 for naproxen; 2.6, 7.3, and 9.7 for amoxicillin; 1.42 and 14.0 for phenacetin; and 7.9 for hydrochlorothiazide.
group does not affect the bromine reactivity, and therefore k1 and k2 present similar values for amoxicillin. However, the deprotonation of the primary amine, and especially of the phenolic moiety,
increases the reactivity considerably, with both being the active groups for HOBr attack. A maximum value of kapp is expected at pH around 9.5 – (pKa HOBr + pKa3)/2 – followed by a decrease of kapp
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at higher pH due to the deprotonation of HOBr to yield OBr (which is a much weaker electrophile). Similarly, HOBr could attack the aromatic ring and the secondary-amine of metoprolol or hydrochlorothiazide, and the aromatic ring and the amide group of phenacetin. In these cases, the aromatic ring is not activated, thus hindering the HOBr attack and leading to low reactivity. Finally, HOBr may attack the aromatic ring of naproxen, which is not activated and presents low reactivity. The reaction rate of naproxen with bromine decreases with pH due to the deprotonation of HOBr to OBr, and the deprotonation of the carboxylate group has little effect on the electron density of the aromatic ring due to its distance from the ring (Pinkston and Sedlak, 2004). Comparing these results obtained for the bromination of the selected pharmaceuticals with those obtained for the chlorination published in an earlier paper (Acero et al., 2010), one observes that the rate constants for the reactions with bromine are greater than those with chlorine. Thus, while the values of k1, k2, and k3 are about one order of magnitude higher for bromine than for chlorine, the value of k4 for amoxicillin is roughly two orders of magnitude higher for bromine. This greater difference for k4 can be explained by taking into account that k4 represents mainly the reaction of HOBr with the phenolate moiety of amoxicillin. As previously reported, bromine is about three orders of magnitude more reactive towards phenols than chlorine (Acero et al., 2005). However, it is only about one order of magnitude more reactive than chlorine towards primary amines such as glycine (Lee and von Gunten, 2009), which explains the differences between k1, k2, and k3 for HOBr and HOCl. 3.2. Bromination of pharmaceuticals in water matrices The simultaneous removal of the selected pharmaceuticals in the water matrices described in the Experimental Section (i.e., the groundwater PZ, the surface water from a public reservoir PA, and the secondary effluent from a WWTP plant BA) was studied in order to assess the influence of the main operating parameters (nature of the water matrix, pH, and bromine dose) on the efficiency of the pharmaceutical bromination process at 20 °C. Table 4 summarizes the experimental conditions applied to these experiments, together with shows the removals obtained for the pharmaceuticals after 2 min of reaction for naproxen, and 60 min for the other pharmaceuticals. There are no data for amoxicillin due to its extremely fast rate of degradation, which resulted in total elimination even at short reaction times. Firstly, the influence of the water matrix was established. From the results in Table 4, and by comparing experiments performed at the same pH and with a similar bromine dose, one observes that the elimination of each pharmaceutical followed the trend PZ > PA > BA waters, which agrees with the sequence of increasing Abs and TOC values (BA > PA > PZ). The bromine consumption rate followed the trend BA > PA > PZ, showing that the increasing content of organic and inorganic matter consumes greater amounts of the oxidant, consequently leaving less bromine available for the removal of the pharmaceuticals. Regarding the bromine dose, the removals in Table 4 confirm the positive influence of this factor on the elimination as was to be expected from the increase in oxidant exposure. Finally, with respect to the influence of pH, one observes that it was strongly positive between pH 4 and 9 for phenacetin, moderately positive for metoprolol and hydrochlorothiazide, but negative for naproxen. This pH effect is coherent with the values of kapp for each pharmaceutical listed in Tables 2A and 2B for different values of the pH. Since the apparent rate constants for the bromination reaction were deduced from experiments in UP water, one must test whether these kinetic constants kapp are useful for the prediction of the
elimination of these compounds in a real water matrix. As in the previously performed chlorination study (Acero et al., 2010), the concentration profile of a pharmaceutical present in a water can be determined at any reaction time from the expression:
Z t ½Ph ¼ ½Ph0 expðkapp CTÞ ¼ ½Ph0 exp kapp ½Br2 dt
ð14Þ
0
where the bromine exposure (CT) is defined as the integral of the bromine concentration over reaction time, and was determined from the experimental bromine concentrations measured over the course of the reaction. Hence, the pharmaceutical concentration profile was calculated from Eq. (14) in which the values of kapp for each pharmaceutical at the selected pH had been using Eqs. (10)–(13). This procedure was followed for the three water systems selected (PZ, PA, and BA). Fig. 2 shows the results for the PA water taken as example, with the results for the PZ and BA waters being similar. As observed, the agreement between experimental and theoretical values was fairly good, confirming that the rate constants determined in pure water are indeed useful for the prediction of the oxidation of these pharmaceuticals during the bromination of natural waters and secondary effluents. Finally, a set of experiments was performed in which the PZ and BA waters were treated with chlorine (70 lM) at pH 7 and 20 °C in the presence of different amounts of bromide (0–3.75 lM). The goal of these experiments was to evaluate the influence of the presence of bromide on the chlorination of contaminants in real waters, since chlorine reacts with bromide yielding bromine according to Eq. (1). The residual concentrations of the selected pharmaceuticals after total chlorine consumption in the experiments performed with BA secondary effluent is depicted in Fig. 3. Amoxicillin is not included in the figure since it was completely oxidized even with chlorine alone. One observes that the oxidation of the selected pharmaceuticals was faster when bromide was present than when it was absent, with this effect being more pronounced for higher bromide concentrations. Also, the final removals of the pharmaceuticals in the experiments performed with chlorine alone (70 lM) were 3.4%, 26.1%, 3.0%, and 17.5% for metoprolol, naproxen, phenacetin, and hydrochlorothiazide, respectively, were less than those obtained in a similar experiment performed with BA water and only 40 lM of bromine (Table 4). These results are consistent with the higher apparent rate constants obtained for the reactions between these pharmaceuticals and HOBr. A similar tendency was observed for the PZ water, although now the final removals of the selected pharmaceuticals were greater because of the lower NOM content of this water. These results thus show that the presence of bromide in wastewaters and drinking waters in the range of 10 to several hundred Table 4 Removals obtained at 60 min of reaction (except for naproxen, measured at 2 min) during bromination of pharmaceuticals in water matrices. Matrix
[bromine] (lM)
pH
X2 min Nap (%)
X60 min Met (%)
X60 min Phen (%)
X60 min Hctz (%)
PZ PZ PZ PZ PZ PA PA PA PA PA BA BA BA BA BA
30 30 40 50 50 30 30 40 50 50 30 30 40 50 50
4.0 9.0 6.5 4.0 9.0 4.0 9.0 6.5 4.0 9.0 4.0 9.0 6.5 4.0 9.0
100 92.0 100 100 100 100 86.0 100 100 96.7 34.7 19.8 27.0 42.8 21.9
17.3 32.0 43.7 40.5 40.0 8.7 18.9 24.4 24.5 21.0 7.7 17.5 13.6 17.4 14.5
17.1 73.4 95.6 37.9 100 7.2 36.2 33.2 19.7 34.5 7.0 14.5 7.1 14.5 19.3
26.4 82.7 64.0 42.4 100 24.1 46.7 32.7 25.2 42.8 17.4 17.2 25.2 22.4 28.5
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The elimination of these substances in the water matrices was determined theoretically by using a model that takes into account the previously evaluated kapp rate constants, leading to fairly good agreement between the calculated and the experimental values. The presence of low concentrations of bromide in wastewaters and drinking waters slightly accelerates the oxidation of the selected pharmaceuticals during chlorine disinfection.
1.0
[Ph], M
0.8
0.6 Metoprolol
0.4
Naproxen Phenacetin Amoxicillin
0.2
Acknowledgements
Hydrochlorothiazide
The authors gratefully acknowledge financial support from the Ministerio de Ciencia e Innovación of Spain through Projects CTQ 2010-14823 and CSD2006-00044.
0.0 20
0
40
60
time, min Fig. 2. Evolution of the pharmaceutical concentrations in the bromination of PA water. [Ph]0 = 1 lM; [Bromine]0 = 40 lM; pH = 6.5. Symbols represent experimental data; lines represent theoretical predictions.
1.0 0.8
[Ph], M
0
0.6
0.63 0.94
0.4
1.25 1.88 2.50
0.2
3.13
0.0
3.75
Met
Nap
Phen
Hctz
Fig. 3. Influence of bromide concentration on the residual concentration of the selected pharmaceuticals during chlorination of BA water. Experimental conditions: 20 °C; pH 7.0; [chlorine]0 = 70 lM; [Ph]0 = 1 lM.
lg L1 slightly accelerates the oxidation of the selected pharmaceuticals during chlorine disinfection. But the positive effect of the presence of bromide leading to bromine oxidation is partially hindered by the more rapid reaction of bromine than chlorine with reactive moieties of the NOM such as amine or phenolic moieties (Westerhoff et al., 2004). 4. Conclusions The present results lead to the following conclusions: The bromination process provided high reaction rates for amoxicillin, intermediate rates for naproxen, while the three remaining pharmaceuticals presented similar rate constants in the slow range. The kapp values obtained confirm the strong influence of pH on these bromination rate constants. A reaction mechanism was proposed which allowed the intrinsic rate constants for the elementary bromination reactions of each pharmaceutical to be evaluated. In the simultaneous bromination of the five pharmaceuticals in three water matrices, the elimination decreased in the sequence PZ > PA > BA, which agrees with the sequence of increasing NOM present. The trend of pharmaceutical elimination was: amoxicillin > naproxen hydrochlorothiazide phenacetin metoprolol, which agrees with the kapp values obtained in the individual oxidation of the compounds in UP water.
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